Clinical trial NCT03157635: Study to Assess Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Healthy Volunteers and Participants With Paroxysmal Nocturnal Hemoglobinuria
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Paroxysmal Hemoglobinuria, Nocturnal
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Chugai Pharmaceutical
First posted: 2017-05-17
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Part 1: Percentage of Participants With Dose-Limiting Events (DLEs)
timeFrame: Baseline up to approximately 3 months
measure: Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to approximately 3 months
measure: Part 2: Percentage of Participants With AEs and SAEs
timeFrame: Baseline up to approximately 8 months
measure: Part 3: Percentage of Participants With AEs and SAEs
timeFrame: Baseline up to approximately 8 months
measure: Part 4: Percentage of Participants With AEs and SAEs
timeFrame: Baseline up to approximately 8 months
measure: Part 2: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
timeFrame: Baseline up to Day 224
measure: Part 3: Terminal Complement Activity as Assessed by Ex Vivo Liposome Lysis in Serum Using the LIA
timeFrame: Baseline up to Day 224
measure: Part 4: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
timeFrame: Baseline up to Day 224
measure: OLE: Percentage of Participants With AEs and SAEs
timeFrame: OLE: Week 21 up to Week 567
Secondary outcomes:
measure: Part 1: Terminal Complement Activity as Assessed by Ex Vivo Liposome Immunoassay (LIA)
timeFrame: 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)
measure: Part 2: Serum Lactate Dehydrogenase (LDH) Levels
timeFrame: 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
measure: Part 3: Serum LDH Levels
timeFrame: 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
measure: Part 4: Serum LDH Levels
timeFrame: 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
measure: Part 1: Total Complement Component 5 (C5) Concentration
timeFrame: 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
measure: Part 2: Total C5 Concentration
timeFrame: 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
measure: Part 3: Total C5 Concentration
timeFrame: 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
measure: Part 4: Total C5 Concentration
timeFrame: 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
measure: Part 1: Free C5 Concentration
timeFrame: 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
measure: Part 2: Free C5 Concentration
timeFrame: 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
measure: Part 3: Free C5 Concentration
timeFrame: 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
measure: Part 4: Free C5 Concentration
timeFrame: 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
measure: Part 2: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Day 64
timeFrame: Baseline, Day 64
measure: Part 3: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 50, 78, 106, and 134
timeFrame: Baseline, Day 8, 22, 50, 78, 106, 134
measure: Part 4: Change From Baseline in Fatigue as Measured by FACIT-Fatigue Scale Score at Day 8, 22, 57, 85, 113 and 134
timeFrame: Baseline, Day 8, 22, 57, 85, 113, 134
measure: 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
timeFrame: Baseline, Day 64
measure: Part 3: Change From Baseline in HRQoL as Measured by EORTC QLQ-C30 Score at Day 78 and 134
timeFrame: Baseline, Day 78, 134
measure: Part 4: Change From Baseline in HRQoL as Measured by EORTC QLQC30 Score at Day 85 and 134
timeFrame: Baseline, Day 85, 134
measure: Part 2: Participant Treatment Satisfaction as Measured by Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Day 8, 22, 36, 50 and 64
timeFrame: Baseline, Day 8, 22, 36, 50, 64
measure: Part 3: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 50
timeFrame: Baseline, Day 8, 50
measure: Part 4: Participant Treatment Satisfaction as Measured by TSQM Score at Day 8 and 57
timeFrame: Baseline, Day 8, 57
measure: Part 2: Number of Packed Red Blood Cell (RBC) Units Transfused per Participant
timeFrame: Baseline up to Day 224
measure: Part 3: Number of Packed RBCs Units Transfused per Participant
timeFrame: Baseline up to Day 224
measure: Part 4: Number of Packed RBCs Units Transfused per Participant
timeFrame: Baseline up to Day 224
measure: Part 2: Percentage of Participants With Packed RBC Units Transfused
timeFrame: Baseline up to Day 224
measure: Part 3: Percentage of Participants With Packed RBC Units Transfused
timeFrame: Baseline up to Day 224
measure: Part 4: Percentage of Participants With Packed RBC Units Transfused
timeFrame: Baseline up to Day 224
measure: Part 1: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab
timeFrame: Part 1: Day 1 up to Day 91 (assessed at predose [Hour 0] on Day 1; on Days 14, 28, 56, 84, and 91)
measure: Part 2: Percentage of Participants With ADAs to Crovalimab
timeFrame: Part 2: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 50, 106, 134); Days 29, 224
measure: Part 3: Percentage of Participants With ADAs to Crovalimab
timeFrame: Part 3: Day 1 up to Day 106 assessed at predose [Hour 0] on Days 1, 8, 29, 64, and 106; Day 224
measure: Part 4: Percentage of Participants With ADAs to Crovalimab
timeFrame: Day 1 up to Day 224 (assessed at predose [Hour 0] on Days 1, 8, 29, 113); Days 134, 224
measure: OLE: Total C5 Concentration
timeFrame: OLE: Predose (Hour 0) on Week 36 up to Week 521
measure: OLE: Serum LDH Levels
timeFrame: OLE: Predose (Hour 0) on Week 28 up to Week 521
measure: OLE: Terminal Complement Activity in Serum as Assessed by Ex Vivo Liposome Immunoassay (LIA)
timeFrame: OLE: Week 36 up to Week 521
measure: Part 2: Percentage of Participants With LDH Below Upper Limit of Normal (ULN)
timeFrame: Baseline up to Day 224
measure: Part 3: Percentage of Participants With LDH Below ULN
timeFrame: Baseline up to Day 224
measure: Part 4: Percentage of Participants With LDH Below ULN
timeFrame: Baseline up to Day 224
measure: Part 2: Percentage of Participants With Complement Suppression
timeFrame: Baseline up to Day 134
measure: Part 3: Percentage of Participants With Complement Suppression
timeFrame: Baseline up to Day 134
measure: Part 4: Percentage of Participants With Complement Suppression
timeFrame: Baseline up to Day 134
measure: Part 2: Monthly Rate of pRBC Transfusions per Participant
timeFrame: Baseline up to 10 years
measure: Part 3: Monthly Rate of pRBC Transfusions per Participant
timeFrame: Baseline up to 10 years
measure: Part 4: Monthly Rate of pRBC Transfusions per Participant
timeFrame: Baseline up to 10 years
measure: Part 2: Proportion of Transfusion-Free Participants
timeFrame: Baseline up to 10 years
measure: Part 3: Proportion of Transfusion-Free Participants
timeFrame: Baseline up to 10 years
measure: Part 4: Proportion of Transfusion-Free Participants
timeFrame: Baseline up to 10 years
measure: Part 2: Annual Rate of Transfusion Avoidance per Participant
timeFrame: Baseline up to 10 years
measure: Part 3: Annual Rate of Transfusion Avoidance per Participant
timeFrame: Baseline up to 10 years
measure: Part 4: Annual Rate of Transfusion Avoidance per Participant
timeFrame: Baseline up to 10 years
measure: Part 2: Annual Rate of Breakthrough Hemolysis (BTH)
timeFrame: Baseline up to 10 years
measure: Part 3: Annual Rate of Breakthrough Hemolysis (BTH)
timeFrame: Baseline up to 10 years
measure: Part 4: Annual Rate of Breakthrough Hemolysis (BTH)
timeFrame: Baseline up to 10 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut hematologie Centre Hayem CHU paris Saint-Louis Lariboisiere F Widal Hopital St Louis
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Budapest
country: Hungary
facility: Semmelweis Egyetem, 1. Szamu Belgyogyaszati Klinika, Diabetologia
city: Kaposvar
country: Hungary
facility: Kaposi Mor Teaching Hospital, Dept of Internal Medicine/Hematology
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
state: Lazio
city: Miyagi
country: Japan
facility: Tohoku University Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Tokyo
country: Japan
facility: NTT Medical Center Tokyo
city: Tokyo
country: Japan
facility: Tokyo Medical University Hospital
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hosp
city: Groningen
country: Netherlands
facility: Pra International Group B.V
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
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.