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

• ClinicalTrials.gov Identifier: NCT03920865
• Recruitment Status: Completed
• First Posted: April 19, 2019
• Last Update Posted: January 10, 2020
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Muscular Atrophy, Spinal	Drug: Risdiplam	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 16, 2019
• Actual Primary Completion Date: January 2, 2020
• Actual Study Completion Date: January 2, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1; Participants with mild hepatic impairment and demographically matched healthy participants with normal hepatic function will be enrolled. Participants will receive a single oral dose of 5 mg risdiplam.	Drug: Risdiplam; 5 milligram (mg) oral dose administered in fasted state
Experimental: Part 2; Participants with moderate hepatic impairment and demographically matched healthy participants with normal hepatic function will be enrolled. Participants will receive a single oral dose of 5 mg risdiplam.	Drug: Risdiplam; 5 milligram (mg) oral dose administered in fasted state

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration-Time Curve from Time 0 to Infinity (AUCinf) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
2. Area Under the Plasma Concentration-Time Curve from time 0 to the Last Measurable Concentration (AUClast) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
   This measure will be used for pharmacokinetics (PK) comparison if AUCinf cannot be estimated with sufficient accuracy
3. Maximum Observed Plasma Concentration (Cmax) of Risdiplam [ Time Frame: Day 1 to Day 24 ]

Secondary Outcome Measures :

1. Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
2. Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
3. Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
4. Terminal Elimination Rate Constant (λz) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
5. Adjusted Coefficient for Determination of Exponential Fit (R2-adjusted) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
6. Apparent Total Clearance (CL/F) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
7. Fraction of Drug Unbound [ Time Frame: Day 1 to Day 24 ]
   Risdiplam and Metabolite (M1), as appropriate
8. Molecular Weight-Adjusted Metabolite-To-Parent Ratio for AUCinf, Cmax, and AUClast [ Time Frame: Day 1 to Day 24 ]
9. Percentage of Participants with Adverse Event (AE) or Serious Adverse Event (SAE) [ Time Frame: From Screening to Day 28 ]

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:

• 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

Contacts and Locations

Locations

United States, Florida

Clinical Pharmacology of Miami, Inc.

Miami, Florida, United States, 33014

Orlando Clinical Research Center

Orlando, Florida, United States, 32809

United States, Texas

American Research Corporation Inc.

San Antonio, Texas, United States, 78215

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03920865
• Other Study ID Numbers: BP40995
• First Posted: April 19, 2019
• Last Update Posted: January 10, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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

Additional relevant MeSH terms:

Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases; Risdiplam; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs