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CompletedNCT03277274Updated Sep 25, 2019Results posted

A Study to Evaluate the Effect of Hepatic Impairment on the Single Dose Pharmacokinetics (PK) of Intravenous TAK-954

A Phase 1 interventional study of TAK-954 in Hepatic Impairment and Healthy Volunteers, sponsored by Takeda. Completed at 2 sites in 2 countries. Open to participants aged 18 Years to 75 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-09-25.

Sponsored by Takeda · Phase 1, Interventional, and Other

Phase
Phase 1
Study type
Interventional
Enrollment
25
Allocation
Non-randomized
Ages
18 Years to 75 Years
Sex
All
01

Study summary

The purpose of this study is to evaluate the effect of varying degrees of hepatic function on the single dose PK of IV TAK-954.

Read the detailed description

The drug being tested in this study is called TAK-954. This study will evaluate the safety and tolerability of single intravenous doses of TAK-954 in participants with varying degrees of hepatic function.

The study will enroll approximately up to 32 participants. Participants will be enrolled in one of the 4 treatment groups based on their degree of hepatic impairment which will be determined based on Child-Pugh Score as follow:

  • Group 1 TAK-954 0.2 mg: Mild Hepatic Impairment (Child Pugh Class A)
  • Group 2 TAK-954 0.2 mg: Moderate Hepatic Impairment (Child Pugh Class B)
  • Group 3 TAK-954 0.2 mg: Severe Hepatic Impairment (Child Pugh Class C)
  • Group 4 TAK-954 0.2 mg: Healthy Participants

The Child-Pugh classification will assess the severity of 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy grade) on a scale of 1 (none) to 3 (moderate). Total hepatic impairment score ranges from 5 (mild) to 15 (severe) where higher score indicates more severity.

All participants will receive a single dose of TAK-954 0.2 mg on Day 1.

This study may have a full study design, where Group 1 to Group 4 will enroll approximately 8 participants in each group or a reduced study design, where no participants will be enrolled in Group 1 and approximately 8 participants will be enrolled in Group 2 to Group 4.

This multi-center trial will be conducted in Czech Republic and Slovakia. The overall time to participate in this study is approximately 7 weeks. Participants will remain confined to the clinic for 4 days, with 2 further out-patient visits, and will make a final visit to the clinic 10-14 days after receiving their last dose of TAK-954 for a follow-up assessment.

02

Conditions studied

  • Hepatic Impairment
  • Healthy Volunteers

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Keywords

  • Drug Therapy
03

Who can participate

Ages eligible
18 Years to 75 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Inclusion criteria

  1. Male and female participants (non-childbearing potential), with a body mass index (BMI) between 18 to 35 kilogram per square meter (kg/m\^2) (All participants).
  2. Participants with hepatic impairment who are medically stable as determined by the investigator, based on medical history and clinical evaluations including physical examinations, clinical laboratory tests, vital sign measurements, and 12-lead ECGs performed at the Screening Visit and at check-in on Day -1 (Group 1 to 3).
  3. Healthy participants (Group 4).

Exclusion criteria

Exclusion Criteria:

Participants who have:

  1. A history of hepatic carcinoma, hepatorenal syndrome, or presence of a liver mass by ultrasound, CT or MRI, or acute liver disease caused by an infection or drug toxicity (Group 1 to 3).
  2. Have severe hepatic encephalopathy ([greater than] > Grade II Portal Systemic Encephalopathy Score) (Group 1 to 3).
  3. Surgical porto-systemic shunts, including transjugular intrahepatic portosystemic shunt (Group 1 to 3).
  4. A history of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than 1 month prior to trial entry (Group 1 to 3).
  5. Bilirubin levels above 5 times the upper limit of normal (ULN) at screening or Day -1 for Groups 1 and 2, there is no limit for Group 3.
  6. Severe/advanced ascites and/or pleural effusion which requires emptying and albumin supplementation, as judged by the investigator (Group 1 to 3).
  7. Renal creatinine clearance (CLcr) less than or equal to (\<=) 50 milliliter per minute (mL/min), calculated using the Cockcroft-Gault equation from the serum creatinine measurement taken at screening (Group 1 to 3).
  8. Who have a history of clinically significant endocrine, gastrointestinal (GI) (including motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases will be excluded from the trial (Group 4).
04

Study design

Phase
Phase 1
Primary purpose
Other
Allocation
Non-randomized
Intervention model
Sequential assignment
Masking
None (open label)
Enrollment
25 participants (actual)

Study arms

  • Experimental
    Group 1 Mild Hepatic Impairment: TAK-954 0.2 mg

    TAK-954 0.2 milligram (mg), intravenous, administered as 60-minute infusion, once on Day 1.

    Drug: TAK-954

  • Experimental
    Group 2 Moderate Hepatic Impairment: TAK-954 0.2 mg

    TAK-954 0.2 mg, intravenous, administered as 60-minute infusion, once on Day 1.

    Drug: TAK-954

  • Experimental
    Group 3 Severe Hepatic Impairment: TAK-954 0.2 mg

    TAK-954 0.2 mg, intravenous, administered as 60-minute infusion, once on Day 1.

    Drug: TAK-954

  • Experimental
    Group 4 Healthy Participants: TAK-954 0.2 mg

    TAK-954 0.2 mg, intravenous, administered as 60-minute infusion, once on Day 1.

    Drug: TAK-954

Interventions

  • DrugTAK-954

    TAK-954 intravenous infusion.

05

What researchers measure

Primary outcomes

  1. Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free)

    Time frame: Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion

  2. AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free)

    Time frame: Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion

  3. AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free)

    Time frame: Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion

Secondary outcomes

  1. Number of Participants With Clinically Significant Physical Examination Findings

    Time frame: Up to 14 days after the last dose of study drug (Day 15)

  2. Number of Participants With Markedly Abnormal Electrocardiograms (ECGs)

    Time frame: Up to 14 days after the last dose of study drug (Day 15)

  3. Number of Participants With Markedly Abnormal Values of Vital Signs

    Time frame: Up to 14 days after the last dose of study drug (Day 15)

  4. Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values

    Time frame: Up to 14 days after the last dose of study drug (Day 15)

  5. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)

    Time frame: Baseline up to 30 days after last dose of study drug (Day 31)

06

Results

Posted Sep 25, 2019

Participant flow

Participants took part in the study at 2 investigative sites in Czech Republic and Slovakia from 09 November 2017 to 10 September 2018.

Participant flow — Overall Study
MilestoneHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
Started8107
Completed8107
Not completed000

Outcome measures

PrimaryCmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free)
Time frame:
Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion
Reported as:
Geometric mean · nanogram per milliliter (ng/mL)
Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free)
nanogram per milliliter (ng/mL)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
TAK-954 (Total)2.629 ± 19.12.440 ± 25.31.893 ± 35.4
TAK-954 (Free)0.1381 ± 15.60.1799 ± 24.40.1778 ± 23.1
Statistical analysis
  • Healthy Participants: TAK-954 0.2 mg vs Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.579
  • Healthy Participants: TAK-954 0.2 mg vs Group C, Severe Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.026
  • Healthy Participants: TAK-954 0.2 mg vs Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.020
  • Healthy Participants: TAK-954 0.2 mg vs Group C, Severe Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.031
PrimaryAUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free)
Time frame:
Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion
Reported as:
Geometric mean · hour*nanogram per milliliter (h*ng/mL)
AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free)
hour*nanogram per milliliter (h*ng/mL)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
TAK-954 (Total)28.57 ± 19.223.57 ± 26.220.19 ± 32.7
TAK-954 (Free)1.501 ± 12.01.737 ± 23.01.898 ± 19.3
Statistical analysis
  • Healthy Participants: TAK-954 0.2 mg vs Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.151
  • Healthy Participants: TAK-954 0.2 mg vs Group C, Severe Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.017
  • Healthy Participants: TAK-954 0.2 mg vs Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.129
  • Healthy Participants: TAK-954 0.2 mg vs Group C, Severe Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.023
PrimaryAUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free)
Time frame:
Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion
Reported as:
Geometric mean · h*ng/mL
AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free)
h*ng/mLHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
TAK-954 (Total)31.30 ± 20.125.44 ± 27.122.60 ± 34.3
TAK-954 (Free)1.643 ± 13.81.875 ± 24.02.122 ± 21.8
Statistical analysis
  • Healthy Participants: TAK-954 0.2 mg vs Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.138
  • Healthy Participants: TAK-954 0.2 mg vs Group C, Severe Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.029
  • Healthy Participants: TAK-954 0.2 mg vs Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.201
  • Healthy Participants: TAK-954 0.2 mg vs Group C, Severe Hepatic Impairment: TAK-954 0.2 mg · ANOVA · p = 0.023
SecondaryNumber of Participants With Clinically Significant Physical Examination Findings
Time frame:
Up to 14 days after the last dose of study drug (Day 15)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Physical Examination Findings
ParticipantsHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
Number of Participants With Clinically Significant Physical Examination Findings000
SecondaryNumber of Participants With Markedly Abnormal Electrocardiograms (ECGs)
Time frame:
Up to 14 days after the last dose of study drug (Day 15)
Reported as:
Count of participants · Participants
Number of Participants With Markedly Abnormal Electrocardiograms (ECGs)
ParticipantsHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
Number of Participants With Markedly Abnormal Electrocardiograms (ECGs)002
SecondaryNumber of Participants With Markedly Abnormal Values of Vital Signs
Time frame:
Up to 14 days after the last dose of study drug (Day 15)
Reported as:
Count of participants · Participants
Number of Participants With Markedly Abnormal Values of Vital Signs
ParticipantsHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
Number of Participants With Markedly Abnormal Values of Vital Signs011
SecondaryNumber of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values
Time frame:
Up to 14 days after the last dose of study drug (Day 15)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values
ParticipantsHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values000
SecondaryNumber of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time frame:
Baseline up to 30 days after last dose of study drug (Day 31)
Reported as:
Count of participants · Participants
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
ParticipantsHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)231

Adverse events

Collected over TEAEs are adverse events that started after the first dose of study drug and no more than 30 days (Day 31) after the last dose of study drug. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Healthy Participants: TAK-954 0.2 mg0/8 (0%)0/8 (0%)2/8 (25%)
Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg0/10 (0%)0/10 (0%)3/10 (30%)
Group C, Severe Hepatic Impairment: TAK-954 0.2 mg0/7 (0%)0/7 (0%)1/7 (14.3%)
Most frequent other events
Most frequent other events
EventHealthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mg
DiarrhoeaGastrointestinal disorders1/82/101/7
HeadacheNervous system disorders1/80/100/7
FlatulenceGastrointestinal disorders0/81/100/7

Baseline characteristics

The safety set consisted of all participants who were enrolled and received the study drug.

Age, Continuous
Age, Continuous(years)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Mean58.5 ± 9.4655.6 ± 12.2557.9 ± 12.8857.2 ± 11.21
Sex: Female, Male
Sex: Female, Male(Participants)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Female3418
Male56617
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Hispanic or Latino0000
Not Hispanic or Latino810725
Unknown or Not Reported0000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
American Indian or Alaska Native0000
Asian0000
Native Hawaiian or Other Pacific Islander0000
Black or African American0000
White810725
More than one race0000
Unknown or Not Reported0000
Region of Enrollment
Region of Enrollment(Participants)Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Czech Republic3328
Slovakia57517
Weight
Weight(kilogram (kg))Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Mean89.95 ± 17.09886.77 ± 19.82387.19 ± 21.33187.90 ± 18.667
Body Mass Index (BMI)
Body Mass Index (BMI)(kilogram per square meter (kg/m^2))Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Mean31.1 ± 3.1830.4 ± 5.0227.9 ± 6.1829.9 ± 4.87
Height
Height(centimeter (cm))Healthy Participants: TAK-954 0.2 mgGroup B, Moderate Hepatic Impairment: TAK-954 0.2 mgGroup C, Severe Hepatic Impairment: TAK-954 0.2 mgTotal
Mean169.8 ± 11.30168.0 ± 10.47176.1 ± 6.28170.8 ± 10.01
07

Study locations

2 sites
  • PRA CZ, s.r.o
    Praha 7, Praha 170 00, Czechia
  • Summit Center of Clinical Research
    Bratislava, 83101, Slovakia
08

References and documents

Study documents

  • Study protocol · Oct 6, 2017
  • Statistical analysis plan · Sep 5, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

09

Registry details

Key details

Study ID
NCT03277274
Lead sponsor
Takeda
Responsible party
Sponsor
First posted
Sep 11, 2017
Start date
Nov 9, 2017
Primary completion
Sep 1, 2018
Completion
Sep 10, 2018
Results posted
Sep 25, 2019
Last update
Sep 25, 2019

Study contacts

Medical Director
study director · Takeda

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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