非典型溶血性尿毒综合征的治疗
摘要
研究背景
非典型溶血性尿毒综合征（atypical haemolytic uraemic syndrome, aHUS)是一种罕见的紊乱性疾病，特征为血小板减少、微血管病性溶血性贫血和急性肾损伤。该疾病主要由遗传或者获得性补体调节蛋白调节异常引起，约40%的患者年龄小于18岁。就先前历史来看，肾功能衰竭和死亡通常是该病的常见结果。然而，对于aHUS日益深刻的理解促使新兴治疗手段的发现。
研究目的
目的在于评估干预措施对aHUS的利弊效果。
检索策略
我们利用与该综述相关的术语检索法检索了Cochrane肾脏与移植试验注册库（Cochrane Kidney and Transport Register of Studies）中截至2020年9月3日的、关于随机对照试验（RCTs）的研究。注册库中的研究是通过检索Cochrane对照试验中心注册库（Cochrane Central Register of Controlled Trials, CENTRAL）、MEDLINE和EMBASE、会议记录、国际临床试验注册库（International Clinical Trials Register, ICTRP）检索门户以及临床试验注册平台确定的。我们还检索了MEDLINE（OVID）1946年至2020年7月27日以及EMBASE（OVID）1974年至2020年7月27日的非随机对照试验。
纳入排除标准
纳入的所有随机或非随机对照临床试验均将干预疗法与安慰剂、干预疗法与支持疗法或两种及更多治疗干预疗法进行对照。鉴于所讨论疾病的罕见性质，所有治疗aHUS干预方法的前瞻性单臂研究均被纳入。
资料收集与分析
两位研究人员从已获研究中独立提取了预先指定的资料数据，并使用以现有Cochrane标准为基准的最新开发工具，对偏倚风险进行评估。由于统计荟萃分析不恰当，因此对数据进行了定性分析。
主要结果
我们纳入了五项单臂研究，所有的这些研究均对治疗aHUS的手段进行了终端补体抑制方面的评估。四项研究评估了短效 C5 抑制剂依库珠单抗，一项研究评估了长效 C5 抑制剂拉武珠单抗。综述中纳入的所有研究均为非随机、单臂设计。因此，偏倚风险较高，也很难从这些低质量证据中得出确切结论。在三项评估依库丽单抗的主要研究中共纳入一百名受试者，在一项次要研究中报道了37名受试者的进一步数据。在拉武珠单抗的研究中共纳入58名受试者。在接受依库丽单抗疗法26周之后，无一例受试者死亡且需要透析的受试者数量减少了70%。在26周时，研究观察到60%的受试者出现了完全血栓性微血管病（thrombotic microangiopathic, TMA）反应；两年时观察数据达到了65%。在接受拉武珠单抗治疗的26周后，四例受试者死亡（7%），并在54%的受试者身上观察到了完全血栓性微血管病反应。在两种单抗治疗的研究中，受试者的估算肾小球滤过率和健康相关的生活质量均出现了实质性的改善。42%的受试者身上出现了严重的不良反应事件，两例接受依库珠单抗治疗的受试者出现了脑膜炎球菌感染。
作者结论
与历史数据对比，五项单臂研究得出的低质量证据显示，终端补体抑制可能为aHUS受试者提供了有利的结果。随机对照试验不太可能在aHUS中操作进行。因此未来的单臂试验资料和长期随访数据需要进行更为仔细周全的考虑，以便更好地理解治疗持续时间、不良后果以及与终末补体抑制相关的疾病复发风险。
PICO
简语概要
对于非典型溶血性尿毒综合征，最有效的治疗方法是什么？
研究问题是什么？
溶血性尿毒综合征（Haemolytic uraemic syndrome, HUS）是一种由于小血管阻塞导致血细胞破坏以及一些器官出现机能障碍的疾病。这种病最常见于肾脏。它一般由感染引起，通常是大肠杆菌感染，也与腹泻有一定关联。溶血性尿毒综合征中罕见的一种被称为非典型溶血性尿毒综合征（atypical HUS, aHUS），它是一种更具侵袭性的疾病。一般由遗传或者获得性蛋白质异常引起。这些蛋白质参与控制我们的免疫系统‐‐‐“补体”的一部分。在罹患该病的患者中，几乎有一半人的年龄小于18岁。在过去，aHUS的诊断和预后不良有关，患者通常会恶化发展成为肾功能衰竭以及死亡。近年来，对于这种疾病的更加深刻的理解促使治疗手段变得更为有效。本综述旨在通过系统性地检索可获得的证据评估这些治疗手段的有效性，以获得治疗aHUS的最佳方法。
我们做了什么？
我们广泛检索文献并发现了五项测试aHUS治疗方法的研究。其中四项研究使用的治疗方法是依库珠单抗，一项研究使用的治疗方法是拉武珠单抗。这两种最近研发的药物发挥作用的形式相类似，并在其他医疗条件下也显示出较好的前景。
我们发现了什么？
纳入的研究显示，大多数接受两种药物治疗的受试者的肾功能得到很大改善，其中很大一部分受试者的肾功能已经改善到足以停止透析治疗的程度。血液中疾病活动的标记物也出现了显著改善。在为期26周的治疗过程中，接受依库珠单抗治疗的受试者无一例死亡，虽然有两名受试者死于脑膜炎双球菌感染，但这是治疗的可能结果。尽管接受拉武珠单抗治疗的四名受试者死亡，但是研究认为他们并非死于该药物治疗。对于接受这两种药物治疗的受试者，他们的生活质量得到了显著提升。
结论
aHUS是一种极其罕见的疾病类型，如果得不到治疗通常是致命的。因此，我们发现，没有一项研究将一种治疗方法和另一种治疗方法进行对比，抑或是将接受一种治疗方法与未接受治疗进行对比。相反，纳入的研究给予所有受试者两种药物治疗，研究结果也仅仅与这两种药物研发前的历史数据进行比较。在综述中，这产生了实质性的偏倚。因此，来源于该研究的任何建议，可信度都十分有限。尽管如此，现存的最佳证据表明，既使用依库珠单抗又使用拉武珠单抗的治疗方法对于aHUS患者来说是有效的，也显示出相较于先前治疗较高的优越性。
Authors' conclusions
Summary of findings
| Eculizumab versus placebo or alternative treatment for children and adults aHUS | ||||||
| Patient or population: children and adults with aHUS Settings: inpatient Intervention: eculizumab Comparison: placebo or alternative treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Risk with placebo or alternative treatment | Risk with eculizumab treatment | |||||
| Death | N/A | 1/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | All 100 patients were alive at 26 weeks. There was 1 death in the 37 patients who were subsequently followed up over 2 years |
| Requirement for KRT | N/A | N/A | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | 37/100 were undergoing dialysis at initiation of eculizumab therapy. Of these patients, 11 (30%) continued to require regular dialysis after 26 weeks of treatment representing a 70% reduction in dialysis requirement. At 2 years, 3/37 patients included within the secondary study remained dialysis‐dependent compared with 7 at baseline (57% reduction) |
| Disease remission | N/A | 60/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | 60/100 patients treated with eculizumab achieved complete TMA response after 26 weeks of treatment. Median time to complete TMA response was 56 ‐ 60 days. In a cohort of patients followed up for 2 years, 65% maintained complete TMA response at this time point |
| Change in eGFR | N/A | N/A | N/A | 88 (3 single‐arm studies) | ⊕⊝⊝⊝ | In patients treated with eculizumab, mean change in eGFR over 26 weeks was 33 ± 34 mL/min/1.73 m². At 2 years, eGFR had improved by ≥ 15 mL/min/1.73 m² in 37 patients (49%) |
| HRQoL | N/A | N/A | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | In 49 patients aged ≥ 12 years treated with eculizumab, 67% demonstrated a clinically significant improvement in EQ‐5D score. In 22 paediatric patients treated with eculizumab the mean improvement in FACIT‐F score was 19.7 (improvement of > 4.7 considered clinically meaningful) |
| Adverse events | N/A | 100/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | Adverse events occurred in 100% of patients treated with eculizumab. Serious adverse events occurred in 37% of patients. The most commonly reported events included diarrhoea (23%), fever (21%), headache (19%), upper respiratory tract infection (19%), cough (17%) and urinary tract infection (10%) |
| Meningococcal infection | N/A | 2/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | Meningococcal infection occurred in 2 patients (2%) treated with eculizumab |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Ravulizumab versus placebo or alternative treatment for adults with aHUS | ||||||
| Patient or population: adults with aHUS Settings: inpatient Intervention: ravulizumab Comparison: placebo or alternative treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Risk with placebo or alternative treatment | Risk with ravulizumab treatment | |||||
| Death | N/A | 4/58 | N/A | 58 (1 single‐arm study) | ⊕⊝⊝⊝ | Four deaths occurred, including one in a patient ultimately excluded based on eligibility criteria but who had received one dose of ravulizumab. No deaths were considered treatment‐related by the study investigators |
| Requirement for KRT | N/A | N/A | N/A | 56 (1 single‐arm study) | ⊕⊝⊝⊝ | 29/56 were undergoing dialysis at initiation of ravulizumab therapy. Of these patients, 12 (41%) continued to require regular dialysis after 26 weeks of treatment representing a 59% reduction in dialysis requirement |
| Disease remission | N/A | 30/56 | N/A | 56 (1 single‐arm study) | ⊕⊝⊝⊝ | 30/56 patients treated with ravulizumab achieved complete TMA response after 26 weeks of treatment. Median time to complete TMA response was 86 days |
| Change in eGFR | N/A | N/A | N/A | 56 (1 single‐arm study) | ⊕⊝⊝⊝ | In patients treated with ravulizumab, mean change in eGFR over 26 weeks was 35 ± 35 mL/min/1.73 m² |
| HRQoL | N/A | N/A | N/A | 44 (1 single‐arm study) | ⊕⊝⊝⊝ | A clinically meaningful improvement in FACIT‐F score (≥ 3‐point increase) was observed in 84% of patients treated with ravulizumab |
| Adverse events | N/A | 58/58 | N/A | 58 (1 single‐arm study) | ⊕⊝⊝⊝ | Adverse events occurred in 100% of patients treated with ravulizumab. Serious adverse events occurred in 52% of patients. The most commonly reported events included headache (36%), diarrhoea (31%), vomiting (26), hypertension (22%), nausea (22%) and urinary tract infection (17%) |
| Meningococcal infection | N/A | 0/58 | N/A | 58 (1 single‐arm study) | ⊕⊝⊝⊝ | No patients treated with ravulizumab developed meningococcal infection |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
Background
Description of the condition
Haemolytic uraemic syndrome (HUS) is a form of thrombotic microangiopathy (TMA) which affects adults and children and is characterised by thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury (AKI) (Noris 2009). The term HUS encompasses several different disease processes which can be broadly divided into infection‐induced HUS, HUS secondary to a pre‐existing condition, or atypical HUS (aHUS) (Loirat 2016).
Around 90% of cases of HUS are considered infection‐induced and are most typically associated with either Shiga toxin‐producing Escherichia coli (STEC) or Streptococcus pneumoniae (Ariceta 2009). STEC‐associated cases are often (but not always) preceded by the onset of bloody diarrhoea (Besbas 2006). Pre‐existing conditions leading to the development of HUS include autoimmune diseases, stem cell or solid organ transplantation, and certain malignancies. This category of HUS can also be associated with certain drugs and with pregnancy (Fakhouri 2017).
The remainder of cases fall into the category of aHUS. Classically this term has been used to describe HUS associated with dysregulation of the alternative complement pathway due to either inherited or acquired dysfunction of complement regulatory proteins (Noris 2009). Further subdivision of this group is now possible, including recognition of those with anti‐factor H autoantibodies (a subgroup which accounts for ~10% of paediatric aHUS) (Fremeaux‐Bacchi 2013). More recently the definition of aHUS has been broadened to include other rare forms of HUS including diacylglycerol kinase E and Cobalamin C deficiency, as well as HUS with no clear precipitant (Loirat 2016).
The incidence of aHUS based on this broader classification is 0.23 to 0.42 cases/million population/year, with around 35% to 42% of cases occurring in children under the age of 18 (Fremeaux‐Bacchi 2013; Sheerin 2016).
Diagnosis is based on the presence of thrombocytopenia, microangiopathic haemolysis, and kidney injury and the exclusion of other forms of HUS or thrombotic thrombocytopenic purpura (TTP). A genetic or acquired abnormality of complement regulation can be identified in around 50% of cases, however therapeutic interventions are often required before this information is available (Sheerin 2016).
Historically up to 25% of people die during the acute illness (Kaplan 2014). Of those surviving, 50% require acute kidney replacement therapy (KRT) of whom a significant proportion never recover native kidney function and require long‐term KRT (Constantinescu 2004; Noris 2009).
Description of the intervention
Plasma exchange and plasma infusion have been the main treatments for aHUS since the early 1990s and work by replacing absent or removing abnormal complement proteins within the body. Although death rates decreased significantly following the introduction of plasma therapies a proportion of patients struggle to tolerate regular plasma therapy and relapse following discontinuation of treatment (Lara 1999; Noris 2005). Various other agents including corticosteroids, antiplatelet agents and thrombolytics have been studied with varying results. Liver transplantation has also been used as a treatment for aHUS in a small number of patients with known genetic complement factor deficiencies (Saland 2009). As certain complement factors such as factor H and factor I are produced in the liver successful transplantation, either alone or with combined kidney transplant, has the potential to cure aHUS in this subset of patients (Coppo 2016). However, this intervention is not without significant risk of morbidity and death and is not available in all centres (Remuzzi 2005).
Eculizumab, a humanised monoclonal antibody, targets complement component C5 in an attempt to halt the dysregulated activation of the complement pathway, reducing endothelial injury and subsequent organ dysfunction. Eculizumab is now recognised as the treatment of choice for paroxysmal nocturnal haemoglobinuria (PNH), a condition which also involves dysregulated terminal complement activation. Several studies have shown it to be effective for this indication with an acceptable safety profile (Hillmen 2013; Kanakura 2011). More recently, a longer‐acting C5 inhibitor, ravulizumab, has demonstrated non‐inferiority to eculizumab for the treatment of PNH with the additional benefit of reduced dosing frequency (Lee 2019; Kulasekararaj 2019). Both eculizumab and ravulizumab may therefore be superior to plasma therapy in the treatment of aHUS due to the ability to “switch off” abnormal complement activity.
Why it is important to do this review
A previous Cochrane Review has identified and evaluated interventions for HUS but this was not specific to aHUS (Michael 2009). Importantly, this review was conducted prior to the widespread use of eculizumab for the treatment of aHUS. We therefore considered it important to carry out this review in order to identify and evaluate emerging interventions for aHUS given the recent advances in our understanding of disease pathogenesis and directed treatment.
Objectives
This review aims to evaluate the benefits and harms of interventions for aHUS.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs), quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) and non‐randomised studies which compare an intervention with placebo, an intervention with supportive therapy, or two or more interventions for aHUS were included. Given the rare nature of the condition in question, prospective single‐arm studies of any intervention for aHUS were also included.
Types of participants
Inclusion criteria
Studies including patients of all ages with a confirmed diagnosis of aHUS. This diagnosis is defined as all three of:
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Evidence of kidney impairment (raised serum creatinine (SCr) or equivalent biomarker which meets local criteria for AKI)
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Evidence of thrombocytopenia (platelet count < 150 x 109/L)
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Evidence of haemolysis (lactate dehydrogenase (LDH) above upper limit of normal, haptoglobin count below the lower limit of normal, evidence of fragmented red blood cells in a peripheral blood smear, or presence of schistocytes)
Exclusion criteria
The following patient groups were excluded.
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Patients with evidence of STEC infection
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Patients with evidence of Streptococcus pneumoniae infection
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Patients with evidence of ADAMTS‐13 deficiency (level at or below 10% in plasma)
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Patients with evidence of HUS as a consequence of a pre‐existing condition or disease including malignancy, haematopoietic stem cell transplantation, solid organ transplantation, infections, autoimmune conditions, malignant hypertension, and drug‐induced HUS
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Patients with pregnancy‐associated HUS.
Types of interventions
Any intervention for aHUS was considered including, but not limited to, eculizumab, ravulizumab, plasma exchange, plasma infusion, anti‐platelet agents, thrombolytics, immunosuppressants, corticosteroids, and liver transplantation.
Types of outcome measures
Primary outcomes
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Death (any cause)
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Requirement for KRT
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Successful remission as defined independently by each study. This may involve normalisation or stabilisation of platelet count, resolution of haemolysis, or resolution of AKI.
Secondary outcomes
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Change in SCr or glomerular filtration rate (GFR)
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Persistent requirement for plasma therapy
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Degree of proteinuria: as evidenced by urinalysis, urine protein:creatinine ratio (UPCR), or 24‐hour urine protein measurement
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Presence of hypertension: as evidenced by the need for, and number of, antihypertensive agents
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Kidney biopsy changes: as there is no standardised system for reporting the varied biopsy changes associated with aHUS, we planned to report subjective scales as presented in each paper individually, e.g. mild/moderate/severe, an estimation of severity such as presence/percentage of crescents, an estimation of acute activity if provided‐ for example by endothelial cell swelling, lumen narrowing or thrombi formation in the interlobular arteries, arterioles and glomerular capillaries as well as information on chronicity by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis present on the biopsy
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Health‐related quality of life (HRQoL): as no disease specific tools exist, currently validated tools such as questionnaires like the 36 Item Short‐Form Survey, EuroQoL 5 Domain tool, COnsensus‐based Standards for the selection of health status Measurement INstruments (COSMIN) and the Evaluating Measures of Patient‐Reported Outcomes (EMPRO) are appropriate
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Adverse events
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Meningococcal infection.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Kidney and Transplant Register of Studies up to 3 September 2020 through contact with the Information Specialist using search terms relevant to this review. The register contains studies identified from the following sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
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Weekly searches of MEDLINE OVID SP
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Searches of kidney and transplant journals, and the proceedings and abstracts from major kidney and transplant conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected kidney and transplant journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website under CKT Register of Studies.
MEDLINE(OVID) 1946 to 27 July 2020 and EMBASE (OVID) 1974 to 27 July 2020 were searched for non‐RCTs.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
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Reference lists of review articles, relevant studies, and clinical practice guidelines.
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Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described was used to obtain titles and abstracts of studies relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however studies and reviews that included relevant data or information on studies were retained initially. Two authors then independently assessed retrieved abstracts and, if necessary, the full text of these studies, to determine which studies satisfied the inclusion criteria.
Data extraction and management
Data extraction was carried out independently by two authors using standardised data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses.
Assessment of risk of bias in included studies
Three independent risk of bias assessment tools were assigned to analyse risk of bias in RCTs, non‐randomised studies and single‐arm studies. For each included study, two authors independently assessed risk of bias using the assigned tool. It was our intention, where possible, to evaluate risk of bias in RCTs using the Cochrane risk of bias tool (Appendix 2), in non‐RCTs (where there was direct comparison between two or more treatment arms, or with a historical or external comparator) using the ROBINS‐I tool (Sterne 2016), and in single‐arm studies using a newly developed tool designed specifically for this purpose (Appendix 3).
The recently designed tool for assessing risk of bias in single‐arm studies considered the following items.
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Selection bias
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Lead time bias/immortal time bias
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Confounding by indication
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Misclassification bias/information bias
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Bias from natural recovery/regression to the mean
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Bias due to adjunctive therapies
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Attrition bias
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Selective reporting of outcomes.
Measures of treatment effect
For dichotomous outcomes results were to be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment the mean difference (MD) was to be used, or the standardised mean difference (SMD) if different scales were used. Due to the nature of the included studies these analyses were not possible.
Unit of analysis issues
There were no unit of analysis issues.
Dealing with missing data
Any further information required from the original author was requested by written correspondence (e.g. emailing corresponding author). Evaluation of important numerical data such number of patients screened, randomised as well as intention‐to‐treat, as‐treated and per‐protocol population was carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals were investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) were critically appraised (Higgins 2011).
Assessment of heterogeneity
If suitable studies were identified, we planned to first assess heterogeneity by visual inspection of the forest plot and subsequently quantify statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). Due to the nature of the included studies no such assessment was possible. Due to the inclusion of non‐randomised and single‐arm studies, it was anticipated that a greater degree of heterogeneity would be apparent among included studies and this was taken into account when considering potential sources of bias.
Assessment of reporting biases
If possible, funnel plots were to be used to assess for the potential existence of small study bias (Higgins 2011).
Data synthesis
Unadjusted data from included RCTs were to be pooled using the random‐effects model or the fixed‐effect model however this was not possible. It was our intention to combine data from non‐randomised studies for meta‐analysis only when such data were considered to be significantly free from bias and heterogeneity as assessed independently by two authors, however again this was not possible. In such circumstances, consideration would be given to analyse adjusted, rather than unadjusted, effect estimates as an inverse‐variance weighted average. Where pooling of data was not appropriate then qualitative data synthesis only was performed.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis was to be used to explore possible sources of heterogeneity (e.g. participants or interventions). Heterogeneity among participants could be related to their age, whether they were being treated for a first presentation or relapse of aHUS, specific complement mutations identified, whether they required acute KRT, or whether or not they had developed aHUS after a kidney transplant. Heterogeneity in interventions could be related to the dosage and duration of therapies used, as well as co‐interventions and previous treatments.
Sensitivity analysis
If suitable data were acquired, we planned to perform sensitivity analyses in order to explore the influence of the following factors on effect size.
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Repeating the analysis excluding unpublished studies
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Repeating the analysis taking account of risk of bias, as specified
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Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
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Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
Summary of findings and assessment of the certainty of the evidence
We planned to present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We planned to present the following outcomes in the 'Summary of findings' tables.
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Death (any cause)
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Requirement for KRT
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Disease remission
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Persistent elevation of SCr and/or GFR of < 60 mL/min/1.73 m²
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Persistent requirement for plasma therapy
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Adverse events due to treatment.
Results
Description of studies
See Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
Results of the search
We performed an initial search of Cochrane Kidney and Transplant's Specialised Register (including CENTRAL, MEDLINE and EMBASE) in November 2017. From this initial search we identified 81 records. Further searches were conducted in February 2019 (yielding a further six records) and September 2020 (yielding a further 20 records) providing a total of 107 records. Two records were identified through additional searching of record references. After screening titles and abstracts and full‐text review, five studies (36 reports) were included, 59 studies (67 reports) were excluded, and six ongoing studies were identified (EUCTR2017‐001082‐24; EudraCT2014‐001032‐11; NCT01757431; NCT03131219; NCT03205995; UMIN000014869) These six studies and will be assessed in a future update of this review (Figure 1).
Study flow diagram.
Included studies
All five included studies were of non‐randomised, single‐arm design and evaluated terminal complement inhibition in patients with aHUS without a comparator group. Four studies evaluated eculizumab, a short‐acting C5 inhibitor (Fakhouri 2016; Greenbaum 2016; Legendre 2013; Licht 2015), and one study evaluated ravulizumab, a longer‐acting C5 inhibitor (Rondeau 2020). More information is presented in the Characteristics of included studies section. Licht 2015 reported two‐year extension data from Legendre 2013 and thus describes the same patient population. It has therefore been described as a secondary study, with the remainder of the included studies described as primary studies. All included studies were sponsored by Alexion Pharmaceuticals who are responsible for manufacturing both eculizumab and ravulizumab.
Given the rare nature of the condition in question all four primary studies recruited patients from multiple sites. Two studies (Fakhouri 2016; Legendre 2013) included patients from Europe and North America. Greenbaum 2016 included patients from Europe, North America, and Australia, and Rondeau 2020 included patients from Europe, North America, Australia, and Asia.
All included patients had a diagnosis of aHUS with similar diagnostic criteria used within each study (Characteristics of included studies). Legendre 2013 subdivided participants into two sub‐studies; those with progressive TMA with resistance to plasma therapy, and those with a chronic aHUS phenotype receiving maintenance plasma therapy. In all other primary studies there was no such subdivision. Of note, Rondeau 2020 was the only study to exclude patients requiring chronic haemodialysis at baseline.
Greenbaum 2016 focused on the paediatric aHUS population, including patients aged one month to 18 years. Legendre 2013 included adolescent and adult patients (≥12 years) in both sub‐studies, and Fakhouri 2016 and Rondeau 2020 included only adult patients (≥ 18 years). As Licht 2015 is an extension of Legendre 2013, this study also involved adolescent and adult patients.
There were 158 patients included in the four primary studies with further data reported from 37 patients in the secondary study. The age range was five months to 80 years with 28 of the 158 included primary patients under the age of 18 years (18%). Total duration of therapy was 26 weeks in all four primary studies. Two studies (Fakhouri 2016; Legendre 2013) used a dosing regimen of intravenous eculizumab 900 mg once/week for 4 weeks, 1,200 mg at week 5, and then 1,200 mg every 2 weeks. Paediatric dosing of eculizumab (Greenbaum 2016) was based upon weight with dosing sufficient to ensure that > 95% of patients had complete and sustained terminal complement inhibition and to provide peak plasma concentrations within a target range of 50 to 700 mg/mL. Ravulizumab dosing was based upon weight with an initial intravenous loading dose of 2400 to 3000 mg followed by maintenance doses of 3000 to 3600 mg on day 15 and every 8 weeks thereafter.
Plasma therapy and/or plasma exchange was used as additional therapy in the eculizumab studies where required (Fakhouri 2016; Greenbaum 2016; Legendre 2013; Licht 2015), however was not permitted in the ravulizumab study (Rondeau 2020).
Excluded studies
We excluded 59 studies (67 records). Reasons for exclusion included retrospective study design, incorrect patient population, duplicate data, and incorrect study outcomes.
We contacted two authors to enquire about unpublished data discussed in abstracts, and to seek clarification where data discussed in papers appeared to represent a subgroup of a larger published study. One author confirmed that the data represented analysis of patient cohorts published elsewhere and the study was grouped accordingly (Van De Kar 2014). The other author confirmed that the study did not meet our inclusion criteria (Khandelwal 2016).
Risk of bias in included studies
All included studies within the review were of non‐randomised, single‐arm design. Thus, the overall risk of bias is high, limiting the confidence in the results of this review. Despite this, some single‐arm studies are subject to higher degrees of bias than others, and certain forms of bias can largely be eliminated with effective single‐arm study design. The following assessment was compiled using the Cochrane risk of bias in single‐arm studies assessment tool (Appendix 3).
As all included studies were non‐randomised, single‐arm studies, there was no blinding of participants or investigators. It was therefore clear which patients were receiving either eculizumab or ravulizumab (all included patients) and this will have influenced results.
Eligibility criteria were clearly described and were similar in all studies thus reducing the possibility of selection bias. However, as all included studies were of single‐arm design it was not possible to compare eligibility criteria with studies with comparator groups. The process of patient recruitment was not clearly defined in any of the included studies. Given the rarity of the condition it is likely that all eligible participants encountered during the recruitment period were recruited, but this is not specifically reported.
In three of the four primary studies (Fakhouri 2016; Greenbaum 2016; Rondeau 2020) the time between recruitment and initiation of therapy was minimal. In Legendre 2013 participants in the first sub‐study were treated within 3 days, however those in the second sub‐study underwent an eight‐week observation period following recruitment and prior to initiation of treatment which may have increased the potential for lead time bias.
Eculizumab and ravulizumab dosing and outcome measures were clearly defined at the outset in all studies reducing the potential for misclassification or information bias.
Outcome variables were generally measured at outset and at end‐point in all studies (e.g. requirement for dialysis, degree of kidney impairment, requirement for plasma therapy). Previous studies of aHUS have demonstrated that prior to the advent of effective therapies the natural course of the condition if untreated is likely to be death. It is likely, therefore, that bias from natural recovery was negligible in all studies.
The requirement for plasma therapy (the main adjunctive therapy used) both before, during and after the treatment period was well described in all studies where it was permitted.
All four primary studies clearly documented reasons for participant withdrawal, which was uncommon. Three primary studies were analysed based on an intention to treat basis (Fakhouri 2016; Greenbaum 2016; Legendre 2013). Rondeau 2020 included all initially enrolled and treated participants in their safety analysis, however, excluded two participants from their full analysis on the basis of ineligibility.
There was no evidence of selective reporting in any of the included studies.
Effects of interventions
See: Summary of findings 1 Eculizumab versus placebo or alternative treatment for children and adults with atypical haemolytic uraemic syndrome (aHUS); Summary of findings 2 Ravulizumab versus placebo or alternative treatment for adults with atypical haemolytic uraemic syndrome (aHUS)
Either eculizumab or ravulizumab therapy was the sole intervention in all five included studies with no comparator groups. Meta‐analysis was therefore not feasible, and a descriptive analysis was performed.
Death (any cause)
Eculizumab
All 100 patients included within the three primary studies were alive at 26 weeks (completion of initial eculizumab treatment period). Of the 37 patients included in Licht 2015, one patient (3%) had died at two years. This was as a result of complications of intestinal haemorrhage which were thought to be unrelated to eculizumab therapy.
Ravulizumab
Of the 58 patients included within the safety analysis, four patients (7%) had died by 26 weeks. None of these deaths were thought to be related to the study drug and were caused by septic shock (2), intracerebral haemorrhage, and cerebral artery thrombosis.
Requirement for kidney replacement therapy
Eculizumab
There were 37/100 patients included in the primary studies who were undergoing dialysis at initiation of eculizumab therapy. Of these patients, 26 discontinued regular dialysis after 26 weeks of treatment representing a 70% reduction in dialysis requirement. At two years, 3/37 patients included within the secondary study remained dialysis‐dependent compared with 7/37 at baseline (57% reduction) (Licht 2015).
Ravulizumab
Unlike the eculizumab studies, patients undergoing chronic haemodialysis for established end‐stage kidney disease (ESKD) at baseline were excluded from Rondeau 2020, although patients undergoing haemodialysis due to AKI as a result of aHUS were included. Dialysis was discontinued in 17/29 patients who required dialysis at baseline (59%).
Disease remission
Eculizumab
Disease remission, or complete TMA response, was defined similarly by each of the three included primary eculizumab studies. In all three studies the definition included haematological normalisation (platelet count maintained ≥ 150 x 109/L and LDH maintained below the upper limit of normal on two separate measurement ≥ four weeks apart) and either improvement (≥ 25% reduction in SCr from baseline) (Greenbaum 2016; Legendre 2013) or preservation (< 25% increase in SCr from baseline) (Fakhouri 2016) of kidney function. Sixty percent of patients achieved complete TMA response after 26 weeks of eculizumab treatment. Median time to complete TMA response was 56 days in one study involving adult patients (Fakhouri 2016) and 60 days in a study involving patients < 18 years (Greenbaum 2016). Follow‐up data from Licht 2015 showed that 65% of patients (37) had achieved complete TMA response at two years.
Ravulizumab
Complete TMA response was defined by Rondeau 2020 as platelet count normalisation (≥ 150 x 109/L), LDH normalisation (< 246 U/L), and ≥ 25% improvement in SCr from baseline at two separate assessments obtained at least 28 days apart. Fifty‐four percent of patients achieved complete TMA response during the 26‐week treatment period. The median time to complete TMA response was 86 days.
Kidney function
Eculizumab
Mean increase in eGFR over 26 weeks was 33 ± 34 mL/min/1.73 m²for patients in the three primary studies (88 patients). Baseline eGFR was not reported. eGFR improved by ≥15 mL/min/1.73 m² in 50% of patients at 26 weeks. At two years, eGFR had improved by ≥15 mL/min/1.73 m² in 37 patients (49%) (Licht 2015).
Ravulizumab
Mean increase in eGFR over 26 weeks in those treated with ravulizumab was 35 ± 35 mL/min/1.73 m² (56 patients). eGFR improved by at least one eGFR category in 47 patients with available data (68%).
Requirement for plasma therapy
Eculizumab
Prior to the widespread use of eculizumab, treatment of aHUS largely depended upon regular plasma therapy (including plasma exchange). At initiation of eculizumab 81 patients (81%) were receiving plasma therapy. After 26 weeks of treatment, two patients (2%) remained reliant upon plasma therapy, representing a 98% reduction in requirement for this time‐ and labour‐intensive treatment.
Ravulizumab
Plasma therapy was not permitted as an adjunctive treatment in the ravulizumab study.
Proteinuria
Eculizumab
Change in degree of proteinuria was only assessed by one primary study (Legendre 2013) and by the secondary study (Licht 2015). At baseline, 26 patients (70%) had ≥ 1+ proteinuria on dipstick urinalysis. Of this group, 18 patients (69%) had a reduction of ≥ 1 proteinuria ‘grade’ (as assessed by dipstick urinalysis) after 26 weeks. This figure increased to 85% at two years (Licht 2015). Baseline UPCR was 2.46 ±1.74 g/mmol with a mean reduction in UPCR of 0.74 ±0.75 g/mmol after 26 weeks (37 patients).
Ravulizumab
Proteinuria was not assessed by Rondeau 2020.
Blood pressure
This outcome was not reported by any of the included studies.
Renal biopsy change
This outcome was not reported by any of the included studies.
Health‐related quality of life
Eculizumab
HRQoL was measured in all studies using a variety of tools including EQ‐5D, 36‐Item Short From Health Survey (SF‐36), and Functional Assessment of Chronic Illness – Fatigue (FACIT‐F) (adult and paediatric versions). Of the adult and adolescent population (age ≥ 12 years), 67% demonstrated a clinically meaningful improvement (> 0.06) in EQ‐5D score (49 patients). Greenbaum 2016 used a paediatric FACIT‐F tool to demonstrate a mean improvement in score of 19.7, with an improvement of > 4.7 considered clinically meaningful (22 patients) (Lai 2007).
Ravulizumab
Rondeau 2020 assessed HRQoL using the adult FACIT‐F score at baseline and at 26 weeks. A clinically meaningful improvement (≥ 3‐point increase) was observed in 44 patients with available data (84%).
Adverse events
Eculizumab
Serious adverse events occurred in 37% of patients included within the primary eculizumab studies. Adverse events occurred in 100% of patients. The most commonly reported events included diarrhoea (23%), fever (21%), headache (19%), upper respiratory tract infection (19%), cough (17%), and urinary tract infection (10%). Reporting of adverse events was incomplete in two of three primary studies (Fakhouri 2016; Greenbaum 2016). Fakhouri 2016 reported all serious adverse events and adverse events occurring in > 15% of patients. Greenbaum 2016 reported all adverse events but only serious adverse events occurring in ≥ 2 patients. All serious adverse events and adverse events were clearly reported by Legendre 2013.
Ravulizumab
Although only 56 patients with confirmed eligibility were included within the complete analysis for this study, all patients (58) treated with at least one dose of ravulizumab were included within the safety analysis. At least one adverse event occurred in all patients, and serious adverse events occurred in 52%. The most frequent adverse events observed were headache (36%), diarrhoea (31%), vomiting (26), hypertension (22%), nausea (22%), and urinary tract infection (17%). The most common serious adverse events (occurring in ≥ 3% of patients) included malignant hypertension (3%) and infections including pneumonia (5%), and septic shock (3%).
Meningococcal infection
Eculizumab
Meningococcal infection occurred in two patients (2%) in the primary studies. One patient developed meningococcal meningitis which led to permanent discontinuation of eculizumab therapy. A second patient developed meningococcal sepsis and was hospitalised but was able to continue eculizumab. In both cases the patients recovered. Both patients had received meningococcal vaccination against serogroups A, C, W, and Y but had not been prescribed long‐term antibiotics.
Ravulizumab
No episodes of meningococcal infection were reported within the ravulizumab study.
Discussion
Summary of main results
This review evaluates the best available evidence for current interventions for aHUS. In four single‐arm studies, terminal complement inhibition (either eculizumab or ravulizumab) was used to treat 158 patients over a period of 26 weeks with no comparator groups. A fifth study described two‐year follow‐up data from a subset patients treated with eculizumab.
Death at 26 weeks was zero in each of the eculizumab studies, and of the selected 37 patients which formed the two‐year follow‐up only one died. In the ravulizumab study death was 7% at 26 weeks. Plasma exchange/infusion has been the historical standard of care for aHUS prior to the introduction of C5 inhibitors. Observational data of patients with aHUS treated with plasma exchange/infusion describe death rates of up to 8% at first presentation and 11% at three years in one series (Noris 2010), and 4% after median follow‐up of 45 months in another (Fremeaux‐Bacchi 2013). While longer term data are lacking, reported death rates for eculizumab in particular are notably improved.
Substantial improvements were seen in kidney function, haematological parameters, and quality of life after 26 weeks of therapy in all studies. All studies showed an overall reduction in the number of patients with a requirement for KRT following treatment, ranging from a reduction of 57% (Legendre 2013) to 82% (Greenbaum 2016). At 26 weeks, 35% of patients who were KRT‐dependent at baseline and treated with either eculizumab or ravulizumab remained KRT‐dependent. Historically, patients treated with plasma therapies have demonstrated rates of KRT dependency of up to 67% (Noris 2010). Haematological remission was achieved in 58% of patients at 26 weeks. Longer term data are limited, but effects with eculizumab appear to be maintained at two years with 65% of patients in the secondary study achieving complete TMA response by this time point. Again, this compares favourably with observational data of patients treated with plasma therapies with one series reporting partial or complete response in ~50% of those treated with plasma exchange or infusion, but with fewer patients maintaining this response in the long term (Noris 2010).
Adverse events were common in all included studies. Licht 2015 identified four patients (11% of that study group) undergoing extended therapy who suffered serious adverse events (accelerated hypertension, asymptomatic bacteriuria, and hypertension). Less serious adverse events were common, and most often occurred during the first six months of treatment. Legendre 2013 reported that, while there were no “infection related” events, all patients had at least one serious adverse event in their first sub‐trial, while 50% had serious adverse events in their second sub‐trial. While the authors do not ascribe all of these events directly to eculizumab, they included hypertension, peritonitis, influenza, and a venous disorder not otherwise specified. All events resolved within 26 weeks of treatment and did not necessitate interruption to the treatment regime. Greenbaum 2016 reported similarly high levels of treatment‐emergent adverse events in 20/22 patients, the most common being fever, cough, abdominal pain, diarrhoea, and upper respiratory tract infection. The most serious events occurred in an infant and child less than 12 years of age – viral induced bone marrow suppression (parainfluenza type 3), wrist fracture and acute respiratory failure. Fifty nine percent of patients reported one or more serious adverse event, one of which led to treatment discontinuation. All patients included within the safety analysis of Rondeau 2020 suffered at least one adverse event and > 50% suffered a serious adverse event. Three patients discontinued ravulizumab because of a serious adverse event. Despite this, the authors report that none of the serious adverse events observed were considered 'unexpected'. All patients were vaccinated against meningococcal infection. Despite this, two patients treated with eculizumab developed meningococcal infections, both of whom recovered.
The included studies offer little evidence to guide discontinuation of C5 inhibitor therapy. Eculizumab and ravulizumab are both expensive, and thus guidance on when, if at all, these drugs can be safely withdrawn in patients with aHUS without risking relapse is an important consideration.
Thirty‐four patients included within the four primary studies had previously undergone kidney transplantation with recurrence of aHUS post‐transplant and outcomes following treatment with either eculizumab or ravulizumab in this setting suggest efficacy. Several retrospective case‐series have suggested positive outcomes with eculizumab following kidney transplantation in patients with aHUS as a measure to maintain remission, rather than treat recurrent disease (Alpay 2019; Bhalla 2019), but this was not assessed in this review. Similarly, our search strategy did not identify any studies which prospectively evaluated liver transplantation (either combined or in associated with kidney transplantation) as a treatment for aHUS. Although this treatment is likely to decline further following the widespread adoption of C5 inhibitor therapy as the mainstay of aHUS treatment, case report data suggests there may still be a role for liver transplantation in select cases where treatment with C5 inhibitors has failed (Coppo 2016).
Overall completeness and applicability of evidence
All studies were well conducted and data were largely complete. However, follow‐up is limited and kidney biopsy data, which would have been a useful supplementary measure of kidney outcomes, is absent. We assessed the risk of bias as being high due to the single‐arm nature of the studies and as a result the certainty of the evidence is low. This is primarily due to study limitation biases detected with the risk of bias in single‐arm studies assessment tool (Appendix 3).
Quality of the evidence
We conducted this review according to the processes described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), however, deviated when assessing risk of bias in single‐arm studies, instead using a new tool developed by Cochrane for this purpose.
This review is limited by the sole inclusion of single‐arm studies which presents a number of important confounders. The lack of an internal control leaves all studies open to bias and misinterpretation making any inference about intervention effect much less powerful, with conclusions drawn based upon comparisons with historical registry data of aHUS outcomes.
Potential biases in the review process
While this review was conducted according to methods developed by the Cochrane Collaboration, some bias may be present in the review process. We searched for all relevant studies using sensitive and validated strategies in major medical databases and grey literature sources. However, it is possible that some studies (such as unpublished data and studies with negative or no effects) were not identified. There is extensive multicentre collaboration in the field and a number of patient cohorts reappear in multiple abstracts and papers. Every effort was taken to ensure no patients have been included more than once or inadvertently excluded.
Agreements and disagreements with other studies or reviews
No previous Cochrane reviews have specifically evaluated interventions for aHUS. Michael 2009 previously published Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura, however this was prior to the advent of C5 inhibitor therapy for aHUS and did not include non‐randomised or single‐arm studies. It therefore did not include any studies examining interventions for aHUS.
To our knowledge, this is the only systematic review of interventions for aHUS to have been published since the majority of the landmark C5 inhibitor studies were published. A previous review by Rathbone 2013 was conducted in 2013 and includes results from Legendre 2013 as well as several retrospective studies. Our review is largely in agreement with this review.
Study flow diagram.
| Eculizumab versus placebo or alternative treatment for children and adults aHUS | ||||||
| Patient or population: children and adults with aHUS Settings: inpatient Intervention: eculizumab Comparison: placebo or alternative treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Risk with placebo or alternative treatment | Risk with eculizumab treatment | |||||
| Death | N/A | 1/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | All 100 patients were alive at 26 weeks. There was 1 death in the 37 patients who were subsequently followed up over 2 years |
| Requirement for KRT | N/A | N/A | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | 37/100 were undergoing dialysis at initiation of eculizumab therapy. Of these patients, 11 (30%) continued to require regular dialysis after 26 weeks of treatment representing a 70% reduction in dialysis requirement. At 2 years, 3/37 patients included within the secondary study remained dialysis‐dependent compared with 7 at baseline (57% reduction) |
| Disease remission | N/A | 60/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | 60/100 patients treated with eculizumab achieved complete TMA response after 26 weeks of treatment. Median time to complete TMA response was 56 ‐ 60 days. In a cohort of patients followed up for 2 years, 65% maintained complete TMA response at this time point |
| Change in eGFR | N/A | N/A | N/A | 88 (3 single‐arm studies) | ⊕⊝⊝⊝ | In patients treated with eculizumab, mean change in eGFR over 26 weeks was 33 ± 34 mL/min/1.73 m². At 2 years, eGFR had improved by ≥ 15 mL/min/1.73 m² in 37 patients (49%) |
| HRQoL | N/A | N/A | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | In 49 patients aged ≥ 12 years treated with eculizumab, 67% demonstrated a clinically significant improvement in EQ‐5D score. In 22 paediatric patients treated with eculizumab the mean improvement in FACIT‐F score was 19.7 (improvement of > 4.7 considered clinically meaningful) |
| Adverse events | N/A | 100/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | Adverse events occurred in 100% of patients treated with eculizumab. Serious adverse events occurred in 37% of patients. The most commonly reported events included diarrhoea (23%), fever (21%), headache (19%), upper respiratory tract infection (19%), cough (17%) and urinary tract infection (10%) |
| Meningococcal infection | N/A | 2/100 | N/A | 100 (4 single‐arm studies) | ⊕⊝⊝⊝ | Meningococcal infection occurred in 2 patients (2%) treated with eculizumab |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Ravulizumab versus placebo or alternative treatment for adults with aHUS | ||||||
| Patient or population: adults with aHUS Settings: inpatient Intervention: ravulizumab Comparison: placebo or alternative treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Risk with placebo or alternative treatment | Risk with ravulizumab treatment | |||||
| Death | N/A | 4/58 | N/A | 58 (1 single‐arm study) | ⊕⊝⊝⊝ | Four deaths occurred, including one in a patient ultimately excluded based on eligibility criteria but who had received one dose of ravulizumab. No deaths were considered treatment‐related by the study investigators |
| Requirement for KRT | N/A | N/A | N/A | 56 (1 single‐arm study) | ⊕⊝⊝⊝ | 29/56 were undergoing dialysis at initiation of ravulizumab therapy. Of these patients, 12 (41%) continued to require regular dialysis after 26 weeks of treatment representing a 59% reduction in dialysis requirement |
| Disease remission | N/A | 30/56 | N/A | 56 (1 single‐arm study) | ⊕⊝⊝⊝ | 30/56 patients treated with ravulizumab achieved complete TMA response after 26 weeks of treatment. Median time to complete TMA response was 86 days |
| Change in eGFR | N/A | N/A | N/A | 56 (1 single‐arm study) | ⊕⊝⊝⊝ | In patients treated with ravulizumab, mean change in eGFR over 26 weeks was 35 ± 35 mL/min/1.73 m² |
| HRQoL | N/A | N/A | N/A | 44 (1 single‐arm study) | ⊕⊝⊝⊝ | A clinically meaningful improvement in FACIT‐F score (≥ 3‐point increase) was observed in 84% of patients treated with ravulizumab |
| Adverse events | N/A | 58/58 | N/A | 58 (1 single‐arm study) | ⊕⊝⊝⊝ | Adverse events occurred in 100% of patients treated with ravulizumab. Serious adverse events occurred in 52% of patients. The most commonly reported events included headache (36%), diarrhoea (31%), vomiting (26), hypertension (22%), nausea (22%) and urinary tract infection (17%) |
| Meningococcal infection | N/A | 0/58 | N/A | 58 (1 single‐arm study) | ⊕⊝⊝⊝ | No patients treated with ravulizumab developed meningococcal infection |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
