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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

  • Result First Posted

    February 21, 2021

  • Last update posted

    February 21, 2021

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:Muscular Atrophy, Spinal
  • Intervention/Treatment: Drug: Risdiplam
  • Phase: Phase 1

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • 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 2019
  • Actual Primary Completion Date: January 2020
  • Actual Study Completion Date: January 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. Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) [ Time Frame: 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 ]
  • 2. Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 [ Time Frame: 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 ]
  • 3. Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 [ Time Frame: 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 ]
  • 4. Part 2: AUCinf of Risdiplam and M1 [ Time Frame: 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 ]
  • 5. Part 2: AUClast of Risdiplam and M1 [ Time Frame: 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 ]
  • 6. Part 2: Cmax of Risdiplam and M1 [ Time Frame: 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 Outcome Measures: 1. Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 [ Time Frame: 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 ]
  • 2. Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 [ Time Frame: 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 ]
  • 3. Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 [ Time Frame: 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 ]
  • 4. Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 [ Time Frame: 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 ]
  • 5. Part 1: Apparent Total Clearance (CL/F) of Risdiplam [ Time Frame: 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 ]
  • 6. Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 [ Time Frame: 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 ]
  • 7. Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 [ Time Frame: 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 ]
  • 8. Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 [ Time Frame: 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 ]
  • 9. Part 2: Tmax of Risdiplam and M1 [ Time Frame: 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 ]
  • 10. Part 2: t1/2 of Risdiplam and M1 [ Time Frame: 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 ]
  • 11. Part 2: %AUCextrap of Risdiplam and M1 [ Time Frame: 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 ]
  • 12. Part 2: λz of Risdiplam and M1 [ Time Frame: 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 ]
  • 13. Part 2: CL/F of Risdiplam and M1 [ Time Frame: 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 ]
  • 14. Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 [ Time Frame: 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 ]
  • 15. Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 [ Time Frame: 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 ]
  • 16. Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 [ Time Frame: 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 ]
  • 17. Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 31 Days ]
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Eligibility Criteria

  • Ages Eligible for Study: 18 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 150 millimetre of mercury (mmHg) or 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

Contacts

Locations

United States, Florida
Clinical Pharmacology of Miami, Inc.
Miami

United States, Florida
Orlando Clinical Research Center
Orlando

United States, Texas
American Research Corporation Inc.
San Antonio

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 History of Changes
  • Other Study ID Numbers: BP40995
  • First Posted: April 19, 2019 Key Record Dates
  • Last Update Posted: February 21, 2021
  • Last Verified: January 2021
  • 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: Atrophy
    Muscular Atrophy
    Muscular Atrophy, Spinal
  • Study Type: Interventional
  • Study Design: Allocation: Non-Randomized;Intervention Model: Parallel Assignment;Masking: None (Open Label);Primary Purpose: Treatment
  • Condition: Muscular Atrophy, Spinal
  • Interventions : Drug: Risdiplam
  • Enrollment: 26

Participant flow

  • Recruitment Details
  • Pre-assignment Details

  • Arm/Group title Normal Hepatic Function Moderate Hepatic Impairment Mild Hepatic Impairment
  • Arm/Group Description All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2. All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study. All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.
    Period Title: Overall Study
  • Started 10 8 8
  • Completed 10 8 8
  • Not Completed 0 0 0
  • Reason Not Completed
Baseline Characteristics
  • Arm/Group title TotalNormal Hepatic FunctionModerate Hepatic ImpairmentMild Hepatic Impairment
  • Arm/Group Description Total of all reporting groupsAll participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2.All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study.All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.
  • Overall Number of Baseline Participants 261088
  • Baseline Analysis Population Description [Not Specified]
Outcome Measures

1. PrimaryOutcome

  • Title Part 2: Cmax of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: ng/mL
  • 4.13
    4.10
    25.0
    29.9
  • Statistical Analysis Overview
    • Comparison Group Selection Part 2: Cmax of Risdiplam and M1
    • Comments
    • Type of Statistical Test Other
    • Comments Descriptive statistics.
  • Method of Estimation
    • Estimation Parameter Ratio of Geometric Least Squares Means
    • Estimated Value 0.991
    • Confidence Interval (2-Sided ) 90.0%
      0.81 to 1.21
    • Estimation Comments [Not Specified]

2. PrimaryOutcome

  • Title Part 2: AUClast of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h*ng/mL
  • 259
    243
    947
    1020

3. PrimaryOutcome

  • Title Part 2: AUCinf of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h*ng/mL
  • 275
    261
    971
    1040
  • Statistical Analysis Overview
    • Comparison Group Selection Part 2: Cmax of Risdiplam and M1, Part 2: AUClast of Risdiplam and M1, Part 2: AUCinf of Risdiplam and M1
    • Comments
    • Type of Statistical Test Other
    • Comments Descriptive statistics.
  • Method of Estimation
    • Estimation Parameter Ratio of Geometric Least Squares Means
    • Estimated Value 0.947
    • Confidence Interval (2-Sided ) 90.0%
      0.74 to 1.21
    • Estimation Comments [Not Specified]

4. PrimaryOutcome

  • Title Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: ng/mL
  • 3.92
    3.73
    22.8
    21.7
  • Statistical Analysis Overview
    • Comparison Group Selection Part 2: Cmax of Risdiplam and M1, Part 2: AUClast of Risdiplam and M1, Part 2: AUCinf of Risdiplam and M1, Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1
    • Comments
    • Type of Statistical Test Other
    • Comments Descriptive statistics.
  • Method of Estimation
    • Estimation Parameter Ratio of Geometric Least Squares Means
    • Estimated Value 0.953
    • Confidence Interval (2-Sided ) 90.0%
      0.715 to 1.27
    • Estimation Comments [Not Specified]

5. PrimaryOutcome

  • Title Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h*ng/mL
  • 245
    197
    961
    773

6. PrimaryOutcome

  • Title Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1)
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h*ng/mL
  • 263
    222
    987
    792
  • Statistical Analysis Overview
    • Comparison Group Selection Part 2: Cmax of Risdiplam and M1, Part 2: AUClast of Risdiplam and M1, Part 2: AUCinf of Risdiplam and M1, Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1, Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1, Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1)
    • Comments
    • Type of Statistical Test Other
    • Comments Descriptive statistics.
  • Method of Estimation
    • Estimation Parameter Ratio of Geometric Least Squares Means
    • Estimated Value 0.842
    • Confidence Interval (2-Sided ) 90.0%
      0.588 to 1.21
    • Estimation Comments [Not Specified]

7. SecondaryOutcome

  • Title Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
  • Description An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
  • Time Frame Up to 31 Days
Outcome Measure Data
  • Analysis Population Description The safety population included all participants who received a dose of risdiplam.
  •  
  • Arm/Group title Normal Hepatic Function ParticipantsPart 2Part 1
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 1088
  • Measure Type: Number
    Unit of Measure: Percentage of Participants
  • With at least one SAE 0.0
    12.5
    0.0
  • With at least one AE 0.0
    12.5
    62.5

8. SecondaryOutcome

  • Title Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Ratio
  • 0.262
    0.227

9. SecondaryOutcome

  • Title Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Ratio
  • 0.158
    0.131

10. SecondaryOutcome

  • Title Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Ratio
  • 0.271
    0.239

11. SecondaryOutcome

  • Title Part 2: CL/F of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: L/h
  • 5.15
    4.79

12. SecondaryOutcome

  • Title Part 2: λz of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h-1
  • 0.0198
    0.0201
    0.0139
    0.0152

13. SecondaryOutcome

  • Title Part 2: %AUCextrap of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Percentage (%) of AUCextrap
  • 5.68
    6.58
    2.41
    1.90

14. SecondaryOutcome

  • Title Part 2: t1/2 of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h
  • 35.0
    34.5
    49.9
    45.6

15. SecondaryOutcome

  • Title Part 2: Tmax of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Moderate Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Moderate Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with moderate hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Median (Full Range)
    Unit of Measure: hours (h)
  • 11.00
    (4.0 to 24.0)
    24.00
    (10.0 to 24.03)
    4.00
    (1.0 to 4.0)
    2.00
    (1.0 to 4.0)

16. SecondaryOutcome

  • Title Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Ratio
  • 0.245
    0.244

17. SecondaryOutcome

  • Title Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Ratio
  • 0.164
    0.165

18. SecondaryOutcome

  • Title Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 87
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Ratio
  • 0.255
    0.258

19. SecondaryOutcome

  • Title Part 1: Apparent Total Clearance (CL/F) of Risdiplam
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 88
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: L/h
  • 5.07
    6.31

20. SecondaryOutcome

  • Title Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8788
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h-1
  • 0.0182
    0.0211
    0.0126
    0.0168

21. SecondaryOutcome

  • Title Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8788
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: Percentage (%) of AUCextrap
  • 6.28
    7.49
    2.53
    2.34

22. SecondaryOutcome

  • Title Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8788
  • Measure Type: Geometric Mean (Geometric Coefficient of Variation)
    Unit of Measure: h
  • 38.2
    32.9
    55.0
    41.3

23. SecondaryOutcome

  • Title Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1
  • Description
  • Time Frame 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
Outcome Measure Data
  • Analysis Population Description The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
  •  
  • Arm/Group title Risdiplam M1 Metabolite - Normal Hepatic FunctionRisdiplam M1 Metabolite - Mild Hepatic ImpairmentRisdiplam - Normal Hepatic FunctionRisdiplam - Mild Hepatic Impairment
  • Arm/Group Description Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
  • Overall Number of Participants Analyzed 8888
  • Measure Type: Median (Full Range)
    Unit of Measure: hours (h)
  • 10.00
    (4.0 to 24.0)
    10.00
    (4.0 to 24.0)
    4.00
    (2.0 to 4.0)
    4.00
    (2.0 to 4.0)
Adverse Events
  • Time Frame Up to 31 days post-dose
  • Adverse Event Reporting Description The safety population included all participants who received a dose of risdiplam.
  •  
  • Arm/Group Title Moderate Hepatic ImpairmentMild Hepatic ImpairmentNormal Hepatic Function
  • Arm/Group Description All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study.All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2.

Serious Adverse Events

  • Mild Hepatic Impairment Moderate Hepatic Impairment Normal Hepatic Function
  • Affected / at Risk (%) Events Affected / at Risk (%) Events Affected / at Risk (%) Events
  • Total 0/8 (0.00%) 1/8 (12.50%) 1 0/10 (0.00%)
  • Gastrointestinal disorders
  • Upper gastrointestinal haemorrhage 0 /8 (0.00%) 0 1 /8 (12.50%) 1 0 /10 (0.00%) 0

Show Other (Not Including Serious) Adverse Events

  • Mild Hepatic Impairment Moderate Hepatic Impairment Normal Hepatic Function
  • Affected / at Risk (%) Events Affected / at Risk (%) Events Affected / at Risk (%) Events
  • Total 1/8 (12.50%) 1 0/8 (0.00%) 0/10 (0.00%)
  • Ear and labyrinth disorders
  • Ear pain 1 /8 (12.50%) 1 0 /8 (0.00%) 0 0 /10 (0.00%) 0
  • Gastrointestinal disorders
  • Vomiting 2 /8 (25.00%) 2 0 /8 (0.00%) 0 0 /10 (0.00%) 0
  • Dyspepsia 1 /8 (12.50%) 1 0 /8 (0.00%) 0 0 /10 (0.00%) 0
  • Diarrhoea 1 /8 (12.50%) 1 0 /8 (0.00%) 0 0 /10 (0.00%) 0
  • General disorders
  • Chest discomfort 1 /8 (12.50%) 1 0 /8 (0.00%) 0 0 /10 (0.00%) 0
  • Skin and subcutaneous tissue disorders
  • Pruritus 1 /8 (12.50%) 1 0 /8 (0.00%) 0 0 /10 (0.00%) 0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights

Results Point of Contact

  • Name/Title:Medical Communications
  • Organization:Hoffmann-La Roche
  • Phone:800 821-8590
  • EMail:genentech@druginfo.com
  • ClinicalTrials.gov Identifier: NCT03920865 History of Changes
  • Other Study ID Numbers: BP40995
  • First Submitted: April 17, 2019
  • First Posted: April 19, 2019
  • Results First Submitted: December 16, 2020
  • Results First Posted: February 21, 2021
  • Last Update Posted: February 21, 2021