COMMODORE 3: 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 Details
Study Description
Brief Summary
This study will enrol participants aged 12 years or older with a body weight >= 40 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Crovalimab 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
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.
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Outcome Measures
Primary Outcome Measures
- Mean Percentage of Participants with Hemolysis Control [Week 5 through Week 25]
Measured by LDH =< 1.5 x ULN (as measured at the central laboratory).
- Change from Baseline to Week 25 in Percentage of Participants who achieve Transfusion Avoidance (TA) [Baseline, Week 25]
TA is defined as participants who are packed Red Blood Cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines.
Secondary Outcome Measures
- Percentage of Participants with Breakthrough Hemolysis (BTH) [Baseline through Week 25]
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.
- Percentage of Participants with Stabilization of Hemoglobin [Baseline through Week 25]
Stabilized hemoglobin is defined as avoidance of a >= 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion.
- Mean Change in Fatigue [Baseline up to Week 25]
Assessed by the FACIT-Fatigue Questionnaire (for adults aged >= 18 years).
- Percentage of Participants with Adverse Events (AEs) [Up to 2 years]
Determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.
- Percentage of Participants with Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (including meningococcal meningitis) [Up to 2 years]
- Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation [Up to 2 years]
- Trough Serum Concentration of Crovalimab over time [Up to 2 years]
- Serum Concentrations of Crovalimab at specified timepoints [Up to 2 years]
- Percentage of Participants with Anti-Crovalimab Antibodies [Up to 2 years]
- Change over time in PD biomarkers including complement activity [Up to 2 years]
Assessed by a Liposome Immunoassay (LIA)
- Change over time in total and free C5 concentration [Up to 2 years]
- Observed Value in Reticulocyte Count (count/mL) [Up to 2 years]
- Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) [Up to 2 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Body weight >= 40 kg at screening.
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Willingness and ability to comply with all study visits and procedures.
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Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry.
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Lactate Dehydrogenase Levels >= 2x the upper limit of normal (ULN) at screening.
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Participants who have at least four transfusions during 12 months prior to screening (documented in the medical record).
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Presence of one or more of the following PNH-related signs or symptoms within 3 months of screening.
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Vaccination against Neisseria meningitidis < 3 years prior to initiation of study treatment or within 7 days after the first drug administration.
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Vaccination against Haemophilius influenzae type B and Streptococcus pneumonia according to national vaccination recommendations.
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For participants receiving other therapies (e.g., immunosuppressants, corticosteroids): stable dose for >= 28 days prior to screening and up to the first drug administration.
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Adequate hepatic and renal function.
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Women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 6 months after the final dose of crovalimab.
Exclusion Criteria:
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Current or previous treatment with a complement inhibitor.
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History of allogeneic bone marrow transplantation.
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History of Neisseria meningitidis infection within 6 months prior to screening and up to first drug administration.
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Known or suspected immune or hereditary complement deficiency.
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Known HIV infection with CD4 count < 200 cells/µl within 24 weeks prior to screening.
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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.
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Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration.
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Presence of fever (>= 38˚C) within 7 days before the first drug administration.
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Splenectomy < 6 months before screening.
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History of malignancy within 5 years prior to screening and up to the first drug administration.
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Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the final dose of study treatment.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The First Hospital of Jilin University | Changchun City | China | 130021 | |
| 2 | West China Hospital, Sichuan University | Chengdu | China | 610041 | |
| 3 | Guangdong General Hospital | Guangzhou | China | 510080 | |
| 4 | Institute of Hematology and Hospital of Blood Disease | Tianjin City | China | 300020 | |
| 5 | Tianjin Medical University General Hospital | Tianjin | China | 300052 | |
| 6 | Union Hospital Tongji Medical College Huazhong University of Science and Technology | Wuhan City | China | 430023 |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- YO42311