Clinical trial NCT03920865: A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function
Official title: An Open-Label, Single-Dose, Parallel-Group, Two-Part Study to Evaluate the Pharmacokinetics and Safety of Risdiplam in Subjects With Mild or Moderate Hepatic Impairment Compared to Subjects With Normal Hepatic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Muscular Atrophy, Spinal
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-04-19
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multi-center, open-label, non-randomized, parallel-group, 2-part study to evaluate the effect of hepatic impairment on the PK and safety and tolerability of a single oral dose of risdiplam compared to matched healthy participants with normal hepatic function.


Eligibility criteria: Inclusion Criteria:

All Participants:

* BMI between 18.0 and 36.0 kilograms per square metre (kg/m2), inclusive, and body weight \> / = 50 kg
* Females must not be pregnant or lactating and must be of non-childbearing potential
* Male participants (whether surgically sterilized or not) with female partners of childbearing potential must use methods of contraception from Screening until 4 months after their dose of the study drug as detailed in the protocol
* Male participants must not donate sperm from Check-in (Day -1) until 4 months after their dose of the study drug

Participants with Normal Hepatic Function Only:

* Matched to participants with mild or moderate hepatic function in sex, age, BMI, and smoking status
* In good health, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations

Participants with Hepatic Impairment Only:

* Documented chronic stable liver disease
* Currently on a stable medication regimen, defined as not starting new drug(s) or changing drug dose(s) within 3 months of administration of study drug
* Anemia secondary to hepatic disease will be acceptable, if hemoglobin \>/= 9 gram per decilitre (g/dL). Participants must have a platelet count \</= 35 000 platelets

Exclusion Criteria:

All Participants

* Significant history or clinical manifestation of any metabolic, allergic, dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder
* History of significant hypersensitivity, intolerance, or allergy to any drug compound, constituents or excipients of the study drug, food, or other substance
* History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered
* Ventricular dysfunction or history of risk factors for Torsades de Pointes
* Evidence of hepatorenal syndrome and estimated creatinine clearance range \< 60 millilitre per minute (mL/min) or abnormal sodium and potassium levels
* Clinically significant physical examination abnormality
* History of diabetes mellitus
* Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort
* Positive human immunodeficiency virus (HIV) test
* Participation in a clinical study involving administration of an investigational drug prior to dosing
* Smoke more than 10 cigarettes or use the equivalent tobacco- or nicotine-containing products per day
* Receipt of blood products within 2 months prior to study
* Donation of blood, plasma, or platelets prior to Screening
* Poor peripheral venous access
* Have previously completed or withdrawn from this study or any other study investigating risdiplam, and have previously received the investigational product

Participants with Normal Hepatic Function Only:

* Confirmed supine blood pressure \> 150 millimetre of mercury (mmHg) or \< 90 mmHg
* Positive test for hepatitis B or C virus
* Clinically significant abnormal laboratory values
* Significant history or clinical manifestation of hepatic disorder
* History or presence of liver disease or liver injury
* Use or intend to use any prescription medications/products within 14 days prior to dosing

  -. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to dosing
* Use or intend to use any non-prescription medications/products within 7 days prior to dosing

Participants with Hepatic Impairment Only:

* Confirmed supine blood pressure \> 159 mmHg or \< 90 mmHg
* Values outside the normal range for liver function tests that are not consistent with their hepatic condition
* Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic encephalopathy
* Use of prescription drugs within 14 days of study drug administration
* Recent history of, or the treatment of, esophageal bleeding
* Presence of a portosystemic shunt
* Recent history of paracentesis
* Current functioning organ transplant or are waiting for an organ transplant
* Evidence of severe ascites
* History or current symptoms of hepatic encephalopathy Grade 2 or above

Primary outcomes:
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1)
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: AUCinf of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: AUClast of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: Cmax of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Secondary outcomes:
measure: Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Apparent Total Clearance (CL/F) of Risdiplam
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: Tmax of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: t1/2 of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: %AUCextrap of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: λz of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: CL/F of Risdiplam and M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1
timeFrame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
measure: Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 31 Days
Other outcomes:
Locations:
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, Inc.
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
city: San Antonio
country: United States
facility: American Research Corporation Inc.
state: Texas
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: