A Study to Investigate the Pharmacokinetics and Safety of Remibrutinib in Participants With Hepatic Impairment Compared With Matched Healthy Participants

• ClinicalTrials.gov Identifier: NCT05753592
• Recruitment Status: Recruiting
• First Posted: March 3, 2023
• Last Update Posted: May 6, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This study will be conducted in 2 parts. Part 1 will comprise of participants with mild and moderate HI and matching healthy control participants with normal hepatic function. Part 2 will comprise of participants with severe HI and matching healthy control participants with normal hepatic function.

Each study part will comprise of a screening period of up to 28 days, a baseline evaluation on Day -1, and a treatment period including up to 8 days of safety and PK data collection. Participants will be domiciled from Day -1 through Day 8.

All participants will receive 25 mg remibrutinib b.i.d. orally on Days 1 and 2, and a morning oral dose of 25 mg remibrutinib on Day 3. PK samples will be collected pre dose on Day 3 and until 72 hours post Day 3 dosing. Throughout the study, safety assessments will include physical examinations, ECGs, vital signs, clinical laboratory evaluations (hematology, chemistry, urinalysis and coagulation) and AE / serious adverse event (SAE) monitoring.

The Investigator and Novartis will conduct a joint interim review of safety and PK data from Part 1 before proceeding to Part 2.

Part 2 will only begin if administration of remibrutinib in Part 1 is deemed safe and tolerable by the Investigator and Novartis to proceed in participants with severe HI. Depending on the outcome of the interim review, administration of a lower dose of remibrutinib in severe HI participants and their matching healthy control participants may be considered.

Part 2 will also include sentinel dosing where one participant with severe HI will receive the first dose of remibrutinib at least 1 week before the remaining participants. If the Investigator concludes that there are no emergent safety concerns for the sentinel participant, then dosing will commence for the remaining participants.

Study Completion evaluations will occur on Day 8, followed by a post-study safety follow up contact (e.g. follow-up telephone call, email) approximately 30 days after the last administration of study treatment. The total study duration for each participant is expected to be up to approximately 62 days, including the Screening period and the follow-up contact.

Condition or disease	Intervention/treatment	Phase
Hepatic Impairment	Drug: Part 1; LOU064 (Remibrutinib); Drug: Part 2; LOU064 (Remibrutinib)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Study to Investigate the Pharmacokinetics and Safety of Remibrutinib (LOU064) in Participants With Hepatic Impairment Compared to Matched Healthy Participants With Normal Hepatic Function
• Actual Study Start Date: October 31, 2022
• Estimated Primary Completion Date: May 19, 2023
• Estimated Study Completion Date: May 19, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1; LOU064 (Remibrutinib); Mild and Moderate HI participants and matching healthy participants	Drug: Part 1; LOU064 (Remibrutinib); 25 mg remibrutinib (5.5 days)
Experimental: Part 2; LOU064 (Remibrutinib); Severe HI participants and matching healthy participants	Drug: Part 2; LOU064 (Remibrutinib); 25 mg remibrutinib (5.5 days)

Outcome Measures

Primary Outcome Measures :

1. Cmax [ Time Frame: 72 hours ]
   The maximum (peak) observed concentration following multiple-dose administration (mass/volume)
2. AUCtau [ Time Frame: 72 hours ]
   The AUC from time zero to the end of the dosing interval (tau) following multiple-dose administration (mass*time/volume)
3. AUClast [ Time Frame: 72 hours ]
   The area under the curve (AUC) from time zero to the last measurable concentration sampling time (mass*time/volume)
4. Tmax [ Time Frame: 72 hours ]
   The time to reach maximum (peak)concentration following multiple-dose administration (time)
5. T1/2 [ Time Frame: 72 hours ]
   The elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve (time)

Secondary Outcome Measures :

1. Unbound fraction; Cmax [ Time Frame: 8 days ]
   The maximum (peak) observed concentration following multiple-dose administration (mass/volume)
2. Number of participants with adverse events [ Time Frame: 8 days ]
   An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.
3. Unbound fraction; AUCtau [ Time Frame: 8 days ]
   The AUC from time zero to the end of the dosing interval (tau) following multiple-dose administration (mass*time/volume)
4. Unbound fraction; AUClast [ Time Frame: 8 days ]
   The area under the curve (AUC) from time zero to the last measurable concentration sampling time (mass*time/volume)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

All participants

• Male and non-childbearing potential female participants 18 to 70 years of age, inclusive, at Screening.
• Must be a non-smoker or a light smoker who smokes no more than 10 cigarettes (or equivalent) per day, at Screening. Smokers must agree to smoke no more than 5 cigarettes (or equivalent) per day from check-in until after Study Completion evaluations.

Participants with mild, moderate and severe HI (Groups 1, 2 and 3)

• Must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18.0 to 35.0 kg/m2, inclusive, at Screening.
• Has impaired hepatic function as defined by the Child-Pugh classification for severity of liver disease and has a Child-Pugh score in line with one of the following HI groups at Screening:
• Group 1; mild (Class A); Child-Pugh score 5-6, inclusive.
• Group 2; moderate (Class B); Child-Pugh score 7-9, inclusive.
• Group 3; severe (Class C); Child-Pugh score 10-15, inclusive.
• Participants with other stable medical disorders such as controlled diabetes, hyperlipidemia, hypothyroidism, etc., may be eligible as long as they are considered appropriate for enrollment as determined by the Investigator by past medical history, physical examination, ECG and clinical laboratory tests at Screening.

Healthy control participants (Group 4)

• Each healthy participant must match the age (± 10 years) and body weight (± 20%) of participants in Groups 1 and 2 (Part 1) and/or Group 3 (Part 2).
• Must be in good health as determined by medical history, physical examination, ECG and clinical laboratory tests at Screening.

Exclusion Criteria:

All participants

• History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
• History or presence of malignancy of any organ system (other than treated localized basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years of Screening, regardless of whether there is evidence of local recurrence or metastases.
• History or presence of any ongoing, chronic or recurrent infectious disease (including tuberculosis, atypical mycobacterioses, listeriosis, aspergillosis).

Participants with mild and moderate HI (Groups 1 and 2)

• Severe complications of liver disease within the preceding 3 months of Screening.
• Emergency room visit or hospitalization due to liver disease within the preceding 3 months of Screening.
• Has received liver transplant at any time in the past and/or is on immunosuppressant therapy at Screening.
• Clinically significant abnormal findings in physical examination, ECG or clinical laboratory evaluations, not consistent with known liver disease. Participants having had myocardial infarction < 5 years of Screening are not eligible to participate, participants having had myocardial infarction ≥ 5 years of Screening can be eligible to participate.

Participants with severe HI (Group 3)

• Severe complications of liver disease within the preceding 3 months of Screening.
• Emergency room visit or hospitalization due to liver disease within the preceding 1 month of Screening.
• Has received liver transplant at any time in the past and/or is on immunosuppressant therapy at Screening.
• Clinically significant abnormal findings in physical examination, ECG or clinical laboratory evaluations, not consistent with known liver disease. Participants having had myocardial infarction < 5 years of Screening are not eligible to participate, participants having had myocardial infarction ≥ 5 years of Screening can be eligible to participate.
• Encephalopathy Grade 3 or worse within 28 days of planned first dosing of study treatment.
• Serum ammonia level > 200 μg/dL at Screening or Baseline.
• INR > 2.3 at Screening or Baseline.
• Transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting.Documented presence of esophagus varices (stage III or IV) based on the evaluation of the participant's medical history at Screening and Baseline.
• History, clinical evidence or suspicion of a hepato-cellular carcinoma (HCC) based on sonographical and/or laboratory results (i.e. α-Fetoprotein (AFP) > 12 IU/mL [2 × upper limit of normal [ULN] at screening).
• Severe ascites and/or pleural effusion.
• Participants with clinical evidence or suspected acute liver failure as judged by the Investigator.

Healthy control participants (Group 4)

• Significant illness which has not resolved within 2 weeks prior to first dosing of study treatment.
• Liver disease or liver injury as indicated by abnormal liver function tests at Screening. Any single parameter of alanine aminotransferase (ALT), AST, gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) exceeding 1.2 x upper limit of normal (ULN) or ≥ 1.5 x ULN total bilirubin (TBL) OR any elevation above ULN of more than one parameter of ALT, AST, GGT, ALP or TBL.
• Hemoglobin levels below 11.0 g/dL for males and 10.0 g/dL for females at Screening or Baseline.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals

Locations

Hungary

Novartis Investigative Site; Recruiting

Szikszo, Hungary, 3800

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05753592
• Other Study ID Numbers: CLOU064A2101
• First Posted: March 3, 2023
• Last Update Posted: May 6, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Remibrutinib (LOU064); hepatic impairment; PK, safety; tolerability; Child-Pugh

Additional relevant MeSH terms:

Liver Diseases; Digestive System Diseases; Remibrutinib; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action