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

NCT03157635 | Active Not Recruiting Phase 1

• 3 other identifiers: BP391442016-002128-102023-506287-14-00
• Study Type: interventional
• Target: 59
• Locations: 7 countries
• Sites: 14

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

Outcome Measures

Primary Outcomes (9)

• 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 567

Secondary Outcomes (52)

• 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 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 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 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: 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

Study Arms (9)

Part 1 (Healthy Volunteers): Crovalimab

EXPERIMENTAL

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.

Drug: Crovalimab

Part 1 (Healthy Volunteers): Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Part 2 (PNH Participants): Crovalimab

EXPERIMENTAL

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.

Drug: Crovalimab

Part 3 (PNH Participants): Crovalimab QW

EXPERIMENTAL

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.

Drug: Crovalimab

Part 3 (PNH Participants): Crovalimab Q2W

EXPERIMENTAL

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.

Drug: Crovalimab

Part 3 (PNH Participants): Crovalimab Q4W

EXPERIMENTAL

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.

Drug: Crovalimab

Part 4 (eculizumab pretreated PNH Participants): Crovalimab

EXPERIMENTAL

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.

Drug: Crovalimab

Part 4 (treatment naïve PNH Participants): Crovalimab

EXPERIMENTAL

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

OLE (PNH Participants): Crovalimab

EXPERIMENTAL

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

Interventions

Crovalimab DRUG

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

OLE (PNH Participants): Crovalimab; Part 1 (Healthy Volunteers): Crovalimab; Part 2 (PNH Participants): Crovalimab; Part 3 (PNH Participants): Crovalimab Q2W; Part 3 (PNH Participants): Crovalimab Q4W; Part 3 (PNH Participants): Crovalimab QW; Part 4 (eculizumab pretreated PNH Participants): Crovalimab; Part 4 (treatment naïve PNH Participants): Crovalimab

Placebo DRUG

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

Part 1 (Healthy Volunteers): Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead
• Chugai Pharmaceutical: collaborator

Study Sites (14)

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

Paris, 75475, France

Location

Uniklinik RWTH Aachen

Aachen, 52074, Germany

Location

Universitätsklinikum Essen

Essen, 45122, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia

Budapest, 1083, Hungary

Location

Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology

Kaposvár, 7400, Hungary

Location

Policlinico Universitario Agostino Gemelli

Rome, Lazio, 00168, Italy

Location

Tohoku University Hospital

Miyagi, 980-8574, Japan

Location

Osaka University Hospital

Osaka, 565-0871, Japan

Location

NTT Medical Center Tokyo

Tokyo, 141-8625, Japan

Location

Tokyo Medical University Hospital

Tokyo, 160-0023, Japan

Location

University of Tsukuba Hospital

Tsukuba, 305-8576, Japan

Location

Pra International Group B.V

Groningen, 9713 GZ, Netherlands

Location

Seoul National University Hosp

Seoul, 110-744, South Korea

Location

Related Publications (1)

• 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.

  PMID: 31978221 DERIVED

Related Links

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

MeSH Terms

Conditions

Hemoglobinuria, Paroxysmal

Condition Hierarchy (Ancestors)

Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2016
• First Posted: May 17, 2017
• Study Start: November 14, 2016
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: February 17, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); FR (1); DE (3); NL (1); KR (1); JP (5); HU (2)