A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition (COMMODORE 3)

• ClinicalTrials.gov Identifier: NCT04654468
• Recruitment Status: Active, not recruiting
• First Posted: December 4, 2020
• Results First Posted: June 5, 2023
• Last Update Posted: March 5, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: November 30, 2020
• First Posted Date: December 4, 2020
• Results First Submitted Date: February 6, 2023
• Results First Posted Date: June 5, 2023
• Last Update Posted Date: March 5, 2024
• Actual Study Start Date: March 17, 2021
• Actual Primary Completion Date: February 10, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2023)

• Mean Percentage of Participants With Hemolysis Control [ Time Frame: From Week 5 up to Week 25 ]
  A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by lactate dehydrogenase (LDH) ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. The dependent variable was the binary indicator for hemolysis control. Independent variables are categorical effects of visits, continuous baseline LDH.
• Difference in Percentage of Participants With Transfusion Avoidance (TA) From Baseline Through Week 25 and Within 24 Weeks Prior to Screening [ Time Frame: 24 Weeks Prior to Screening, Baseline to Week 25 ]
  TA was defined as participants who were packed red blood cell (pRBC) transfusion-free and did not require transfusion per protocol-specified guidelines. TA within 24 weeks prior to screening was based on the pRBC transfusion history in the medical records. Reported in this outcome measure is the difference in the percentage of participants between "baseline through Week 25" and "within 24 weeks prior to screening". 95% Confidence Interval (CI) for the difference between the percentage of participants with transfusion avoidance between Pre-screening and Post-baseline is calculated using the Newcombe method. Screening= Day -28 to Day -1 and Baseline= Day 1.

Original Primary Outcome Measures (submitted: November 30, 2020)

• Mean 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).
• Change from Baseline to Week 25 in Percentage of Participants who achieve Transfusion Avoidance (TA) [ Time Frame: 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.

Current Secondary Outcome Measures (submitted: February 6, 2023)

• Percentage of Participants With Breakthrough Hemolysis (BTH) [ Time Frame: Baseline, Week 25 ]
  BTH was 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)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2xULN after a prior LDH reduction to ≤1.5xULN from the start of study treatment. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to have experienced a BTH event. Percentages have been rounded off to the first decimal point.
• Percentage of Participants With Stabilized Hemoglobin [ Time Frame: Baseline, Week 25 ]
  Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to not have hemoglobin stabilization.
• Change From Baseline in Fatigue in Adults Aged >=18 Years [ Time Frame: Baseline, Week 2, Week 5, Week 9, Week 17, Week 25 ]
  Fatigue was assessed using functional assessment of chronic illness therapy-fatigue (FACIT-F) scale. FACIT-F is a self-assessment questionnaire with a 7-day recall period and 13 items evaluating fatigue and its impact on daily life activities. Items are scored on a response scale that ranges from 0 ("not at all") to 4 ("very much so"). Relevant items are reverse scored, and all the items are summed to create a total score range from 0 to 52, with 0 being the worst possible score and 52 being the best possible score. A higher score indicates low fatigue severity. A positive mean change indicates improvement. FACIT-F was assessed in adult participants only. FACIT-F assessment was unintentionally missed in the Schedule of Activities (SoA) table, which site used to guide the assessments at each timepoint. Therefore, data were not collected at Week 25.
• Percentage of Participants With Adverse Events (AEs) [ Time Frame: Up to 7 years ]
• 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 ]
• Trough Serum Concentration of Crovalimab Over Time [ Time Frame: Up to 7 years ]
• Serum Concentrations of Crovalimab [ Time Frame: Up to 7 years ]
• Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab [ Time Frame: Up to 7 years ]
• Terminal Complement Activity as Measured by Liposome Immunoassay (LIA) [ Time Frame: Up to 7 years ]
• Change Over Time in Total and Free C5 Concentration [ Time Frame: Up to 7 years ]
• Observed Value in Absolute Reticulocyte Count [ Time Frame: Up to 7 years ]
• Observed Value in Free Hemoglobin [ Time Frame: Up to 7 years ]
• Observed Value in Haptoglobin [ Time Frame: Up to 7 years ]
• Percent Change From Baseline in Absolute Reticulocyte Count [ Time Frame: Baseline, Week 25 ]
• Percent Change From Baseline in Free Hemoglobin [ Time Frame: Baseline, Week 25 ]
• Percent Change From Baseline in Haptoglobin [ Time Frame: Baseline, Week 25 ]

Original Secondary Outcome Measures (submitted: November 30, 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.
• Mean 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 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 years ]
• Percentage of Participants with Adverse Events (AEs) leading to Study Drug Discontinuation [ Time Frame: Up to 2 years ]
• Trough Serum Concentration of Crovalimab over time [ Time Frame: Up to 2 years ]
• Serum Concentrations of Crovalimab at specified timepoints [ Time Frame: Up to 2 years ]
• Percentage of Participants with Anti-Crovalimab Antibodies [ Time Frame: Up to 2 years ]
• Change over time in PD biomarkers including complement activity [ Time Frame: Up to 2 years ]
  Assessed by a Liposome Immunoassay (LIA)
• Change over time in total and free C5 concentration [ Time Frame: Up to 2 years ]
• Observed Value in Reticulocyte Count (count/mL) [ Time Frame: Up to 2 years ]
• Observed Value in Free Hemoglobin and Haptoglobin (mg/dL) [ Time Frame: Up to 2 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 Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition
• Official Title: A Phase III, Multicenter, Single Arm Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition
• Brief Summary: This study will enrol participants aged 12 years or older with a body weight >= 40 kilograms (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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group 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.

Study Arms

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.

Intervention: Drug: Crovalimab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 6, 2021): 51
• Original Estimated Enrollment (submitted: November 30, 2020): 50
• Estimated Study Completion Date: February 18, 2028
• Actual Primary Completion Date: February 10, 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 Levels >= 2x the ULN at screening.
• Participants who have at least four transfusions during 12 months prior to screening (documented in the medical record).
• Presence of one or more of the following PNH-related signs or symptoms within 3 months of screening.
• Vaccination against Neisseria meningitidis serotypes A, C, W, and Y < 3 years prior to initiation of study treatment (Day 1)
• Vaccination against Haemophilius influenzae type B and Streptococcus pneumonia according to national vaccination recommendations.
• For participants receiving other therapies (e.g., immunosuppressants, corticosteroids): stable dose for >= 28 days prior to screening and up to the first drug administration.
• Adequate hepatic and renal function.
• Women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 46 weeks (approximately 10.5 months) after the final dose of crovalimab.
• Platelet count >=30,000 cubic millimeter (mm^3) at screening
• ANC > 500/μl at screening

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 drug administration.
• Known or suspected immune or hereditary complement deficiency.
• Known HIV infection with CD4 count < 200 cells per microlitre (cells/µl) within 24 weeks prior to screening.
• 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.
• Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration.
• Presence of fever (>= 38˚C) within 7 days before the first drug administration.
• Splenectomy < 6 months before screening.
• History of malignancy within 5 years prior to screening and up to the first drug administration.
• Pregnant or intending to become pregnant during the study or within 46 weeks (10.5 months) after the final dose of study treatment.
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04654468
• Other Study ID Numbers: YO42311
• 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
• Product Manufactured in and Exported from the U.S.: Yes

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: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

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