The global aHUS Registry (US National Institutes of Health www.ClinicalTrials.gov Identifier NCT01522183) was initiated in April 2012 with the support of Alexion Pharmaceuticals, Inc. The objectives of the aHUS Registry are as follows: 1) to assess the long-term effects of aHUS, including clinical outcomes such as TMA complications, and morbidity and mortality in aHUS patients receiving eculizumab treatment or other disease management; and 2) to collect and evaluate safety and effectiveness data specific to the use of eculizumab in aHUS patients.
Scientific oversight, governance and coordination are provided by an independent scientific advisory board (SAB), whose members offer expertise in key specialties related to management of aHUS (e.g., adult and pediatric nephrologists, hematologists, and/or transplant nephrologists/surgeons) and also include representation from Alexion Pharmaceuticals, Inc. The term of SAB membership is 2 years. A member may serve more than one term and also may terminate their membership at any time by notifying the SAB Chairperson.
The SAB coordinates development of scientific publications, including advising on analyses and scientific questions of interest, providing feedback on publication goals and logistics, contributing to the publication plan, establishing criteria for review/approval of external requests for analyses and publications, reviewing publication drafts and counseling individuals who publish data collected from the aHUS Registry. Registry participants and nonparticipating physicians may request data access or specific analyses by submitting a concept sheet or contacting the SAB through the Registry website (when available) for evaluation.
The protocol was approved by the institutional review board at each participating center or by an independent ethics committee, where required, and was conducted in accordance with International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki. All patients provided written informed consent before study participation.
The forthcoming global aHUS Registry website will be programmed and maintained by a vendor specializing in the development of web-based electronic data collection systems. Investigators will have access to the secure website of the aHUS Registry for entering and accessing patient data online, which will then be stored at a secure and confidential location. Physicians will be able to access the aHUS Registry website at any time for the following purposes: entering and editing data, accessing important documents (frequently asked questions, reminders, etc.), responding to online queries, accessing posted news items, sending/responding to messages, posing questions and accessing standard reports, including enrollment statistics and site-specific patient data reports.
Written informed consent is provided by patients or their parents/guardians, as deemed applicable by institutional review boards and/or independent ethics committees. Clinicians were encouraged to enroll patients of all ages who have already received a clinical diagnosis of aHUS. Diagnosis of aHUS is not performed as part of the Registry protocol. Patients are not required to have an identified complement gene mutation or factor H autoantibody, nor are they required to have previous or ongoing treatment with eculizumab. Individuals with evidence of Shiga toxin-producing Escherichia coli infection or with ADAMTS13 activity ≤5 % (the level consistent with a diagnosis of thrombotic thrombocytopenic purpura) are excluded.
All necessary disease history information will be gathered from the patient’s medical records. During enrollment and every 6 months thereafter, the following data are collected as available: patient demographics, medical and disease history, symptomatology, appropriate laboratory results (including those from genetic tests), TMA complications, associated treatments and concomitant medications, clinical and patient-reported outcomes, safety of eculizumab and information regarding treatment or disease management. During each assessment period, physicians will note changes in a patient’s clinical status since the last assessment period. Symptoms and signs listed on the case report forms are renal (edema, hypertension, proteinuria), gastrointestinal (liver necrosis, hepatitis, pancreatitis, diabetes mellitus), cardiovascular (cardiac insufficiency/failure, vasculopathy/atherosclerosis, tachycardia), central nervous system (confusion, focal neurological deficit, ocular defects, headache) and pulmonary (hemorrhage, edema, shortness of breath). Clinicians have the option to list additional symptoms for these organ systems. Occurrences of multisystemic symptoms (i.e., symptoms/signs categorized under more than one organ system) also are recorded. Baseline values were defined as those collected at time of Registry enrollment or before the first dose of eculizumab (for patients who received eculizumab). Safety evaluations included adverse events and/or side effects associated with eculizumab treatment and other management strategies and measurement of human anti-human antibodies. Adverse events of interest included meningococcal and other serious infections, malignancy, renal impairment, hepatic impairment, sepsis and infusion reactions.
The data cutoff for this analysis was September 30, 2014. Patients with all of the following data were included in the current analysis of enrollment characteristics: 1) date of birth, gender, Registry enrollment date; 2) knowledge of treatment with eculizumab or no previous eculizumab treatment; and 3) for eculizumab-treated patients, date of first eculizumab dose. Patients were stratified by age at enrollment into the Registry.
Descriptive statistical analysis was performed to summarize demographics and clinical data. Proportions were calculated for categorical measures and summary statistics (n, mean, standard deviation and median) for continuous measures. All data analyses were performed in a validated statistical programming environment using SAS® statistical software version 9.2.