E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atypical Hemolytic Uremic Syndrome (aHUS) |
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E.1.1.1 | Medical condition in easily understood language |
aHUS is a rare disease, characterized by damage to the lining of small blood vessels, leading to red blood cell destruction, blood clots, and kidney damage. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079841 |
E.1.2 | Term | Atypical hemolytic uremic syndrome |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the effect of crovalimab in complement inhibitor treatment-naive (Naive) patients |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of crovalimab in Naive and Switch (switching from either eculizumab or ravulizumab treatment to crovalimab) patients • To evaluate the overall safety and tolerability of crovalimab • To evaluate the pharmacokinetics of crovalimab as well as confirm the dosing strategy for patients weighing < 40 kilograms (kg) • To evaluate the immune response to crovalimab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In addition to Naive and Switch patients (described above), Pretreated patients (patients who previously received treatment and then discontinued either eculizumab or ravulizumab and/or with a known C5 single nucleotide polymorphism [SNP]) will be enrolled as a separate third Cohort. For ALL (Naive, Switch, and Pretreated) Cohorts: • Age >=28 days and <18 years (at the time of signing the Informed Consent Form or Assent Form) • Body weight >=5 kg at screening • Vaccination against Neisseria meningitidis serotypes A, C, W, and Y < 3 years prior to initiation of crovalimab treatment. Vaccination against serotype B should be administered in accordance with current local guidelines or standard-of-care, as applicable for patients with complement deficiency • For female patients of childbearing potential, an agreement to remain abstinent or use contraception, and must have a negative serum pregnancy test result within 7 days prior to initiation of crovalimab • Patients with a prior kidney transplant are eligible, if they have a known history of complement-mediated aHUS prior to the kidney transplant
For Naive Cohort ONLY: • Onset of initial TMA presentation, as defined by a patient with all of the following laboratory findings, within 28 days prior to the first dose of crovalimab: – Platelet count < LLN, and – LDH >= 1.5 x ULN, and – Hemoglobin <= LLN (adjusted for age and sex), and – Serum creatinine >= 97.5th percentile for age. Patients who require dialysis for acute kidney injury are also eligible.
NOTE: If the patient has been receiving plasma exchange/plasma infusion (PE/PI), the patient’s eligibility must be ascertained based on the above qualifying laboratory findings, obtained at onset of initial TMA presentation (prior to receiving any PE/PI) and must be within 28 days of the first crovalimab dose. The qualifying laboratory findings, even if obtained prior to screening, can be used as screening values to enroll the patient, but only if documented in the medical records.
For Switch Cohort ONLY: • Documented treatment with either eculizumab or ravulizumab, according to the local product label for aHUS. Eculizumab treatment received for at least 90 days. Patients switching from IV ravulizumab must have received at least two maintenance doses. • Clinical evidence of response to either eculizumab or ravulizumab
For Pretreated Cohort only: • Onset of TMA recurrence <=28 days prior to first crovalimab administration • Received and subsequently discontinued treatment with either eculizumab or ravulizumab, for a minimum of 5.5 drug half-lives • For C5 SNP patients: Known C5 polymorphism AND documented treatment with either eculizumab or ravulizumab for aHUS, with poorly controlled TMA
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E.4 | Principal exclusion criteria |
For ALL (Naive, Switch, and Pretreated) Cohorts: • Diagnosis of thrombotic thrombocytopenic purpura (TTP), Shiga toxin–producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), clinical suspicion of pneumococcal HUS,. • TMA secondary to cobalamin C defect • TMA related to diacylglycerol kinase-E (DGKE) nephropathy • TMA associated with non-aHUS related renal disease • Positive direct Coombs test • Identified drug exposure-related TMA • History of bone marrow transplant or organ transplant, other than kidney transplant • Chronic dialysis, within 90 days prior to first crovalimab administration, and/or end stage renal disease (ESRD) • History of a kidney disease other than aHUS, affecting renal function • History of Neisseria meningitidis infection within 6 months of study renrollment • Known or suspected immune deficiency (e.g., history of frequent recurrent infections) • Positive human immunodeficiency virus (HIV) test • Life expectancy of < 4 weeks • Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration • Presence of fever (>=38 Degrees Celsius) within 7 days before the first drug administration • Patient with active or evolving multisystem organ dysfunction or failure • Immunized with a live attenuated vaccine within 1 month before first drug administration • Known systemic sclerosis (scleroderma), systemic lupus erythematosus (SLE), or anti-phospholipid antibody positivity or syndrome • Patients receiving chronic intravenous immunoglobulin (IVIg) within 8 weeks prior to start of screening, unless for unrelated medical condition • Female patients who are pregnant, are breastfeeding, or have the intention of becoming pregnant during the study or within 46 weeks after the final dose of the study treatment • Splenectomy < 6 months prior to screening • Use of tranexamic acid within 7 days prior to screening • Concurrent disease, treatment, procedure or surgery, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose any additional risk for the patient, or would, in the opinion of the investigator, preclude the patient's safe participation in and completion of the study For Naive Cohort ONLY: • First initiation of PE/PI more than 28 days prior to first crovalimab administration • Last PE/PI completed less than 2 hours prior to first crovalimab administration • Current or previous treatment with a complement inhibitor For Switch Cohort and Switching C5 SNP patients ONLY: • Receiving PE/PI within 8 weeks of the first crovalimab administration (Switch Cohort ONLY) • Positive for hepatitis B surface antigen (HBsAg) at screening • Positive for hepatitis C virus (HCV) antibody at screening • History of or ongoing cryoglobulinemia at screening
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Proportion of patients with cTMAr |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
For Naive and Switch Cohorts: 1. Change from baseline to Week 25 in dialysis requirement status 2. Observed value and change from baseline in estimated glomerular filtration rate (eGFR) 3. Proportion of patients with change from baseline in chronic kidney disease (CKD) stage classified as improved, stable (no change), or worsened based on the National Kidney Foundation Chronic Kidney Disease Stage 4. Observed value and change from baseline in hematologic parameters 5. Incidence and severity of adverse events 6. Change in targeted vital signs and clinical laboratory test results 7. Incidence and severity of injection site reactions, infusion related reactions, hypersensitivity, malignant hypertension, and infections 8. Incidence of adverse events leading to study drug discontinuation 9. Serum concentration of crovalimab 10. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab 11. Change from baseline in fatigue as measured by the Pediatric Quality of Life Inventory (PedsQLTM) Multidimensional Fatigue Scale (MFS) and physical functioning as measured by the PedsQL Core in pediatric patients aged 2 to < 18 years old 12. Change from baseline in physical functioning and physical symptoms as measured by the PedsQL Infant Scale in pediatric patients under 2 years old 13. Change from baseline in the number of missed days of daycare or school 14. For patients who discontinue crovalimab, describe the clinical course of patients who discontinue crovalimab after achieving cTMAr For Naive and Pretreated Cohorts: 15. Proportion of patients with platelet count >= LLN 16. Proportion of patients with normalization of LDH 17. Proportion of patients with >=25% decrease in serum creatinine from baseline 18. Time to complete TMA response (cTMAr) 19. Duration of cTMAr, among patients who achieved cTMAr 20. Proportion of patients with cTMAr 21. Proportion of patients with increase in hemoglobin >=20 g/L, in the absence of a transfusion For Switch Cohort ONLY: 22. Proportion of patients with maintained TMA control (mTMAc) from baseline through Week 25 23. Incidence and severity of clinical manifestations of drug-target-drug complexes (DTDCs) in patients who switched to crovalimab treatment from either eculizumab or ravulizumab treatment 24. Serum concentration of eculizumab or ravulizumab 25. In adolescents (12 - 17 years), proportion of patients with preference for crovalimab, after switching from eculizumab or ravulizumab, as assessed by a Patient Preference Questionnaire (PPQ) developed by the Sponsor 26. In children younger than 12 years old, proportion of caregivers with preference for crovalimab, after switching from eculizumab or ravulizumab, as assessed by the caregiver-reported version of the PPQ developed by the Sponsor
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 to 4. Baseline to Week 25 2-5-9. Up to 8 years 10. At baseline (prevalence) and up to 8 years (incidence) 11-12. Up to 8 years 13. Baseline to Week 25 14. Up to 8 years 15-17. At Week 25 18-19. Up to 8 years 20-22. At Week 25 23. From baseline to Week 10 24. Day 1 25-26. At Week 17
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Brazil |
Canada |
China |
France |
Hungary |
Israel |
Italy |
Japan |
Poland |
South Africa |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of this study is defined as the date when the last patient’s last visit occurs or the date at which the last data point required for the final statistical analysis is collected, whichever occurs last. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 8 |