Enzyme replacement therapy for Anderson-Fabry disease

  • Review
  • Intervention

Authors


Abstract

Background

Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers.

Objectives

To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease.

Search methods

We searched 'Clinical Trials' on The Cochrane Library, MEDLINE, EMBASE, LILACS and the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 11 September 2012). The original search was performed in September 2008.

Date of the most recent search of the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register: 11 September 2012.

Selection criteria

Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease.

Data collection and analysis

Two authors selected relevant trials, assessed methodological quality and extracted data.

Main results

Six trials comparing either agalsidase alfa or beta in 223 participants fulfilled the selection criteria.

Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval (CI) -3.79 to -0.41); at up to five months, mean difference -1.90 (95% CI -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% CI -3.66 to -0.34). There was a significant difference in pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% CI -3.92 to -0.28) but not at other time-points. Neither trial reported deaths.

One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% CI -2.09 to -1.31); heart, mean difference -0.90 (95% CI -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% CI -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain.

Only one trial compared agalsidase alfa to agalsidase beta. There was no significant difference between the groups for any adverse events, risk ratio 0.36 (95% CI 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; 95% CI 0.03 to 2.57).

Authors' conclusions

Six small, poor quality randomised controlled trials provide no robust evidence for use of either agalsidase alfa and beta to treat Anderson-Fabry disease.

Résumé scientifique

Lenzymothérapie de substitution pour la maladie d'Anderson-Fabry

Contexte

La maladie d'Anderson-Fabry est un défaut du métabolisme des glycosphingolipides lié au chromosome X. L'insuffisance rénale progressive est une source majeure de morbidité, les complications supplémentaires sont dordre cardio- et cérébro-vasculaires. La survie est réduite chez les hommes affectés et les femmes porteuses symptomatiques.

Objectifs

Évaluer l'efficacité et la sécurité de lenzymothérapie de substitution par rapport à d'autres interventions, un placebo ou à l'absence d'intervention, pour traiter la maladie d'Anderson-Fabry.

Stratégie de recherche documentaire

« Nous avons recherché «Essais Cliniques» dans La Bibliothèque Cochrane , MEDLINE, EMBASE, LILACS et le registre des essais sur la mucoviscidose et autres maladies génétiques sur les erreurs innées du métabolisme (date de la recherche la plus récente : 11 septembre 2012). La recherche originale a été effectuée en septembre 2008.

Date de la recherche la plus récente dans le registre des essais sur la mucoviscidose et autres maladies génétiques et les erreurs innées du metabolisme du groupe Cochrane: 11 septembre 2012.

Critères de sélection

Essais contrôlés randomisés de l'agalsidase alfa ou bêta chez les participants présentant un diagnostic de la maladie d'Anderson-Fabry.

Recueil et analyse des données

Deux auteurs ont sélectionné les essais pertinents, évalué la qualité méthodologique et extrait les données de manière indépendante.

Résultats principaux

Six essais comparant l'agalsidase soit alfa soit bêta chez 223 participants remplissaient les critères de sélection.

Les deux essais comparant l'agalsidase alfa à un placebo avaient pour critère de jugement la concentration du globotriaosylcéramide dans le plasma et les tissus ; les résultats agrégés nétaient pas significatifs. Un essai avait rendu compte des scores de douleur, il y avait une amélioration statistiquement significative pour les participants recevant un traitement au bout de trois mois, la différence moyenne était de -2,10 (intervalle de confiance (IC) de -3,79 et -0,41) ; au bout de cinq mois, la différence moyenne était de -1,90 (IC à 95 % -3,65 et -0,15) ; et au bout de six mois, différence moyenne = -2,00 (IC à 95 % -3.66 à -0,34). Il y avait une différence significative dans la qualité de vie liée à la douleur après cinq mois et jusqu'à six mois, la différence moyenne était de-2,10 (IC à 95 % -3,92 à -0,28), mais pas à d'autres points-temps. Aucun essai ne rapportait de décès.

L'un des trois essais comparant l'agalsidase bêta à un placebo rendaient compte de la concentration du globotriaosylcéramide dans le plasma et les tissus et rapportait une amélioration significative : Pour les reins la différence moyenne était de -1,70 (IC à 95 % -2,09 et -1,31) ; pour le cœur, la différence moyenne était de-0,90 (IC à 95% -1.18 à -0,62) ; et de résultats composite ( complications rénales, cardiaques et cérébrovasculairs, et décès), la différence moyenne était de -4,80 (IC à 95%, entre -5,45 et -4.15). Il n'y avait aucune différence significative entre les groupes en termes de décès ; aucun essai ne rendait compte de la douleur.

Seule un essai comparait l'agalsidase alfa à l'agalsidase bêta. Il n'y avait aucune différence significative entre les groupes pour aucun des événements indésirables, le risque relatif était de 0,36 (IC à 95 % 0,08 à 1,59), et pour les événements indésirables graves ; le risque relatif était de 0,30 ; IC à 95 % 0,03 à 2,57).

Conclusions des auteurs

Six esais contrôlés randomisés de petite taille de qualité médiocre ne fournissent aucune preuve robuste en faveur de l'utilisation de l'agalsidase soit alfa soit betat pour le traitement de la maladie d'Anderson-Fabry.

Plain language summary

Enzyme replacement therapy for Anderson-Fabry disease

Anderson-Fabry disease is a rare X-linked recessive (inherited) lysosomal storage disease. Lysosomal disorders are triggered when a particular enzyme exists in too small an amount or is missing altogether; thus substances that should be broken down by the enzyme and recycled build up in the cell. This can cause a wide range of symptoms which affect the entire body. The kidneys, heart and brain can be affected and this can result in major illness and reduced life expectancy among affected individuals. Symptomatic males and females with Anderson-Fabry disease have been described within the literature, although the appearance of clinical signs may be delayed and more variable among females.

The review is based on six clinical trials that enrolled 223 participants. The trials used different formulations of the enzyme. Two trials compared agalsidase alfa to placebo; three trials compared agalsidase beta to placebo; and one trial compared agalsidase alfa to agalsidase beta. We analysed the three sets of data separately. Limited evidence from six small poor quality randomised controlled trials shows no robust evidence for use of both agalsidase beta and alfa to treat Anderson-Fabry disease. New trials should be undertaken with adequate sample size to detect possible differences among the treatment groups. Evaluating the same clinical outcomes should clarify the comparable effects of using the two current enzyme formulations (i.e. agalsidase alfa and agalsidase beta). Data on outcomes are being prospectively collected through surveillance or registry-based programs, as post-marketing commitments made by the sponsors.

Résumé simplifié

Lenzymothérapie de substitution pour la maladie d'Anderson-Fabry

La maladie d'Anderson-Fabry est un maladie rare du stockage lysosomal liée au chromosome X (héréditaire récessive). Les troubles lysosomaux sont déclenchés quand une enzyme particulière est présente en quantité trop petite ou nulle, et que les substances qui devaient être dissociées par l'enzyme et recyclées s'accumulent dans les cellules. Cela peut entraîner un large éventail de symptômes qui affectent le corps entier. Les reins, le cœur et le cerveau peut être affectés et cela peut provoquer une maladie grave et une réduction de l'espérance de vie chez les personnes touchées. Aussi bien des hommes que des femmes symptomatiques avec une maladie d'Anderson-Fabry ont été décrits dans la littérature, bien que l'apparition des signes cliniques peut être retardée et plus variable chez les femmes.

La revue est basée sur six essais cliniques portant sur 223 participants. Les essais utilisaient différentes formulations de l'enzyme. Deux essais comparaient l'agalsidase alfa à un placebo ; trois essais comparaient l'agalsidase bêta à un placebo ; et un essai comparait l'agalsidase alfa à l'agalsidase bêta. Nous avons analysé les trois jeux de données séparément. Des preuves limitées issues de six petits essais contrôlés randomisés de qualité médiocre ne montre aucune preuve robuste en faveur de l'utilisation de l'agalsidase, tant bêta qu'alfa pour traiter la maladie d'Anderson-Fabry. De nouveaux essais devraient être menées avec une taille d'échantillon adéquate pour détecter d'éventuelles différences entre les groupes de traitement. Evaluer les mêmes critères de jugement cliniques devraient permettre de clarifier les effets comparables des deux formulations de l'enzyme actuelles (c. par ex. l'agalsidase alfa et l'agalsidase bêta). Les données sur les résultats font lobjet dune collecte prospective à partir des programmes de surveillance ou des registres, tels que ceux des sponsors après la mise sur le marché.

Notes de traduction

Modification post hox : Nous allons également prendre en compte d'autres questionnaires validés sur la douleur.

Traduit par: French Cochrane Centre 20th November, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Please see glossary in the appendicies for definition of terms used throughout the review (Appendix 1).

Description of the condition

Anderson-Fabry disease (AFD) is an X-linked recessive multi-systemic disorder caused by a deficiency of the lysosomal enzyme alpha–galactosidase A (AGAL). The incidence of AFD is estimated at 1 in 117,000 live births for males (Meikle 1999); although recent newborn screening surveys suggest that the incidence may be much higher, up to 1 in 3100 (Spada 2006). Although the vast majority of reports have focused on the symptomatic male patients, females with AFD can develop disease-related problems. However, clinical expression among females tends to be more variable and onset of symptoms tends to occur at a later age (Wilcox 2008).

Clinically, AFD is characterized by major renal, cardiac and cerebrovascular complications; consequent to the progressive deposition of an incompletely metabolized substrate (Gb3) in multiple cell types, and attendant mechanisms of tissue injury that remain to be more fully defined. Alterations in vascular reactivity and a propensity for thrombo-embolic disease are believed to play a role in the increased risk for particular problems, such as stroke. Recently studies have shown that a deacylated form of Gb3 (globotriaosylsphingosine, lyso-Gb3 ) is elevated in plasma obtained from individuals with AFD. Lyso-Gb3 is a potent inhibitor of AGAL and alpha–galactosidase B (N-acetylgalactosaminidase), and it has been found to promote smooth muscle cell proliferation in vitro (Aerts 2008).

Renal and cardiac failure represent major sources of morbidity, and likely account for the reduced survival among affected males and females (wherein median age of death is 50 to 57 years and 70 to 72 years, respectively). In conjunction, pain crises, acroparaesthesia, hearing loss and gastrointestinal problems lead to significant reduction in patients’ health-related quality of life. Although the vast majority of reports have focused on the symptomatic male patients, females with AFD can develop disease-related problems. However, clinical expression among females tends to be more variable and onset of symptoms tends to occur at a later age. The expression of the disease in females appears to be influenced by the particular AGAL mutation and the pattern of X chromosome inactivation in each organ (Wang 2007).

Description of the intervention

Enzyme replacement therapy (ERT) for AFD represents the first specific treatment. It consists of the regular intravenous infusion of a recombinant enzyme formulation. Two forms of recombinant AGAL exist; specifically, agalsidase alfa (Replagal, Shire Human Genetic Therapies, Cambridge, MA) and agalsidase beta (Fabrazyme, Genzyme Corporation, Cambridge, MA). Agalsidase alfa is generated by the activation of the AGAL gene in a continuous human cell line; whereas agalsidase beta is produced in a Chinese hamster ovary (CHO) mammalian cell expression system, transduced with the human AGAL sequence. Both enzyme preparations are approved in Europe and many other countries, but in the United States the Federal Drug Administration approved only agalsidase beta (Eng 2001; Schiffmann 2001). Administration of ERT is usually once every two weeks, using a dose of 0.2 mg/kg body weight when using agalsidase alfa or 1 mg/kg for agalsidase beta.

How the intervention might work

Intravenous enzyme infusions appear to be reasonably well tolerated, with reported infusion reaction of about 10%; mostly consisting of fever and transient rigors of mild to moderate intensity. A proportion of people with AFD receiving ERT have sero-converted (i.e. developed antibodies); the frequency of antibodies against agalsidase alfa and agalsidase beta has been reported at 55% and 83% of individuals treated respectively (Eng 2001; Schiffmann 2001). Antibody formation did not influence clinical efficacy or outcomes in either of the initial clinical studies undertaken, and antibody titres usually decreased over time. In a few cases, IgE antibodies have been reported after infusion of agalsidase beta (Eng 2001). Recent studies have shown the presence of antibodies may influence the Gb3 storage in skin capillaries and Gb3 excretion in urine, although no relation between antibody formation and plasma Gb3 levels or clinical outcome has been established thus far (Hollack 2009).

Why it is important to do this review

A systematic review is needed to establish the evidence base for the effectiveness and safety of ERT for treating AFD.

Objectives

To evaluate the effectiveness and safety of ERT compared to other interventions, placebo or no interventions, for treating AFD.

Methods

Criteria for considering studies for this review

Types of studies

Randomized and quasi-randomized controlled clinical trials.

Types of participants

Individuals with AFD of any age and any degree of disease severity. Diagnosis should be established either by accepted criteria based on concentration of enzyme activity or by mutation analysis.

Types of interventions

Enzyme replacement therapy (agalsidase beta or agalsidase alfa) in any amount given for a period of at least one month compared to: each other; another intervention (fat-restricted diet, drugs, exercises, etc); no intervention; or to placebo.

Types of outcome measures

Primary outcomes
  1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue (i.e. endothelial cells)

  2. Death

  3. Pain (measured by the McGill Pain Questionnaire*)

    1. Acroparaesthesia (measured by the intensity and duration of acroparaesthesia as reported by the individual)

    2. Fabry crises

*Post hoc change: we will also consider other validated pain questionnaires.

Secondary outcomes
  1. Effect of therapy on renal function (e.g. increase in serum creatinine and proteinuria; creatinine and insulin clearance)

  2. Symptoms and complications of disease (such as occurrence of renal failure, skin, cerebrovascular and cardiac complications) based on the following observations: serum creatinine level, proteinuria (ratio of urinary protein to urinary creatinine in mg/dL), ratio of urinary albumin to urinary creatinine (in mg/dL), 12-lead electrocardiography, echocardiography, neurologic examination, head magnetic resonance imaging, exercise tolerance, and AFD symptom assessment

  3. Parameters: echocardiographic (such as thickness of cardiac structures, left ventricular volume, measures of systolic and diastolic function, heart rate)

  4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens; glomeruli and mesangial widening

  5. Adverse effects of treatment (including severe adverse effects such as dyspnoea, malaise, hypertension and gastrointestinal symptoms, and antibody formation), based on the type and frequency of adverse events in treated patients and those on placebo. It should be noted that certain adverse events may represent AFD complications, and thus may not necessarily be related to the recombinant enzyme formulation

  6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000)

  7. Costs

Search methods for identification of studies

There were no language restriction and the trials were identified from the sources listed below.

Electronic searches

Relevant trials were identified from the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register using the term: FABRY.

The Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated with each new issue of The Cochrane Library), quarterly searches of MEDLINE and the prospective handsearching of one journal - Journal of Inherited Metabolic Disease. Unpublished work were identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference and the SHS Inborn Error Review Series. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.

Date of the most recent search of the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register: 11 September 2012.

We also searched Cochrane Central Register of Controlled Trials (Clinical Trials) (Issue 9, 2012) Ovid EMBASE (1980 to September 2012), PubMed (1980 to September 2012) and the Literature Latino-Americana e do Caribe em Ciências da Saúde - LILACS (1982 to September 2012). These search strategies are listed in the Appendices (Appendix 2; Appendix 3; Appendix 4; Appendix 5).

In order to maximise sensitivity, the search strategies included terms for enzyme replacement therapy for AFD or Fabry disease. We searched with both subject headings and free text words, and we expected to identify all trials of enzyme replacement therapy for AFD or Fabry disease. The following exhaustive list of synonyms for enzyme replacement therapy for AFD or Fabry disease were used:

((Fabry Disease) OR (Disease, Fabry) OR (Angiokeratoma Corporis Diffusum) OR (Anderson-Fabry Disease) OR (Anderson Fabry Disease) OR (Disease, Anderson-Fabry) OR (Fabry's Disease) OR (Disease, Fabry's) OR (Fabrys Disease)) AND ((agalsidase beta) OR (Fabrazyme) OR (Genzyme brand of AGAL) OR (Agalsidase alfa) OR (Replagal) OR (Shire HGT brand of AGAL)).

Searching other resources

Reference lists of the identified relevant trials were scrutinized for additional citations.

Specialists in the field and authors of the included trials were contacted for any possible unpublished data.

Data collection and analysis

Selection of studies

Two authors (RED and GMP) independently screened the trials identified by the literature search. We resolved discrepancies in results by discussion.

Data extraction and management

Two authors (RED and GMP) independently extracted data. We resolved discrepancies in results by discussion. We used a standard form to extract the following information: characteristics of the trial (design, methods of randomisation); participants; interventions; outcomes (types of outcome measures, timing of outcomes, adverse events).

We presented different enzyme therapies (alfa and beta) as separate interventions as we did not judge these sufficiently comparable to combine.

When possible, outcome data were grouped into those measured at up to one month, over one month and up to three months, over three months and up to six months and over six months and up to 12 months and annually thereafter. In a post hoc change, we also considered other time-points such as 'over five months and up to six months' where multiple data sets from an individual trial were available for a single planned time-point.

Assessment of risk of bias in included studies

We assessed every trial using a simple form and followed the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011).

We assessed the following domains as having either low, unclear or high risk of bias:

  1. randomisation

  2. concealment of allocation

  3. blinding (of participants, caregivers and outcome assessors)

  4. incomplete outcome data

  5. selective reporting

  6. other potential sources of bias

1. Randomisation

Low risk: adequate generation of allocation
Unclear risk: not described in the paper or by contacting authors
High risk: inadequate generation of allocation

2. Concealment of allocation

Low risk: adequate allocation concealment
Unclear risk: not described in the paper or by contacting authors
High risk: inadequate allocation concealment

3. Blinding (of participants, caregivers and outcome assessors)

Low risk: adequately described
Unclear risk: described as blinded, but no information provided
High risk: not blinded

4. Incomplete outcome data

We recorded the rates of withdrawal for each outcome as follows:
Low risk: less than 20% and equal for both groups;
Unclear risk: not reported in paper or by authors;
High risk: greater than 20% or not equal for any comparison groups or both.

5. Selective reporting

We considered the possibility of selective reporting of outcomes when data were not available in the 'Results' section of the published paper, but according to the 'Methods' section these outcome data were collected.

6. Other potential sources of bias

We recorded any other factors we felt might cause bias.

Measures of treatment effect

For dichotomous data (such as death, presence or absence of Fabry crises and adverse effects), we used the risk ratio (RR), with 95% confidence intervals (95% CIs) as the effect measure.

For continuous data (such as changes in Gb3 concentration, echocardiographic parameters, pain and quality of life scores) we used the mean difference (MD) (in which the effect estimates of individual trials are weighted by dispersion measures), with 95% CIs. When standard errors were reported within the trial reports, we converted these to standard deviations (SD = SE x  square root of n).

For time-to-event data (such as effects on renal function) we planned to consider a joint model for longitudinal and discrete time-to-event data in which the discrete event time distribution is modelled as a linear function of the slope of an individual's longitudinal process on the probit scale (Jones 2009). Effect of therapy on renal function (e.g. increase in serum creatinine and proteinuria; creatinine and insulin clearance) would be measured as time-to-event-data or number of events. However, the only trial reporting on this outcome only reported on one time-point, which has been presented as continuous data (Schiffmann 2001).

For other outcomes such as cost, or outcomes where there were insufficient data to enter into the meta-analysis, we planned to present the information narratively.

Unit of analysis issues

We planned to include in the review data from any eligible cross-over trials; we planned to analyse these using a method recommended by Elbourne (Elbourne 2002).

Dealing with missing data

For any new trial which may be included in a future update of this review, we will contact authors to clarify methodological issues (such as generation and allocation concealment, blind method and withdrawals) as well as for any missing outcome data.

Assessment of heterogeneity

We planned to qualify inconsistency among the pooled estimates using the I2 statistic. This illustrates the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2003; Higgins 2011). We considered there to be a low degree of heterogeneity if I2 was below 25%, a moderate degree if I2 between 25% and 50%, and a high degree if I2 was over 50%.

Assessment of reporting biases

We planned to assess publication bias by drawing a funnel plot (trial effect versus trial size), but there were not sufficient trials included in the review. In future analysis, funnel plots will be used in an exploratory data analysis to assess for the potential existence of small trial bias. There are a number of explanations for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design of small trials (Sterne 2001) and publication bias and selective reporting of outcomes. Thus, this exploratory data tool may be misleading (Tang 2000; Thornton 2000) and we will not place undue emphasis on this tool.

Data synthesis

We used the fixed-effect model to analyse data, if in future updates, significant heterogeneity (e.g. I2 higher than 50%) is identified, we will compute pooled estimates of the treatment effect for each outcome under a random-effects model (with two or more trials).

Subgroup analysis and investigation of heterogeneity

For future reviews we plan to investigate heterogeneity by conducting meta-analyses by subgroups as described below.

  1. Types of dosage. We plan to sub-divide dosage in lower dose (less than 2 mg/kg) and higher dose (more than 2 mg/kg). These cut off dosages were chosen arbitrarily.

  2. Duration of intervention. We also plan to sub-divide duration of intervention up to one year and more than one year.These time divisions were chosen arbitrarily.

  3. Age at commencement of treatment, for example, up to the age of 18 years and over age 18 years.

  4. Severity of disease, by less severe and more severe disease (as reported within the trials).

Sensitivity analysis

If we had included an adequate number of trials, we planned to perform a sensitivity analysis to test the robustness of analyses to certain assumptions in the results. In future analysis, we will include the following factors in the sensitivity analysis, separating trials according to:

  1. allocation concealment quality (low risk, high risk or unclear risk);

  2. blinding of participants, caregiver and outcome assessment (low risk, high risk or unclear risk);

  3. rates of withdrawal for each outcome.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

For the original review, we identified 273 references from the electronic searches (El Dib 2010). After initial assessment of these references, 54 were looked at in more detail as being potentially eligible for inclusion. Following the whole verification of the 54 articles, 31 of them were excluded from the review (Excluded studies) Thus, five trials (represented by 23 individual references), which enrolled 187 participants were included in this review (Included studies).

For the first update of the review in 2012, 368 references were identified by the searches. After an initial shift for relevance, we selected seven references for careful consideration and obtained them in full text, when available. Following assessment of the full articles, we included one new trial (five references) (Vedder 2007) and excluded two further trials (Fernhoff 2011; West 2011).

Included studies

Agalsidase alfa versus placebo

Two trials were included in this comparison and are described in detail below (Hughes 2008; Schiffmann 2001).

Trial design

Both trials were described as randomized double-blind placebo-controlled clinical trials (Hughes 2008; Schiffmann 2001). Both trials were for six months (Hughes 2008; Schiffmann 2001), but one had an additional 36 months follow up (Hughes 2008).

Both trials recruited only males and included 15 and 26 participants respectively (Hughes 2008; Schiffmann 2001). The ratio of participants in the treatment and placebo groups varied; one trial achieved an almost equal split, randomising 14 participants to treatment and 12 to placebo (Schiffmann 2001); and the other trial did not state how many participants were in each group (Hughes 2008).

Types of interventions

Both trials compared enzyme replacement therapy (ERT) to placebo. One trial administered agalsidase alfa (Replagal™) every two weeks (dose not given); the other trial used a regimen of 0.2 mg/kg (administered over 40 minutes) every two weeks with an additional follow-up report of more 36 months (Hughes 2008).

Types of outcomes measured

Moore evaluated transversal doppler measurements, left ventricular volume, heart rate and stroke volume. The following Doppler parameters were obtained: peak flow velocity, mean flow velocity, end-diastolic velocity, pulsatility index, and resistance index (Schiffmann 2001).

At baseline and six months, Hughes measured left ventricular mass, QRS duration and levels of Gb3 in cardiac tissue, urine sediment and plasma and adverse effects (Hughes 2008).

Agalsidase beta versus placebo

Three trials were included in this comparison and are described in detail below (Banikazemi 2007; Bierer 2006; Eng 2001).

Trial design

All three trials were described as randomized placebo-controlled clinical trials (Banikazemi 2007; Bierer 2006; Eng 2001); and two of these were described as double-blind (Banikazemi 2007; Eng 2001). Trial duration ranged from five months (Eng 2001) to 35 months (Banikazemi 2007).

The number of participants included in each trial ranged from six (Bierer 2006) to 82 (Banikazemi 2007) and the three trials randomized mostly males (Banikazemi 2007; Bierer 2006; Eng 2001). The ratio of participants in the treatment and placebo groups varied across trials; two had a ratio of 2:1 treatment-to-placebo (Banikazemi 2007; Bierer 2006); and one had an even split of 29 participants in each group (Eng 2001).

In one trial, the investigators were part of the Genzyme Corporation in Cambridge, Massachussetts (Eng 2001). Only one trial was described as multicenter; there were 26 referral centers in six countries of North America and Europe (Banikazemi 2007).

Types of interventions

All three trials compared enzyme replacement therapy (ERT) to placebo. Each trial compared agalsidase beta (recombinant human alfa-galactosidase A) to placebo (Banikazemi 2007; Bierer 2006; Eng 2001). Two trials used the same dose (1mg/kg intravenously every two weeks), but one gave this dose for 20 weeks (Eng 2001) and the other for up to 35 months (median 18.5 months) (Banikazemi 2007). The final trial gave a dose of 1 mg/kg every other week for 18 months (Bierer 2006).

Types of outcomes measured

Thurberg evaluated urinary creatinine, urinary protein excretion, renal function and dermatologic characteristics of glycolipid accumulation in the dermis (Eng 2001). Measurements were taken at baseline and after infusion 11 at five months.

Banikazemi measured the time to first clinical event (renal, cardiac, or cerebrovascular event or death) (Banikazemi 2007). The following measures were taken: serum creatinine level; proteinuria; ratio of urinary albumin to urinary creatinine; 12-lead electrocardiography; echocardiography; neurologic examination; head magnetic resonance imaging; Brief Pain Inventory; exercise tolerance; plasma globotriaosylceramide level; Fabry symptom assessment; physical examination; blood chemistries; urinalysis; IgG antibody titers to agalsidase beta; and optional skin biopsy. All measurements were taken at baseline; serum creatinine levels were measured every four weeks, and all other baseline measures were repeated every 12 weeks, except for echocardiography, head magnetic resonance imaging, and exercise tolerance, which were repeated every 24 weeks. The estimated glomerular filtration rate (GFR) was determined by using the 4-variable Modification of Diet in Renal Disease formula.

Bierer measured cardiopulmonary exercise performance, forced expiratory volume and forced vital capacity every three months over an 18-month period (Bierer 2006).

Agalsidase alfa versus agalsidase beta

One trial was included in this comparison and is described in detail below (Vedder 2007).

Trial design

The trial was described as a randomized clinical trial, with patients being treated for a period of at least 12 months. A total of 36 patients (18 males and 18 females) were included in the trial. A total of 34 patients had at least 12 months of follow-up and a sub-group of patients (25 out of 34) was followed for more than 24 months of treatment. Two female patients withdrew after six months of agalsidase treatment.

Types of interventions

Patients were treated with either agalsidase alfa or agalsidase beta at an equal dose of 0.2 mg/kg bi-weekly.

Types of outcomes measured

Reduction in left ventricular mass after 12 and 24 months of treatment was considered the primary outcome. The authors also evaluated the occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine.

Excluded studies

Following the whole verification of the 56 articles, 33 of them were excluded from the review (Alamartine 2005; Banikasemi 2005; Beck 2004; Beer 2006; Breunig 2006; Cartwright 2004; Elliott 2006; Eto 2005; Fernhoff 2011; Germain 2007; Guffon 2002; Guffon 2004; Hajioff 2006; Hilz 2004; Jardim 2006; Jardim 2006b; Kalliokoshi 2006; Kampmann 2002; Kobayashi 2005; Kosch 2004; Linthorst 2004; Linthorst 2006; Mignani 2004; Mills 2004; Pisani 2005; Ramaswami 2007; Ries 2006; Schiffmann 2003; Schiffmann 2006; Spinelli 2004; Utsumi 2005; Weidemann 2003; West 2011). The main reasons for exclusion being that these were case series, cohort studies, or retrospective studies.

Risk of bias in included studies

Agalsidase alfa versus placebo

Generation of randomisation sequence

Hughes did not give a description regarding the generation of allocation; thus, this trial was classified as having an unclear risk of bias. (Hughes 2008).

For the Moore trial, it was stated that a randomization schedule was prepared prior to the start of the trial. Randomization was blocked to minimize imbalances between groups, however the authors did not report the method used for this, therefore we also classified it as unclear (Schiffmann 2001).

Allocation concealment

For the Hughes trial there was no description regarding the concealment of allocation; thus, this was judged to have an unclear risk of bias (Hughes 2008).

The other trial was classified as having a low risk of bias (Schiffmann 2001). The randomization schedule was prepared prior to the start of the trial and was provided to an unblinded pharmacist in the research pharmacy; no medical or sponsor personnel had access to the randomization code until the trial was completed (Schiffmann 2001).

Blinding

The Hughes trial was stated as being double-blind (Hughes 2008). All data were independently analysed by Royal Free Hospital investigators; the data remained blinded until the database was unlocked and the statistical analyses performed (Hughes 2008). We therefore judge this to be at a low risk of bias regarding this domain.

Moore did not describe any blinding process, therefore it was classified as having an unclear risk of bias (Schiffmann 2001).

Incomplete outcome data

There was no mention of withdrawals, drop outs or ITT in the Hughes trial, therefore we judged this to have an unclear risk of bias (Hughes 2008).

Moore describes four withdrawals and gives reasons for these; one participant, randomized to the placebo trial arm, withdrew from the trial for personal reasons and three further participants (one from the ERT group and two from the placebo group) declined the follow-up acetazolamide challenge arm of the trial at completion of the trial (Schiffmann 2001). However, ITT was not described in this trial. Overall, we have assessed this domain as having a low risk of bias (Schiffmann 2001).

Selective reporting

We judged both included trials to be free of selective reporting and having a low risk of bias (Hughes 2008; Schiffmann 2001).

Other potential sources of bias

We did not identify any other potential sources of bias (Hughes 2008; Schiffmann 2001).

Agalsidase beta versus placebo

Generation of randomisation sequence

The generation of allocation from the Banikazemi trial presented a low risk of bias as the randomisation codes were described as being computer-generated (Banikazemi 2007). The other two trials were described as randomized, but no details were given of how the sequences were generated; therefore these trials presented an unclear risk of bias (Bierer 2006; Eng 2001).

Allocation concealment

One trial was classified as having a low risk of bias since the randomization codes were maintained centrally at a secure location (Banikazemi 2007).

For the trials by Bierer and Thurberg there was no description regarding the concealment of allocation; thus, these trials were classified as having an unclear risk of bias (Bierer 2006; Eng 2001).

Blinding

In the Banikazemi trial, materials were packaged identically, and the sponsor staff, investigators, and participants were blinded to treatment allocation leading to a low risk of bias (Banikazemi 2007). The trial by Thurberg was described as double blind, however, information was only provided in relation to two outcomes. It was stated that each renal biopsy was reviewed under light microscopy by three independent renal pathologists who were blinded to treatment status of the patient at the time of biopsy; immunofluorescence trials were scored blinded (Eng 2001). Bierer reported that this trial was double blind, but provided no further details (Bierer 2006). We therefore judge both of these trials to have an unclear risk of bias (Bierer 2006; Eng 2001).

Incomplete outcome data

Withdrawals and drop outs, were noted by Banikazemi to be less than 20% (Banikazemi 2007). The Banikazemi trial used intention-to-treat analysis only in the primary outcome of their trial (time to first clinical event - renal, cardiac, or cerebrovascular event or death). We therefore assessed this as having an unclear risk of bias (Banikazemi 2007).

There was no description regarding withdrawals, drop outs and ITT in either the Bierer or Thurberg trials (Bierer 2006; Eng 2001).

Selective reporting

We judged all three included trials to be free of selective reporting (Banikazemi 2007; Bierer 2006; Eng 2001). The trials reported all the significant and non-significant results. We therefore judge all three trials to have a low risk of bias (Banikazemi 2007; Bierer 2006; Eng 2001).

Other potential sources of bias

While in the Thurberg trial, the investigators were part of the Genzyme Corporation in Cambridge, Massachussetts, we judge this trial to have an unclear risk of bias (Eng 2001).

Agalsidase alfa versus agalsidase beta

Generation of randomisation sequence

Different sets of randomization blocks were applied to both groups in the trial (Vedder 2007). Each block consisted of four envelopes that contained a paper stating agalsidase alfa or beta (i.e., manual randomization); the envelopes were generated by people not involved in obtaining informed consent. Therefore, we classified this trial as having a low risk of bias.

Allocation concealment

The envelopes were checked by two people not involved in obtaining informed consent, thus we classified the trial as having a low risk of bias for this domain (Vedder 2007).

Blinding

This trial was not blinded. The authors stated that "blinding of the enzyme products was not feasible, since the quality and storage life after rebottling could not be guaranteed". Furthermore, the authors reported that envelopes were opened by the investigator in the presence of the patient. Therefore we classified the risk of bias as high (Vedder 2007).

Incomplete outcome data

In the overall analysis, in the agalsidase alfa group 10% of patients withdrew, whereas there were no withdrawals in the agalsidase beta group (Vedder 2007). However, in the LVMass analysis there were withdrawal rates of 50% and 62.5% in the agalsidase alfa and beta groups, respectively. Therefore we classified this trial as having a high risk of bias.

Selective reporting

We judged the trial to be free of selective reporting and therefore classified this domain as having a low risk of bias (Vedder 2007).

Other potential sources of bias

We did not identify any other potential sources of bias (Vedder 2007).

Effects of interventions

We present the data from agalsidase alfa and agalsidase beta separately because of differences in trial design and treatment dose.

Agalsidase alfa versus placebo

Two trials were included in this comparison with a total of 41 participants: Hughes enrolled 15 participants; and Moore enrolled 26 participants (Hughes 2008; Schiffmann 2001).

Primary outcomes
1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue

Two trials reported on this outcome at six months (end of treatment) (Hughes 2008; Schiffmann 2001).There was no statistically significant difference between treatment groups in the plasma Gb3 concentration, MD -2.07 (95% CI -6.64 to 2.50) (Hughes 2008; Schiffmann 2001) (Analysis 1.1). There were also no statistically significant differences between treatment groups regarding the subcategories: urine sediment Gb3, MD -812.00 (95% CI -1897.83 to 273.83); and kidney, MD -2.50 (95% CI -9.47 to -4.47) (Schiffmann 2001) (Analysis 1.2; Analysis 1.3). Hughes did not report a statistically significant difference between the participants receiving agalsidase alfa and those receiving placebo for myocardial Gb3 levels at over three months and up to six months, MD 0.07 (95% CI -0.35 to 0.49) (Hughes 2008) (Analysis 1.4).

2. Death

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

3. Pain (measured by the McGill Pain Questionnaire)
a. Acroparaesthesia

We intended to measure this outcome by the intensity and duration of acroparaesthesia as reported by the individual; however none of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

b. Fabry crises

We planned to present whether the participants had reported the presence or absence of crises as a binary outcome, but none of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

c. The Brief Pain Inventory severity

One trial reported on this outcome (Schiffmann 2001). There was a statistically significant difference favoring the participants receiving agalsidase alfa versus placebo in all the subcategories studied: at over one month and up to three months, MD -2.10 (95% CI -3.79 to -0.41); at over three months and up to five months, MD -1.90 (95% CI -3.65 to -0.15); and at over five months and up to six months, MD -2.00 (95% CI -3.66 to -0.34) (Schiffmann 2001) (Analysis 1.5).

d. The Brief Pain Inventory pain-related quality of life

One trial reported on this outcome (Schiffmann 2001). There was no statistically significant difference between groups in the subcategories studied at over one month and up to three months, MD -0.90 (95% CI -2.73 to 0.93) and at over three months and up to five months, MD -1.80 (95% CI -3.77 to 0.17). However, at over five months and up to six months a significant difference favoring agalsidase alfa was noted, MD -2.10 (95% CI -3.92 to -0.28) (Schiffmann 2001) (Analysis 1.6).

Secondary outcomes
1. Effect of therapy on renal function

One trial reported on this outcome (Schiffmann 2001). Creatinine clearance and inulin clearance were used to estimate glomerular filtration rate. There were no statistically significant difference between both groups in the subcategories creatinine clearance at end of treatment (up to six months), and insulin clearance (up to six months) respectively, MD 10.30 (95% CI -15.37 to 35.97) and MD -0.50 (95% CI -21.36 to 20.36) (Schiffmann 2001) (Analysis 1.7; Analysis 1.8).

There was also no statistically significant difference between groups in the subcategories: glomeruli with mesangial widening at up to six months, MD -14.70 (95% CI -36.72 to 7.32); glomeruli with segmental sclerosis at up to six months and obsolescent glomeruli at up to six months; MD 3.80 (95% CI -2.35 to 9.95) and MD 6.50 (95% CI -8.93 to 21.93) (Schiffmann 2001) (Analysis 1.9; Analysis 1.10; Analysis 1.11).

2. Symptoms and complications of disease (such as renal failure, skin, cerebrovascular and cardiac complications)

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

3. Parameters: echocardiographic

There was no statistically significant difference between groups for mean left ventricular wall thickness, MD -0.79 (95% CI -3.62 to 2.04); left ventricular internal diameter (diastolic), MD -3.70 (95% CI -11.73 to 4.33); left ventricular internal diameter (systolic), MD -2.70 (95%CI -9.91 to 4.51); and left ventricular ejection fraction, MD 1.88 (95%CI -4.68 to 8.44) (Hughes 2008) (Analysis 1.12).

4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

5. Adverse effects of treatment

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000))

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

7. Costs

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

Agalsidase beta versus placebo

Three trials were included in this comparison with a total of 146 participants: Banikazemi enrolled 82 participants; Bierer enrolled 6 participants; and Thurberg enrolled 58 participants (Banikazemi 2007; Bierer 2006; Eng 2001).

Primary outcomes
1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue

One of the included trials reported on this outcome in tissue (Eng 2001). There was a statistically significant difference favoring the participants receiving agalsidase beta versus placebo in three subcategories: kidney, MD -1.70 (95% CI -2.09 to -1.31); heart, MD -0.90 (95% CI -1.18 to -0.62); and composite, MD -4.80 (95% CI -5.45 to -4.15) (Eng 2001) (Analysis 2.1).

None of the included trials reported the effect on plasma concentrations (Banikazemi 2007; Bierer 2006; Eng 2001).

2. Death

There was no statistically significant difference in death as reported in one trial, RR 1.85 (95% CI 0.08 to 43.96) (Analysis 2.2). There was one death from a total of 51 participants in agalsidase beta and no deaths in the placebo group (n = 31) (Banikazemi 2007).

3. Pain (measured by the McGill Pain Questionnaire)
a. Acroparaesthesia

We intended to measure this outcome by the intensity and duration of acroparaesthesia as reported by the individual; however none of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

b. Fabry crises

We planned to present whether the participants had reported the presence or absence of crises as a binary outcome, but none of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

Secondary outcomes
1. Effect of therapy on renal function

The number of renal events (33% increase in serum creatinine level; end-stage renal disease) were reported by Banikazemi; there was no statistically significant difference in the number of events between groups, RR 0.87 (95% CI 0.37 to 2.04) (Banikazemi 2007) (Analysis 2.3).

2. Symptoms and complications of disease (such as renal failure, skin, cerebrovascular and cardiac complications)
a. Cardiac events

Cardiopulmonary exercise test was reported by Bierer (Bierer 2006). There were no significant differences between groups in any of the subcategories evaluated (average heart rate reserve, MD 21.30 (95% CI -1.28 to 43.88); average maximum oxygen uptake measured at peak exercise, MD 0.22 (95% CI -0.94 to 1.38); maximum oxygen uptake measured at peak exercise, MD 2.60 (95% CI -13.16 to 18.36); and oxygen pulse average at peak exercise, MD 2.10 (95% CI -3.67 to 7.87)) (Analysis 2.4).

There were no significant differences in decrease in diastolic blood pressure in the Bierer trial, RR 1.50 (95% CI 0.34 to 6.70) (Bierer 2006) (Analysis 2.5).

Banikazemi reported cardiac events and there was also no significant differences between studied groups RR 0.46 (95% CI 0.11 to 1.90) (Banikazemi 2007) (Analysis 2.6).

b. Cerebrovascular events

There was no significant difference in the number of cerebrovascular events between groups in the Banikazemi trial, RR 0.12 (95% CI 0.01 to 2.48) (Banikazemi 2007) (Analysis 2.7).

c. Percentage of participants achieving zero scores in skin

For participants achieving zero scores in skin at five months, there was a statistically significant difference in the Thurberg trial favoring the participants receiving agalsidase beta versus placebo in two subcategories: superficial endothelial cells, RR 19.67 (95% CI 4.13 to 93.63) and deep endothelial cells, RR 11.00 (95% CI 2.88 to 42.08) (Eng 2001). There was no significant difference between groups in two further sub-categories: smooth muscle cells, RR 1.50 (95% CI 0.10 to 22.62); or in perineurium cells, RR 1.04 (95% CI 0.07 to 15.72) (Analysis 2.8) (Eng 2001).

Thurberg also reported data for participants achieving a zero score or a reduction in skin (Analysis 2.9); there was a statistically significant difference favoring the participants receiving agalsidase beta versus placebo in two subcategories: superficial endothelial cells, RR 2.81 (95% CI 1.72 to 4.59) and deep endothelial cells, RR 2.79 (95% CI 1.67 to 4.67) (Eng 2001). There was no significant difference between groups in two further sub-categories: smooth muscle cells, RR 1.50 (95% CI 0.10 to 22.62); or in perineurium cells, RR 1.49 (95% CI 0.68 to 3.25).

3. Parameters echocardiographic

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

5. Adverse effects of treatment
a. Any adverse event

Two trials reported adverse events; one at over three month and up to six months (Eng 2001) and one at 24 months (Banikazemi 2007).

There were statistically significant differences in favor of placebo regarding rigors at both time-points and combined, RR 16.12 (95% CI 3.35 to 77.58) (Analysis 2.10). Likewise, occurrence of fever at both time-points and combined was statistically significant in favor of placebo, RR 7.84 (95% CI 1.88 to 32.68) (Analysis 2.11). Only Banikazemi reported temperature changed sensation, at 24 months there was no statistically significant difference, RR 3.04 (95% CI 0.37 to 24.82) (Banikazemi 2007) (Analysis 2.12). Likewise only one trial reported chills; there was no statistically significant difference at over three months and up to six months, RR 9.00 (95% CI 0.51 to 159.94) (Eng 2001) (Analysis 2.13). Both trials reported hypertension; there was no statistically significant difference at either time-point or combined, RR 2.94 (95% CI 0.80 to 10.86) (Banikazemi 2007; Eng 2001) (Analysis 2.14). Only one trial reported vomiting, chest pain and fatigue; there was no statistically significant difference for any of these at 24 months, vomiting RR 8.00 (95% CI 0.47 to 137.27), chest pain RR 6.77 (95% CI 0.39 to 118.36) and fatigue RR 6.77 (95% CI 0.39 to 118.36) (Banikazemi 2007) (Analysis 2.15; Analysis 2.16; Analysis 2.17). Thurberg reported on headache and pain related to Fabry disease at over three months and up to six months (Eng 2001) (Analysis 2.18; Analysis 2.19). Neither outcome showed a statistically significant difference; headache, RR 2.50 (95% CI 0.53 to 11.86); and pain related to Fabry disease, RR 3.00 (95% CI 0.33 to 27.18) (Eng 2001).

b. Any serious adverse events

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000))

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

7. Costs (presented narratively)

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

Agalsidase alfa versus agalsidase beta

One trial was included in this comparison with a total of 34 participants (Vedder 2007).

Primary outcomes
1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue

Vedder reported a median (range) of 3.3 umol/l (1.45 to 6.42) and 3 umol/l (1.89 to 7.85) for 12 and 24 months of treatment, respectively in agalsidade alfa arm, while there was a median (range) of 2.48 umol/l (1.40 to 3.93) and 2.23 umol/l (0.92 to 4.3) for 12 and 24 months of treatment, respectively in agalsidade beta arm.

2. Death

There was a death from multiple cerebral infarctions after 20 months in the agalsidase alfa treatment group, RR 3.00 (95% CI 0.13 to 69.09) (Vedder 2007) (Analysis 3.1).

3. Pain (measured by BPI-3)
a. Acroparaesthesia and Fabry crises

The trial described no significant reduction of pain score (BPI-3) after 12 months of treatment in either of the studied groups: alfa 0 (range 25 to 1); and beta 21.5 (range 24 to 3). The values did not change for analysis at the 24 month time-point (Vedder 2007).

Secondary outcomes
1. Effect of therapy on renal function

The trial reported that renal insufficiency, defined as an increase of serum creatinine greater than 33%, progressed in two patients treated with agalsidase alfa, who had baseline GFR measurements of 22 and 30 ml/min (within 24 months). Furthermore, also in the agalsidase alfa group, progression of renal insufficiency was seen in one other patient after 30 months of treatment (Vedder 2007).

2. Symptoms and complications of disease (such as renal failure, skin, cerebrovascular and cardiac complications)
a. Cardiac events

Two patients suffered from atrial fibrillation after 42 and 36 months of agalsidase beta treatment (Vedder 2007). Furthermore, atrial fibrillation also occurred in a male patient treated with agalsidase alfa for 30 months. There was no statistically significant difference for cardiac events, RR 0.47 (95% CI 0.05 to 4.60) (Vedder 2007) (Analysis 3.2).

b. Cerebrovascular events

The included trial did not report this outcome (Vedder 2007).

c. Percentage of participants achieving zero scores in skin

The included trial did not report this outcome (Vedder 2007).

3. Parameters echocardiographic

The trial reported LVMass (g). There was a median (range) of 244 g (157 to 424) and 294 g (196 to 502) for 12 and 24 months of treatment, respectively in the agalsidase alfa arm, while there was a median (range) of 296 g (169 to 401) and 308 g (196 to 471) for 12 and 24 months of treatment, respectively in the agalsidase beta arm (Vedder 2007).

4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens

The included trial did not report this outcome (Vedder 2007).

5. Adverse effects of treatment
a. Any adverse event

There was no significant difference in the number of any adverse events between groups in the Vedder trial, RR 0.36 (95% CI 0.08 to 1.59) (Vedder 2007) (Analysis 3.3).

b. Any serious adverse events

There was no significant difference in the number of any serious adverse events between groups in the Vedder trial, RR 0.30 (95% CI 0.03 to 2.57) (Vedder 2007) (Analysis 3.4).

6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000))

The included trial did not report on this outcome, but it is included as an outcome in the protocol (Vedder 2007). We contacted the main author for further clarification and hope these data can be included in a future update of this review.

7. Costs (presented narratively)

The included trial did not report this outcome (Vedder 2007).

Discussion

The effectiveness of therapy in reducing the incidence and severity or delaying the onset of AFD-related complications, and its impact on long-term survival is not known at this time. Heterogeneity in clinical expression requires long-term studies in a large cohort of patients, which is being undertaken through observational surveys or patient registries.

It has been shown that ERT for AFD can modify the course of disease in treated patients. Compared with the group of participants receiving placebo, those treated with either agalsidase alfa or agalsidase beta experienced a reduction in Gb3 concentration in plasma and tissues. Although this finding is indicative of ‘proof of concept’, its clinical significance is uncertain as the trials examined did not provide specific information on correlation with clinical events or survival. Trial results indicated an effect of ERT on neuropathic pain, cardiac morphology and renal function, and a positive influence on health-related quality of life. However, additional information from trials including a greater number of participants is required. It is likely that advanced disease stage prior to the start of treatment influenced outcome. Trials in asymptomatic or oligo-symptomatic individuals may provide information on the effectiveness of therapy in preventing or delaying the onset of symptoms or disease-related complications (Ramaswami 2007; Ries 2006; Ries 2007; Wraith 2008).

Treatment with ERT appears to be relatively well-tolerated. Antibody formation has been reported in a significant proportion of treated individuals. Although trials indicate that the presence of neutralizing antibodies may potentially influence therapeutic outcome, in the absence of controlled trials no definitive conclusions can be provided at this time. Infusion-related adverse events may be controlled by the use of pre-medication and the administration of the enzymes at a slower rate. Treatment is widely available, based on the country of origin for patients in the registry programs.

In the agalsidase alfa comparison, even though we used a random-effects model (to better deal with heterogeneity), we found a high level of heterogeneity (I2 = 91%) in the outcome plasma Gb3 at up to six months. This method assumes that the effects being estimated in the different trials are not identical, but follow some distribution. In this case the effect may have varied due to different population or intervention characteristics (such the dose, duration and regimen).

We included six trials in this systematic review, that were of low methodological quality; mainly, providing results that were presented in a manner that made statistical analysis difficult. For future updates of this review, we will contact authors to clarify the methodological issues.

Authors' conclusions

Implications for practice

Limited evidence from five small poor quality randomised controlled trials shows no robust evidence for use of either agalsidase alfa or beta to treat AFD. The long-term influence of ERT on risk of morbidity and mortality related to AFD remains to be established. Careful evaluation is needed to ascertain the possible benefit of using concomitant medications (such as angiotension converting enzyme inhibitors for their reno-protective properties or antiplatelet aggregating agents for primary and secondary stroke prevention) in affected individuals whether receiving ERT or not. There is also a need to understand prognostic determinants and therapeutic outcome, which may allow stratification of patients and identification of the subset of patients most likely to achieve the best results with treatment.

Implications for research

This review highlights the need for continued research into the use of ERT for AFD. Currently, there are investigations into other therapeutic approaches, such as substrate reduction therapy and enzyme enhancement with pharmacologic chaperones, which might have therapeutic value. Subsequent trials should help define the use of ERT and other options (as these become available and considered either in combination or as monotherapy) in the management of people with AFD. Given the rarity of AFD and evidence of an ERT-treatment effect, it is not deemed ethical to proceed with new trials including a placebo group. Data on outcomes are being prospectively collected through surveillance or registry-based programs, as post-marketing commitments made by the sponsors.

Acknowledgements

We would like to thank Tracey Remmington and Nikki Jahnke from the Cystic Fibrosis & Genetics Disorders Group for their outstanding help and Julia Mortimer from the Heart Group for her help during the preparation of this review.

Data and analyses

Download statistical data

Comparison 1. Agalsidase alfa versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Plasma Gb32 Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 At up to 6 months239Mean Difference (IV, Random, 95% CI)-2.07 [-6.64, 2.50]
2 Urine sediment Gb31 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Kidney Gb31 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Myocardial globotriaosylceramide levels1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Over 3 months and up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 The Brief Pain Inventory Severity1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Over one month and up to three months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Over three months and up to five months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 Over five months and up to six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 The Brief Pain Inventory pain-related quality of life1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Over one month and up to three months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Over three months and up to five months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 Over five months and up to six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Creatinine clearance1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Insulin clearance1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Glomeruli with mesangial widening1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Glomeruli with segmental sclerosis1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Obsolescent glomeruli1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
11.1 At up to 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Echocardiographic data on left ventricular structure and function over three months and up to six months1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
12.1 Mean left ventricular wall thickness (mm)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12.2 Left ventricular internal diameter (mm) (diastolic)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12.3 Left ventricular internal diameter (mm) (systolic)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12.4 Left ventricular ejection fraction1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Agalsidase alfa versus placebo, Outcome 1 Plasma Gb3.

Analysis 1.2.

Comparison 1 Agalsidase alfa versus placebo, Outcome 2 Urine sediment Gb3.

Analysis 1.3.

Comparison 1 Agalsidase alfa versus placebo, Outcome 3 Kidney Gb3.

Analysis 1.4.

Comparison 1 Agalsidase alfa versus placebo, Outcome 4 Myocardial globotriaosylceramide levels.

Analysis 1.5.

Comparison 1 Agalsidase alfa versus placebo, Outcome 5 The Brief Pain Inventory Severity.

Analysis 1.6.

Comparison 1 Agalsidase alfa versus placebo, Outcome 6 The Brief Pain Inventory pain-related quality of life.

Analysis 1.7.

Comparison 1 Agalsidase alfa versus placebo, Outcome 7 Creatinine clearance.

Analysis 1.8.

Comparison 1 Agalsidase alfa versus placebo, Outcome 8 Insulin clearance.

Analysis 1.9.

Comparison 1 Agalsidase alfa versus placebo, Outcome 9 Glomeruli with mesangial widening.

Analysis 1.10.

Comparison 1 Agalsidase alfa versus placebo, Outcome 10 Glomeruli with segmental sclerosis.

Analysis 1.11.

Comparison 1 Agalsidase alfa versus placebo, Outcome 11 Obsolescent glomeruli.

Analysis 1.12.

Comparison 1 Agalsidase alfa versus placebo, Outcome 12 Echocardiographic data on left ventricular structure and function over three months and up to six months.

Comparison 2. Agalsidase beta versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Microvascular endothelial deposits of globotriaosylceramide1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Kidney - over three months and up to six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Heart - over three months and up to six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Composite - over three months and up to six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Death (intention-to-treat population)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Renal events (intention-to-treat population)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Cardiopulmonary exercise test1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Average heart rate reserve1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Average maximum oxygen uptake measured at peak exercise (L/minutes)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 Maximum oxygen uptake measured at peak exercise (ml/kg/mins)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.4 Oxygen pulse average at peak exercise1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Cardiopulmonary exercise test1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Decrease in diastolic blood pressure16Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.34, 6.70]
6 Cardiac events182Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.11, 1.90]
7 Cerebrovascular events (intention-to-treat population)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8 Participants achieving zero scores in skin over three months and up to six months1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8.1 Superficial endothelial cells1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 Deep endothelial cells1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8.3 Smooth muscle cells1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8.4 Perineurium1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Participants achieving zero score or reduction in skin over three months and up to six months1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9.1 Superficial endothelial cells1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9.2 Deep endothelial cells1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9.3 Smooth muscle cells1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9.4 Perineurium1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Adverse event: Rigors2140Risk Ratio (M-H, Fixed, 95% CI)16.12 [3.35, 77.58]
10.1 Over three and up to six months158Risk Ratio (M-H, Fixed, 95% CI)29.0 [1.81, 464.38]
10.2 At 24 months182Risk Ratio (M-H, Fixed, 95% CI)10.94 [1.54, 77.95]
11 Adverse event: Fever2140Risk Ratio (M-H, Fixed, 95% CI)7.84 [1.88, 32.68]
11.1 Over three and up to six months158Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.92, 53.36]
11.2 At 24 months182Risk Ratio (M-H, Fixed, 95% CI)8.51 [1.18, 61.58]
12 Adverse event: Temperature changed sensation1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
12.1 At 24 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Adverse event: Chills1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
13.1 Over three and up to six months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14 Adverse event: Hypertension2140Risk Ratio (M-H, Fixed, 95% CI)2.94 [0.80, 10.86]
14.1 Over three and up to six months158Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.38, 129.74]
14.2 At 24 months182Risk Ratio (M-H, Fixed, 95% CI)2.13 [0.47, 9.60]
15 Adverse event: Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
15.1 At 24 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
16 Adverse event: Chest pain1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
16.1 At 24 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
17 Adverse event: Fatigue1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
17.1 At 24 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
18 Adverse event: Headache1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
18.1 Over three and up to six months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
19 Adverse event: Pain related to Fabry Disease1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
19.1 Over three and up to six months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Agalsidase beta versus placebo, Outcome 1 Microvascular endothelial deposits of globotriaosylceramide.

Analysis 2.2.

Comparison 2 Agalsidase beta versus placebo, Outcome 2 Death (intention-to-treat population).

Analysis 2.3.

Comparison 2 Agalsidase beta versus placebo, Outcome 3 Renal events (intention-to-treat population).

Analysis 2.4.

Comparison 2 Agalsidase beta versus placebo, Outcome 4 Cardiopulmonary exercise test.

Analysis 2.5.

Comparison 2 Agalsidase beta versus placebo, Outcome 5 Cardiopulmonary exercise test.

Analysis 2.6.

Comparison 2 Agalsidase beta versus placebo, Outcome 6 Cardiac events.

Analysis 2.7.

Comparison 2 Agalsidase beta versus placebo, Outcome 7 Cerebrovascular events (intention-to-treat population).

Analysis 2.8.

Comparison 2 Agalsidase beta versus placebo, Outcome 8 Participants achieving zero scores in skin over three months and up to six months.

Analysis 2.9.

Comparison 2 Agalsidase beta versus placebo, Outcome 9 Participants achieving zero score or reduction in skin over three months and up to six months.

Analysis 2.10.

Comparison 2 Agalsidase beta versus placebo, Outcome 10 Adverse event: Rigors.

Analysis 2.11.

Comparison 2 Agalsidase beta versus placebo, Outcome 11 Adverse event: Fever.

Analysis 2.12.

Comparison 2 Agalsidase beta versus placebo, Outcome 12 Adverse event: Temperature changed sensation.

Analysis 2.13.

Comparison 2 Agalsidase beta versus placebo, Outcome 13 Adverse event: Chills.

Analysis 2.14.

Comparison 2 Agalsidase beta versus placebo, Outcome 14 Adverse event: Hypertension.

Analysis 2.15.

Comparison 2 Agalsidase beta versus placebo, Outcome 15 Adverse event: Vomiting.

Analysis 2.16.

Comparison 2 Agalsidase beta versus placebo, Outcome 16 Adverse event: Chest pain.

Analysis 2.17.

Comparison 2 Agalsidase beta versus placebo, Outcome 17 Adverse event: Fatigue.

Analysis 2.18.

Comparison 2 Agalsidase beta versus placebo, Outcome 18 Adverse event: Headache.

Analysis 2.19.

Comparison 2 Agalsidase beta versus placebo, Outcome 19 Adverse event: Pain related to Fabry Disease.

Comparison 3. Agalsidase alfa versus agalsidase beta
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2 Cardiac events1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3 Any adverse event1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4 Any serious adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Agalsidase alfa versus agalsidase beta, Outcome 1 Death.

Analysis 3.2.

Comparison 3 Agalsidase alfa versus agalsidase beta, Outcome 2 Cardiac events.

Analysis 3.3.

Comparison 3 Agalsidase alfa versus agalsidase beta, Outcome 3 Any adverse event.

Analysis 3.4.

Comparison 3 Agalsidase alfa versus agalsidase beta, Outcome 4 Any serious adverse events.

Appendices

Appendix 1. Glossary

TermExplanation
AcroparaesthesiaPain, tingling and numbness of the hands and forearms
AngiokeratomaSkin condition characterized by intradermal hemangioma over which there is thickening of the epidermis
Angiokeratoma corporis diffusumX-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, also known as Anderson-Fabry disease
CardiacRelating to the the heart
Cerebro-vascular diseaseGroup of brain dysfunctions related to disease, usually an obstruction, of the blood vessels supplying the brain
DeacylatedDescribing a compound from which one or more acyl groups (an organic radical derived from an organic acid by the removal of the carboxylic hydroxyl group) has been removed
DermatologicRelating to the skin
DyspnoeaDebilitating symptom or experience of unpleasant or uncomfortable respiratory (breathing) sensations
EchocardiographyStandard ultrasound techniques imaging two-dimensional slices of the heart to diagnose cardiovascular disease
ElectrocardiographyTransthoracic interpretation of the electrical activity of the heart captured and externally recorded by skin electrodes
EndothelialThin layer of cells that line the interior surface of blood vessels
GastrointestinalRelating to the digestive system
GlobotriaosylceramideType of glycolipid compound which accumulates in the blood vessel walls of people with Fabry disease as a result of a deficiency in alpha-galactosidase A, a lysosomal enzyme
Glomerular filtration rateVolume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman´s capsule (a cup-like sac at the beginning of the tubular component of a nephron in the mammalian kidney) per unit time
Glomeruli Capillary tuft surrounded by Bowman's capsule in nephrons of the vertebrate kidney
GlycosphingolipidItSubtype of glycolipids containing the amino alcohol sphingosine; a ceramide (a sphingolipid) linked to one or more sugars via the terminal hydroxyl group
IgE antibodiesType of immunoglobulin made by the body which are implicated in allergic reactions
IgG antibodiesType of immunoglobulin involved in fighting foreign bodies, bacterial and viral infections
Left ventricular ejection fractionFraction of blood pumped out of the left ventricle with each heart beat
LyonizationPhenomenon wherein one of the two copies of the X chromosome present in female mammals is inactivated
Lysosomal hydrolase alpha-galactosidaseEnzyme involved in glycolipid catabolism, which requires an acidic environment as maintained in the lysosome
Lysosomal inclusionsStorage bodies associated with lysosomal dysfunction, usually a deficiency of an enzyme involved in catabolism
Mammalian cell expression systemElements involved in the translation of genetic information to form a particular protein
Mesangial wideningThickening of the mesangium, a part of the renal glomerulus between capillaries
Microvascular diseaseAngiopathy or condition affecting small blood vessels in the body
Myocardial infarctionCommonly known as a heart attack, resulting from an interruption of blood supply to part of the heart
Neurologic diseaseDisorder of the brain, spinal cord and nerves
NeuropathicReferring to disorders of the peripheral nervous system
Parametric dataParametric statistical tests assume that the data are 'normally distributed', that is, when graphed, the data follow a 'bell shaped curve'
Perineurium cellsCells from the perineurium, the middle layer of the protective perineural sheath surrounding peripheral nerves
ProteinuriaPresence of an excess of serum proteins in the urine
RenalRelating to the kidneys
Segmental sclerosisScarring or degeneration, often used in relation to disease of a kidney section
Sero-convertedDevelopment of antibodies in the blood as a result of the introduction of a foreign body, infection or immunization
Serum creatinineBy-product of metabolism that is measured in serum as a indicator of kidney function
SubstrateMolecule that is acted upon by an enzyme
Thrombo-embolicBlocking of a blood vessel by a blood clot dislodged from its site of origin
TransducedConversion of one type of energy or signal into another; in genetics the introduction of DNA into a different cell type, to induce the formation of the corresponding gene product
Urinary albuminPresence of albumin, a protein, in the urine
X-linkedRelating to genes or characteristics or conditions carried on the X chromosome

Appendix 2. Search strategy - Clincal Trials (The Cochrane Library, Issue 1, 2008)

Search Strategy
((Fabry Disease) OR (Disease, Fabry ) OR (Angiokeratoma Corporis Diffusum) OR (Anderson-Fabry Disease) OR (Anderson Fabry Disease) OR (Disease, Anderson-Fabry) OR (Fabry's Disease) OR (Disease, Fabry's) OR (Fabrys Disease)) AND ((agalsidase beta) OR (Fabrazyme) OR (Genzyme brand of agalsidase beta))

Appendix 3. Search strategy - EMBASE (1980 - September 2008)

Search Strategy

1. Randomized controlled trial/

2. Controlled study/

3. Randomization/

4. Double blind procedure/

5. Single blind procedure/

6. Clinical trial/

7. (clinical adj5 trial$).ti,ab,hw.

8. ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).ti,ab,hw.

9. Placebo/

10. Placebo$.ti,ab,hw.

11. Random$.ti,ab,hw.

12. Methodology.sh.

13. latin square.ti,ab,hw.

14. crossover.ti,ab,hw.

15. cross-over.ti,ab,hw.

16. Crossover Procedure/

17. Drug comparison/

18. Comparative study/

19. (comparative adj5 trial$).ti,ab,hw.

20. (control$ or prospectiv$ or volunteer$).ti,ab,hw.

21. exp "Evaluation and Follow Up"/

22. Prospective study/

23. or/1-22

24. animal/ not (human/ and animal/)

25. 23 not 24

Appendix 4. Search strategy - PubMed (1966 - September 2008)

Search Strategy
randomized controlled trial [Publication Type] OR controlled clinical trial [Publication Type] OR randomized controlled trials [MeSH Terms] OR random allocation [MeSH Terms] OR double blind method [MeSH Terms] OR single blind method [MeSH Terms] OR clinical trial [Publication Type] OR clinical trials [MeSH Terms] OR (clinical* [Text Word] AND trial* [Text Word]) OR single* [Text Word] OR double* [Text Word] OR treble* [Text Word] OR triple* [Text Word] OR placebos [MeSH Terms] OR placebo* [Text Word] OR random* [Text Word] OR research design [MeSH Terms] OR comparative study [MeSH Terms] OR evaluation studies [MeSH Terms] OR follow-up studies [MeSH Terms] OR prospective studies [MeSH Terms] OR control* [Text Word] OR prospectiv* [Text Word] OR volunteer* [Text Word]

Appendix 5. Search strategy - LILACS (1982 - September 2008)

Search Strategy
(Pt randomized controlled trial) OR (Pt controlled clinical trial) OR (Mh randomized controlled trials) OR (Mh random allocation) OR (Mh double blind method) OR (Mh single blind method) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Pt clinical trial) OR (Ex E05.318.760.535$) OR (Tw clin$) AND (Tw trial$) OR (Tw ensa$) OR (Tw estud$) OR (Tw experim$) OR (Tw investiga$) OR (Tw singl$) OR (Tw simple$) OR (Tw doubl$) OR (Tw doble$) OR (Tw duplo$) OR (Tw trebl$) OR (Tw trip$) AND (Tw blind$) OR (Tw cego$) OR (Tw ciego$) OR (Tw mask$) OR (Tw mascar$) OR (Mh placebos) OR (Tw placebo$) OR (Tw random$) OR (Tw randon$) OR (Tw casual$) OR (Tw acaso$) OR (Tw azar) OR (Tw aleator$) OR (Mh research design) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Ct comparative study) OR (Ex E05.337$) OR (Mh follow-up studies) OR (Mh prospective studies) OR (Tw control$) OR (Tw prospectiv$) OR (Tw volunt$) OR (Tw volunteer$) AND NOT ((Ct animal) AND NOT (Ct human and Ct animal))

Feedback

Comment on use of Cochrane methodology for rare, chronic, progressive diseases, 28 July 2010

Summary

Comment 1

In the Cochrane review of enzyme replacement therapies (ERT) for Fabry disease, you conclude that the randomized controlled trials with agalsidase alfa and agalsidase beta did not provide robust evidence for the use of either product. In the same review, it is acknowledged that ERT can have a positive effect on, among others, renal function and cardiac morphology. Health care providers may have great difficulty in putting this combination of contradictory statements in the right context. In our opinion, this confusion may result from the Cochrane review methodology itself which is based on the assessment of randomized, placebo-controlled studies1.  This has limitations in very rare, chronic, progressive diseases where patient numbers are very low and long-term administration of placebo may be considered unethical.

Fabry disease is a rare, inherited, lifelong, progressive disorder of metabolism. Conventional proof of treatment efficacy in more common diseases requires adequately powered long-term, placebo-controlled studies of clinical outcome; however, these are simply not possible in Fabry disease. Short-term trials, mostly of 6-months duration, have explored initial effects of ERT on existing symptoms and/or GL-3 storage2, 3. Collection of longitudinal data for analysis of changes in renal function and left ventricular hypertrophy, however, typically requires multiple years of follow-up that is only possible in an open-label study setting where patients are receiving active treatment as intravenous infusions every two weeks4-6. The Cochrane review methodology, unfortunately, systematically excludes such important open-label studies. There is a risk that the positive effects of ERT on major causes of morbidity and mortality in Fabry disease are not taken into account when making therapeutic decisions based on your review.

The main conclusion is that the current studies were too small but, as acknowledged by the authors, the Fabry population is extremely small and heterogeneous which makes it extraordinarily difficult to conduct additional larger-scale, placebo-controlled or open-label clinical trials. Pooling of data from the small studies performed in this orphan population and analyzing outcome measures individually lacks adequate statistical power to draw conclusions. Using an aggregate definition of a clinical event as in the Phase 4 study of agalsidase beta7, was a creative response to these difficulties and did increase statistical power; a similar approach may be applicable to a meta-analysis.  These challenges will remain the same for any new therapy developed for this rare disease and others, and appropriate understanding of this situation is necessary to make advances in the treatment of ultra-orphan diseases.

A recent systematic review performed by experts in the field of Fabry disease8 did include both randomized controlled trials and open-label studies and provides caregivers with a different view of the overall outcomes with ERT.

Comment 2

We noted a few inaccuracies in the text that we want to bring to the authors’ attention. We wonder why the authors have chosen to refer to the Phase 3 studies by Thurberg et al and Moore et al9,10.  These are sub-studies specifically investigating histology and regional cerebral blood flow, respectively, in the Phase 3 agalsidase beta and alfa study cohorts. The correct references for the publications of the full sets of data are Eng et al 2001 and Schiffmann et al 2001.2, 3

Comment 3

Moreover, auditory loss is mentioned as the outcome measure of the study by Hughes et al (page 19). Perhaps the authors can explain why this outcome measure was selected for this cardiac study.

Comment 4

The conflict of interest section does not mention the author’s involvement in the algasidase studies.

Conflict of Interests

Vinciane Pirard, MD, is an employee of Genzyme Europe BV, a subsidiary of Genzyme Corporation, the manufacturer of agalsidase beta.

References

1.    Elphick HE, Tan A, Ashby D, Smyth RL. Systematic reviews and lifelong diseases. BMJ 2002;325:381-4.

2.    Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A--replacement therapy in Fabry's disease. New England Journal of Medicine 2001;345:9-16.

3.    Schiffmann R, Kopp JB, Austin HA, 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001;285:2743-9.

4.    Germain DP, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. Journal of the American Society of Nephrology 2007;18:1547-57.

5.    Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrology Dialysis Transplantation 2006;21:345-54.

6.    Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation 2009;119:524-9.

7.    Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Annals of Internal Medicine 2007;146:77-86.

8.    Schaefer RM, Tylki-Szymanska A, Hilz MJ. Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. Drugs 2009;69:2179-205.

9.    Thurberg BL, Randolph Byers H, Granter SR, Phelps RG, Gordon RE, O'Callaghan M. Monitoring the 3-year efficacy of enzyme replacement therapy in fabry disease by repeated skin biopsies. Journal of Investigative Dermatology 2004;122:900-8

10.  Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease. BMC Neurology 2002;2:4.

Reply

Response 1

The practice of evidence-based medicine should be a systematic process, which includes: the formulation of a relevant clinical question based on the patient’s clinical status; literature search(es) for relevant clinical articles; critical analysis of evidence regarding their validity and applicability; and, lastly, transfer of the important findings to clinical practice1. When researching information on interventions or prevention, we seek studies that best fit this mould, which means that the systematic reviews offer level 1 evidence responses for health-care decision making1. The systematic reviews include primary studies (clinical trials) which are methodologically appropriate and stringent, and are potentially bias-free. Therefore, our Cochrane review aimed to evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease through a systematic review of randomized controlled trials.

Systematic reviews, however, are criticized for frequently offering inconsistent evidence and an absence of straightforward recommendations2. Their value seems to be depreciated when the conclusions are uncertain or based on less than the highest grading of evidence3. A study has found that the majority of Cochrane reviews highlight the poor evidence, or absence of evidence, for the healthcare questions covered4.  The study found that Cochrane systematic reviews were about evenly split between those in which the authors concluded that the intervention was beneficial and those in which the evidence neither supported nor refuted the intervention tested4. Around half of the reviews analysed in this study (47.83%) did not offer enough evidence for clinical practice, and the authors asked for further research4. In only 0.98% of the 1016 reviews did the authors not consider it necessary to undertake further investigation, despite not finding sufficient evidence to support or refute the intervention4. Even when the reviews found evidence to support the intervention for use in clinical practice, a large percentage of authors considered this evidence was limited, and suggested that further research would be worthwhile (43.01%)4. Although systematic reviews are regarded as level 1 evidence for decision-making with regard to healthcare therapies, it was observed that most systematic review authors concluded that there was insufficient evidence to answer the questions around therapeutic strategies for treatment and prevention of diseases4.

In very rare, chronic, progressive diseases the same should apply. In other words, if the purpose is to assess effectiveness and safety of an intervention on rare disease we should map the knowledge through a systematic review of randomized controlled trials. The limitation here would not be the design of the study, but it would be the sample size evaluated by the included studies. Therefore, a systematic review could bring together the small clinical trials and when appropriate plot their results into a meta-analysis. One of the aims of a meta-analysis is to more powerfully estimate the true "effect size" as opposed to a smaller "effect size" derived in a single study under a given single set of assumptions and conditions.

In addition, the use of placebo is fully justified as to its non-malfeasance or methodology requirement: “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists”5 and “However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

  • where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

  • where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.” 5

The systematic review cited above (Schaefer RM et al 2009), examined a total of 9 RCTs and 23 open-label studies, noting that in the majority endpoints represented subclinical parameters rather than clinical outcomes. As acknowledged by the authors, writing and editorial support in preparation of the article was received from Genzyme Europe BV and Hester van Lier of Excerpta Medica.

Response 2

Regarding the Phase 3 studies by Thurberg et al and Moore et al. These are sub-studies specifically investigating histology and regional cerebral blood flow, respectively, in the Phase 3 agalsidase beta and alfa study cohorts. We have therefore amended the study IDs in the review and the main reference for the previously listed Thurberg 2004 study will now be Eng 2001, and for Moore 2002 this will be Schiffmann 2001 as suggested.

Response 3

When we performed the systematic review we also aimed to map the outcomes that the primary studies evaluated. Therefore, we decided to cite all the outcomes reported within primary studies, even those not listed as outcomes of interest within our review. Besides all other inclusion criteria, we required that there had to be at least one of our pre-defined outcomes reported within a study in order for it to be eligible for inclusion. With regards to auditory loss in the table for Hughes 2008 (Characteristics of included studies), this was not a primary outcome. We note, however, that not all outcomes were fully listed within the ‘Characteristics of included studies’ table for the Hughes 2008 study and we have amended this within the review. The relevant section within the table now lists all reported outcomes and is as follows: 

The primary efficacy endpoint was myocardial Gb3 content; the secondary efficacy endpoint was reduction of the left ventricular mass by MRI assessment. In addition, QRS duration and levels of Gb3 in cardiac tissue, urine sediment and plasma, echocardiography, electrocardiography, pure-tone audiometry, impedance audiometry and otoacoustic emission testing were also performed. Adverse events were computed.

When we state positive effect on, among others, renal function and cardiac morphology, we believe our interpretation of the data suggested treatment appears to modify disease course, with outcome influenced by disease stage, and perhaps better in those who initiated treatment at an earlier disease stage. But the responses reported are often focused on single organ/system function, and the extent to which treatment impacts survival and quality of life approximating normal or that of the general population remains to be demonstrated.

Response 4

This has been updated to correctly reflect the authors’ conflicts of interest. Thank you for highlighting this omission. The text inserted is as follows:

El Dib R has no conflict of interest to declare. Pastores GM  is the recipient of research grants from Actelion, Amicus, Biomarin, Genzyme, Protalix and Shire HGT (pharmaceutical and biotechnology companies engaged in drug development programs for lysosomal storage disorders).

References
  1. Mulrow CD, Cook DJ, Davidoff F. Systematic Reviews: critical links in the great chain of evidence. Annals of Internal Medicine. 1997; 126: 389-391.

  2. Browman GP. Essence of evidence-based medicine: a case report. Journal of Clinical Oncology. 1999(7); 17:1969.

  3. Egger M, Smith GD, Phillips NA. Meta-analysis: principles and procedures. BMJ. 1997; 315.

  4. El Dib RP, Atallah NA, Andriolo RB. Mapping the Cochrane evidence for decision-making in health care. Journal of Evaluation in Clinical Practice 2007; 13(4):689-92.

  5. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects 2000.

Contributors

All comments made by: Vinciane Pirard, MD, Genzyme, The Netherlands.

Response from review authors: Regina P El Dib and Gregory M Pastores.

Feedback Editor: John Walter.

Managing Editor: Tracey Remmington.

Co-ordinating Editor: Alan Smyth

What's new

DateEventDescription
12 December 2012New citation required but conclusions have not changedDespite the addition of one new included trial, the conclusions remain the same as those in the original review (El Dib 2010).
12 December 2012New search has been performed

One new trial has been included in the review (Vedder 2007). Two trials have been added to the excluded studies (Fernhoff 2011; West 2011).

Data and information have been included for a 'Agalsidase alfa versus agalsidase beta' comparison group (Vedder 2007).

History

Protocol first published: Issue 3, 2007
Review first published: Issue 5, 2010

DateEventDescription
15 February 2012AmendedContact details updated.
15 February 2011Feedback has been incorporated

Feedback, along with a response has been added to this review.

In the Included studies section, the study IDs previously listed as Thurberg 2004 and Moore 2002 have been changed to Eng 2001 and Schiffmann 2001, to more accurately reflect the primary study reports. Furthermore, all outcomes reported by Hughes are now listed in full in the tables (Characteristics of included studies) (Hughes 2008).

The Declarations of interest section has been updated.

20 September 2008New citation required and conclusions have changedSubstantive amendment

Contributions of authors

Regina P El Dib (RED) was responsible for the conception of this review and also for the design and overall co-ordination of the protocol. RED is the guarantor of the review.

RED was responsible for developing the search strategy, undertaking searches, screening search results, organising retrieval of papers. Both RED and Gregory M Pastores (GMP) were responsible for screening retrieved papers against the inclusion criteria, appraising quality of papers and extracting data. RED wrote to authors of papers for additional information and located potentially relevant unpublished or ongoing trials. RED provided additional data about papers and obtained and screened data on unpublished trials. RED was responsible for data management for the review and entering data into RevMan. RED and GMP analysed and interpreted the data and wrote up the results. RED provided a methodological perspective; and GMP provided a clinical perspective.

Declarations of interest

R El Dib and P Nascimento have no conflict of interest to declare. GM Pastores is the recipient of research grants and support from Actelion, Amicus, Biomarin, Genzyme/Sanofi, Protalix/Pfizer, and Shire HGT; pharmaceutical and biotechnology companies engaged in drug development programs for lysosomal storage disorders.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Provided by CAPES, Brazil.

Differences between protocol and review

The Assessment of risk of bias in included studies section was updated from the protocol given the new guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

We decided for our secondary outcome 'Pain' we would also consider other validated pain questionnaires as well as the previously stated McGill Pain Questionnaire.

While analysing available data we agreed to also considered other time-points as well as those originally stated where multiple data sets from an individual trial were available for a single a priori planned time-point.

Notes

Post hoc change: we will also consider other validated pain questionnaires.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Banikazemi 2007

Methods

Trial design: double-blind RCT.

Multicenter

Setting: 41 referral centers (university or research hospitals) in nine countries in North America and Europe.

Period: February 2001 to January 2004.

Sample size: reported (80 participants to provide 80% power for detecting a treatment effect on the basis of log-ranking testing by using a 10% drop-out rate; a 14-month enrolment period and 18 months of follow-up; type I error of 0.05 (2-sided); and expected events rates over 2 years of 40% and 10% for participants in the placebo and agalsidase-beta groups, respectively, as predicted by an estimated 20% to 30% decline per year in estimated).

Participants

Of the 252 patients screened, 82 eligible patients (ITT population) were treated at 26 sites in 6 countries.

Mean age: agalsidase-beta group 46.9 years and, placebo group 44.3 years.

Sex: agalsidase-beta group 88% men and 12% women and, placebo group 87% man and 13 % women.

Inclusion criteria: participants were at least 16 years of age with clinical evidence of AFD.

Exclusion criteria: participants who were undergoing dialysis or were schedule for kidney transplantation; those with documented transient ischemic attacks, ischemic stroke, unstable angina, or myocardial infarction with 3 months of trial entry; and those with confounding conditions or other clinically significant comorbid conditions.

Interventions

Intravenous infusion of agalsidase beta (mg/kg of body weight) (n = 51) or placebo every two weeks (n = 31).

Follow up: 18 months.

Outcomes

Primary end point: the time to first clinical event (renal, cardiac, or cerebrovascular event or death).

A renal event was defined as a 33% increase in serum creatinine level from baseline (2 consecutive values) or end-stage kidney disease requiring long-term dialysis or transplantation.

A cardiac event was defined as myocardial infarction; new symptomatic arrhythmia requiring antiarrhythmic medication, pacemaker, direct current cardioversion, or defibrillator implantation; unstable angina defined by national practice guidelines and accompanied by electrocardiographic changes resulting in hospitalization; or worsening congestive heart failure requiring hospitalization.

A cerebrovascular event was defined as a stroke or transient ischemic attack documented by a physician. participants were allowed to transition to open-label agalsidase beta after an independent adjudication board confirmed that a primary end point event had occurred.

The following measures were also performed at baseline and at the final trial visit or time of trial withdrawal: serum creatinine level; proteinuria; ratio of urinary albumin to urinary cretinine; 12-lead electrocardiography; echocardiography; neurologic examination; head magnetic resonance imaging; Brief Pain Inventory; exercise tolerance; plasma globotriaosylceramide level; Fabry symptom assessment; physical examination; blood chemistries; urinalysis; IgG antibody titers to agalsidase beta; and optional skin biopsy. Safety monitoring included physician evaluation and documentation of adverse events.

Notes

The Genzyme Corporation and the National Center for Research Resources supported the trial.

For future updates of this review, we will contact authors to clarify methodological issues.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization codes were computer-generated.
Allocation concealment (selection bias)Low riskRandomization codes were maintained centrally at a secure location. The 2:1 randomization scheme was blocked (block size of 3, which was not revealed to investigators) at each site.
Blinding (performance bias and detection bias)
All outcomes
Low riskTrial materials were packaged identically, and sponsor staff, investigators, and patients were blinded to treatment allocation.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWithdrawals and drop outs, were noted by Banikazemi to be less than 20%. ITT was used for the primary outcome only.
Selective reporting (reporting bias)Low risk 
Other biasUnclear riskThe Genzyme Corporation and the National Center for Research Resources supported the trial.

Bierer 2006

Methods

Trial design: RCT.

Single-center or multicenter: not reported.

Setting: not reported.

Period: not reported.

Sample size: not reported.

Participants

15 individuals with AFD, but only 6 participants were randomized (4 treatment; 2 placebo).

Sex: 5 male, and 1 female.

Mean age: male was 35 years and female was 42 years.

Interventions

Placebo (saline) or enzyme replacement therapy (agalsidase beta 1 mg/kg every other week - Fabrazyme).

Follow up: 18 months.

OutcomesCardiopulmonar exercise test, forced expiratory volume and forced vital capacity. History and physical examination, a baseline electrocardiogram, transthoracic echocardiogram, and a pulmonary function test (spirometry) were also performed.
Notes

First, the authors compared baseline cardiopulmonary exercise tests performed noninvasively, next, they assessed the impact of alfa galactosidase A on exercise tolerance by serial non-invasive cardiopulmonary exercise tests. The six participants randomized were part of a phase IV trial evaluating enzyme replacement therapy. 9 additional participants completed invasive cardiopulmonary exercise tests as baseline examinations. These participants did not have follow-up exercise tests and were not randomized to drug or placebo, neither evaluated in this systematic review.

The funding was provided by Genzyme Corporation.

For future updates of this review, we will contact authors to clarify methodological issues.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated as "randomized".
Allocation concealment (selection bias)Unclear riskUnclear
Blinding (performance bias and detection bias)
All outcomes
Unclear riskStated as "randomized in a double-blind fashion".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot discussed.
Selective reporting (reporting bias)Low risk 
Other biasHigh riskThe funding was provided by Genzyme Corporation.

Eng 2001

Methods

Trial design: phase-3 double-blind RCT.

Single-center or multicenter: not reported.

Setting: not reported.

Period: not reported.

Sample size: not reported.

Participants

58 participants with AFD (56 males) (29 each group).

Age average in the placebo group 28.4 years and in the treated group 32.0 years.

Inclusion criteria: patients should be over 16 years old, with alfa-galactosidases levels in the plasma lesser than 1.5 nmol/hour/mL or levels of leucocytes activity smaller than 4 nmol/hour/mg and, levels of creatine lesser than or equal to 2.2 mg/dL.

Exclusion criteria: participants who had carried through renal transplant or were carrying through dialysis.

Interventions

Patients received placebo or alfa-galactosidases 1 mg/kg intravenously every 2 weeks.

Follow up: 5 months.

OutcomesPrimay endpoint was percentage of patients in whom renal microvascular endothelial deposits og Gb3 were cleared. It was also evaluated the histologic clearance of microvascular endothelial deposits of Gb3 in the endomyocardium and skin, changes in the level of pain and the quality of life, urinary creatine, urinary proteic excretion, renal function and dermatological characteristics of glicolipides accumulation in the dermis. The individual scores for the kidney-, heart-, and skin-biopsy specimes and the composite scores for all three types of specimens were compared at baseline and after the week-20 infusion.
Notes

Authors of the trial belonged to Genzyme Corporation, Cambridge, Massachusetts, USA.

For future updates of this review, we will contact authors to clarify methodological issues.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated as "randomized".
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskStated as "double-blind". Information given on two outcomes: each renal biopsy was reviewed under light microscopy by three independent renal pathologists who were blinded to treatment status of the patient at the time of biopsy; immunofluorescence trials were scored blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot discussed.
Selective reporting (reporting bias)Low risk 
Other biasUnclear riskAuthors of the trial belonged to Genzyme Corporation, Cambridge, Massachusetts, USA.

Hughes 2008

Methods

Trial design: double-blind RCT.

Single-center or multicenter: not reported.

Setting: not reported.

Period: not reported.

Sample size: not reported.

Participants

15 male with AFD.

Age: average of 37 years.

Interventions

The participants received placebo (N=8) or enzyme replacement therapy with alfa agalsidase 0.2 mg/kg every 40 minutes, twice a week and, an additional of more 36 months.

Follow up: 6 months.

OutcomesThe primary efficacy endpoint was myocardial Gb3 content; the secondary efficacy endpoint was reduction of the left ventricular mass by MRI assessment. In addition, QRS duration and levels of Gb3 in cardiac tissue, urine sediment and plasma, echocardiography, electrocardiography, pure-tone audiometry, impedance audiometry and otoacoustic emission testing were also performed. Adverse events were computed.
Notes

No conflict of interest reported by the trial investigators.

For future updates of this review, we will contact authors to clarify methodological issues.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind. All data were independently analysed by Royal Free Hospital investigators. The data remained blinded until the database was unlocked and the statistical analyses performed.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described.
Selective reporting (reporting bias)Low risk 
Other biasLow riskNo conflict of interest reported by the trial investigators.

Schiffmann 2001

Methods

Trial design: double-blinded placebo RCT.

Single-center or multicenter: not reported.

Setting: the Clinical Research Center of the National Institutes of Health.

Period: 6 months.

Sample size: not reported.

Participants

26 males with AFD.

Age ranged between 16 and 56 years.

InterventionsPlacebo or alfa-galactosidase A, twice a week managed intravenously.
Outcomes

Transversal Doppler, left ventricular volume, heart rate, stroke volume, cerebral blood flow.

The following Doppler parameters were obtained: peak flow velocity, mean flow velocity, end-diastolic velocity, pulsatility index, and resistance index.

Neuropathic pain measured by the Brief Pain Inventory, renal function and struction, cardiac function, storage material, quantitative sensory testing, skin biopsy, and Gb3 analyses.

Notes

No conflict of interest reported by the trial investigators.

For future updates of this review, we will contact authors to clarify methodological issues.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskA randomization schedule was prepared prior to the start of the trial. Randomization was
blocked to minimize imbalances between trial groups.
Allocation concealment (selection bias)Unclear riskRandomization schedule was prepared prior to the start of the trial and was provided to an unblinded pharmacist in the research pharmacy at the National Institutes of Health. No other medical or sponsor personnel had access to the randomization code until the trial was completed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThere was no detail whether clinicians/patients/outcome assessors were blinded to the treatment groups.
Incomplete outcome data (attrition bias)
All outcomes
Low risk1 participant, randomized to the placebo trial arm, withdrew from the trial for personal reasons and 3 further participants (1 from the ERT group and 2 from the placebo group) declined the follow-up acetazolamide challenge arm of the trial at completion of the trial. A further patient had suffered a lacunar infarct 10 years prior to commencement of the present trial.
Selective reporting (reporting bias)Low risk 
Other biasLow riskNo conflict of interest reported by the trial investigators.

Vedder 2007

  1. a

    AFD: Anderson-Fabry disease
    ITT: intention-to-treat
    RCT: randomized controlled trial

Methods

Trial design: open-label RCT.

Multicenter.

Setting: two centers in Norway (the Academic Medical Center and the Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital).

Period: May 2002 and December 2004.

Sample size: reported (90% and an alpha of 5% (one-sided), it was predicted that at least 18 patients (9 in each group) with an increased LVmass were required, i.e. a 10% larger reduction in LVmass by agalsidase alfa treatment than agalsidase beta treatment).

Participants

36 randomized patients (18 males and 18 females).

Age range: 19 and 76 years.

InterventionsAgalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly for at least 12 months.
Outcomes

Primary endpoint:

  • Reduction of left ventricular mass on echocardiography

Secondary endpoints:

  • Improvement of renal function as measured by GFR.

  • Reduction of glycolipid accumulation in skin tissue (LM and biochemistry).

  • Reduction in pain as measured by the BPI.

  • Reduction in glycosphingolipid in plasma and 24-hour urine.

Tertiary endpoint:

  • Quality of life scores (SF-36).

  • Treatment failure defined as:

    • progression of renal disease (33% increase in serum creatinin, need for dialysis or transplantation);

    • progression of cardiac disease (new infarction, need for cardioversion, or anti-arrythmic drugs, heart-failure necessitating hospitalization);

    • occurrence of a new CVA as diagnosed by a neurologist or new lacunar infarctions on magnetic resonance imaging (MRI) as assessed by an experienced neuroradiologist.

NotesInternational Standard Randomized Clinical Trial: ISRCTN45178534
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPermuted block randomisation, with a block size of 4 patients. Manual randomization, envelopes generated by people not involved in obtaining informed consent.
Allocation concealment (selection bias)Low riskEnvelopes checked by 2 people not involved in obtaining informed consent.
Blinding (performance bias and detection bias)
All outcomes
High riskThe authors reported that the envelopes were opened by the investigator in the presence of the patient.
Incomplete outcome data (attrition bias)
All outcomes
High riskIn the LVMass analysis there were withdrawal rates of 50% and 62.5% in the agalsidase alfa and beta groups, respectively.
Selective reporting (reporting bias)High riskQuality of life is included as an outcome in the protocol, but not stated in the paper. However, we contacted the author to know if they have assessed this outcome. The author replied and said that they evaluated the QoL using SF36 questionnaires, but for the analysis presented in the paper, they did not use these data. They are willing to send us the data and we will include these in a future update.
Other biasLow riskNo conflict of interest was reported by the trial investigators.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Alamartine 2005Case series.
Banikasemi 2005Case series.
Beck 2004Cohort study.
Beer 2006Case series.
Breunig 2006Case series.
Cartwright 2004Case series.
Elliott 2006Cohort study.
Eto 2005Case series (all participants received 1 mg/kg of agalsidase beta, no comparator treatment). The authors reported the results of an open-label phase-2 study that was undertaken to evaluate whether ethnic differences exist that would affect agalsidase beta treatment of Fabry patients.
Fernhoff 2011Case series.
Germain 2007Case series (58 patients who had classic Fabry disease and completed a 20-week, double-blind, randomized, placebo-controlled, phase-3 study of agalsidase were transitioned to an open-label extension trial to receive bi-weekly 1 mg/kg agalsidase for up to an additional 54 months, no placebo).
Guffon 2002Case series.
Guffon 2004Case-control study.
Hajioff 2006Case series.
Hilz 2004Cohort study.
Jardim 2006Case series.
Jardim 2006bCase series.
Kalliokoshi 2006Case series.
Kampmann 2002Controlled trial with a cross-over to open label.
Kobayashi 2005Case series.
Kosch 2004Case series.
Linthorst 2004Case series.
Linthorst 2006Case series.
Mignani 2004Case series.
Mills 2004Case series.
Pisani 2005Case series.
Ramaswami 2007Case series.
Ries 2006Case series.
Schiffmann 2003Case series.
Schiffmann 2006Case series (participants who had completed a 6-month randomized placebo-controlled trial enrolled in an open-label extension study. All the participants received agalsidase alfa o.2 mg/kg).
Spinelli 2004Case series.
Utsumi 2005Case series.
Weidemann 2003Case series.
West 2011Cohort study.

Ancillary