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):
- Evidence of a population of peripheral blood cells (erythrocytes, granulocytes, or preferably both) deficient in glycosyl phosphatidylinositol–anchored proteins detected by flow cytometric analysis.
- Complete blood count, reticulocyte count, serum concentration of lactate dehydrogenase, bilirubin (fractionated), and haptoglobin.
- 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).
According to the International Paroxysmal Nocturnal Hemoglobinuria Interest Group (I-PIG), paroxysmal nocturnal hemoglobinuria is classified in three categories:
- classic paroxysmal nocturnal hemoglobinuria,
- 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
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
- 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).
- Iron replacement therapy when iron stores are deficient, and folic acid supplementation because of the high red cell turnover in these patients.
- 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
- Glucocorticoids (prednisone) (Firkin 1968).
- Whole blood or packed red blood cell transfusion (Guasch 1969).
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.
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.
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
We plan at least two separate comparisons:
1. Eculizumab versus placebo.
2. Eculizumab versus other treatment: best available therapy.
Types of outcome measures
- Overall survival defined as the time from randomization until death from any cause, and measured in the intent-to-treat population (FDA 2007).
- All-cause mortality.
- Health-related quality of life and fatigue assessed by a validated scale.
- Any fatal or non-fatal thrombotic event.
- Transformation to myelodysplastic syndrome and acute myelogenous leukemia.
- 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.
- Development, and recurrence of aplastic anemia on treatment.
- Transfusion independence.
- 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.
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:
- The Clinical Trials Search Portal of the World Health Organization (WHO) (apps.who.int/trialsearch/).
- The Metaregister of Controlled Trials: http://www.controlled-trials.com/mrct/.
- ClinicalTrials.gov (http://clinicaltrials.gov/).
B) We will search the following conference proceedings from 2000 to present, if they are not included in CENTRAL:
- American Society of Hematology (ASH) (www.hematology.org).
- European Hematology Association (EHA) (http://www.ehaweb.org/).
- American Society for Clinical Oncology (ASCO) (www.asco.org).
- European Society of Medical Oncology (ESMO) (http://www.esmo.org/).
C) We will also search the following websites:
- Food and Drug Administration (www.fda.gov).
- European Medicines Agency (www.ema.europa.eu/).
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:
- Generation of allocation sequence
- Allocation concealment
- Blinding (of participants, personnel and outcome assessors)
- Incomplete outcome data
- Selective reporting
- 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):
- All-cause mortality.
- Any fatal or non-fatal thrombotic event.
- Adverse events (serious and non-serious)
- Transformation to myelodysplastic syndrome and acute myelogenous leukemia.
- Development, and recurrence of aplastic anemia on treatment.
- Transfusion independence,
- Withdrawal due to any reason.
For the following continuous outcomes we will calculate the standardized mean difference (SMD) with 95% CI:
- 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.
- 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).
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:
- Duration of follow up.
- Type of paroxysmal nocturnal hemoglobinuria: classical, subclinical or associated with other bone marrow disorders.
- Aplastic anemia.
- Thrombotic episodes.
- PIG-A mutation status at screening.
- 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.
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:
- 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.
- 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.
We thank the editors and the editorial base of the Cochrane Haematological Malignancies Review Group for their comments.
Appendix 1. Medical glossary
Appendix 2. CENTRAL search strategy
Appendix 3. MEDLINE (Ovid) search strategy
Appendix 4. EMBASE search strategy
Appendix 5. LILACS search strategy
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
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):
2. Study eligibility
* 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.
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.
4. Participants and trial characteristics
If trial included a combination:
5. Types of outcomes
Were withdrawals described? Yes? No? not clear?
7. Contact with study authors
8. References to other trials
Contributions of authors
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
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
- No sources of support supplied
- Iberoamerican Cochrane Center, Spain.Academic
- Cochrane Hematological Malignancies Group, Germany.Academic