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

Paroxysmal Hemoglobinuria, Nocturnal Clinical Trial

— COMPOSER  

Official 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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03157635
• Other study ID #: BP39144
• Secondary ID: 2016-002128-1020
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: November 14, 2016
• Est. completion date: January 31, 2026

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 59
• Est. completion date: January 31, 2026
• Est. primary completion date: January 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 to become pregnant during the study, including the OLE period, within 46 weeks (approximately 10.5 months) after the final dose of crovalimab

Related Conditions & MeSH terms

• Hemoglobinuria
• Hemoglobinuria, Paroxysmal
• Paroxysmal Hemoglobinuria, Nocturnal

Intervention

Drug:
• Crovalimab
Crovalimab will be administered as per schedule described in individual arm.
• Placebo
Placebo will be administered as per schedule described in Part 1 placebo arm.

Locations

Country	Name	City	State
France	Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre Benite
Germany	Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.	Aachen
Germany	Universitätsklinikum Essen; Klinik für Hämatologie	Essen
Germany	Elblandklinikum Riesa; Klinik fuer Haematologie Onkologie und Gastroenterologie	Riesa
Germany	Universitätsklinikum Ulm; Institut für Klinische Transfusionsmedizin	Ulm
Hungary	Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia	Budapest
Hungary	Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology	Kaposvar
Italy	A.O. UNIVERSITARIA FEDERICO II DI NAPOLI;Dipartimento di Medicina Clinica e Chirurgia	Napoli	Campania
Italy	Policlinico Universitario Agostino Gemelli	Roma	Lazio
Italy	Ospedale Di Vicenza; Nefrologia, Ematologia	Vicenza	Veneto
Japan	Tohoku University Hospital	Miyagi
Japan	Osaka University Hospital; Hematology and Oncology	Osaka
Japan	NTT Medical Center Tokyo	Tokyo
Japan	Tokyo Medical University Hospital	Tokyo
Japan	University of Tsukuba Hospital; Hematology	Tsukuba
Korea, Republic of	Seoul National University Hosp; Dept Internal Med Hem Onc	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Netherlands	Pra International Group B.V	Groningen

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Chugai Pharmaceutical

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Percentage of Participants With Dose-Limiting Events (DLEs)		Baseline up to approximately 3 months
Primary	Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)		Baseline up to approximately 3 months
Primary	Part 2: Percentage of Participants With AEs and SAEs		Baseline up to approximately 8 months
Primary	Part 3: Percentage of Participants With AEs and SAEs		Baseline up to approximately 8 months
Primary	Part 4: Percentage of Participants With AEs and SAEs		Baseline up to approximately 8 months
Primary	Part 2: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)		Baseline up to Day 224
Primary	Part 3: Terminal Complement Activity as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA		Baseline up to Day 224
Primary	Part 4: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)		Baseline up to Day 224
Primary	OLE: Percentage of Participants With AEs and SAEs		OLE: Week 21 up to Week 567
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 78 and 134		Baseline, Day 78, 134
Secondary	Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 85 and 134		Baseline, Day 85, 134
Secondary	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
Secondary	Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 50		Baseline, Day 8, 50
Secondary	Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 57		Baseline, Day 8, 57
Secondary	Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant		Baseline up to Day 224
Secondary	Part 3: Number of Packed RBCs Units Transfused per Participant		Baseline up to Day 224
Secondary	Part 4: Number of Packed RBCs Units Transfused per Participant		Baseline up to Day 224
Secondary	Part 2: Percentage of Participants With Packed RBC Units Transfused		Baseline up to Day 224
Secondary	Part 3: Percentage of Participants With Packed RBC Units Transfused		Baseline up to Day 224
Secondary	Part 4: Percentage of Participants With Packed RBC Units Transfused		Baseline up to Day 224
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	OLE: Total C5 Concentration		OLE: Predose (Hour 0) on Week 36 up to Week 521
Secondary	OLE: Serum LDH Levels		OLE: Predose (Hour 0) on Week 28 up to Week 521
Secondary	OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)		OLE: Week 36 up to Week 521
Secondary	Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN)		Baseline up to Day 224
Secondary	Part 3: Percentage of Participants With LDH Below ULN		Baseline up to Day 224
Secondary	Part 4: Percentage of Participants With LDH Below ULN		Baseline up to Day 224
Secondary	Part 2: Percentage of Participants With Complement Suppression		Baseline up to Day 134
Secondary	Part 3: Percentage of Participants With Complement Suppression		Baseline up to Day 134
Secondary	Part 4: Percentage of Participants With Complement Suppression		Baseline up to Day 134
Secondary	Part 2: Monthly Rate of pRBC Transfusions per Participant		Baseline up to 10 years
Secondary	Part 3: Monthly Rate of pRBC Transfusions per Participant		Baseline up to 10 years
Secondary	Part 4: Monthly Rate of pRBC Transfusions per Participant		Baseline up to 10 years
Secondary	Part 2: Proportion of Transfusion-Free Participants		Baseline up to 10 years
Secondary	Part 3: Proportion of Transfusion-Free Participants		Baseline up to 10 years
Secondary	Part 4: Proportion of Transfusion-Free Participants		Baseline up to 10 years
Secondary	Part 2: Annual Rate of Transfusion Avoidance per Participant		Baseline up to 10 years
Secondary	Part 3: Annual Rate of Transfusion Avoidance per Participant		Baseline up to 10 years
Secondary	Part 4: Annual Rate of Transfusion Avoidance per Participant		Baseline up to 10 years
Secondary	Part 2: Annual Rate of Breakthrough Hemolysis (BTH)		Baseline up to 10 years
Secondary	Part 3: Annual Rate of Breakthrough Hemolysis (BTH)		Baseline up to 10 years
Secondary	Part 4: Annual Rate of Breakthrough Hemolysis (BTH)		Baseline up to 10 years

External Links

•   Adaptive clinical trial to assess safety, efficacy, PK and PD of crovalimab in Paroxysmal Nocturnal Hemoglobinuria (PNH)