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 patients in the Naïve and Switch (switching from an existing complement inhibitor treatment to crovalimab) patients
•To evaluate the overall safety and tolerability of crovalimab
•To evaluate the pharmacokinetics of crovalimab
•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 |
For all Cohorts (all patients, in the Naïve, Switch and C5 SNP Cohorts, must meet the following criteria for study entry):
•Age >= 12 years
•Body weight >= 40 kg at screening
•Vaccination against Neisseria meningitidis < 3 years prior to initiation of study treatment, in accordance with current local guidelines or standard of care, as applicable in patients with complement deficiency
•For female patients of childbearing potential, an agreement to remain abstinent or use contraception
•Patients with a prior kidney transplant are eligible if they have known history of complement-mediated aHUS prior to the kidney transplant
For Naive Cohort ONLY:
•Evidence of thrombotic microangiopathy (TMA)
•Onset of TMA 28 days prior to first crovalimab administration
For Switch Cohort ONLY:
•Documented treatment with 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 C5 SNP Cohort only:
• Known C5 polymorphism (e.g., Arg885)
• Documented treatment with eculizumab or ravulizumab for aHUS, with poorly controlled TMA, per investigator's assessment |
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E.4 | Principal exclusion criteria |
For all Cohorts (all patients, in the Naïve, Switch and C5 SNP Cohorts, must meet the following criteria for study entry):
• Diagnosis of TTP, Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS), Pneumococcal HUS
• TMA secondary to cobalamin C defect
• TMA related to diacylglycerol kinase (DGKE) nephropathy
• TMA associated with non-aHUS related renal disease
• Positive direct Coombs test
• Identified drug exposure-related TMA
• History of organ transplant, other than kidney transplant
• Chronic dialysis, and/or end stage renal disease
• History of a kidney disease, other than aHUS, affecting renal function
• History of Neisseria meningitidis infection within 6 months prior to screening and up to the first drug administration
• Known systemic sclerosis, systemic lupus erythematosus, or anti-phospholipid antibody positivity or syndrome
• Patients receiving chronic IV immunoglobulin (IVIg) within 8 weeks prior to start of screening, unless for unrelated medical condition
• Female patients who are pregnant, breastfeeding, or have the intention of becoming pregnant during the study or within 6 months 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:
•Current or previous treatment with a complement inhibitor
•Received plasma exchange/plasma infusion for 28 days or longer prior to the start of screening for aHUS
For Switch Cohort and C5 SNP Cohort ONLY (additional exclusion criteria for Switch patients and for patients with a C5 polymorphism):
•Positive for hepatitis B surface antigen (HBsAg) at screening (does not apply to C5 SNP patients who received their last dose of eculizumab or ravulizumab more than 6 months ago)
•Positive for hepatitis C virus (HCV) antibody at screening (does not apply to C5 SNP patients who received their last dose of eculizumab or ravulizumab more than 6 months ago). Patients who are seropositive for HCV but without detectable HCV RNA are eligible
•History of or ongoing cryoglobulinemia at screening (does not apply to C5 SNP patients who received their last dose of eculizumab or ravulizumab more than 6 months ago) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Proportion of patients with complete TMA response (cTMAr) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From baseline to Week 25 |
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E.5.2 | Secondary end point(s) |
For BOTH Cohorts:
1. Dialysis requirement status (yes/no) change
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 stage
4. Observed value and change from baseline in hematologic parameters
5. In adults (>= 18 years), change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire
6. Incidence and severity of adverse events
7. Change in targeted vital signs and clinical laboratory test results
8. Incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, malignant hypertension, and infections
9. Incidence of adverse events leading to study drug discontinuation
10. Serum concentrations of crovalimab
11. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab
For Naive Cohort ONLY:
12. Proportion of patients with platelet count >= LLN
13. Proportion of patients with normalization of LDH
14. Proportion of patients with >= 25% decrease in serum creatinine from baseline
15. Time to cTMAr
16. Duration of cTMAr
17. Proportion of patients with cTMAr
For Switch Cohort ONLY:
18. Proportion of patients with maintained TMA control (mTMAc)
19. Incidence and severity of clinical manifestations of drug-target-drug complexes in patients who switched to crovalimab treatment from either eculizumab or ravulizumab treatment
20. Serum concentration of eculizumab or ravulizumab |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From baseline to Week 25
2-10. Up to 5 years
11. At baseline (prevalence) and up to 5 years (incidence)
12-14. At Week 25
15-16. Up to 5 years
17. At Week 25
18. Up to 5 years
19. From baseline to Week 10
20. Day 1 |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 |
Australia |
Brazil |
Canada |
China |
Israel |
Korea, Republic of |
Mexico |
Peru |
South Africa |
Turkey |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Luxembourg |
Poland |
Spain |
United Kingdom |
Czechia |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 9 |