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

• Register: EUCTR
• Last refreshed on: 14 October 2024
• Main ID: EUCTR2016-002128-10-FR
• Date of registration: 08/09/2017
• Prospective Registration: No
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A Study to Assess Safety, Effectiveness, Pharmacokinetics, and Pharmacodynamics of RO7112689 in Healthy Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria
• Scientific title: An adaptive Phase I/II study to assess safety, efficacy, pharmacokinetics and pharmacodynamics of RO7112689 in healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH)
• Date of first enrolment: 17/08/2017
• Target sample size: 49
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002128-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Germany, Hungary, Italy, Japan, Korea, Republic of, Netherlands

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
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
Parts 2 and 3 (PNH patients only)
- Male or female patients between the age of 18 and 75 years
- Hepatitis B patients can be enrolled if their LFT values are less than 2 xULN and there is no liver function impairment
- 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)
- Patient has been vaccinated with Neisseria meningitidis 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)
- Stable dose for >= 28 days prior to screening of other therapies
(immunosuppressant therapy, corticosteroids, iron supplements)
- Negative pregnancy test for women of childbearing potential Part 2 only (currently untreated PNH patients who are candidates for treatment with complement inhibitors only):
- 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
Part 3 only (PNH patients currently treated with eculizumab only):
- PNH patients who have been treated continuously with eculizumab for at least 3 months preceding enrollment in the trial
- Patients receive regular infusions of eculizumab
OLE only - PNH patients:
- PNH patients who have completed Parts 2 and 3 respectively
- PNH patients who derived, in the Investigator's opinion, benefit from treatment with RO7112689
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 40
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 9

Exclusion criteria:
Parts 1, 2, and 3:
- 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
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
- History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease
- Congenital or acquired complement deficiency
- Carriers of Neisseria meningitides based on cultures from nasopharyngeal swabs
Parts 2 and 3 (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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Paroxysmal nocturnal hemoglobinuria (PNH)
MedDRA version: 20.0 Level: LLT Classification code 10055629 Term: Paroxysmal nocturnal hemoglobinuria System Organ Class: 100000012950

Intervention(s)

Product Code: RO7112689/F01
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: Not available
CAS Number: 1917321-26-6
Current Sponsor code: RO7112689
Other descriptive name: C5 inh MAb, SKY59, RO/CH7092230
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 170-
Pharmaceutical form of the placebo: Solution for injection/infusion
Route of administration of the placebo: Intravenous use
Pharmaceutical form of the placebo: Solution for injection/infusion
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: Part 1
•Characterize the PD effects of a single-dose of RO7112689 on complement activity (CA) & other related biomarkers
•Describe the single-dose pharmacokinetic (PK) profile of RO7112689
•Assess the bioavailability of subcutaneous (SC) administration of RO7112689
Part 2 & 3
•Describe the multiple-dose PK properties of RO7112689 in treatment naïve patients (Pts) with PNH and PNH Pts switching treatment to RO7112689
•Characterize other PD effects of RO7112689
•Characterize the exposure-response relationship of RO7112689 following different SC dosing regimens
•Assess the efficacy, Pt-related outcomes & treatment satisfaction of RO7112689 in treatment naïve Pts with PNH, and/or PNH Pts switching treatment to RO7112689
Parts 1, 2 & 3
•Explore the PK/PD relationship of single-ascending & multiple doses of RO7112689 on CA & other related biomarkers
•Evaluate the immunogenicity of RO7112689 in HVs and in Pts with PNH
OLE
•Assess long term PK and PD data for RO7112689

Main Objective: Part 1
•Evaluate the safety and tolerability of single doses of RO7112689 in healthy volunteers (HVs)
Part 2 and 3
•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 RO7112689
•Evaluate the pharmacodynamic (PD) effect of multiple doses of RO7112689 on complement activity in patients with PNH
Open Label Extension (OLE)
•Assess the long term safety of RO7112689

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

Timepoint(s) of evaluation of this end point: Safety and PD (Parts 1, 2, and 3):
1-5. Approximately 6 months for Part 1; approximately 8 months for Parts 2 and 3;up to a maximum of two years from entry into OLE

Secondary Outcome(s)

Secondary end point(s): Efficacy (Parts 2 and 3):
1. Change in LDH
2. Change in free-haemoglobin
3. Proportion of patients with stabilized haemoglobin levels
4. Change in fatigue as measured by the functional assessment of chronic illness therapy fatigue
5. 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. Number of packed RBC units transfused per patient
7. Time to (1) first transfusion or (2) persistent elevation of LDH
8. Proportion of patients with LDH below ULN
9. Proportion of patients with complement suppression throughout the dosing interval
PK (Parts 1, 2, and 3):
10. Pharmacokinetic profile of RO7112689; Cmax, Tmax, AUC, T1/2, bioavailability following SC administration

Timepoint(s) of evaluation of this end point: Efficacy and PK (Parts 1, 2, and 3):
1-10. Approximately 6 months for Part 1; approximately 8 months for Parts 2 and 3; up to a maximum of two years from entry into OLE

Secondary ID(s)

2016-002128-10-NL

BP39144

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 11/07/2017
Contact: