Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria
Phase 1
Active, not recruiting
- Conditions
- Paroxysmal Hemoglobinuria, Nocturnal
- Interventions
- Drug: CrovalimabDrug: Placebo
- Registration Number
- NCT03157635
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 59
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
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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 to become pregnant during the study, including the OLE period, within 46 weeks (approximately 10.5 months) after the final dose of crovalimab
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Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 3 (PNH Participants): Crovalimab QW Crovalimab Participants will receive crovalimab at a dose of 1000 mg on Day 1 and 170 mg weekly (QW) starting on Day 8 for a maximum treatment duration of 5 months. Part 2 (PNH Participants): Crovalimab Crovalimab PNH participants will receive 3 single ascending doses (375 mg IV, 500 mg IV, 1000 mg IV 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. Part 1 (Healthy Volunteers): Placebo Placebo Healthy participants will receive a single dose of crovalimab matching placebo in each dose-escalation cohort of Part 1. Part 1 (Healthy Volunteers): Crovalimab 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) intravenous (IV) infusion. Doses are planned to be escalated up to Cohort 5. Part 3 (PNH Participants): Crovalimab Q2W Crovalimab Participants will receive crovalimab at a dose of 1000 mg on Day 1 and 340 mg every 2 weeks (Q2W) for a maximum treatment duration of 5 months. Part 3 (PNH Participants): Crovalimab Q4W Crovalimab Participants will receive crovalimab at a dose of 1000 mg on Day 1 and 680 mg every 4 weeks (Q4W) starting on Day 8 for a maximum treatment duration of 5 months. Part 4 (eculizumab pretreated PNH Participants): Crovalimab Crovalimab PNH Participants pretreated with eculizumab will receive crovalimab: Participants \>/= 100 kilograms (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 subcutaneous (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. Part 4 (treatment naïve PNH Participants): Crovalimab 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. OLE (PNH Participants): Crovalimab 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.
- Primary Outcome Measures
Name Time Method Part 4: Percentage of Participants With AEs and SAEs Baseline up to approximately 8 months 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 Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to approximately 3 months Part 3: 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 2: Percentage of Participants With AEs and SAEs Baseline up to approximately 8 months Part 1: Percentage of Participants With Dose-Limiting Events (DLEs) Baseline up to approximately 3 months OLE: Percentage of Participants With AEs and SAEs OLE: Week 21 up to Week 567
- Secondary Outcome Measures
Name Time Method OLE: Total C5 Concentration OLE: Predose (Hour 0) on Week 36 up to Week 521 Part 1: Terminal Complement Activity as Assessed by Ex Vivo Liposome Immunoassay (LIA) 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: Serum LDH Levels 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 2: Total C5 Concentration 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: Total C5 Concentration 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 1: Total Complement Component 5 (C5) Concentration 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: 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 Baseline, Day 64 Part 2: Serum Lactate Dehydrogenase (LDH) Levels 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 Part 4: Serum LDH Levels 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 1: Free C5 Concentration 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: Free C5 Concentration 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: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 50, 78, 106, and 134 Baseline, Day 8, 22, 50, 78, 106, 134 Part 4: Number of Packed RBCs Units Transfused per Participant Baseline up to Day 224 Part 4: Total C5 Concentration 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 3: Free C5 Concentration 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 Part 4: Free C5 Concentration 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 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 64 Baseline, Day 64 Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 78 and 134 Baseline, Day 78, 134 Part 3: Number of Packed RBCs Units Transfused per Participant Baseline up to Day 224 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, 50, 106, 134); Days 29, 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); Days 134, 224 Part 4: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 57, 85, 113 and 134 Baseline, Day 8, 22, 57, 85, 113, 134 Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 57 Baseline, Day 8, 57 Part 3: 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 LDH Below Upper Limit of Normal (ULN) Baseline up to Day 224 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 8 and 50 Baseline, Day 8, 50 Part 4: Percentage of Participants With Packed RBC Units Transfused Baseline up to Day 224 Part 3: Percentage of Participants With ADAs to Crovalimab 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 LDH Below ULN Baseline up to Day 224 Part 2: Monthly Rate of pRBC Transfusions per Participant Baseline up to 10 years Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 85 and 134 Baseline, Day 85, 134 Part 2: Number of Packed Red Blood Cell (RBC) 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 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 3: Monthly Rate of pRBC Transfusions per Participant Baseline up to 10 years Part 4: Monthly Rate of pRBC Transfusions per Participant Baseline up to 10 years Part 2: Annual Rate of Transfusion Avoidance per Participant Baseline up to 10 years Part 3: Annual Rate of Transfusion Avoidance per Participant Baseline up to 10 years Part 3: Annual Rate of Breakthrough Hemolysis (BTH) Baseline up to 10 years OLE: Serum LDH Levels OLE: Predose (Hour 0) on Week 28 up to Week 521 Part 2: Proportion of Transfusion-Free Participants Baseline up to 10 years Part 4: Annual Rate of Transfusion Avoidance per Participant Baseline up to 10 years OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA) OLE: Week 36 up to Week 521 Part 4: Percentage of Participants With LDH Below ULN Baseline up to Day 224 Part 4: Percentage of Participants With Complement Suppression Baseline up to Day 134 Part 2: Annual Rate of Breakthrough Hemolysis (BTH) Baseline up to 10 years Part 3: Proportion of Transfusion-Free Participants Baseline up to 10 years Part 4: Proportion of Transfusion-Free Participants Baseline up to 10 years Part 4: Annual Rate of Breakthrough Hemolysis (BTH) Baseline up to 10 years
Trial Locations
- Locations (19)
Elblandklinikum Riesa; Klinik fuer Haematologie Onkologie und Gastroenterologie
🇩🇪Riesa, Germany
Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis
🇫🇷Paris, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre Benite, France
Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology
🇭🇺Kaposvar, Hungary
A.O. UNIVERSITARIA FEDERICO II DI NAPOLI;Dipartimento di Medicina Clinica e Chirurgia
🇮🇹Napoli, Campania, Italy
Universitätsklinikum Essen; Klinik für Hämatologie
🇩🇪Essen, Germany
Tokyo Medical University Hospital
🇯🇵Tokyo, Japan
Seoul National University Hosp; Dept Internal Med Hem Onc
🇰🇷Seoul, Korea, Republic of
Universitätsklinikum Ulm; Institut für Klinische Transfusionsmedizin
🇩🇪Ulm, Germany
NTT Medical Center Tokyo
🇯🇵Tokyo, Japan
Pra International Group B.V
🇳🇱Groningen, Netherlands
Policlinico Universitario Agostino Gemelli
🇮🇹Roma, Lazio, Italy
Ospedale Di Vicenza; Nefrologia, Ematologia
🇮🇹Vicenza, Veneto, Italy
Osaka University Hospital; Hematology and Oncology
🇯🇵Osaka, Japan
University of Tsukuba Hospital; Hematology
🇯🇵Tsukuba, Japan
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Tohoku University Hospital
🇯🇵Miyagi, Japan
Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.
🇩🇪Aachen, Germany
Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia
🇭🇺Budapest, Hungary