A Study Evaluating The Safety, Pharmacokinetics, and Efficacy Of Crovalimab Versus Eculizumab In Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Complement Inhibitors (COMMODORE 1)

• ClinicalTrials.gov Identifier: NCT04432584
• Recruitment Status: Recruiting
• First Posted: June 16, 2020
• Last Update Posted: May 10, 2024
• Sponsor: Hoffmann-La Roche
• Collaborator: Chugai Pharmaceutical
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: June 3, 2020
• First Posted Date: June 16, 2020
• Last Update Posted Date: May 10, 2024
• Actual Study Start Date: September 30, 2020
• Estimated Primary Completion Date: September 1, 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 23, 2022)

• Percentage of Participants with Adverse Events (AEs) and by Severity [ Time Frame: Up to approximately 8 years ]
  Determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5 (CTCAE v5).
• Percentage of Participants with Injection- Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (including Meningococcal Meningitis) [ Time Frame: Up to approximately 8 years ]
• Percentage of Participants with Adverse Events (AEs) Leading to Study Drug Discontinuation [ Time Frame: 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 [ Time Frame: Up to approximately 8 years ]

• Original Primary Outcome Measures (submitted: June 12, 2020): Mean Percentage Change in Lactate Dehydrogenase (LDH) levels [ Time Frame: Baseline up to Week 25 ]

Current Secondary Outcome Measures (submitted: November 23, 2022)

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

Original Secondary Outcome Measures (submitted: June 12, 2020)

• Percentage of Participants who achieve Transfusion Avoidance (TA) [ Time Frame: Baseline through Week 25 ]
  TA is defined as participants who are packed RBC transfusion-free and do not require transfusion per protocol-specified guidelines.
• Percentage of Participants with Breakthrough Hemolysis (BTH) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline up to Week 25 ]
  Assessed by the FACIT-Fatigue Questionnaire (for adults aged >= 18 years).
• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to 2.5 years ]
  Determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5 (CTCAE v5).
• Percentage of Participants with Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (including meningococcal meningitis) [ Time Frame: Up to 2.5 years ]
• Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation [ Time Frame: Up to 2.5 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 [ Time Frame: Up to 2.5 years ]
• Serum Concentrations of Crovalimab or Eculizumab over time [ Time Frame: Up to 2.5 years ]
• Serum Concentrations of Ravulizumab at the time of Crovalimab Initiation [ Time Frame: Baseline ]
• Percentage of Participants with Anti-Crovalimab Antibodies [ Time Frame: Up to 2.5 years ]
• Change in PD biomarkers including complement activity over time [ Time Frame: Up to 2.5 years ]
  Assessed by a Liposome Immunoassay (LIA) and total C5 concentration
• Change over time in free C5 concentration in crovalimab-treated participants [ Time Frame: Up to 2.5 years ]
• Observed Value in Reticulocyte Count (count/mL) [ Time Frame: Up to 2.5 years ]
• Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) [ Time Frame: Up to 2.5 years ]
• Change in Reticulocyte Count (count/mL) [ Time Frame: Baseline up to Week 25 ]
• Change in Free Hemoglobin and Haptoglobin (mg/dL) [ Time Frame: Baseline up to Week 25 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating The Safety, Pharmacokinetics, and Efficacy Of Crovalimab Versus Eculizumab In Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Complement Inhibitors
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Paroxysmal Nocturnal Hemoglobinuria

Intervention

• 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.
• Drug: Eculizumab
  Eculizumab will be administered at a dose of 900 mg every 2 weeks, as per the dosing schedule described above.

Study Arms

• Experimental: Arm A (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.
  Intervention: Drug: Crovalimab
• Active Comparator: Arm B (Eculizumab)
  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.
  Intervention: Drug: Eculizumab
• Experimental: Arm C (Crovalimab) (Exploratory)
  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.
  Intervention: Drug: Crovalimab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 23, 2022): 190
• Original Estimated Enrollment (submitted: June 12, 2020): 250
• Estimated Study Completion Date: September 1, 2029
• Estimated Primary Completion Date: September 1, 2029 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: BO42161 https://forpatients.roche.com/; 888-662-6728 (U.S. and Canada); global-roche-genentech-trials@gene.com

• Listed Location Countries: Australia, Belgium, Brazil, Canada, Colombia, Czechia, Estonia, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Saudi Arabia, Singapore, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Israel, Mexico, Slovakia

Administrative Information

• NCT Number: NCT04432584
• Other Study ID Numbers: BO42161; 2020-000597-26 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Chugai Pharmaceutical

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: May 2024