A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition

Study Overview
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Brief Summary
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This study will enrol participants aged 12 years or older with a body weight >= 40 kilograms (kg) diagnosed with PNH who have not been previously treated with complement inhibitor therapy. Approximately 50 participants will be treated with Crovalimab for at least 24 weeks.

Official Title
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A Phase III, Multicenter, Single Arm Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: Crovalimab


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 Levels >= 2x the ULN at screening. Participants who have at least four transfusions during 12 months prior to screening (documented in the medical record). Presence of one or more of the following PNH-related signs or symptoms within 3 months of screening. Vaccination against Neisseria meningitidis serotypes A, C, W, and Y < 3 years prior to initiation of study treatment (Day 1) Vaccination against Haemophilius influenzae type B and Streptococcus pneumonia according to national vaccination recommendations. For participants receiving other therapies (e.g., immunosuppressants, corticosteroids): stable dose for >= 28 days prior to screening and up to the first drug administration. Adequate hepatic and renal function. Women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 46 weeks (approximately 10.5 months) after the final dose of crovalimab. Platelet count >=30,000 cubic millimeter (mm^3) at screening ANC > 500/μl at screening 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 drug administration. Known or suspected immune or hereditary complement deficiency. Known HIV infection with CD4 count < 200 cells per microlitre (cells/µl) within 24 weeks prior to screening. Infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 28 days prior to screening and up to the first drug administration, or oral antibiotics within 14 days prior to screening and up to the first drug administration. Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration. Presence of fever (>= 38˚C) within 7 days before the first drug administration. Splenectomy < 6 months before screening. History of malignancy within 5 years prior to screening and up to the first drug administration. Pregnant or intending to become pregnant during the study or within 46 weeks (10.5 months) after the final dose of study treatment. 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.

Ages Eligible for Study
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Minimum Age: 12 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percentage of Participants With Hemolysis Control | A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by lactate dehydrogenase (LDH) ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. The dependent variable was the binary indicator for hemolysis control. Independent variables are categorical effects of visits, continuous baseline LDH. | From Week 5 up to Week 25 | 
| Difference in Percentage of Participants With Transfusion Avoidance (TA) From Baseline Through Week 25 and Within 24 Weeks Prior to Screening | TA was defined as participants who were packed red blood cell (pRBC) transfusion-free and did not require transfusion per protocol-specified guidelines. TA within 24 weeks prior to screening was based on the pRBC transfusion history in the medical records. Reported in this outcome measure is the difference in the percentage of participants between baseline through Week 25 and within 24 weeks prior to screening. 95% Confidence Interval (CI) for the difference between the percentage of participants with transfusion avoidance between Pre-screening and Post-baseline is calculated using the Newcombe method. Screening= Day -28 to Day -1 and Baseline= Day 1. | 24 Weeks Prior to Screening, Baseline to Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Breakthrough Hemolysis (BTH) | BTH was 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 grams per deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2xULN after a prior LDH reduction to ≤1.5xULN from the start of study treatment. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to have experienced a BTH event. Percentages have been rounded off to the first decimal point. | Baseline, Week 25 | 
| Percentage of Participants With Stabilized Hemoglobin | Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to not have hemoglobin stabilization. | Baseline, Week 25 | 
| Change From Baseline in Fatigue in Adults Aged >=18 Years | Fatigue was assessed using functional assessment of chronic illness therapy-fatigue (FACIT-F) scale. FACIT-F is a self-assessment questionnaire with a 7-day recall period and 13 items evaluating fatigue and its impact on daily life activities. Items are scored on a response scale that ranges from 0 (not at all) to 4 (very much so). Relevant items are reverse scored, and all the items are summed to create a total score range from 0 to 52, with 0 being the worst possible score and 52 being the best possible score. A higher score indicates low fatigue severity. A positive mean change indicates improvement. FACIT-F was assessed in adult participants only. FACIT-F assessment was unintentionally missed in the Schedule of Activities (SoA) table, which site used to guide the assessments at each timepoint. Therefore, data were not collected at Week 25. | Baseline, Week 2, Week 5, Week 9, Week 17, Week 25 | 
| Percentage of Participants With Adverse Events (AEs) |  | 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 | 
| Trough Serum Concentration of Crovalimab Over Time |  | Up to 7 years | 
| Serum Concentrations of Crovalimab |  | Up to 7 years | 
| Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab |  | Up to 7 years | 
| Terminal Complement Activity as Measured by Liposome Immunoassay (LIA) |  | Up to 7 years | 
| Change Over Time in Total and Free C5 Concentration |  | Up to 7 years | 
| Observed Value in Absolute Reticulocyte Count |  | Up to 7 years | 
| Observed Value in Free Hemoglobin |  | Up to 7 years | 
| Observed Value in Haptoglobin |  | Up to 7 years | 
| Percent Change From Baseline in Absolute Reticulocyte Count |  | Baseline, Week 25 | 
| Percent Change From Baseline in Free Hemoglobin |  | Baseline, Week 25 | 
| Percent Change From Baseline in Haptoglobin |  | Baseline, Week 25 |