Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria

• Register: ClinicalTrials.gov
• Last refreshed on: 11 March 2024
• Main ID: NCT03157635
• Date of registration: 01/11/2016
• Prospective Registration: Yes
• Primary sponsor: Hoffmann-La Roche
• Public title: Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria COMPOSER
• Scientific title: An Adaptive Phase I/II Study to Assess Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Crovalimab in Healthy Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Date of first enrolment: November 14, 2016
• Target sample size: 59
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03157635
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 1/Phase 2

Countries of recruitment

France, Germany, Hungary, Italy, Japan, Korea, Republic of, Netherlands

Contacts

• Name: Clinical Trials
• Affiliation: Hoffmann-La Roche

Key inclusion & exclusion criteria

Inclusion Criteria:

Part 1 (HVs only):

- Healthy male volunteers, aged between 21 and 55 years inclusive

- Participants with a negative hepatitis B surface antigen (HBsAg), hepatitis B core
antibody (HBcAb), hepatitis C antibody, and human immunodeficiency virus (HIV) test
result

- Participants who have been vaccinated against hepatitis B

- No evidence of Neisseria meningococci in nasopharyngeal swab

- Neisseria meningitidis vaccination against serogroups B and A, C, W, and Y

- Non-smokers, or former smokers, who have not smoked for at least 60 days prior to
screening

Parts 2, 3 and 4 (PNH participants only):

- Male or female participants with PNH between 18 and 75 years of age

- Neisseria meningitidis vaccination in accordance with most current local guidelines or
standard of care (SOC) for participants at increased risk for meningococcal disease
(Part 2 and 4)

- Participant has been vaccinated with Neisseria meningitidis vaccine(s) in accordance
with most current local guidelines or SOC for participants at increased risk for
meningococcal disease or is being revaccinated if applicable (Part 3 and 4)

- Antibiotic prophylaxis for meningococcal infection must be initiated prior to
initiation of crovalimab therapy if the time period between initial Neisseria
meningitidis vaccination and first dose of crovalimab is less than 2 weeks (Part 2 and
4)

- Antibiotic prophylaxis of meningococcal infection may be initiated prior to initiation
of crovalimab therapy based on local guidelines or SOC for participants at increased
risk for meningococcal disease e.g., splenectomized patients (Parts 2 and 4)

- Stable dose for greater than or equal to (>/=) 28 days prior to screening of other
therapies (immunosuppressant therapy, corticosteroids, iron supplements)

Part 2 and 4 (currently untreated PNH participants who are candidates for treatment with
complement inhibitors only):

- PNH participants who have not been treated with any complement inhibitor or if
previously treated stopped treatment due to lack of efficacy based on a single
missense C5 heterozygous mutation

- Serum LDH levels at least 1.5-fold above the ULN at screening

- Hepatitis B participants can be enrolled if their liver function test values are less
than 2 x ULN and there is no liver function impairment

Part 3 and 4 (PNH participants currently treated with eculizumab only):

- PNH participants who have been treated continuously with eculizumab for at least 3
months preceding enrollment in the trial

- Participants receive regular infusions of eculizumab

- Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core
antibody (HBcAb), hepatitis C antibody, and HIV test result

OLE only - PNH participants:

- PNH participants who have completed Parts 2, 3 and 4 respectively

- PNH participants who derived, in the investigator's opinion, benefit from treatment
with crovalimab

- Vaccination currency for Neisseria meningitidis serotypes A, C, W, Y and B should be
maintained throughout the OLE

All Parts:

- Female participants should use proper means of contraception

Exclusion Criteria:

Part 1 (HVs only):

- Any clinically relevant history or the presence of moderate to severe respiratory,
renal, hepatic, gastrointestinal, hematological, lymphatic, neurological,
cardiovascular, psychiatric, musculoskeletal, or connective tissue disease

- Any major illness within 1 month before the screening

- Prior splenectomy

- History of clinically significant hypersensitivity (example: drugs, excipients) or
allergic reactions

- History or presence of clinically significant electrocardiogram (ECG) abnormalities or
cardiovascular disease

- Any contra-indication for receiving Neisseria meningitides vaccination and antibiotic
prophylaxis therapy as required in the study

- Congenital or acquired complement deficiency

- Carriers of Neisseria meningitides based on cultures from nasopharyngeal swabs

- Known active viral, bacterial or fungal infection including herpes, herpes zoster or
cold sores, during the last 14 days prior to first study drug administration

- Signs of parasitic infection (example: eosinophilia, diarrhea)

- History of significant recurrent infections in the opinion of the investigator

Parts 2, 3 and 4 - PNH participants only:

- Evidence of moderate to severe concurrent renal, liver, cardiac, pulmonary or
gastrointestinal disease not related to PNH as determined by the investigator

- History of an illness that, in the opinion of the study investigator, might confound
the results of the study or that poses an additional risk to the participant by his or
her participation in the study

- History of bone marrow transplantation

- Treatment with azathioprine or erythrocyte-stimulating agents within 14 days prior to
first study drug administration

- Splenectomy <1 year before start of crovalimab.

Part 3 and 4 - PNH patients only:

- Any evidence of sero-positive auto-immune connective tissue diseases (such as systemic
lupus erythematosus, or rheumatoid arthritis)

- Any evidence of active inflammatory conditions (including inflammatory bowel disease,
or cryoglobulinemia)

All Parts:

- Under active therapy with intravenous immunoglobulin (IVIG)

- Mentally incapacitated or history of a clinically significant psychiatric disorder
over the previous 5 years

- Known or suspected hereditary complement deficiency

- History of meningococcal meningitis

- History of allergic or anaphylactic reactions to human, humanized, or murine
monoclonal antibodies or known hypersensitivity to any constituent of the product

- Any major episode of infection requiring hospitalization or treatment with intravenous
(IV) antibiotics within 28 days prior to screening or oral antibiotics within 2 weeks
prior to screening and up to first study drug administration

- History of or currently active primary or secondary immunodeficiency, including known
history of human immunodeficiency virus (HIV) infection

- Evidence of chronic active hepatitis C infection

- Evidence of malignant disease including myelodysplastic syndrome, or malignancies
diagnosed within the previous 5 years

- Pregnant or breastfeeding, or intending t


Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Paroxysmal Hemoglobinuria, Nocturnal

Intervention(s)

Drug: Crovalimab

Drug: Placebo

Primary Outcome(s)

Part 1: Percentage of Participants With Dose-Limiting Events (DLEs) [Time Frame: Baseline up to approximately 3 months]

Part 4: Percentage of Participants With AEs and SAEs [Time Frame: Baseline up to approximately 8 months]

Part 2: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Time Frame: Baseline up to Day 224]

OLE: Percentage of Participants With AEs and SAEs [Time Frame: OLE: Week 21 up to Week 567]

Part 2: Percentage of Participants With AEs and SAEs [Time Frame: Baseline up to approximately 8 months]

Part 3: Terminal Complement Activity as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA [Time Frame: Baseline up to Day 224]

Part 4: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Time Frame: Baseline up to Day 224]

Part 3: Percentage of Participants With AEs and SAEs [Time Frame: Baseline up to approximately 8 months]

Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time Frame: Baseline up to approximately 3 months]

Secondary Outcome(s)

Part 2: Free C5 Concentration [Time Frame: Part 2: Predose (Hour 0), EOI (1 Hour), Hours 2, 6, 10-12 on Day 1; Days 2, 5, 9, 15, 29, 224; predose [Hour 0], EOI [1 Hour], Hours 10-12 on Days 8, 22; predose [Hour 0] on Day 36, 43, 50, 64, 78, 92, 106, 120, 134]

Part 3: Annual Rate of Transfusion Avoidance per Participant [Time Frame: Baseline up to 10 years]

Part 3: Free C5 Concentration [Time Frame: Part 3: Predose (Hour 0), EOI (1 Hour), Hours 2, 6 on Day 1; predose (Hour 0), on Days 2, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 106; Day 224]

OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Time Frame: OLE: Week 36 up to Week 521]

OLE: Total C5 Concentration [Time Frame: OLE: Predose (Hour 0) on Week 36 up to Week 521]

Part 1: Terminal Complement Activity as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Time Frame: Part 1: Baseline up to Day 91 (assessed at predose [Hour 0], end of infusion [EOI] [1 Hour], Hours 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 91)]

Part 3: Percentage of Participants With Complement Suppression [Time Frame: Baseline up to Day 134]

Part 3: Proportion of Transfusion-Free Participants [Time Frame: Baseline up to 10 years]

Part 2: Annual Rate of Breakthrough Hemolysis (BTH) [Time Frame: Baseline up to 10 years]

Part 2: Participant Treatment Satisfaction as Measured by Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Day 8, 22, 36, 50 and 64 [Time Frame: Baseline, Day 8, 22, 36, 50, 64]

Part 1: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab [Time Frame: Part 1: Day 1 up to Day 91 (assessed at predose [Hour 0] on Day 1; on Days 14, 28, 56, 84, and 91)]

Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN) [Time Frame: Baseline up to Day 224]

Part 4: Monthly Rate of pRBC Transfusions per Participant [Time Frame: Baseline up to 10 years]

Part 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 64 [Time Frame: Baseline, Day 64]

Part 4: Annual Rate of Breakthrough Hemolysis (BTH) [Time Frame: Baseline up to 10 years]

Part 4: Percentage of Participants With ADAs to Crovalimab [Time Frame: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 29, 113); Days 134, 224]

Part 2: Serum Lactate Dehydrogenase (LDH) Levels [Time Frame: Predose (Hour 0), Hours 10-12 on Days 1, 8; Days 2, 5, 9, 15, 22, 29, 36, 43, 50, 64, 78, 92, 106, 120, 134, 224]

OLE: Serum LDH Levels [Time Frame: OLE: Predose (Hour 0) on Week 28 up to Week 521]

Part 2: Monthly Rate of pRBC Transfusions per Participant [Time Frame: Baseline up to 10 years]

Part 1: Free C5 Concentration [Time Frame: Part 1: Predose (Hour 0), EOI (1 Hour), Hours 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 91]

Part 4: Percentage of Participants With Complement Suppression [Time Frame: Baseline up to Day 134]

Part 1: Total Complement Component 5 (C5) Concentration [Time Frame: Part 1: Predose (Hour 0), EOI (1 Hour), Hours 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 91]

Part 2: Annual Rate of Transfusion Avoidance per Participant [Time Frame: Baseline up to 10 years]

Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant [Time Frame: Baseline up to Day 224]

Part 3: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 50, 78, 106, and 134 [Time Frame: Baseline, Day 8, 22, 50, 78, 106, 134]

Part 2: Percentage of Participants With ADAs to Crovalimab [Time Frame: Part 2: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 50, 106, 134); Days 29, 224]

Part 3: Total C5 Concentration [Time Frame: Part 3: Predose (Hour 0), EOI (1 Hour), Hours 2 and 6 on Day 1; predose (Hour 0), on Days 2, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 106; Day 224]

Part 2: Proportion of Transfusion-Free Participants [Time Frame: Baseline up to 10 years]

Part 3: Annual Rate of Breakthrough Hemolysis (BTH) [Time Frame: Baseline up to 10 years]

Part 4: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 57, 85, 113 and 134 [Time Frame: Baseline, Day 8, 22, 57, 85, 113, 134]

Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 78 and 134 [Time Frame: Baseline, Day 78, 134]

Part 2: Percentage of Participants With Complement Suppression [Time Frame: Baseline up to Day 134]

Part 2: Percentage of Participants With Packed RBC Units Transfused [Time Frame: Baseline up to Day 224]

Part 3: Percentage of Participants With LDH Below ULN [Time Frame: Baseline up to Day 224]

Part 3: Serum LDH Levels [Time Frame: Part 3: Predose (Hour 0), Hours 10-12 on Day 1; predose (Hour 0), on Days 2, 8, 15, 22, 29, 36, 64, 78, 92, 106, 134; Day 224]

Part 4: Free C5 Concentration [Time Frame: Part 4: Predose (Hour 0), EOI (1 Hour), Hours 2, 6 on Day 1; predose (Hour 0), on Days 2, 8, 15, 22, 29, 57, 85, 113; Days 43, 134, 224]

Part 4: Serum LDH Levels [Time Frame: Part 4: Predose (Hour 0), Hour 6 on Day 1; predose (Hour 0), on Days 2, 8, 15, 22, 29, 43, 57, 85, 113, 134; Day 224]

Part 2: Change From Baseline in Health-Related Quality of Life (HRQoL) as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Score at Day 64 [Time Frame: Baseline, Day 64]

Part 4: Proportion of Transfusion-Free Participants [Time Frame: Baseline up to 10 years]

Part 2: Total C5 Concentration [Time Frame: Part 2: Predose (Hour 0), EOI (1 Hour), Hours 2, 6, 10-12 on Day 1; Days 2, 5, 9, 15, 29, 224; predose [Hour 0], EOI [1 Hour], Hours 10-12 on Days 8, 22; predose [Hour 0] on Days 36, 43, 50, 64, 78, 92, 106, 120, 134]

Part 3: Number of Packed RBCs Units Transfused per Participant [Time Frame: Baseline up to Day 224]

Part 3: Percentage of Participants With ADAs to Crovalimab [Time Frame: Part 3: Day 1 up to Day 106 assessed at predose [Hour 0] on Days 1, 8, 29, 64, and 106; Day 224]

Part 3: Percentage of Participants With Packed RBC Units Transfused [Time Frame: Baseline up to Day 224]

Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 85 and 134 [Time Frame: Baseline, Day 85, 134]

Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 50 [Time Frame: Baseline, Day 8, 50]

Part 4: Annual Rate of Transfusion Avoidance per Participant [Time Frame: Baseline up to 10 years]

Part 4: Number of Packed RBCs Units Transfused per Participant [Time Frame: Baseline up to Day 224]

Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 57 [Time Frame: Baseline, Day 8, 57]

Part 4: Percentage of Participants With Packed RBC Units Transfused [Time Frame: Baseline up to Day 224]

Part 4: Percentage of Participants With LDH Below ULN [Time Frame: Baseline up to Day 224]

Part 3: Monthly Rate of pRBC Transfusions per Participant [Time Frame: Baseline up to 10 years]

Part 4: Total C5 Concentration [Time Frame: Part 4: Predose (Hour 0), EOI (1 Hour), Hours 2, 6 on Day 1; predose (Hour 0), on Days 2, 8, 15, 22, 29, 57, 85, 113; Days 43, 134, 224]

Secondary ID(s)

2016-002128-10

BP39144

2023-506287-14-00

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Chugai Pharmaceutical