COMPOSER: Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria
Study Details
Study Description
Brief Summary
This is a Phase I/II, first-in-human study consisting of four sequential parts and an open-label extension (OLE). The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single doses of crovalimab will be evaluated in healthy volunteers (HV) during part 1. The safety, tolerability, PK and PD of multiple doses of crovalimab will be evaluated in participants with paroxysmal nocturnal hemoglobinuria (PNH) in parts 2, 3, 4, and OLE of the study. Efficacy of crovalimab will be evaluated in Parts 2, 3, and 4.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1 (Healthy Volunteers): Crovalimab Healthy participants will receive a single dose of crovalimab in each dose-escalation cohort of Part 1. Crovalimab will be administered at a starting dose of 75 milligrams (mg). Doses are planned to be escalated up to Cohort 5. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Placebo Comparator: Part 1 (Healthy Volunteers): Placebo Healthy participants will receive a single dose of crovalimab matching placebo in each dose-escalation cohort of Part 1. |
Drug: Placebo
Placebo will be administered as per schedule described in Part 1 placebo arm.
|
| Experimental: Part 2 (PNH Participants): Crovalimab PNH participants will receive 3 single ascending doses (375 mg IV, 500 mg IV, 1000 mg of crovalimab) on Days 1, 8, and 22 followed by weekly crovalimab administrations up to a maximum of 5 months. Weekly crovalimab administrations will start no earlier than Day 36. The starting dose of Part 2 is based on data from Part 1 of the study. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Experimental: Part 3 (PNH Participants): Crovalimab QW Participants will receive crovalimab at a dose of 1000 mg on Day 1 and 170 mg QW on Day 8 for a maximum treatment duration of 5 months. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Experimental: Part 3 (PNH Participants): Crovalimab Q2W Participants will receive crovalimab at a dose of 1000 mg on Day 1 and 340 mg Q2W for a maximum treatment duration of 5 months. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Experimental: Part 3 (PNH Participants): Crovalimab Q4W Participants will receive crovalimab at a dose of 1000 mg on Day 1 and 680 mg Q4W starting on Day 8 for a maximum treatment duration of 5 months. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Experimental: Part 4 (eculizumab pretreated PNH Participants): Crovalimab PNH Participants pretreated with eculizumab will receive crovalimab: Participants >/= 100 kg: loading dose of 1500 mg IV on day 1; Participants < 100 kg: loading dose of 1000 mg IV on day 1. In all Participants, the remainder of the loading series schedule will be 340 mg SC on Days 2, 8, 15, and 22. For Participants >/= 100 kg, maintenance dosing will be 1020 mg SC on week 5 and then Q4W thereafter. Patients < 100 kg will receive a maintenance dose of 680 mg SC on the same schedule. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Experimental: Part 4 (treatment naïve PNH Participants): Crovalimab Treatment naïve PNH Participants will receive: Participants >/= 100 kg: loading dose of 1500 mg IV on day 1; Participants < 100 kg: loading dose of 1000 mg IV on day 1. In all Participants, the remainder of the loading series schedule will be 340 mg SC on Days 2, 8, 15, and 22. For Participants >/= 100 kg, maintenance dosing will be 1020 mg SC on week 5 and then Q4W thereafter. Patients < 100 kg will receive a maintenance dose of 680 mg SC on the same schedule. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
| Experimental: OLE (PNH Participants): Crovalimab PNH Participants who participated in Parts 2, 3 and 4 and who derive clinical benefit from crovalimab may enroll into OLE. Participants will either receive 680 mg SC Q4W (body weight >/= 40 kg to < 100 kg) or 1020 mg SC Q4W (body weight >/= 100 kg) for up to a maximum treatment duration of ten years from entry into OLE. |
Drug: Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
|
Outcome Measures
Primary Outcome Measures
- Part 1: Percentage of Participants With Dose-Limiting Events (DLEs) [Baseline up to approximately 3 months]
- Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to approximately 3 months]
- Part 2: Percentage of Participants With AEs and SAEs [Baseline up to approximately 8 months]
- Part 3: Percentage of Participants With AEs and SAEs [Baseline up to approximately 8 months]
- Part 4: Percentage of Participants With AEs and SAEs [Baseline up to approximately 8 months]
- Part 2: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Baseline up to Day 224]
- Part 3: Terminal Complement Activity as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA [Baseline up to Day 224]
- Part 4: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Baseline up to Day 224]
- OLE: Percentage of Participants With AEs and SAEs [OLE: Week 21 up to Week 545]
Secondary Outcome Measures
- Part 1: Terminal Complement Activity as Assessed by Ex Vivo Liposome Immunoassay (LIA) [Part 1: Baseline up to Day 91 (assessed at predose [Hr 0], end of infusion [EOI] [1 Hr], Hr 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84, 91)]
- Part 2: Serum Lactate Dehydrogenase (LDH) Levels [Predose (Hr0), Hr 10-12 on Days 1, 8; Days 2, 5, 9, 15, 22, 29, 36, 43, 50, 64, 78, 92, 106, 120, 134, 224]
- Part 3: Serum LDH Levels [Part 3: Predose (Hr 0), Hr 10-12 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 57, 71, 85, 99, 113, 127, 134; Day 224]
- Part 4: Serum LDH Levels [Part 4: Predose (Hr 0), Hr 10-12 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 57, 71, 85, 99, 113, 127, 134; Day 224]
- Part 1: Total Complement Component 5 (C5) Concentration [Part 1: Predose (Hr 0), EOI (1 Hr), Hr 2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84, 91]
- Part 2: Total C5 Concentration [Part 2: Predose (Hr 0), EOI (1 Hr), Hr 2, 6, 10-12 on Day 1; Days 2, 5, 9, 15, 29, 224; predose [Hr 0], EOI [1 Hr], Hr 10-12 on Days 8, 22; predose [Hr 0] on Day 36, 43, 50, 64, 78, 92, 106, 120, 134]
- Part 3: Total C5 Concentration [Part 3: Predose (Hr 0), EOI (1 Hr), Hr 2, 6 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99, 113, 134; Day 224]
- Part 4: Total C5 Concentration [Part 4: Predose (Hr 0), EOI (1 Hr), Hr 2, 6 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99, 113, 134; Day 224]
- Part 1: Free C5 Concentration [Part 1: Predose (Hr 0), EOI (1 hr), Hr2, 6, 12 on Day 1; Days 2, 3, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84, 91]
- Part 2: Free C5 Concentration [Part 2: Predose (Hr 0), EOI (1 Hr), Hr 2, 6,10-12 on Day 1; Days 2, 5, 9, 15, 29, 224; predose [Hr 0], EOI [1 Hr], Hr 10-12 on Days 8, 22; predose [Hr 0] on Day 36, 43, 50, 64, 78, 92, 106, 120, 134]
- Part 3: Free C5 Concentration [Part 3: Predose (Hr 0), EOI (1 hr), Hr 2, 6 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99, 113, 134; Day 224]
- Part 4: Free C5 Concentration [Part 4: Predose (Hr 0), EOI (1 hr), Hr 2, 6 on Day 1; predose (Hr 0), on Days 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99, 113, 134; Day 224]
- Part 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 8, 22, 36, 50 and 64 [Baseline, Day 8, 22, 36, 50, 64]
- Part 3: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 2, 8, 15, 29, 57 [Baseline, Day 2, 8, 15, 29, 57]
- Part 4: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 2, 8, 15, 29, 57 [Baseline, Day 2, 8, 22, 57, 85, 113, 134]
- 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 8, 22, 36, 50, and 64 [Baseline, Day 8, 22, 36, 50, 64]
- Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 2, 8, 15, 29, 57 [Baseline, Day 2, 8, 15, 29, 57]
- Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 2, 8, 15, 29, 57 [Baseline, Day 1, 85, 134]
- Part 2: Participant Treatment Satisfaction as Measured by Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Day 8, 22, 36, 50 and 64 [Baseline, Day 8, 22, 36, 50, 64]
- Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 2, 8, 15, 29, 57 [Baseline, Day 2, 8, 15, 29, 57]
- Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 2, 8, 15, 29, 57 [Baseline, Day 1, 8, 57]
- Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant [Baseline up to Day 224]
- Part 3: Number of Packed RBCs Units Transfused per Participant [Baseline up to Day 224]
- Part 4: Number of Packed RBCs Units Transfused per Participant [Baseline up to Day 224]
- Part 2: Percentage of Participants With Packed RBC Units Transfused [Baseline up to Day 224]
- Part 3: Percentage of Participants With Packed RBC Units Transfused [Baseline up to Day 224]
- Part 4: Percentage of Participants With Packed RBC Units Transfused [Baseline up to Day 224]
- Part 1: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab [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 ADAs to Crovalimab [Part 2: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8; on Days 29, 50, 106, 134, and 224)]
- Part 3: Percentage of Participants With ADAs to Crovalimab [Part 3: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 29, 57, 99, 134; on Day 224)]
- Part 4: Percentage of Participants With ADAs to Crovalimab [Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 29, 113, 134; on Day 224)]
- OLE: Total C5 Concentration [OLE: Predose (Hr 0) on Week 36 up to Week 521]
- OLE: Serum LDH Levels [OLE: Predose (Hr 0) on Week 28 up to Week 521]
- OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) [OLE: Week 36 up to Week 521]
- Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN) [Baseline up to Day 224]
- Part 3: Percentage of Participants With LDH Below ULN [Baseline up to Day 224]
- Part 4: Percentage of Participants With LDH Below ULN [Baseline up to Day 224]
- Part 2: Percentage of Participants With Complement Suppression [Baseline up to Day 134]
- Part 3: Percentage of Participants With Complement Suppression [Baseline up to Day 134]
- Part 4: Percentage of Participants With Complement Suppression [Baseline up to Day 134]
- Part 2: Monthly Rate of pRBC Transfusions per Participant [Baseline up to 5 years]
- Part 3: Monthly Rate of pRBC Transfusions per Participant [Baseline up to 5 years]
- Part 4: Monthly Rate of pRBC Transfusions per Participant [Baseline up to 5 years]
- Part 2: Proportion of Transfusion-Free Participants [Baseline up to 5 years]
- Part 3: Proportion of Transfusion-Free Participants [Baseline up to 5 years]
- Part 4: Proportion of Transfusion-Free Participants [Baseline up to 5 years]
- Part 2: Annual Rate of Transfusion Avoidance per Participant [Baseline up to 5 years]
- Part 3: Annual Rate of Transfusion Avoidance per Participant [Baseline up to 5 years]
- Part 4: Annual Rate of Transfusion Avoidance per Participant [Baseline up to 5 years]
- Part 2: Annual Rate of Breakthrough Hemolysis (BTH) [Baseline up to 5 years]
- Part 3: Annual Rate of Breakthrough Hemolysis (BTH) [Baseline up to 5 years]
- Part 4: Annual Rate of Breakthrough Hemolysis (BTH) [Baseline up to 5 years]
Eligibility Criteria
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
-
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
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis | Paris | France | 75475 | |
| 2 | Centre Hospitalier Lyon Sud | Pierre Benite | France | 69495 | |
| 3 | Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm. | Aachen | Germany | 52074 | |
| 4 | Universitätsklinikum Essen; Klinik für Hämatologie | Essen | Germany | 45122 | |
| 5 | Elblandklinikum Riesa; Klinik fuer Haematologie Onkologie und Gastroenterologie | Riesa | Germany | 01589 | |
| 6 | Universitätsklinikum Ulm; Institut für Klinische Transfusionsmedizin | Ulm | Germany | 89081 | |
| 7 | Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia | Budapest | Hungary | 1083 | |
| 8 | Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology | Kaposvar | Hungary | 7400 | |
| 9 | A.O. UNIVERSITARIA FEDERICO II DI NAPOLI;Dipartimento di Medicina Clinica e Chirurgia | Napoli | Campania | Italy | 80136 |
| 10 | Policlinico Universitario Agostino Gemelli | Roma | Lazio | Italy | 00168 |
| 11 | Ospedale Di Vicenza; Nefrologia, Ematologia | Vicenza | Veneto | Italy | 36100 |
| 12 | Tohoku University Hospital | Miyagi | Japan | 980-8574 | |
| 13 | Osaka University Hospital; Hematology and Oncology | Osaka | Japan | 565-0871 | |
| 14 | NTT Medical Center Tokyo | Tokyo | Japan | 141-8625 | |
| 15 | Tokyo Medical University Hospital | Tokyo | Japan | 160-0023 | |
| 16 | University of Tsukuba Hospital; Hematology | Tsukuba | Japan | 305-8576 | |
| 17 | Severance Hospital, Yonsei University Health System | Seoul | Korea, Republic of | 03722 | |
| 18 | Seoul National University Hosp; Dept Internal Med Hem Onc | Seoul | Korea, Republic of | 110-744 | |
| 19 | Pra International Group B.V | Groningen | Netherlands | 9728 NZ |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- BP39144
- 2016-002128-10