A Study Evaluating The Safety, Pharmacokinetics, and Efficacy Of Crovalimab Versus Eculizumab In Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Complement Inhibitors

Study Overview
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Brief Summary
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A study designed to evaluate the safety of crovalimab with eculizumab in participants with PNH currently treated with complement inhibitors. This study will enroll approximately 190 participants.

Official Title
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A Phase III, Randomized, Open-Label, Active-Controlled, Multicenter Study Evaluating The Safety, Pharmacokinetics, Pharmacodynamic And Efficacy of Crovalimab Versus Eculizumab In Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently 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. Treated with eculizumab or ravulizumab for PNH for at least 3 months prior to Day 1. Lactate Dehydrogenase Levels =< 2x the upper limit of normal (ULN) at screening. Willingness and ability to comply with all study visits and procedures. Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry. Vaccination against Neisseria meningitidis serotypes A, C, W, and Y < 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 (refrain from heterosexual intercourse) 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: History of allogeneic bone marrow transplantation. 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 was greater: participants enrolled in an eculizumab or ravulizumab interventional study are eligible provided they fulfill eligibility (e.g., are willing and able to comply with the study assessments) and stop their participation in current trial before randomisation/enrolment. Positive for Active Hepatitis B and C infection (HBV/HCV). 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. 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>Participants will receive a loading series of crovalimab comprised of an intravenous (IV) dose on Day 1, followed by weekly crovalimab subcutaneous (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 continue Q4W (every 4 weeks) thereafter for a total of 24 weeks of study treatment. 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>|
| Active Comparator: Arm B (Eculizumab)<br>Participants will receive an approved maintenance dose of eculizumab starting on Day 1 and Q2W (every 2 weeks) thereafter for a total of 24 weeks of study treatment. After 24 weeks of study eculizumab treatment, participants will have the option to switch to crovalimab or to discontinue from the study after completion of 10 weeks of safety follow-up. | Drug: Eculizumab<br>* Eculizumab will be administered at a dose of 900 mg every 2 weeks, as per the dosing schedule described above.<br>|
| Experimental: Arm C (Crovalimab) (Exploratory)<br>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 with Adverse Events (AEs) and by Severity | Determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5 (CTCAE v5). | Up to approximately 8 years | 
| Percentage of Participants with Injection- Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (including Meningococcal Meningitis) |  | Up to approximately 8 years | 
| Percentage of Participants with Adverse Events (AEs) Leading to Study Drug Discontinuation |  | Up to approximately 8 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 or Ravulizumab Treatment |  | Up to approximately 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentrations of Crovalimab or Eculizumab Over Time |  | Up to approximately 8 years | 
| Serum Concentrations of Ravulizumab at the time of Crovalimab Initiation |  | Baseline | 
| Percentage of Participants with Anti-Crovalimab Antibodies |  | Up to approximately 8 years | 
| Change in Pharmacodynamic (PD) Biomarker Complement Activity (CH50) Over Time |  | Up to approximately 8 years | 
| Change Over Time in Free C5 Concentration in Crovalimab-Treated Participants |  | Up to approximately 8 years | 
| Observed Value in Reticulocyte Count (count/mL) |  | Up to approximately 8 years | 
| Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) |  | Up to approximately 8 years | 
| Change in Reticulocyte Count (count/mL) |  | Baseline up to Week 25 | 
| Absolute Change in Free Hemoglobin and Haptoglobin (mg/dL) |  | Baseline up to Week 25 |