Autoimmune and Chronic Inflammatory Diseases
Conditions
Keywords
Remibrutinib (LOU064), Renal impairment, PK, Safety, Tolerability
Brief summary
The purpose of this study is to support the development of remibrutinib dosing recommendations for patients with impaired renal function.
Detailed description
This is a Phase 1, open-label, non-randomized study to evaluate the PK after five administrations of remibrutinib in participants with severe RI compared to matched healthy control participants with normal renal function.The purpose of this study is to support the development of remibrutinib dosing recommendations for patients with impaired renal function.
Interventions
DRUGremibrutinib
Tablet with oral route of administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: All participants (Group 1 \& 2) * Male and non-childbearing potential female participants 18 to 75 years of age, inclusive, at Screening. * Must be a non-smoker or a light smoker who smokes no more than 10 cigarettes (or equivalent, including use of nicotine products) 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 severe RI (Group 1) * 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. * Seated vital signs must be within the following ranges at Screening and Baseline: 1. body temperature, 35.0 to 37.5°C, inclusive. 2. systolic blood pressure, 90 to 159 mmHg, inclusive. 3. diastolic blood pressure, 60 to 99 mmHg, inclusive. 4. pulse rate, 50 to 99 bpm, inclusive. * Have impaired renal function as determined by eGFR using the CKD-EPI Creatinine - Cystatin C equation (2021), in the following group at Screening: severe RI; eGFR \<30 mL/min, not requiring dialysis. * Have stable renal function with no clinically significant change in renal status prior to first dosing of study treatment as determined by the Investigator and is not currently or has not been previously on hemodialysis for at least 1 year. Participants with other stable medical disorders such as controlled diabetes, hyperlipidemia, hypothyroidism, arterial hypertension 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 2) * Each healthy participant must match the age (± 10 years), body weight (± 20%), race, ethnicity and sex of an individual participant in Group 1. * Must weigh at least 50 kg to participate in the study and must have a BMI within the range of 18.0 to 35.0 kg/m2 inclusive, at Screening. * Must be in good health as determined by medical history, physical examination, ECG, vital signs and clinical laboratory tests at Screening. * Has normal renal function with eGFR greater than or equal to 90 mL/min, determined using the CKD-EPI Creatinine - Cystatin C equation (2021) at Screening. Actual creatinine clearance computed over a 24-hour urine collection may be used in place of or in conjunction with the CKD-EPI Creatinine - Cystatin C equation (2021), at the Investigator's discretion. Key
Exclusion criteria
All participants (Group 1 \& 2) * Use of other investigational drugs within 5 half-lives or 30 days prior to first dosing of study treatment, whichever is longer, as far as known. * History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes. * Use of prescription drugs, OTC medications, or herbal supplements (within the last 2 weeks prior to first dosing, or use of cannabis/marijuana, within the last 4 weeks prior to initial dosing. * Participants not willing to abstain from food and beverages known to inhibit or induce CYP3A4 from 7 days prior to first dosing and until their respective EoS visit. * 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 a history of bone marrow failure or cytopenia will be excluded from the study. * Is on immunosuppressant therapy or immunomodulators therapy less than or equal to 4 weeks prior to first dosing. * Any single parameter of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) exceeding 1.2 x upper limit of normal (ULN) or greater than or equal to 1.5 x ULN total bilirubin (TBL) OR any elevation above ULN of more than one parameter of ALT, AST, GGT, ALP, or TBL. * Known or suspected diagnosis of Gilbert's syndrome. Participants with severe RI (Group 1) * Clinically significant abnormal findings in physical examination, ECG, or clinical laboratory evaluations, extending over findings related to the known renal disease. * Participants having had myocardial infarction \< 2 years of Screening are not eligible to participate, participants having had myocardial infarction greater than or equal to 2 years of Screening can be eligible to participate. * Clinically significant illness within 2 weeks prior to first dosing that may jeopardize safety of the study participant and/or alter the study results as judged by the Investigator. * Participants with end stage renal disease requiring dialysis. Healthy control participants (Group 2) * Any clinical laboratory parameters (e.g. hemoglobin, platelets, leukocytes, neutrophils) outside of local laboratory ranges at Screening unless judged not clinically significant by the Investigator. * Significant illness which has not resolved within 2 weeks prior to first dosing of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax, ss of remibrutinib in blood | Up to 72 hours postdose | The maximum (peak) observed concentration following multiple-dose administration |
| AUCtau,ss of remibrutinib in blood | Up to 72 hours postdose | The area under the curve (AUC) from time zero to the end of the dosing interval (tau) following multiple-dose administration |
| Ae0-12h,ss of remibrutinib in urine | Up to 12 hours postdose | Amount of unchanged drug excreted in the urine collection interval from time zero to 12 hours following multiple-dose administration |
| CLr,ss of remibrutinib in urine | Up to 12 hours postdose | Renal clearance following multiple-dose administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events and serious adverse events | From Day 1 to end of study (up to 30 days after last administration of study treatment) | Number of participants with adverse events and serious adverse events |
| Plasma protein binding of remibrutinib (unbound fraction) | 1 hour postdose | Fraction unbound based on protein binding data |
| Cmax,ss,u of remibrutinib in plasma | Up to 72 hours post dose | The maximum (peak) observed unbound plasma drug concentration following multiple-dose administration |
| AUCtau,ss,u of remibrutinib in plasma | Up to 72 hours post dose | The unbound AUC calculated to the end of a dosing interval (tau) following multiple dose administration |
| AUClast,ss,u of remibrutinib in plasma | Up to 72 hours post dose | The AUC from time zero to the last measurable unbound concentration sampling time (tlast) following multiple-dose administration |
| AUClast,ss of remibrutinib in blood | Up to 72 hours postdose | The AUC from time zero to the last measurable concentration sampling time |
| Tmax,ss of remibrutinib in blood | Up to 72 hours postdose | The time to reach maximum (peak) concentration following multiple-dose administration |
| T1/2 of remibrutinib in blood | Up to 72 hours postdose | The elimination half-life associated with the terminal slope |
| CL/F,ss of remibrutinib in blood | Up to 72 hours postdose | Oral clearance following multiple-dose administration |
Countries
United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed