search
Back to results

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

Primary Purpose

Paroxysmal Hemoglobinuria, Nocturnal

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Crovalimab
Placebo
Sponsored by
Hoffmann-La Roche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Paroxysmal Hemoglobinuria, Nocturnal

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Placebo Comparator

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Part 1 (Healthy Volunteers): Crovalimab

Part 1 (Healthy Volunteers): Placebo

Part 2 (PNH Participants): Crovalimab

Part 3 (PNH Participants): Crovalimab QW

Part 3 (PNH Participants): Crovalimab Q2W

Part 3 (PNH Participants): Crovalimab Q4W

Part 4 (eculizumab pretreated PNH Participants): Crovalimab

Part 4 (treatment naïve PNH Participants): Crovalimab

OLE (PNH Participants): Crovalimab

Arm Description

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.

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

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.

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Part 1: Percentage of Participants With Dose-Limiting Events (DLEs)
Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Part 2: Percentage of Participants With AEs and SAEs
Part 3: Percentage of Participants With AEs and SAEs
Part 4: Percentage of Participants With AEs and SAEs
Part 2: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Part 3: Terminal Complement Activity as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA
Part 4: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
OLE: Percentage of Participants With AEs and SAEs

Secondary Outcome Measures

Part 1: Terminal Complement Activity as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Part 2: Serum Lactate Dehydrogenase (LDH) Levels
Part 3: Serum LDH Levels
Part 4: Serum LDH Levels
Part 1: Total Complement Component 5 (C5) Concentration
Part 2: Total C5 Concentration
Part 3: Total C5 Concentration
Part 4: Total C5 Concentration
Part 1: Free C5 Concentration
Part 2: Free C5 Concentration
Part 3: Free C5 Concentration
Part 4: Free C5 Concentration
Part 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 64
Part 3: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 50, 78, 106, and 134
Part 4: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 57, 85, 113 and 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 64
Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 78 and 134
Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 85 and 134
Part 2: Participant Treatment Satisfaction as Measured by Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Day 8, 22, 36, 50 and 64
Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 50
Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 57
Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant
Part 3: Number of Packed RBCs Units Transfused per Participant
Part 4: Number of Packed RBCs Units Transfused per Participant
Part 2: Percentage of Participants With Packed RBC Units Transfused
Part 3: Percentage of Participants With Packed RBC Units Transfused
Part 4: Percentage of Participants With Packed RBC Units Transfused
Part 1: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab
Part 2: Percentage of Participants With ADAs to Crovalimab
Part 3: Percentage of Participants With ADAs to Crovalimab
Part 4: Percentage of Participants With ADAs to Crovalimab
OLE: Total C5 Concentration
OLE: Serum LDH Levels
OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN)
Part 3: Percentage of Participants With LDH Below ULN
Part 4: Percentage of Participants With LDH Below ULN
Part 2: Percentage of Participants With Complement Suppression
Part 3: Percentage of Participants With Complement Suppression
Part 4: Percentage of Participants With Complement Suppression
Part 2: Monthly Rate of pRBC Transfusions per Participant
Part 3: Monthly Rate of pRBC Transfusions per Participant
Part 4: Monthly Rate of pRBC Transfusions per Participant
Part 2: Proportion of Transfusion-Free Participants
Part 3: Proportion of Transfusion-Free Participants
Part 4: Proportion of Transfusion-Free Participants
Part 2: Annual Rate of Transfusion Avoidance per Participant
Part 3: Annual Rate of Transfusion Avoidance per Participant
Part 4: Annual Rate of Transfusion Avoidance per Participant
Part 2: Annual Rate of Breakthrough Hemolysis (BTH)
Part 3: Annual Rate of Breakthrough Hemolysis (BTH)
Part 4: Annual Rate of Breakthrough Hemolysis (BTH)

Full Information

First Posted
November 1, 2016
Last Updated
September 4, 2023
Sponsor
Hoffmann-La Roche
Collaborators
Chugai Pharmaceutical
search

1. Study Identification

Unique Protocol Identification Number
NCT03157635
Brief Title
Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria
Acronym
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)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 14, 2016 (Actual)
Primary Completion Date
March 31, 2031 (Anticipated)
Study Completion Date
June 10, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
Collaborators
Chugai Pharmaceutical

4. Oversight

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Hemoglobinuria, Nocturnal

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
59 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1 (Healthy Volunteers): Crovalimab
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 1 (Healthy Volunteers): Placebo
Arm Type
Placebo Comparator
Arm Description
Healthy participants will receive a single dose of crovalimab matching placebo in each dose-escalation cohort of Part 1.
Arm Title
Part 2 (PNH Participants): Crovalimab
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 3 (PNH Participants): Crovalimab QW
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 3 (PNH Participants): Crovalimab Q2W
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 3 (PNH Participants): Crovalimab Q4W
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 4 (eculizumab pretreated PNH Participants): Crovalimab
Arm Type
Experimental
Arm Description
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.
Arm Title
Part 4 (treatment naïve PNH Participants): Crovalimab
Arm Type
Experimental
Arm Description
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.
Arm Title
OLE (PNH Participants): Crovalimab
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Crovalimab
Intervention Description
Crovalimab will be administered as per schedule described in individual arm.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo will be administered as per schedule described in Part 1 placebo arm.
Primary Outcome Measure Information:
Title
Part 1: Percentage of Participants With Dose-Limiting Events (DLEs)
Time Frame
Baseline up to approximately 3 months
Title
Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame
Baseline up to approximately 3 months
Title
Part 2: Percentage of Participants With AEs and SAEs
Time Frame
Baseline up to approximately 8 months
Title
Part 3: Percentage of Participants With AEs and SAEs
Time Frame
Baseline up to approximately 8 months
Title
Part 4: Percentage of Participants With AEs and SAEs
Time Frame
Baseline up to approximately 8 months
Title
Part 2: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Time Frame
Baseline up to Day 224
Title
Part 3: Terminal Complement Activity as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA
Time Frame
Baseline up to Day 224
Title
Part 4: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Time Frame
Baseline up to Day 224
Title
OLE: Percentage of Participants With AEs and SAEs
Time Frame
OLE: Week 21 up to Week 567
Secondary Outcome Measure Information:
Title
Part 1: Terminal Complement Activity as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Time Frame
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)
Title
Part 2: Serum Lactate Dehydrogenase (LDH) Levels
Time Frame
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
Title
Part 3: Serum LDH Levels
Time Frame
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
Title
Part 4: Serum LDH Levels
Time Frame
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
Title
Part 1: Total Complement Component 5 (C5) Concentration
Time Frame
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
Title
Part 2: Total C5 Concentration
Time Frame
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
Title
Part 3: Total C5 Concentration
Time Frame
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
Title
Part 4: Total C5 Concentration
Time Frame
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
Title
Part 1: Free C5 Concentration
Time Frame
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
Title
Part 2: Free C5 Concentration
Time Frame
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
Title
Part 3: Free C5 Concentration
Time Frame
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
Title
Part 4: Free C5 Concentration
Time Frame
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
Title
Part 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 64
Time Frame
Baseline, Day 64
Title
Part 3: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 50, 78, 106, and 134
Time Frame
Baseline, Day 8, 22, 50, 78, 106, 134
Title
Part 4: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 57, 85, 113 and 134
Time Frame
Baseline, Day 8, 22, 57, 85, 113, 134
Title
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
Time Frame
Baseline, Day 64
Title
Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 78 and 134
Time Frame
Baseline, Day 78, 134
Title
Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 85 and 134
Time Frame
Baseline, Day 85, 134
Title
Part 2: Participant Treatment Satisfaction as Measured by Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Day 8, 22, 36, 50 and 64
Time Frame
Baseline, Day 8, 22, 36, 50, 64
Title
Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 50
Time Frame
Baseline, Day 8, 50
Title
Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 57
Time Frame
Baseline, Day 8, 57
Title
Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant
Time Frame
Baseline up to Day 224
Title
Part 3: Number of Packed RBCs Units Transfused per Participant
Time Frame
Baseline up to Day 224
Title
Part 4: Number of Packed RBCs Units Transfused per Participant
Time Frame
Baseline up to Day 224
Title
Part 2: Percentage of Participants With Packed RBC Units Transfused
Time Frame
Baseline up to Day 224
Title
Part 3: Percentage of Participants With Packed RBC Units Transfused
Time Frame
Baseline up to Day 224
Title
Part 4: Percentage of Participants With Packed RBC Units Transfused
Time Frame
Baseline up to Day 224
Title
Part 1: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab
Time Frame
Part 1: Day 1 up to Day 91 (assessed at predose [Hour 0] on Day 1; on Days 14, 28, 56, 84, and 91)
Title
Part 2: Percentage of Participants With ADAs to Crovalimab
Time Frame
Part 2: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 50, 106, 134); Days 29, 224
Title
Part 3: Percentage of Participants With ADAs to Crovalimab
Time Frame
Part 3: Day 1 up to Day 106 assessed at predose [Hour 0] on Days 1, 8, 29, 64, and 106; Day 224
Title
Part 4: Percentage of Participants With ADAs to Crovalimab
Time Frame
Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 29, 113); Days 134, 224
Title
OLE: Total C5 Concentration
Time Frame
OLE: Predose (Hour 0) on Week 36 up to Week 521
Title
OLE: Serum LDH Levels
Time Frame
OLE: Predose (Hour 0) on Week 28 up to Week 521
Title
OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
Time Frame
OLE: Week 36 up to Week 521
Title
Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN)
Time Frame
Baseline up to Day 224
Title
Part 3: Percentage of Participants With LDH Below ULN
Time Frame
Baseline up to Day 224
Title
Part 4: Percentage of Participants With LDH Below ULN
Time Frame
Baseline up to Day 224
Title
Part 2: Percentage of Participants With Complement Suppression
Time Frame
Baseline up to Day 134
Title
Part 3: Percentage of Participants With Complement Suppression
Time Frame
Baseline up to Day 134
Title
Part 4: Percentage of Participants With Complement Suppression
Time Frame
Baseline up to Day 134
Title
Part 2: Monthly Rate of pRBC Transfusions per Participant
Time Frame
Baseline up to 10 years
Title
Part 3: Monthly Rate of pRBC Transfusions per Participant
Time Frame
Baseline up to 10 years
Title
Part 4: Monthly Rate of pRBC Transfusions per Participant
Time Frame
Baseline up to 10 years
Title
Part 2: Proportion of Transfusion-Free Participants
Time Frame
Baseline up to 10 years
Title
Part 3: Proportion of Transfusion-Free Participants
Time Frame
Baseline up to 10 years
Title
Part 4: Proportion of Transfusion-Free Participants
Time Frame
Baseline up to 10 years
Title
Part 2: Annual Rate of Transfusion Avoidance per Participant
Time Frame
Baseline up to 10 years
Title
Part 3: Annual Rate of Transfusion Avoidance per Participant
Time Frame
Baseline up to 10 years
Title
Part 4: Annual Rate of Transfusion Avoidance per Participant
Time Frame
Baseline up to 10 years
Title
Part 2: Annual Rate of Breakthrough Hemolysis (BTH)
Time Frame
Baseline up to 10 years
Title
Part 3: Annual Rate of Breakthrough Hemolysis (BTH)
Time Frame
Baseline up to 10 years
Title
Part 4: Annual Rate of Breakthrough Hemolysis (BTH)
Time Frame
Baseline up to 10 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
Centre Hospitalier Lyon Sud
City
Pierre Benite
ZIP/Postal Code
69495
Country
France
Facility Name
Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Universitätsklinikum Essen; Klinik für Hämatologie
City
Essen
ZIP/Postal Code
45122
Country
Germany
Facility Name
Elblandklinikum Riesa; Klinik fuer Haematologie Onkologie und Gastroenterologie
City
Riesa
ZIP/Postal Code
01589
Country
Germany
Facility Name
Universitätsklinikum Ulm; Institut für Klinische Transfusionsmedizin
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia
City
Budapest
ZIP/Postal Code
1083
Country
Hungary
Facility Name
Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology
City
Kaposvar
ZIP/Postal Code
7400
Country
Hungary
Facility Name
A.O. UNIVERSITARIA FEDERICO II DI NAPOLI;Dipartimento di Medicina Clinica e Chirurgia
City
Napoli
State/Province
Campania
ZIP/Postal Code
80136
Country
Italy
Facility Name
Policlinico Universitario Agostino Gemelli
City
Roma
State/Province
Lazio
ZIP/Postal Code
00168
Country
Italy
Facility Name
Ospedale Di Vicenza; Nefrologia, Ematologia
City
Vicenza
State/Province
Veneto
ZIP/Postal Code
36100
Country
Italy
Facility Name
Tohoku University Hospital
City
Miyagi
ZIP/Postal Code
980-8574
Country
Japan
Facility Name
Osaka University Hospital; Hematology and Oncology
City
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
NTT Medical Center Tokyo
City
Tokyo
ZIP/Postal Code
141-8625
Country
Japan
Facility Name
Tokyo Medical University Hospital
City
Tokyo
ZIP/Postal Code
160-0023
Country
Japan
Facility Name
University of Tsukuba Hospital; Hematology
City
Tsukuba
ZIP/Postal Code
305-8576
Country
Japan
Facility Name
Severance Hospital, Yonsei University Health System
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Name
Seoul National University Hosp; Dept Internal Med Hem Onc
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Facility Name
Pra International Group B.V
City
Groningen
ZIP/Postal Code
9728 NZ
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/innovation/process/clinical -trials/data-sharing/)
Citations:
PubMed Identifier
31978221
Citation
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.
Results Reference
derived
Links:
URL
https://www.pioneeringhealthcare.com/pnh/
Description
Adaptive clinical trial to assess safety, efficacy, PK and PD of crovalimab in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Learn more about this trial

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

We'll reach out to this number within 24 hrs