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

NCT ID: NCT03157635

Last Updated: 2025-11-17

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 59 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-11-14
• Study Completion Date: 2026-01-31

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.

Conditions

Paroxysmal Hemoglobinuria, Nocturnal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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) intravenous (IV) infusion. Doses are planned to be escalated up to Cohort 5.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

Part 1 (Healthy Volunteers): Placebo

Healthy participants will receive a single dose of crovalimab matching placebo in each dose-escalation cohort of Part 1.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo will be administered as per schedule described in Part 1 placebo arm.

Part 2 (PNH Participants): 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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

Part 3 (PNH Participants): Crovalimab QW

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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

Part 3 (PNH Participants): Crovalimab Q2W

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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

Part 3 (PNH Participants): Crovalimab Q4W

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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

Part 4 (eculizumab pretreated PNH Participants): 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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

Crovalimab

Intervention Type: DRUG

Crovalimab will be administered as per schedule described in individual arm.

Interventions

Crovalimab

Crovalimab will be administered as per schedule described in individual arm.

Intervention Type: DRUG

Placebo

Placebo will be administered as per schedule described in Part 1 placebo arm.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Chugai Pharmaceutical

INDUSTRY

Sponsor Role: collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis

Paris, , France

Uniklinik RWTH Aachen

Aachen, , Germany

Universitätsklinikum Essen

Essen, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia

Budapest, , Hungary

Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology

Kaposvár, , Hungary

Policlinico Universitario Agostino Gemelli

Rome, Lazio, Italy

Tohoku University Hospital

Miyagi, , Japan

Osaka University Hospital

Osaka, , Japan

NTT Medical Center Tokyo

Tokyo, , Japan

Tokyo Medical University Hospital

Tokyo, , Japan

University of Tsukuba Hospital

Tsukuba, , Japan

Pra International Group B.V

Groningen, , Netherlands

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Seoul National University Hosp

Seoul, , South Korea

Countries

France; Germany; Hungary; Italy; Japan; Netherlands; South Korea

References

Roth A, Nishimura JI, Nagy Z, Gaal-Weisinger J, Panse J, Yoon SS, Egyed M, Ichikawa S, Ito Y, Kim JS, Ninomiya H, Schrezenmeier H, Sica S, Usuki K, Sicre de Fontbrune F, Soret J, Sostelly A, Higginson J, Dieckmann A, Gentile B, Anzures-Cabrera J, Shinomiya K, Jordan G, Biedzka-Sarek M, Klughammer B, Jahreis A, Bucher C, Peffault de Latour R. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020 Mar 19;135(12):912-920. doi: 10.1182/blood.2019003399.

Reference Type: DERIVED

PMID: 31978221 (View on PubMed)

Related Links

https://www.pioneeringhealthcare.com/pnh/

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

Other Identifiers

2016-002128-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2023-506287-14-00

Identifier Type: CTIS

Identifier Source: secondary_id

BP39144

Identifier Type: -

Identifier Source: org_study_id