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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)

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ClinicalTrials.gov Identifier: NCT04434092
Recruitment Status : Active, not recruiting
First Posted : June 16, 2020
Last Update Posted : November 18, 2023
Sponsor:
Collaborator:
Chugai Pharmaceutical
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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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. This study will enroll approximately 200 participants.

Condition or disease Intervention/treatment Phase
Paroxysmal Nocturnal Hemoglobinuria Drug: Crovalimab Drug: Eculizumab Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 214 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : October 8, 2020
Actual Primary Completion Date : November 16, 2022
Estimated Study Completion Date : June 30, 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Eculizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (Crovalimab)
Adult Participants will receive an initial intravenous (IV) loading dose on Week 1 Day 1, followed by 4 weekly crovalimab subcutaneous (SC) doses on Week 1 Day 2, then on Weeks 2, 3 and 4. Maintenance dosing will begin at Week 5 and will continue Q4W (every 4 weeks) thereafter, for a total of at least 24 weeks of study treatment.
 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.
Active Comparator: Arm B (Eculizumab)
Adult Participants will receive initial IV weekly doses for 4 weeks which will be followed by Q2W (every 2 weeks) IV administrations starting on Week 5.
 Drug: Eculizumab
Eculizumab will be administered at a dose of 600 mg for the first 4 weeks, followed by maintenance doses of 900 mg starting on Week 5, as per the dosing schedule described above.
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.
 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.


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Mean Change in Fatigue [ Time Frame: Baseline up to Week 25 ]
    Assessed by the FACIT-Fatigue Questionnaire.

  4. 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.

  5. Percentage of Participants with Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (including meningococcal meningitis) [ Time Frame: Up to 7 years ]
  6. Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation [ Time Frame: Up to 7 years ]
  7. 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 ]
  8. Serum concentrations of crovalimab and eculizumab over time [ Time Frame: Up to 6.5 years ]
  9. Percentage of Participants with Anti-Crovalimab Antibodies [ Time Frame: Up to 6.5 years ]
  10. 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

  11. Change over time in free C5 concentration in crovalimab-treated participants [ Time Frame: Up to 6.5 years ]
  12. Observed Value in Reticulocyte Count (count/mL) [ Time Frame: Up to 6.5 years ]
  13. Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) [ Time Frame: Up to 6.5 years ]
  14. Change in Reticulocyte Count (count/mL) [ Time Frame: Baseline up to Week 25 ]
  15. Change in Free Hemoglobin and Haptoglobin (mg/dL) [ Time Frame: Baseline up to Week 25 ]

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, < 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04434092


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Chugai Pharmaceutical
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04434092    
Other Study ID Numbers: BO42162
2019-004931-21 ( EudraCT Number )
First Posted: June 16, 2020    Key Record Dates
Last Update Posted: November 18, 2023
Last Verified: November 2023
Individual Participant Data (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).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemoglobinuria
Hemoglobinuria, Paroxysmal
Proteinuria
Urination Disorders
Urologic Diseases
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Male Urogenital Diseases
Urological Manifestations
 Anemia, Hemolytic
Anemia
Hematologic Diseases
Myelodysplastic Syndromes
Bone Marrow Diseases
Eculizumab
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs