E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) |
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E.1.1.1 | Medical condition in easily understood language |
PNH is a rare acquired disorder that lead to destruction of red blood cells, blood clots, and impaired bone marrow function. |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034042 |
E.1.2 | Term | Paroxysmal nocturnal haemoglobinuria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 efficacy of crovalimab compared to eculizumab |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of crovalimab compared with eculizumab based on the non-inferiority assessment • To evaluate the safety and tolerability of crovalimab compared to eculizumab • To characterize the crovalimab, eculizumab, and ravulizumab pharmacokinetics profile • To evaluate the immune response to crovalimab • To identify and/or evaluate biomarkers that can potentially provide evidence of crovalimab, eculizumab, and ravulizumab activity
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General Inclusion Criteria (All Patients) - Body weight >= 40 kg - Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry evaluation of WBCs, - Vaccination against Neisseria meningitidis < 3 years prior to initiation of study treatment, or, if not previously done, vaccination administered no later than one week after the first drug administration. Vaccination currency should be maintained throughout the study in accordance with most current local guidelines or standard-of-care as applicable in patients with complement deficiency - Platelet count >= 30,000/mm*3 at screening without transfusion support within 7 days of lab testing. - ANC > 500/micro L at screening - For women of childbearing potential: agreement to remain abstinent or use contraception For Patients in Randomized Arms (Arm A and B) - Age >= 18 years - Documented treatment with eculizumab according to the approved dosing recommended for PNH and completion of a minimum of 24 weeks of treatment prior to Day 1 - Lactate dehydrogenase (LDH) <= 1.5 × ULN at screening For Patients in Descriptive Arm (Arm C) - Age <18 old, currently treated with eculizumab OR - Currently treated with ravulizumab OR - Currently treated with eculizumab at higher-than-approved doses OR - Patients with known C5 polymorphism and poorly controlled hemolysis by eculizumab or ravulizumab
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E.4 | Principal exclusion criteria |
- Major Adverse Vascular Event within 6 months prior to first drug administration (Day 1) - History of allogeneic bone marrow transplantation, - Neisseria meningitidis infection within 6 months prior to screening and up to first study drug administration - History of myelodysplastic syndrome with Revised International Prognostic Scoring System (IPSS-R) prognostic risk categories of intermediate, high and very high - Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the final dose of crovalimab, or 3 months after the final dose of eculizumab (or longer if required by the local product label) - 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 - Splenectomy <= 6 months prior to screening - Positive for hepatitis B surface antigen at screening - Positive for hepatitis C virus antibody at screening confirmed by detectable HCV RNA - History of or ongoing cryoglobulinemia at screening
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change from baseline in LDH level averaged over Weeks 21, 23, and 25 LDH measurements |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Baseline to Weeks 21, 23, 25 |
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E.5.2 | Secondary end point(s) |
1. Proportion of patients with transfusion avoidance 2. Proportion of patients with breakthrough hemolysis 3. Proportion of patients with stabilization of hemoglobin 4. Mean change in fatigue as assessed through use of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale 5. Incidence and severity of adverse events 6. Change from baseline in targeted vital signs 7. Change from baseline in targeted clinical laboratory test results 8. Incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, and infections 9. Incidence of adverse events leading to study drug discontinuation 10. Incidence and severity of clinical manifestations of drug-target-drug complex formation in patients who switched to crovalimab treatment from eculizumab or ravulizumab treatment 11. Serum concentration of crovalimab or eculizumab 12. Serum concentration of ravulizumab 13. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab 14. Change over time in pharmacodynamic biomarkers 15. Change over time in free C5 concentration in crovalimab-treated patients 16. Observed value and absolute change in parameters reflecting hemolysis
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. From Baseline to Week 25 5. Up to 7.5 years 6-7. From baseline to 7.5 years 8-9. Up to 7.5 years 10. From baseline to 7.5 years 11. Up to 7.5 years (crovalimab) and up to Week 25 (eculizumab) 12. At baseline 13. At baseline (prevalence) and up to 7.5 years (incidence) 14-16 Up to 7.5 years
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Evaluation of the immune response to Crovalimab. Identification and evaluation of biomarkers that can potentially provide evidence of crovalimab, eculizumab and ravulizumab activity. |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Colombia |
Hong Kong |
Mexico |
Philippines |
Singapore |
Thailand |
Turkey |
Estonia |
Austria |
Belgium |
Brazil |
Canada |
Czechia |
Germany |
Greece |
Hungary |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Portugal |
Romania |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
France |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 remaining patient has completed the last visit (LPLV) as defined by any of the criteria outlined in section 3.2.1. of the protocol- For patients randomized or enrolled to crovalimab; For patients randomized to eculizumab; Discontinuation prior to completion of last treatment; Withdrawal of consent; Loss to follow-up. |
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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 | 6 |