A Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors
- Conditions
- Paroxysmal Nocturnal Hemoglobinuria
- Interventions
- Registration Number
- NCT04434092
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 204
- Body weight ≥ 40 kg at screening (pediatric participants with body weight < 40 kg)
- 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, 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 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B (Eculizumab) Crovalimab Participants will receive loading dose of eculizumab 600 mg on Days 1, 8, 15, and 22, followed by maintenance dose of 900 mg on Day 29 and every 2 weeks (Q2W) thereafter until 24 weeks. Participants may switch to receive crovalimab after 24 weeks of eculizumab treatment. Arm B (Eculizumab) Eculizumab Participants will receive loading dose of eculizumab 600 mg on Days 1, 8, 15, and 22, followed by maintenance dose of 900 mg on Day 29 and every 2 weeks (Q2W) thereafter until 24 weeks. Participants may switch to receive crovalimab after 24 weeks of eculizumab treatment. Arm A (Crovalimab) Crovalimab Crovalimab will be administered at an initial loading dose of 1000 milligrams (mg) (for participants with body weight between 40 and 100 kilograms \[kg\]) or 1500 mg (for participants with body weight ≥ 100 kg), as intravenous (IV) injection on Day 1 of Week 1 followed by four weekly subcutaneous (SC) injections of 340 mg starting on Day 2 of Week 1 and then once weekly (QW) at Weeks 2,3 and 4. Thereafter crovalimab will be administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100 kg) or 1020 mg (for participants with body weight ≥ 100 kg) once every 4 weeks (Q4W) from Week 5 for a total of 24 weeks of study treatment. Participants may continue to receive crovalimab after 24 weeks of treatment up to maximum of 5 years. Arm C (Crovalimab) (Exploratory) Crovalimab Participants with a body weight ≥ 5 to \<12 kg will receive a loading series of crovalimab doses comprised of an IV dose on Day 1 of Week 1, followed by crovalimab SC dose on Day 2 Week 1. Maintenance doses will begin at Week 3 and will be administered Q2W, thereafter. Participants with a body weight ≥ 12 to \< 20 kg and ≥ 20 kg will receive a loading series of crovalimab doses comprised of an IV dose on Day 1 of Week 1, followed by weekly crovalimab SC doses for 4 weeks at Week 1 (Day 2) and then at Weeks 2, 3, and 4. Maintenance doses will begin at Week 5 and will be administered Q2W thereafter, for participants with a body weight ≥ 12 to \< 20 kg and Q4W thereafter, for participants with a body weight \> 20 kg. After 24 weeks of crovalimab treatment, participants who derive benefit from the drug may continue to receive crovalimab.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Hemolysis Control Week 5 through Week 25 Measured by lactate dehydrogenase (LDH) ≤ 1.5 x upper limit of normal (ULN) (as measured at the central laboratory).
Percentage of Participants Who Achieve Transfusion Avoidance (TA) Baseline through 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
Name Time Method 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.
Percentage of Participants With Adverse Events (AEs) Up to 6 years Determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.
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 years Serum Concentrations of Crovalimab and Eculizumab Over Time Up to 6 years Percentage of Participants With Anti-crovalimab Antibodies Up to 6 years Change in Pharmacodynamic (PD) Biomarkers Including Complement Activity (CH50) Over Time Up to 6 years Assessed by a Liposome Immunoassay (LIA) and total C5 concentration.
Change From Baseline in Reticulocyte Count (count/mL) Baseline up to Week 25 Percentage of Participants With AEs Leading to Study Drug Discontinuation Up to 6 years 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 \[hemoglobin \< 10 grams per deciliter (g/dL)\], 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.
Mean Change in Fatigue Baseline up to Week 25 Assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Questionnaire.
Percentage of Participants With Injection-site Reactions, Infusion-related Reactions, Hypersensitivity and Infections (Including Meningococcal Meningitis) Up to 6 years Change Over Time in Free C5 Concentration in Crovalimab-treated Participants Up to 6 years Observed Value in Reticulocyte Count (count/milliliters [mL]) Up to 6 years Observed Value in Free Hemoglobin and Haptoglobin (milligrams per deciliter [mg/dL]) Up to 6 years Change From Baseline in Free Hemoglobin and Haptoglobin (mg/dL) Baseline up to Week 25
Trial Locations
- Locations (61)
Organizacion Medica de Investigacion (OMI)
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Centro Integrado de Oncologia de Curitiba
🇧🇷Curitiba, Paraná, Brazil
*X*CEPHO - Centro de Estudos e Pesquisas em Hematologia e Oncologia
🇧🇷Santo Andre, São Paulo, Brazil
Beneficencia Portuguesa de Sao Paulo
🇧🇷São Paulo, Brazil
Peking Union Medical College Hospital
🇨🇳Beijing, China
Nanfang Hospital, Southern Medical University
🇨🇳Guangzhou, China
The First Affiliated Hospital, Zhejiang University
🇨🇳Hangzhou City, China
Jiangsu Province Hospital
🇨🇳Nanjing, China
Affiliated Hospital of Nantong University
🇨🇳Nantong City, China
Huashan Hospital, Fudan University
🇨🇳Shanghai, China
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