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Intervention Protocol

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Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria

  1. Arturo J Martí-Carvajal1,*,
  2. Vidhu Anand2,
  3. Andrés Felipe Cardona3,
  4. Ivan Solà4

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 28 FEB 2013

DOI: 10.1002/14651858.CD010340


How to Cite

Martí-Carvajal AJ, Anand V, Cardona AF, Solà I. Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD010340. DOI: 10.1002/14651858.CD010340.

Author Information

  1. 1

    Universidad Tecnológica Equinoccial, Facultad de Ciencias de la Salud Eugenio Espejo, Quito, Ecuador

  2. 2

    University of Minnesota, Department of Surgery, Minneapolis, Minnesota, USA

  3. 3

    Institute of Oncology, Fundación Santa Fe de Bogotá, Clinical and Translational Oncology Group, Bogotá, Cundinamarca, Colombia

  4. 4

    Institute of Biomedical Research (IIB Sant Pau), Iberoamerican Cochrane Centre, Barcelona, Catalunya, Spain

*Arturo J Martí-Carvajal, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Quito, Ecuador. arturo.marti.carvajal@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

For a glossary of medical terms, see Appendix 1.

 

Description of the condition

Paroxysmal nocturnal hemoglobinuria is a disorder of the hematopoietic stem cells, but it is not a malignant disease (Parker 2009a; Parker 2012; Pu 2011). The first two cases were reported by William Gull and Paul Strübing between 1866 and 1882, respectively (Rosse 1980; Wilmanns 1982). In 1925, Enneking introduced the term 'paroxysmal nocturnal hemoglobinuria' (Brodsky 2009b). The term 'nocturnal' is misleading, as the hemolysis can occur at any time (Brodsky 2008a).

Paroxysmal nocturnal hemoglobinuria arises as a consequence of nonmalignant clonal expansion of one or more hematopoietic stem cells that have acquired a somatic mutation of the X chromosome gene called phosphatidylinositol glycan class A (PIGA) (Brodsky 2006; Brodsky 2008a; Parker 2012). The protein encoded by PIGA is essential for synthesis of the glycosyl phosphatidylinositol moiety that serves as the membrane anchor for a functionally diverse group of cellular proteins. As a consequence of mutant PIGA, all glycosyl phosphatidylinositol-anchored proteins are deficient on progeny of affected stem cells (Parker 2012). Some important GPI linked proteins are complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), or CD55, and membrane inhibitor of reactive lysis (MIRL), or CD59. These proteins interact with complement proteins, mainly C3b and C4b, and inhibit the convertase complexes thereby halting prolonged activation. The deficiency of these proteins in PNH therefore results in prolonged and uncontrolled activation of the complement pathways, resulting in complement mediated intravascular hemolysis (Parker 2005).

Diagnosis of paroxysmal nocturnal hemoglobinuria is based on the following criteria (Parker 2005):

  1. Evidence of a population of peripheral blood cells (erythrocytes, granulocytes, or preferably both) deficient in glycosyl phosphatidylinositol–anchored proteins detected by flow cytometric analysis.
  2. Complete blood count, reticulocyte count, serum concentration of lactate dehydrogenase, bilirubin (fractionated), and haptoglobin.
  3. Bone marrow aspirate, biopsy, and cytogenetics.

Currently, flow cytometry to detect populations of glycosyl phosphatidylinositol-anchored proteins deficient cells is firmly established as the method of choice for diagnosis and monitoring paroxysmal hemoglobinuria (Borowitz 2010; Richards 2000).

Paroxysmal nocturnal hemoglobinuria is a rare disease with an estimated incidence of 1.3 new cases per one million individuals per year (Borowitz 2010; Brodsky 2008a; Brodsky 2008b).

According to the International Paroxysmal Nocturnal Hemoglobinuria Interest Group (I-PIG), paroxysmal nocturnal hemoglobinuria is classified in three categories:

  1. classic paroxysmal nocturnal hemoglobinuria,
  2. paroxysmal nocturnal hemoglobinuria in the setting of another specified bone marrow disorder (e.g. paroxysmal nocturnal hemoglobinuria/aplastic anemia or paroxysmal nocturnal hemoglobinuria/refractory anemia-myelodysplastic syndrome), and
  3. paroxysmal nocturnal hemoglobinuria-subclinical in the setting of another specified bone marrow disorder (e.g. paroxysmal nocturnal hemoglobinuria-subclinical/aplastic anemia) (Parker 2005; Parker 2009a).

 

Classic paroxysmal nocturnal hemoglobinuria

Patients with classic paroxysmal nocturnal hemoglobinuria have clinical evidence of intravascular hemolysis (reticulocytosis, abnormally high concentration of serum lactate dehydrogenase and indirect bilirubin, and abnormally low concentration of serum haptoglobin) but have no evidence of another defined bone marrow abnormality. A cellular marrow with erythroid hyperplasia and normal or near-normal morphology, but without nonrandom karyotypic abnormalities, is consistent with classic paroxysmal nocturnal hemoglobinuria (Parker 2005).

 

Paroxysmal nocturnal hemoglobinuria in the setting of another specified bone marrow disorder

The patients in this subcategory have clinical and laboratory evidence of hemolysis but also have concomitantly, or have had a history of, a defined underlying marrow abnormality. Bone marrow analysis and cytogenetics are used to determine if paroxysmal nocturnal hemoglobinuria arose in association with aplastic anemia, myelodysplastic syndrome, or other myelopathy (e.g. myelofibrosis). Finding nonrandom karyotypic abnormalities that are associated with a specific bone marrow abnormality may contribute diagnostically (e.g. abnormalities of chromosomes 5q, 7, and 20q are associated with myelodysplastic syndrome) (Parker 2005).

 

Paroxysmal nocturnal hemoglobinuria-subclinical in the setting of another specified bone marrow disorder

The patients in this subcategory have no clinical or laboratory evidence of hemolysis. Small populations of glycosyl phosphatidylinositol–anchored proteins–deficient hematopoietic cells (peripheral blood erythrocytes, granulocytes, or both) are detected by very sensitive flow cytometric analysis. It is observed in association with bone marrow failure syndromes, particularly aplastic anemia and refractory anemia-myelodysplastic (Parker 2005).

 

Non-hematological clinical findings

The intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria involves clinical findings in gastrointestinal, cardiovascular, pulmonary, cerebral, and urogenital systems, as well as clotting disorders which are mediated by the consumption of nitric oxide (Rother 2005; Savage 2007). It is associated with a hypercoagulable state (thrombosis) (al-Hakim 1993; Audebert 2005; Barbui 2010; Dunphy 1994; Gayer 2001; Inafuku 1993). The main non-hematological clinical findings include acute or chronic renal failure (Chow 2001; de Charry 2012; Guasch 2010; Hillmen 2010; Jackson 1992; Nair 2008; Sechi 1988), pulmonary hypertension (Heller 1992; Misztal 2011), and an increasing risk for splanchnic vein thrombosis syndrome called Budd-Chiari (Graham 1996; Hauser 2003; Jain 2010; Jimenez 1999; Hoekstra 2009; Torres 2010; Yin 2009). Visceral thrombosis, cerebrovascular events and pulmonary embolism predict a poor outcome (Ziakas 2008). The exact reason for an increase of thrombosis risk in patients with paroxysmal nocturnal hemoglobinuria is unknown (Brodsky 2009b; van Bijnen 2012a). However, a major role of complement activation has been suggested to explain this clinical finding (van Bijnen 2012b).

 

Prognosis (overall survival)

Paroxysmal nocturnal hemoglobinuria is a chronic disorder associated with significant morbidity and mortality (Harris 1999; Hernandez-Campo 2008; Rachidi 2010). The overall survival at 10 years after diagnosis with paroxysmal nocturnal hemoglobinuria has been variously estimated to be 65% (Socié 1996), 77.6% (Ge 2012). and 68% (Tudela 1993).

 

Description of the intervention

The treatment of paroxysmal nocturnal hemoglobinuria has been largely empirical and symptomatic, with blood transfusions, anticoagulation, and supplementation with folic acid or iron (Luzzatto 2011; Röth 2011). These interventions are mainly aimed to alleviate anemia and thrombotic episodes. The interventions include pharmacological and non-pharmacological interventions.

 

A Interventions for treating hemolytic anemia and diminished hematopoiesis

 

Pharmacological interventions

  1. Glucocorticoids (prednisone) and adrenocorticotropic hormone (ACTH) (Bourantas 1994;Etienne-Martin 1954; Firkin 1968; Funderberg 1954; Hoffman 1952; Leonardi 1955). Prednisone is effective in hemolytic anemia but does not affect the hematopoiesis and the effective doses are generally higher (Parker 2005).
  2. Erythropoietin (Astori 1997; Balleari 1996b; Balleari 1996a; Bourantas 1994; McMullin 1996). Higher doses of erythropoietin and its derivatives may be beneficial, particularly if renal impairment is also present.
  3. Iron replacement therapy when iron stores are deficient, and folic acid supplementation because of the high red cell turnover in these patients.
  4. Immunosuppressive therapy such as antithymocyte globulin and cyclosporine (Ebenbichler 1996; Nakasone 2008; Paquette 1997; Scheinberg 2010). The immunosuppressive agents are an alternative to hematopoietic cell transplantation for aplastic anemia. However, the hemolytic components remain unchanged.
  5. Recombinant granulocyte stimulating factor alone or in combination with cyclosporine in paroxysmal nocturnal hemoglobinuria granulocytopenic patients (Jego 1997; Schubert 1997).

 

Non-pharmacological interventions

  1. Washed red blood cell transfusion (Guasch 1969; Jackson 1992).
  2. Allogeneic hematopoietic stem cell transplantation can cure classic paroxysmal nocturnal hemoglobinuria, but treatment-related toxicity suggests caution for this management approach (Antin 1985; Graham 1996; Kawahara 1992; Lee 2003; Matos-Fernandez 2009; Parker 2011; Raiola 2000; Röth 2011; Woodard 2001). It has been suggested as a therapeutic option in life threatening and resistant disease associated with aplastic anemia, significant neutropenia and thrombocytopenia and severe thrombotic episodes. This treatment is used in every paediatric paroxysmal nocturnal hemoglobinuria patient with bone marrow failure, since children tolerate it better than adults (van den Heuvel-Eibrink 2005).

 

B Interventions for treating thrombotic episodes

 

Pharmacological interventions

  1. Glucocorticoids (prednisone) (Firkin 1968).
  2. Anticoagulant: heparin (Emadi 2009), and warfarin (Hall 2003).

 

Non-pharmacological interventions

  1. Whole blood or packed red blood cell transfusion (Guasch 1969).
  2. Allogeneic hematopoietic stem cell transplantation (Graham 1996; Vergniol 2005).

 

C Pharmacological intervention for preventing hemolytic anemia and severe thrombotic episodes

Eculizumab is a new targeted and disease-modifying treatment strategy that inhibits a section of the complement cascade (Davis 2008; Hill 2005a; Lindorfer 2010; Luzzatto 2010; Rother 2007; Schrezenmeier 2009; Schrezenmeier 2012; Thompson 2007; Woodruff 2011; Weitz 2012). This drug effectively inhibits the formation of the membrane attack complex and intravascular hemolysis (Schrezenmeier 2012; Weitz 2012; Woodruff 2011). Eculizumab has shown significant efficacy with a marked decrease in anemia, fatigue, transfusion requirements, renal impairment, pulmonary hypertension, and risk of severe thromboembolic events, ultimately resulting in improved quality of life and survival (Brodsky 2008c; Brodsky 2009b; Hill 2005a; Hill 2005b; Hill 2010a; Hill 2010b; Hillmen 2004; Hillmen 2006; Kelly 2011; Schubert 2008). There is a need to establish the precise indications for starting treatment with eculizumab, its prophylactic role in thrombotic complications and the consideration of other available choices which include allogeneic hematopoietic cell transplantation and immunosuppressive regimens.

 

Clinical pharmacology of eculizumab

Treatment with eculizumab consists of an infusion of 600 mg over 25 to 45 minutes once a week for four weeks, followed by 900 mg in the fifth week. After this, the dose is maintained at 900 mg, given approximately every two weeks (EMEA 2012). Adverse events like fever, headache, back pain, nasopharyngitis, urinary tract infections, respiratory tract infections, gastrointestinal infections, nausea, fatigue, syncope, accelerated hypertension, infusion reactions, and life-threatening desquamating rash have been reported in patients receiving eculizumab (Dmytrijuk 2008; Knoll 2008).

Eculizumab was approved by the Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria in March 2007 (Dmytrijuk 2008; Dubois 2009; Parker 2007; Parker 2009b). This drug was recommended for approval for the treatment of patients with paroxysmal nocturnal hemoglobinuria with a history of transfusions in the European Union in April 2007 (Parker 2007).

 

How the intervention might work

Eculizumab is a humanized monoclonal antibody that binds specifically to complement protein C5 with high affinity, preventing its cleavage into C5a and C5b, thereby inhibiting complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (Hill 2008; Hill 2010a; McKeage 2011; Parker 2007; Risitano 2009; Risitano 2011; Weitz 2012). C5 being common to all pathways of complement activation, its blockade effectively halts progression of the cascade regardless of the stimuli. Prevention of C5 cleavage also blocks the generation of the potent pro inflammatory C5a and cell lytic molecules C5b-9 (Dmytrijuk 2008). While a dramatic decrease in intravascular hemolysis is found in most trials, many patients still have persistent anemia, reticulocytosis and hemolysis which may be due to immune mediated extravascular hemolysis (Hill 2010a). The mechanism could be CD55-deficient PNH red cells becoming overloaded with C3 fragments because of inhibition of the terminal complement cascade steps by eculizumab (Risitano 2009). However, this is a rare phenomenon and treatment with eculizumab has shown better hemolytic outcomes in terms of higher rates of hemoglobin stabilization, decreased need for transfusion, greater transfusion independence and an overall improvement in quality of life (Dmytrijuk 2008; Hillmen 2006; Schubert 2008).

 

Why it is important to do this review

A number of randomized controlled trials have examined the effects of treatment with eculizumab in paroxysmal nocturnal hemoglobinuria. Controversy exists as to which patients suffering from paroxysmal nocturnal hemoglobinuria should be treated with this drug (Haspel 2008). Eculizumab therapy is associated with risk of infection by Neisseria meningitidis (McKeage 2011) and viral infections such as influenza or viral gastroenteritis (Brodsky 2009a; Brodsky 2009b; Brodsky 2008c). There is risk of Neisseria meningitidis infection even after vaccination, and patients frequently require re-vaccination when on eculizumab treatment. Since eculizumab has no effect on the underlying cellular abnormality in paroxysmal nocturnal hemoglobinuria, treatment, once started, may require prolonged administration. This also raises economic concerns since eculizumab is an expensive drug (Parker 2007). Thus there is a need for a critical appraisal of randomized controlled trials to assess eculizumab in patients with paroxysmal nocturnal hemoglobinuria (Hillmen 2006). This systematic review and meta-analysis analysing the available data might provide more definitive evidence regarding the role and safety of eculizumab in these patients.

Eventually, this Cochrane review will help clinicians to make informed decisions on the use of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To assess the clinical efficacy and safety of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria, and to evaluate which patients might benefit most from its use.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

We will include randomized controlled trials irrespective of their publication status (trials may be unpublished or published as an article, an abstract, or a letter), language and country. No limits will be applied with respect to period of follow-up. We will exclude quasi-randomized trials.

 

Types of participants

We will include any patient with a confirmed diagnosis of paroxysmal nocturnal hemoglobinuria according to the International PNH Interest Group (I-PIG) criteria (Parker 2005). No restrictions will be applied with respect to gender or ethnicity.

 

Types of interventions

Eculizumab

We plan at least two separate comparisons:
1. Eculizumab versus placebo.
2. Eculizumab versus other treatment: best available therapy.

 

Types of outcome measures

 

Primary outcomes

  1. Overall survival defined as the time from randomization until death from any cause, and measured in the intent-to-treat population (FDA 2007).

 

Secondary outcomes

  1. All-cause mortality.
  2. Health-related quality of life and fatigue assessed by a validated scale.
  3. Any fatal or non-fatal thrombotic event.
  4. Transformation to myelodysplastic syndrome and acute myelogenous leukemia.
  5. Adverse events (serious and non-serious). A serious adverse event, defined according to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH-GCP 1997), is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. All other adverse events will be considered non-serious.
  6. Development, and recurrence of aplastic anemia on treatment.
  7. Transfusion independence.
  8. Withdrawal for any reason.

 

Search methods for identification of studies

We will develop the search strategy as indicated in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We will conduct this process with the support of the Cochrane Haematological Malignancies Group (CHMG) Trials Search Co-ordinator (TSC) and adjust it for each database.

 

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library (latest issue)). We will also search MEDLINE (Ovid) (from 1950 to present), EMBASE (from 1980 to present), and LILACS (from 1982 to present). See Appendix 2; Appendix 3; Appendix 4; Appendix 5 for details.

 

Searching other resources

A) We will search the following trial databases for ongoing and unpublished trials:

  1. The Clinical Trials Search Portal of the World Health Organization (WHO) (apps.who.int/trialsearch/).
  2. The Metaregister of Controlled Trials: http://www.controlled-trials.com/mrct/.
  3. ClinicalTrials.gov (http://clinicaltrials.gov/).

B) We will search the following conference proceedings from 2000 to present, if they are not included in CENTRAL:

  1. American Society of Hematology (ASH) (www.hematology.org).
  2. European Hematology Association (EHA) (http://www.ehaweb.org/).
  3. American Society for Clinical Oncology (ASCO) (www.asco.org).
  4. European Society of Medical Oncology (ESMO) (http://www.esmo.org/).

C) We will also search the following websites:

  1. Food and Drug Administration (www.fda.gov).
  2. European Medicines Agency (www.ema.europa.eu/).
  3. http://www.epistemonikos.org/

We will handsearch the references of all identified included trials, of relevant review articles and of current treatment guidelines. We will contact principal investigators to identify any unpublished trials. We will not apply any language restrictions.

 

Data collection and analysis

We will summarize data using standard Cochrane Collaboration methodologies (Higgins 2011a).

 

Selection of studies

Methods for study selection will follow the steps delineated by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Arturo Martí-Carvajal, Vidhu Anand and Andrés Felipe Cardona will screen the titles and abstracts identified from the above sources to identify potential studies for inclusion. If this can not be done satisfactorily from the title and abstract, we will seek a full text version for assessment. We will present the results of the study selection as a flowchart according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Moher 2009).

We will resolve any disagreement through discussion and consensus, or if required, we will consult Ivan Solà.

 

Data extraction and management

We will use a form to extract data. Overall, we will extract and fill in the following data: review, review author and study information, eligibility criteria, characteristics of the participants (age, gender, country), trial design and funding, related variables, intervention duration and dosage, outcomes (Appendix 6). We will extract quality criteria according to risk of bias using the Cochrane Collaboration’s tool for assessing risk of bias: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective reporting; and other bias (Higgins 2011a).

For each eligible trial, two review authors (Arturo Martí-Carvajal and Vidhu Anand) will extract the data using the agreed form in duplicate. We will resolve discrepancies through discussion or, if required, we will consult Andrés Felipe Cardona and Ivan Solà.

Arturo Martí-Carvajal and Vidhu Anand will enter data into Review Manager software (RevMan 2011) and Ivan Solà will check it for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to obtain further details.

 

Assessment of risk of bias in included studies

Arturo Martí-Carvajal, Vidhu Anand and Ivan Solà in pairs will independently assess the risk of bias of each trial using a simple form, and will follow the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We will resolve any discrepancies through discussion or consult Andrés Felipe Cardona .

We will assess the following domains as low risk of bias, unclear or high risk of bias:

  1. Generation of allocation sequence
  2. Allocation concealment
  3. Blinding (of participants, personnel and outcome assessors)
  4. Incomplete outcome data
  5. Selective reporting
  6. Other sources of bias

Overall risk of bias

We will consider low risk of bias trials to be those that adequately generated their allocation sequence; had adequate allocation concealment, adequate blinding, adequate handling of incomplete outcome data; were free of selective outcome reporting; and were free of other bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

We will consider trials in which we assess one of domains as high risk of bias or unclear risk of bias, as trials with high risk of bias.

 

Measures of treatment effect

For the following binary outcomes, we will calculate the relative risk (RR) with 95% confidence intervals (CI):

  1. All-cause mortality.
  2. Any fatal or non-fatal thrombotic event.
  3. Adverse events (serious and non-serious)
  4. Transformation to myelodysplastic syndrome and acute myelogenous leukemia.
  5. Development, and recurrence of aplastic anemia on treatment.
  6. Transfusion independence,
  7. Withdrawal due to any reason.

For the following continuous outcomes we will calculate the standardized mean difference (SMD) with 95% CI:

  1. Health-related quality of life and fatigue assessed by a validated scale,

For time-to-event data, we will calculate the hazard ratio (HR) with 95% CI.

  1. Overall survival.

 

Dealing with missing data

In the case of missing data on participants or missing statistics (such as standard deviations) we will contact the trial authors. If unsuccessful, we will perform sensitivity analysis for worst and best case scenarios according to the Cochrane Handbook for Systematic Reviews of Interventions section 16.1 (Higgins 2011c).

 

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if I² is greater than 30% and either T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. We will investigate possible causes of heterogeneity through subgroup analysis (Deeks 2011).

 

Assessment of reporting biases

We will attempt to assess whether the review is subject to publication bias by using a funnel plot to illustrate variability graphically between trials. We will assess the publication bias if at least 10 trials are available so that it is possible to make judgments about asymmetry, and if asymmetry is present, we will explore causes other than publication bias (Sterne 2011).

 

Data synthesis

We will carry out statistical analysis using Review Manager software (RevMan 2011). If the eligible trials are sufficiently comparable in their clinical characteristics, we will summarize their findings using a random-effects model according to the Cochrane Handbook section 9.4 (Deeks 2011).

 

'Summary of findings' table

We will use the principles of the GRADE system (Guyatt 2011a) to assess the quality of the body of evidence associated with all main outcomes (overall survival, any fatal or non-fatal thrombotic event, adverse events, health-related quality of life, transformation to myelodysplastic syndrome and acute myelogenous leukemia, development and recurrence of aplastic anemia on treatment) and we will construct a 'Summary of findings' (SoF) table using the GRADE profiler software (GRADEPro 2008). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the quality of a body of evidence considers within-study risk of bias, the directness of the evidence, heterogeneity in the data, precision of effect estimates and risk of publication bias (Balshem 2011; Brozek 2011; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2011i; Guyatt 2011j; Guyatt 2012).

 

Subgroup analysis and investigation of heterogeneity

We will devote further efforts to identify possible causes of heterogeneity. We will explore the impact of the included trials' risk of bias and the condition of the individuals by subgroup analyses. We anticipate clinical heterogeneity for the following participant and intervention characteristics:

  1. Age
  2. Duration of follow up.
  3. Type of paroxysmal nocturnal hemoglobinuria: classical, subclinical or associated with other bone marrow disorders.
  4. Aplastic anemia.
  5. Thrombotic episodes.
  6. PIG-A mutation status at screening.
  7. Previous paroxysmal nocturnal hemoglobinuria therapy including dose and duration of therapy.

These different variables justify subgroup analyses. We plan to perform subgroup analysis only for primary outcomes.

 

Sensitivity analysis

We will conduct sensitivity analyses according to the Cochrane Handbook section 9.4 (Deeks 2011).

If sufficient trials are identified, we will conduct a sensitivity analysis excluding:

  1. Those randomized controlled trials at a high risk of bias (see Assessment of risk of bias in included studies). Trials at high risk of bias will not be removed from the main analysis but will be analyzed separately.
  2. Those randomized controlled trials with a total attrition of more than 30%, or where baseline differences between the groups exceed 10%, or both.

We will also conduct a trial sequential analysis (TSA) which is a methodology that combines an information size calculation (cumulated sample sizes of included trials) for meta-analysis with the threshold of statistical significance. TSA is a tool for quantifying the statistical reliability of data in a cumulative meta-analysis adjusting P values for repetitive testing on accumulating data. We will conduct a TSA on binary and continuous outcomes (Brok 2009; Pogue 1997; Pogue 1998; Thorlund 2009; Wetterslev 2008; Wetterslev 2009). Meta-analysis may result in type I errors due to sparse data or due to repeated significance testing when updating meta-analysis with new trials (Brok 2009; Higgins 2011d; Wetterslev 2008). In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries are applied to decide whether a trial could be terminated early because of a sufficiently small P value, that is the cumulative Z-curve crosses the monitoring boundaries (Lan 1983). Sequential monitoring boundaries can be applied to meta-analysis as well, called trial sequential monitoring boundaries (Wetterslev 2008; Wetterslev 2009). In TSA, the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to clarify whether additional trials are needed.The idea in TSA is that if the cumulative Z-curve crosses the boundary, a sufficient level of evidence is reached and no further trials may be needed. If the Z-curve does not cross the boundary then there is insufficient evidence to reach a conclusion. To construct the trial sequential monitoring boundaries the required information size is needed and is calculated as the least number of participants needed in a well-powered single trial (Brok 2009; Pogue 1997; Pogue 1998; Wetterslev 2008). We will apply TSA since it prevents an increase of the risk of type I error (< 5%) due to potential multiple updating in a cumulative meta-analysis, and provides us with important information in order to estimate the level of evidence of the experimental intervention.

Additionally, TSA provides us with important information regarding the need for additional trials and the required sample size of such trials. We will apply trial sequential monitoring boundaries according to a heterogeneity-adjusted required information size based on an a priori 10% relative risk reduction (RRR) (APHIS) employing α = 0.05 and ß = 0.20.

TAS will be conducted using the TSA software (CTU 2011; Thorlund 2011).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

We thank the editors and the editorial base of the Cochrane Haematological Malignancies Review Group for their comments.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Medical glossary


Medical termDefinitionSource

Allogeneic stem cell transplantationThe transfer of stem cells from one individual to another within the same species or between species, or transfer within the same individual. The source and location of the stem cells determines their potency or pluripotency to differentiate into various cell types.http://www.ncbi.nlm.nih.gov/mesh

Abnormal karyotypeA variation from the normal set of chromosomes characteristic of a species.http://www.ncbi.nlm.nih.gov/mesh

Aerolysin

Proaerolysin
A bacterial protein that binds selectively to GPI-APs.

Protoxin secreted by the bacterium Aeromonas hydrophila. The GPI-anchored proteins serve as the receptor for this channel-forming toxin. The toxin does not bind to PNH cells, because they are deficient in GPI-anchored proteins.
Parker 2005

Brodsky 2008a

Bone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.http://www.ncbi.nlm.nih.gov/mesh

Cognate proteinProtein that possesses a glycosylphosphatidylinositol (GPI) attachment signal and is destined to be attached to the cell membrane by a GPI anchor.Brodsky 2008a

ComplementSerum glycoproteins participating in the host defense mechanism of complement activation that creates the complement membrane attack complex.http://www.ncbi.nlm.nih.gov/mesh

CD55Cell-surface GPI-anchored protein that blocks C3 convertase. Its deficiency in paroxysmal nocturnal hemoglobinuria erythrocytes is partly responsible for their increased susceptibility to complement-mediated intravascular hemolysis.Brodsky 2008a

CD59GPI-anchored protein that normally functions to regulate formation of the membrane attack complex by interfering with its assembly.Brodsky 2008a

CytokineNon-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner.http://www.ncbi.nlm.nih.gov/mesh

Erythroid cellsThe series of cells in the red blood cell lineage at various stages of differentiation.http://www.ncbi.nlm.nih.gov/mesh

Fluorescently labelled aerolysin (FLAER)When used for flow cytometric analysis, leukocytes that express GPI-APs bind the fluorescently labelled reagent. Paroxysmal nocturnal hemoglobinuria leukocytes do not bind FLAER because they do not express GPI-APs. Therefore, paroxysmal nocturnal hemoglobinuria leukocytes are identified in the flow cytometric histogram as a population of cells with absent or dim fluorescence.Parker 2005

GeneA DNA sequence in a chromosome which contains the code for a protein and which functions as a template to produce mRNA.Mummery 2011

Glycosyl phosphatidylinositol–anchored proteins (GPI-APs)Highly evolutionarily conserved glycolipid moiety comprising a molecule of phosphatidylinositol, a glycan core containing 3 mannoses, and an ethanolamine phosphate that tethers certain proteins (eg., CD55 and CD59) to the cell membrane.Brodsky 2008a

HaptoglobinPlasma glycoproteins that form a stable complex with hemoglobin to aid the recycling of heme iron. They are encoded in man by a gene on the short arm of chromosome 16.http://www.ncbi.nlm.nih.gov/mesh

HemolysisThe destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity.http://www.ncbi.nlm.nih.gov/mesh

HemoglobinuriaThe presence of free hemoglobin in the urine, indicating hemolysis of erythrocytes within the vascular system. After saturating the hemoglobin-binding proteins (haptoglobins), free hemoglobin begins to appear in the urine.http://www.ncbi.nlm.nih.gov/mesh

HyperplasiaAn increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells.http://www.ncbi.nlm.nih.gov/mesh

KaryotypeThe full set of CHROMOSOMES presented as a systematized array of METAPHASE chromosomes from a photomicrograph of a single CELL NUCLEUS arranged in pairs in descending order of size and according to the position of the CENTROMERE.http://www.ncbi.nlm.nih.gov/mesh

KaryotypingMapping of the karyotype of a cell.http://www.ncbi.nlm.nih.gov/mesh

Lysis/ly·sis/ (li´sis) 1. destruction or decomposition, as of a cell or other substance, under influence of a specific agent. 2. mobilization of an organ by division of restraining adhesions. 3. gradual abatement of the symptoms of a disease.http://medical-dictionary.thefreedictionary.com/

LyticAny agent causing destruction or dissolution of a cell or molecule. Cell lysis is frequently caused by a lysin. lytic, adj.http://medical-dictionary.thefreedictionary.com/

Membrane attack complexComprises C5b, C6, C7, C8, and multiple units of C9. These terminal complement proteins form a channel that causes cell lysis.

A product of complement activation cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target cell membrane and cell lysis. It is formed by the sequential assembly of terminal complement components (COMPLEMENT C5B; COMPLEMENT C6; COMPLEMENT C7; COMPLEMENT C8; and COMPLEMENT C9) into the target membrane. The resultant C5b-8-poly-C9 is the "membrane attack complex" or MAC.
Brodsky 2008a

http://www.ncbi.nlm.nih.gov/mesh

Monoclonal antibodyAntibodies produced by a single clone of cells.http://www.ncbi.nlm.nih.gov/mesh

Neisseria meningitidisA species of gram-negative, aerobic bacteria. It is a commensal and pathogen only of humans, and can be carried asymptomatically in the nasopharynx. When found in cerebrospinal fluid it is the causative agent of cerebrospinal meningitis (meningitis, meningococcal). It is also found in venereal discharges and blood. There are at least 13 serogroups based on antigenic differences in the capsular polysaccharides; the ones causing most meningitis infections being A, B, C, Y, and W-135. Each serogroup can be further classified by serotype, serosubtype, and immunotype.http://www.ncbi.nlm.nih.gov/mesh

PNHParoxysmal nocturnal hemoglobinuria.-

Phosphatidylinositol glycan class A (PIGA) geneOne of more than 20 genes required for the biosynthesis of GPI anchors. The PIGA gene is required for the first step in the pathway; mutations of this gene lead to a marked deficiency in or absence of all GPI-anchored proteins. All patients with PNH to date have been found to harbor clonal PIGA mutations.Brodsky 2008a

ReticulocytosisAn increase in circulating reticulocytes, which is among the simplest and most reliable signs of accelerated erythrocyte production. Reticulocytosis occurs during active blood regeneration (stimulation of red bone marrow) and in certain types of anemia, particularly congenital hemolytic anemia.http://www.ncbi.nlm.nih.gov/mesh

Splanchnic circulationThe circulation of blood through the blood vessels supplying the abdominal viscera.http://www.ncbi.nlm.nih.gov/mesh

Stem cellsA cell that can self-renew and differentiate into one or more cell types.Mummery 2011



 

Appendix 2. CENTRAL search strategy


IDSearch

#1(eculizumab*)

#2soliris*

#3alexion*

#45G1*

#5anti-C5* or antiC5*

#6(#1 OR #2 OR #3 OR #4 OR #5)



 

Appendix 3. MEDLINE (Ovid) search strategy


#Searches

1eculizumab$.tw,kf,ot,nm.

2soliris$.tw,kf,ot.

3alexion$.tw,kf,ot.

45G1-1.tw,kf,ot.

5"5G1.1".tw,kf,ot.

6(anti-C5$ or antiC5$).tw,kf,ot,nm.

7or/1-6 search part Eculizumab

8randomized controlled trial.pt.

9controlled clinical trial.pt.

10randomi?ed.ab.

11placebo.ab.

12clinical trials as topic.sh.

13randomly.ab.

14trial.ti.

15or/8-14

16humans.sh.

1715 and 16 Cochrane RCT-filter

187 and 17 Eculizumab and RCT-filter



 

Appendix 4. EMBASE search strategy


#Searches

1‘Eculizumab’:de

2soliris*:ab,ti

3alexion*:ab,ti

4allogen*:ab,ti

55G1*:ab,ti

6(anti-C5*:ab,ti OR antiC5*:ab,ti)

7#1 OR #2 OR #3 OR #4 OR #5 OR #6

8random*:ab,ti

9placebo*:ab,ti

10‘single’:ab,ti OR

‘double’:ab,ti OR ‘triple’:ab,ti OR ‘treble’:ab,ti

11‘blinded’:ab,ti OR ‘masked’:ab,ti

12#10 AND #11

13‘Controlled clinical trial’:ab,ti

14‘RETRACTED ARTICLE’:de

15#8 OR #9 OR #12 OR #13 OR #14

16(‘animal’:de OR ‘animals’:de NOT

(‘human’:de OR ‘humans’:de)

17#15 NOT #16

18#7 AND #17



 

Appendix 5. LILACS search strategy

http://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/

eculizumab$ OR soliris$ OR alexion$ OR 5G1-1$ OR 5G1.1$ OR anti-C5$ OR antiC5$

 

Appendix 6. Study eligibility screening and data extraction form

 

Eculizumab for treating paroxysmal nocturnal hemoglobinuria

1. Review author and study information

Study ID:

Review author name (First-Last names):  

Member of the Ecuatorian branch of the Iberoamerican Cochrane Network (yes/no):

Date of completion of this form: 

Title of the study:

Language of publication: 

Type of report (e.g. full paper/abstract/unpublished):


First authorJournal/Conference Proceedings etcYear

 

 
  



2. Study eligibility


RCT/Relevant participants (adult patients with PNH and anemia)Relevant interventions (One group received eculizumab)Relevant outcomes (Study evaluated QoL, survival, safety and/or erythroid response)

 

Yes / No / Unclear
 

Yes / No / Unclear
 

Yes / No / Unclear
 

Yes / No* / Unclear

 



 * Issue relates to selective reporting – when authors may have taken measurements for particular outcomes, but not reported these within the paper(s). Review authors should contact trialists for information on possible non-reported outcomes & reasons for exclusion from publication. Study should be listed in ‘Studies awaiting assessment’ until clarified. If no clarification is received after three attempts, study should then be excluded.                                                                   


Do not proceed if any of the above answers are ‘No’. If study to be included in ‘Excluded studies’ section of the review, record below the information (author year) to be inserted into ‘Table of excluded studies’.

 

 

 




Freehand space for comments on study design and treatment:



3. References to trial 

Check other references identified in searches. If there are further references to this trial link the papers now & list below. All references to a trial should be linked under one Study ID in RevMan. 


Code each paperAuthor(s)Journal/Conference Proceedings etcYear

 The paper listed above  

 Further papers  

    



4. Participants and trial characteristics


Participant characteristics

 Further details

Age (mean, median, range, etc) 

Sex of participants (numbers / %, etc) 

Country 

Other

Inclusion criteria: how and where, were participants enrolled, describe any participant risk factors, what criteria were used to diagnose PNH?

Exclusion criteria: were specific groups of people excluded?

PNH subgroups

Total number of randomized participants:

Total available for analysis:




Trial characteristics

 Further details

Date of trial conduction (range)

Single center / multicenter 

Country / countries 

Funders of the trial

How was participant eligibility defined? 

How many people were randomized? 

Number of participants in each intervention group 

Number of participants who received intended treatment 

Number of participants who were analyzed 

Drug treatment(s) used 

Dose / frequency of administration 

Duration of treatment (State weeks / months, etc, if cross-over trial give length of time in each arm) 

Median (range) length of follow-up reported in this paper (state weeks, months or years or if not stated) 

Time-points when measurements were taken during the study 

Time-points reported in the study 

Time-points you are using in RevMan 

Trial design (e.g. parallel / cross-over*) 

Other




Intervention group characteristics

 Further details

Dosage 

Administration route 

Time to administration 

Duration of therapy

Number of participants assigned to this arm:



If trial included a combination:


Intervention characteristics

 Further details

Name of co-intervention 

Dosage 

Administration route 

Time to administration 

Duration of therapy




Control group characteristics

 Further details

Description of control intervention 

Dosage 

Administration route 

Time to administration 

Duration of therapy

Number of participants assigned to this arm:



5. Types of outcomes

Data extraction 


Outcomes relevant to your review

Copy and paste from ‘Types of outcome measures’

 Reported in paper (circle)

Overall survivalYes / No

All-cause mortalityYes / No

Any fatal or non-fatal thrombotic eventYes / No

Anemia response defined as an increasing of ≥ 1 g/L at the end of the follow up.Yes / No

Transformation to myelodysplastic syndrome and acute myelogenous leukemiaYes / No

Leukemia-free survivalYes / No

Serious adverse eventsYes / No

Non-serious adverse eventsYes / No

Health-related quality of life and fatigue assessed by a validated scaleYes / No

Development, and recurrence of aplastic anemia on treatmentYes / No

Transfusion independenceYes / No

Withdrawal due to any reasonYes / No



                   


For binary data

Code of paperOutcomesIntervention group (n)

n = number of participants, not number of events
Control group (n)

n = number of  participants, not number of events

AAll-cause mortality

Anemia response defined as an increasing of ≥ 1 g/L at the end of the follow up.

Transformation to myelodysplastic syndrome and acute myelogenous leukemia

Any fatal or non-fatal thrombotic event

 Serious adverse events  

 Non-serious adverse events  

Development, and recurrence of aplastic anemia on treatment

Transfusion independence

Withdrawal due to any reason



 


Other information which you feel is relevant to the results

Indicate if: any data were obtained from the primary author; if results were estimated from graphs etc; or calculated by you using a formula (this should be stated and the formula given). In general if results not reported in paper(s) are obtained this should be made clear here to be cited in review.

 

 

 

 




For continuous data

Code of paperOutcomesIntervention group (N)

N = number of participants, not number of events (measured as reported by trial authors).
Control group (N)

N = number of  participants, not number of events (measured as reported by trial authors).

BHealth-related quality of life and fatigue  




For time-to-event data


Code of paperOutcomesIntervention group (N)

N = number of participants, not number of events (measured as reported by trial authors). Hazard ratio
Control group (N)

N = number of  participants, not number of events (measured as reported by trial authors). Hazard ratio.

COverall survival



6.Methodological quality 


Allocation of intervention

State here method used to generate allocation and reasons for gradingGrade (circle)

 

 
Adequate (Random)

Inadequate (e.g. alternate)

Unclear



 


Concealment of allocation

Process used to prevent foreknowledge of group assignment in a RCT, which should be seen as distinct from blinding

State here method used to conceal allocation and reasons for gradingGrade (circle)

 Adequate

Inadequate

Unclear



 


Blinding

Person responsible for participants' careYes / No

ParticipantYes / No

Outcome assessorYes / No

Other (please specify)Yes / No

Intention-to-treat

An intention-to-treat analysis is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received it or not.

All participants entering trial 

15% or fewer excluded 

More than 15% excluded 

Not analysed as ‘intention-to-treat’ 

Unclear 



 

 


Free of selective reporting

Grade (circle)

 

 
Adequate

Inadequate

Unclear



Were withdrawals described?    Yes? No?  not clear?  

7. Contact with study authors


Is further information required from the authors? (yes/no)

 




Freehand space for writing actions such as contact with study authors and changes (include name, position, affiliation, contact e-mail)



8. References to other trials 


Did this report include any references to published reports of potentially eligible trials not already identified for this review?

First authorJournal / ConferenceYear of publication

   

Did this report include any references to unpublished data from potentially eligible trials not already identified for this review? If yes, give list contact name and details

 

 



 

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Arturo J Martí-Carvajal conceived and drafted the protocol with comments from Andrés Felipe Cardona, Vidhu Anand and Ivan Solà.

Arturo Marti-Carvajal will be the guarantor of this Cochrane review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

In 2004 and 2007 Arturo Martí-Carvajal was employed by Eli Lilly to run a four-hour workshop on ’How to critically appraise clinical trials on osteoporosis and how to teach this’.This activity was not related to his work with The Cochrane Collaboration or any Cochrane Review.

Vidhu Anand, Andrés Felipe Cardona and Ivan Solà: none known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • No sources of support supplied

 

External sources

  • Iberoamerican Cochrane Center, Spain.
    Academic
  • Cochrane Hematological Malignancies Group, Germany.
    Academic

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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Guyatt 2011d
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Guyatt 2011e
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