A Study to Assess Safety, Effectiveness, Pharmacokinetics, and Pharmacodynamics of RO7112689 in Healthy Volunteers and Patients with Paroxysmal Nocturnal Hemoglobinuria

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients, Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

21 Apr 2017 → ongoing

Decision date (initial)

2024-01-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche AG

External identifiers

EU CT number

2023-506287-14-00

EudraCT number

2016-002128-10

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Pharmacodynamic, Efficacy

1. Part 1:
•Evaluate the safety and tolerability of single doses of crovalimab in healthy
volunteers (HVs)

Part 2, 3, and 4:
• Evaluate the safety and tolerability of RO7112689 for a total duration of 5 months in treatment naïve patients with PNH and PNH patients switching treatment to crovalimab
• Evaluate the pharmacodynamic (PD) effect of multiple doses of crovalimab on complement activity in patients with PNH

Open Label Extension (OLE):
• Assess the long term safety of crovalimab

Secondary objectives 10

1. 1. Part 1: Characterize the PD effects of a single-dose of crovalimab on complement activity and other related biomarkers
2. 2. Part 1: Describe the single-dose pharmacokinetic (PK) profile of crovalimab
3. 3. Part 1: Assess the bioavailability of subcutaneous (SC) administration of crovalimab
4. 4. Parts 2, 3, and 4: Describe the multiple-dose PK properties of crovalimab in treatment naïve patients with PNH and PNH patients switching treatment to crovalimab
5. 5. Parts 2, 3, and 4: Characterize other PD effects of crovalimab
6. 6. Parts 2, 3, and 4: Characterize the exposure-response relationship of crovalimab following different SC dosing regimens
7. 7. Parts 2, 3, and 4: Assess the efficacy, patient-related outcomes and treatment satisfaction of crovalimab in treatment naïve patients with PNH, and/or PNH patients switching treatment to crovalimab
8. 8. Parts 1, 2, 3, and 4: Explore the PK/PD relationship of single-ascending and multiple doses of crovalimab on complement activity and other related biomarkers
9. 9. Parts 1, 2, 3, and 4: Evaluate the immunogenicity of crovalimab in HVs and in patients with PNH
10. 10. Open-label extension (OLE): Assess the long term safety of RO7112689 crovalimab

Conditions and MedDRA coding

Paroxysmal nocturnal hemoglobinuria (PNH)

Study design 5 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 1. Part 1 (HVs only) • Healthy male volunteers between the age of 21 and 55 years • Neisseria meningitidis vaccination against serogroups B and A, C, W, and Y • Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result are eligible for the study • Subjects who have been vaccinated against hepatitis B • Willing to comply with a non-smoking policy during the in-clinic portion of the study
2. 2. Parts 2, 3, and 4 (PNH patients only) • Male or female patients between the age of 18 and 75 years • Neisseria meningitidis vaccination in accordance with most current local guidelines or Standard of Care (SOC) for patients at increased risk for meningococcal disease (Part 2 and Part 4 Arm A) • Patient has been vaccinated with Neisseria meningtidis vaccine(s) in accordance with most current local guidelines or SOC for patients at increased risk for meningococcal disease or is being revaccinated if applicable (Part 3 and Part 4 Arm B) • Stable dose for >= 28 days prior to screening of other therapies (immunosuppressant therapy, corticosteroids, iron supplements) • Negative pregnancy test for women of childbearing potential
3. 3. Part 2 and Part 4 Arm A only (currently untreated PNH patients who are candidates for treatment with complement inhibitors only) • Hepatitis B patients can be enrolled if their LFT values are less than 2 × upper limit of normal (ULN) and there is no liver function impairment. • PNH patients 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
4. 4. Part 3 and Part 4 Arm B only (PNH patients currently treated with eculizumab only) • Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result are eligible for the study. o Subjects sero positive for HCV but adequately treated without detectable HCV RNA are eligible o Subjects who have been vaccinated against hepatitis B are eligible o Subjects sero positive for HBV but adequately treated without detectable HBV DNA are eligible • Patients are adequately controlled based on investigator opinion) • Patients receive regular infusions of eculizumab
5. 5. OLE only – PNH patients • PNH patients who have completed Parts 2, 3, and 4 respectively • PNH patients who derived, in the Investigator’s opinion, benefit from treatment with crovalimab • For women who are not post-menopausal and have not undergone surgical sterilization agreement to remain abstinent or use a contraception method that results in a failure rate of <1% per year, during the treatment period and for 5.5 half-lives or at least 10.5 months after the last dose of crovalimab • Vaccination currency for Neisseria meningitidis serotypes A, C, W, Y and B should be maintained throughout the OLE, according to local guidelines or SOC as applicable in patients with complement deficiency. In the absence of clear local guidelines for Neisseria meningitidis, the Advisory Committee on Immunization Practices (ACIP) 2020 Guidelines are recommended

Exclusion criteria 4

1. 1. Parts 1, 2, 3, and 4: • Known or suspected hereditary complement deficiency • History of meningococcal meningitis • 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 HIV 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
2. 2. Part 1 - HVs only: • Any clinically relevant history or the presence of moderate to severe respiratory, renal, hepatic, gastrointestinal, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, or connective tissue disease. • Any major illness within one month before the screening examination or any febrile illness within 2 weeks prior to screening and up to first study drug administration. • Prior splenectomy • History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease • Congenital or acquired complement deficiency • Carriers of Neisseria meningitidis based on cultures from naso-pharyngeal swabs
3. 3. Parts 2, 3, and 4 - PNH patients 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 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
4. 4. Parts 3 and 4 Arm B (PNH patients only): • Any evidence of seropositive auto-immune connective tissue diseases • Any evidence of active inflammatory conditions

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. 1. Safety (Parts 1, 2, 3, and 4): Incidence of dose-limiting events
2. 2. Safety (Parts 1, 2, 3, and 4): Incidence and severity of adverse events (AEs), serious adverse events and AEs leading to withdrawal
3. 3. PD (Parts 1, 2, 3, and 4): Ex vivo liposome lysis in serum and ex-vivo lysis of antibody-coated erythrocytes
4. 4. PD (Parts 1, 2, 3, and 4): Total and target engaged C5 concentration
5. 5. PD (Parts 1, 2, 3, and 4): Serum Lactate Dehydrogenase (LDH)

Secondary endpoints 10

1. 1. Efficacy (Parts 2, 3, and 4): Change in LDH
2. 2. Efficacy (Parts 2, 3, and 4): Change in free-haemoglobin
3. 3. Efficacy (Parts 2, 3, and 4): Proportion of patients with stabilized haemoglobin levels
4. 4. Efficacy (Parts 2, 3, and 4): Change in fatigue as measured by the functional assessment of chronic illness therapy fatigue
5. 5. Efficacy (Parts 2, 3, and 4): Change in health-related quality of life as measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30
6. 6. Efficacy (Parts 2, 3, and 4): Number of packed RBC units transfused per patient
7. 7. Efficacy (Parts 2, 3, and 4): Time to (1) first transfusion or (2) persistent elevation of LDH
8. 8. Efficacy (Parts 2, 3, and 4): Proportion of patients with LDH below upper limit of normal (ULN)
9. 9. Efficacy (Parts 2, 3, and 4): Proportion of patients with complement suppression throughout the dosing interval
10. 10. PK (Parts 1, 2, 3, and 4): Pharmacokinetic profile of crovalimab Cmax, Tmax, Area under the curve (AUC), T1/2, bioavailability following SC administration

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 4

Locations

4 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications