A Phase III Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors. (COMMODORE 2)

• ClinicalTrials.gov Identifier: NCT04434092
• Recruitment Status: Active, not recruiting
• First Posted: June 16, 2020
• Last Update Posted: May 16, 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 16, 2024
• Actual Study Start Date: October 8, 2020
• Actual Primary Completion Date: November 16, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 18, 2020)

• Percentage of Participants who achieve Transfusion Avoidance (TA) [ Time Frame: Baseline through Week 25 ]
  TA is defined as patients who are packed Red Blood Cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines.
• Percentage of Participants with hemolysis control [ Time Frame: Week 5 through Week 25 ]
  Measured by LDH =< 1.5 x ULN (as measured at the central laboratory).

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

• Percentage of Participants who achieve Transfusion Avoidance (TA) [ Time Frame: Baseline through Week 25 ]
  TA is defined as patients who are packed PBC (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines.
• Percentage of Participants with hemolysis control [ Time Frame: Week 5 through Week 25 ]
  Measured by LDH =< 1.5 x ULN (as measured at the central laboratory).

Current Secondary Outcome Measures (submitted: November 8, 2022)

• 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.
• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to 7 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) [ Time Frame: Up to 7 years ]
• Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation [ Time Frame: Up to 7 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 [ Time Frame: Up to 6.5 years ]
• Serum concentrations of crovalimab and eculizumab over time [ Time Frame: Up to 6.5 years ]
• Percentage of Participants with Anti-Crovalimab Antibodies [ Time Frame: Up to 6.5 years ]
• Change in PD biomarkers including complement activity (CH50) over time [ Time Frame: Up to 6.5 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 6.5 years ]
• Observed Value in Reticulocyte Count (count/mL) [ Time Frame: Up to 6.5 years ]
• Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) [ Time Frame: Up to 6.5 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 ]

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

• 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.
• 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 [ Time Frame: Up to 2.5 years ]
• Serum concentrations of crovalimab and eculizumab over time [ Time Frame: Up to 2.5 years ]
• 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 Phase III Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors.
• Official Title: A Phase III, Randomized, Open-Label, Active-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors.
• 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 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 as specified in the respective arms.
• Drug: Eculizumab
  Eculizumab will be administered as specified in the respective arm.

Study Arms

• Experimental: Arm A (Crovalimab)
  Crovalimab will be administered at an initial loading dose of 1000 milligrams (mg) (for participants with body weight between 40 and 100 kg) or 1500 mg (for participants with body weight >=100kg), 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 100kg) or 1020 mg (for participants with body weight >=100kg) 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.
  Intervention: Drug: Crovalimab
• Active Comparator: Arm B (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.
  Interventions:

  • Drug: Crovalimab
  • Drug: Eculizumab
• Experimental: Arm C (Crovalimab) (Exploratory)
  Paediatric 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: Active, not recruiting
• Actual Enrollment (submitted: February 19, 2024): 204
• Original Estimated Enrollment (submitted: June 12, 2020): 200
• Estimated Study Completion Date: June 30, 2028
• Actual Primary Completion Date: November 16, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 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).

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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, China, France, Germany, Greece, Hong Kong, Japan, Korea, Republic of, Lithuania, Malaysia, Mexico, Netherlands, Philippines, Poland, Portugal, Romania, Singapore, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom
• Removed Location Countries: Belgium, Canada, Chile, Colombia, Czechia, Estonia, Hungary, Ireland, Israel, Italy, Peru, Saudi Arabia, United States

Administrative Information

• NCT Number: NCT04434092
• Other Study ID Numbers: BO42162; 2019-004931-21 ( EudraCT Number ); 2023-506498-36-00 ( Registry Identifier: EU Clinical Trial Number )
• Has Data Monitoring Committee: Yes

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