A Phase III Study Evaluating The Efficacy And Safety Of Crovalimab Versus Eculizumab In Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors.

Study Overview
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Brief Summary
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A study designed to evaluate the non-inferiority of crovalimab compared with eculizumab in participants with PNH who have not been previously treated with complement inhibitor therapy. This study will enroll approximately 200 participants.

Official Title
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A Phase III, Randomized, Open-Label, Active-Controlled, Multicenter Study Evaluating The Efficacy And Safety Of Crovalimab Versus Eculizumab In Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors.

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: Crovalimab
* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight >= 40 kg at screening. Willingness and ability to comply with all study visits and procedures. Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry. LDH level >= 2x ULN at screening (as per local assessment). Vaccination against Neisseria meningitidis serotypes A, C, W, < 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. Women of childbearing potential: agreement to remain abstinent or use contraception during the treatment period and for 10.5 months after the final dose of crovalimab or for 3 months after the final dose of eculizumab (or longer if required by the local product label). Exclusion Criteria: Current or previous treatment with a complement inhibitor. History of allogeneic bone marrow transplantation. History of 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, within 10.5 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). Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within 28 days of screening or within 5 half-lives of that investigational product, whichever is greater. 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 participant, or would, in the opinion of the Investigator, preclude the participant's safe participation in and completion of the study. Splenectomy < 6 months before screening. Positive for Active Hepatitis B and C infection (HBV/HCV). History of or ongoing cryoglobulinemia at screening.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Crovalimab)<br>Adult Participants will receive an initial intravenous (IV) loading dose on Week 1 Day 1, followed by 4 weekly crovalimab subcutaneous (SC) doses on Week 1 Day 2, then on Weeks 2, 3 and 4. Maintenance dosing will begin at Week 5 and will continue Q4W (every 4 weeks) thereafter, for a total of at least 24 weeks of study treatment. | Drug: Crovalimab<br>* Crovalimab will be administered at a dose of 1000 mg IV (for participants with body weight between 40 and 100kg) or 1500 mg IV (for participants with body weight >=100kg) on Week 1 Day 1. On Week 1 Day 2 and on Weeks 2, 3 and 4, it will be administered at a dose of 340 mg SC. For Week 5 and Q4W thereafter, it will be administered at a dose of 680 mg SC (for participants with body weight between 40 and 100kg) or 1020 mg SC (for participants with body weight >=100kg). Dosing schedule will be as described above.<br>|
| Active Comparator: Arm B (Eculizumab)<br>Adult Participants will receive initial IV weekly doses for 4 weeks which will be followed by Q2W (every 2 weeks) IV administrations starting on Week 5. | Drug: Eculizumab<br>* Eculizumab will be administered at a dose of 600 mg for the first 4 weeks, followed by maintenance doses of 900 mg starting on Week 5, as per the dosing schedule described above.<br>|
| Experimental: Arm C (Crovalimab) (Exploratory)<br>Paediatric participants will receive a loading series of Crovalimab comprised of an IV dose on Week 1 Day 1, followed by weekly crovalimab SC doses for 4 weeks on Week 1 (Day 2) then on Weeks 2, 3, and 4. Maintenance SC dosing will begin at Week 5 and will be administered Q4W thereafter. After 24 weeks of crovalimab treatment, participants who derive benefit from the drug may continue to receive crovalimab. | Drug: Crovalimab<br>* Crovalimab will be administered at a dose of 1000 mg IV (for participants with body weight between 40 and 100kg) or 1500 mg IV (for participants with body weight >=100kg) on Week 1 Day 1. On Week 1 Day 2 and on Weeks 2, 3 and 4, it will be administered at a dose of 340 mg SC. For Week 5 and Q4W thereafter, it will be administered at a dose of 680 mg SC (for participants with body weight between 40 and 100kg) or 1020 mg SC (for participants with body weight >=100kg). Dosing schedule will be as described above.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who achieve Transfusion Avoidance (TA) | TA is defined as patients who are packed Red Blood Cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines. | Baseline through Week 25 | 
| Percentage of Participants with hemolysis control | Measured by LDH =< 1.5 x ULN (as measured at the central laboratory). | Week 5 through Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Breakthrough Hemolysis (BTH) | BTH is defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 g/dL], a major adverse vascular event [MAVE; including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH >= 2 x ULN after prior reduction of LDH to =<1.5 x ULN on treatment. | Baseline through Week 25 | 
| Percentage of Participants with Stabilization of Hemoglobin | Stabilized hemoglobin is defined as avoidance of a >= 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. | Baseline through Week 25 | 
| Mean Change in Fatigue | Assessed by the FACIT-Fatigue Questionnaire. | Baseline up to Week 25 | 
| Percentage of Participants with Adverse Events (AEs) | Determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5. | Up to 7 years | 
| Percentage of Participants with Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (including meningococcal meningitis) |  | Up to 7 years | 
| Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation |  | Up to 7 years | 
| Percentage of Participants with clinical manifestations of Drug-Target-Drug Complex (DTDC) formation amongst those participants who switched to crovalimab treatment from eculizumab treatment |  | Up to 6.5 years | 
| Serum concentrations of crovalimab and eculizumab over time |  | Up to 6.5 years | 
| Percentage of Participants with Anti-Crovalimab Antibodies |  | Up to 6.5 years | 
| Change in PD biomarkers including complement activity (CH50) over time | Assessed by a Liposome Immunoassay (LIA) and total C5 concentration | Up to 6.5 years | 
| Change over time in free C5 concentration in crovalimab-treated participants |  | Up to 6.5 years | 
| Observed Value in Reticulocyte Count (count/mL) |  | Up to 6.5 years | 
| Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) |  | Up to 6.5 years | 
| Change in Reticulocyte Count (count/mL) |  | Baseline up to Week 25 | 
| Change in Free Hemoglobin and Haptoglobin (mg/dL) |  | Baseline up to Week 25 |