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A Study of TAK-625 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC)

Primary Purpose

Progressive Familial Intrahepatic Cholestasis (PFIC)

Status
Completed
Phase
Phase 3
Locations
Japan
Study Type
Interventional
Intervention
TAK-625
Sponsored by
Takeda
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Progressive Familial Intrahepatic Cholestasis (PFIC)

Eligibility Criteria

1 Month - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. The participant is Japanese male or female with a body weight >=5.0 kg and who is >=1 year old at the time of informed consent.
  2. The participant has a cholestasis as manifested by total serum bile acid (sBA) >=3^ upper limit of the normal range (ULN) (applies to the primary cohort only).
  3. The participant has an average morning ItchRO (Obs) score >=1.5 during 4 consecutive weeks of the screening period, leading to the baseline visit (Week 0/Visit 2).
  4. The caregiver has completed at least 21 valid* morning ItchRO (Obs) entries during 4 consecutive weeks of the screening period, leading to the baseline visit (Week 0/Visit 2) (*valid=completed and not answered as "I don't know"; the maximum allowed invalidreports=7, no more than 2 invalid reports during the last 7 days before the baseline visit [Week 0/Visit 2]).
  5. The participant has a diagnosis of progressive familial intrahepatic cholestasis (PFIC) based on:

    Chronic cholestasis as manifested by persistent (>6 months) pruritus in addition to biochemical abnormalities and/or pathological evidence of progressive liver disease.

    AND

    For Primary cohort:

    a) The participant has a genetic testing result consistent with disease-causing variation in ABCB11 (PFIC2), based on a genotyping.

    For Supplemental cohort:

    1. The participant has a genetic testing results consistent with disease causing variation in ATP8B1 (PFIC1), ABCB4 (PFIC3), or tight junction protein 2 gene (TJP2) (PFIC4), based on a genotyping.
    2. The participant has a PFIC phenotype without a known mutation or with another known mutation not described above.
    3. The PFIC participant has internal or external biliary diversion surgery history, and the internal or external biliary diversion surgery was reversed.
  6. The participant (whenever possible) and caregiver are able to be contacted by phone for scheduled remote visits (participant contacts [phone calls]).
  7. Both a caregiver and participant above the age of assent are capable of reading and understanding the questionnaires.
  8. The same caregiver should be contacted during this study. The ItchRO (Obs) should be completed by the same caregiver for consistency during this study, even if the participant is an adult (over 18 years old).

Exclusion Criteria:

  1. The diagnosed with PFIC2 due to ABCB11 mutation that predicts complete absence of BSEP function due to the type of ABCB11 mutation (t-PFIC2), based on a genotyping (applies to the primary cohort only).
  2. The participant has a diagnosis of benign recurrent intrahepatic cholestasis indicated by a history of intermittent cholestasis with no disease progression.
  3. The participant has a current or recent history (<1 year) of atopic dermatitis or other non-cholestatic diseases associated with pruritus.
  4. The participant has a previous history of surgical interruption of the enterohepatic circulation (applies to the primary cohort only).
  5. The participant with chronic diarrhea requiring intravenous (IV) fluid or nutritional intervention and/or its sequelae at screening or during the 6 months prior to screening.
  6. The participant has a history of liver transplant or currently requires imminent liver transplant.
  7. The participant with decompensated cirrhosis (international normalized ratio [INR] >1.5, and/or albumin <30 g/L, history, or presence of clinically significant ascites, and/or variceal hemorrhage, and/or encephalopathy).
  8. The participant has an alanine aminotransferase (ALT) or total serum bilirubin (TSB) level >15^ ULN at screening.
  9. The participant has other liver disease.
  10. The participant has any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, including bile salt metabolism in the intestine (eg, inflammatory bowel disease), per investigator discretion.
  11. The participant has a possible malignant liver mass in imaging, including screening ultrasound.
  12. The participant has received bile acid, lipid binding resins or ileal bile acid transporter (IBAT) inhibitors within 28 days prior to screening and throughout the trial.
  13. The participant who has received sodium phenylbutyrate for less than 6 months at the initiation of screening.

Sites / Locations

  • University of Tsukuba Hospital
  • Yokohamashi Tobu Hospital
  • Tsuyama Chuo Hospital
  • Osaka University Hospital
  • Juntendo University Hospital
  • Kyushu University Hospital
  • Kyoto University Hospital
  • Saitama Prefectural Children's Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

TAK-625, Primary cohort

TAK-625, Supplemental cohort

Arm Description

TAK-625 orally, twice daily (BID) for 4 weeks as Dose Escalation Period. The dose in Dose Escalation Period will be increased weekly, 150 mcg/kilograms (kg), 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg. After Dose Escalation Period, TAK-625 600 mcg/kg (or maximum tolerated dose [MTD]), orally, BID up to study completion.

TAK-625 orally, twice daily (BID) for 4 weeks as Dose Escalation Period. The dose in Dose Escalation Period will be increased weekly, 150 mcg/kilograms (kg), 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg. After Dose Escalation Period, TAK-625 600 mcg/kg (or maximum tolerated dose [MTD]), orally, BID up to study completion.

Outcomes

Primary Outcome Measures

Change in the Average Morning ItchRO (Obs) Severity Score between Baseline and Average of Week 15 through Week 26
Change in the average morning ItchRO (Obs) severity score between baseline and average of Week 15 through Week 26 will be reported. Pruritus will be assessed using the Itch caregiver/patient reported outcome (Patient Reported Outcome; PRO) measure (ItchRO) twice a day (once in the morning and once in the evening). Caregivers will rate the severity of pruritus using 5 choices (0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe, I don't know) to describe their pruritus condition. 'I don't know' will be categorized as missing data. Average morning severity score of Week 15 through Week 26 will be calculated from the sum of daily morning scores divided by the number of days from Week 15 to Week 26.

Secondary Outcome Measures

Change in the Average Morning ItchRO (Obs) Frequency Score between Baseline and Average of Week 15 through Week 26
Change in the average morning ItchRO (Obs) frequency score between baseline and average of Week 15 through Week 26 will be reported. Pruritus will be assessed using the Itch caregiver/patient reported outcome (Patient Reported Outcome; PRO) measure (ItchRO) twice a day (once in the morning and once in the evening). Caregivers will rate the frequency of pruritus using 6 choices (0= None, 1= A little bit of the time, 2= Some of the time, 3= Most of the time, 4= Almost all of the time/constantly, I don't know) to describe their pruritus condition. 'I don't know' will be categorized as missing data. Average morning frequency score of Week 15 through Week 26 will be calculated from the sum of daily morning scores divided by the number of days from Week 15 to Week 26.
Change of Total sBA Levels from Baseline to Week 26
Change of total sBA levels from baseline to Week 26 will be reported.
Percentage of Participants who Achieve sBA Well Control from Baseline through Week 26
Percentage of participants who achieve sBA well control from baseline through Week 26 will be reported. The sBA well control defines as a reduction to <102 micro mol/L, or a reduction of >75%, or normalization.
Change in the ItchRO (Obs) Weekly Average Severity between Baseline and Average of Week 15 through Week 26
Change in the ItchRO (Obs) weekly average severity between baseline and average of Week 15 through Week 26 will be reported. Pruritus will be assessed using the Itch caregiver/patient reported outcome (Patient Reported Outcome; PRO) measure (ItchRO) twice a day (once in the morning and once in the evening). Caregivers will rate the severity of pruritus using 5 choices (0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe, I don't know) to describe their pruritus condition. 'I don't know' will be categorized as missing data. Weekly average severity of Week 15 through Week 26 will be calculated from the sum of all daily scores, based on daily maximum of morning and evening severity scores, divided by the number of days from Week 15 to Week 26.

Full Information

First Posted
September 14, 2022
Last Updated
September 28, 2023
Sponsor
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT05543187
Brief Title
A Study of TAK-625 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC)
Official Title
An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in the Treatment of Subjects With Progressive Familial Intrahepatic Cholestasis
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
January 10, 2023 (Actual)
Primary Completion Date
September 4, 2023 (Actual)
Study Completion Date
September 4, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Takeda

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
The main aim of the study is to check if TAK-625 improves symptoms of Progressive Familial Intrahepatic Cholestasis (PFIC), side effect from the study treatment or TAK-625, and how much TAK-625 stays in their blood over time. This will help the study sponsor (Takeda) to work out the best dose to give people in the future. The participants will be treated with TAK-625 for up to the end of study (about 34 months). Participants will visit their study clinic 15 times from the start of study. After 15 times visits, participants will visit their study clinic every 12 weeks up to the end of study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Progressive Familial Intrahepatic Cholestasis (PFIC)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TAK-625, Primary cohort
Arm Type
Experimental
Arm Description
TAK-625 orally, twice daily (BID) for 4 weeks as Dose Escalation Period. The dose in Dose Escalation Period will be increased weekly, 150 mcg/kilograms (kg), 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg. After Dose Escalation Period, TAK-625 600 mcg/kg (or maximum tolerated dose [MTD]), orally, BID up to study completion.
Arm Title
TAK-625, Supplemental cohort
Arm Type
Experimental
Arm Description
TAK-625 orally, twice daily (BID) for 4 weeks as Dose Escalation Period. The dose in Dose Escalation Period will be increased weekly, 150 mcg/kilograms (kg), 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg. After Dose Escalation Period, TAK-625 600 mcg/kg (or maximum tolerated dose [MTD]), orally, BID up to study completion.
Intervention Type
Drug
Intervention Name(s)
TAK-625
Other Intervention Name(s)
Maralixibat chloride
Intervention Description
TAK-625 orally, twice daily (BID)
Primary Outcome Measure Information:
Title
Change in the Average Morning ItchRO (Obs) Severity Score between Baseline and Average of Week 15 through Week 26
Description
Change in the average morning ItchRO (Obs) severity score between baseline and average of Week 15 through Week 26 will be reported. Pruritus will be assessed using the Itch caregiver/patient reported outcome (Patient Reported Outcome; PRO) measure (ItchRO) twice a day (once in the morning and once in the evening). Caregivers will rate the severity of pruritus using 5 choices (0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe, I don't know) to describe their pruritus condition. 'I don't know' will be categorized as missing data. Average morning severity score of Week 15 through Week 26 will be calculated from the sum of daily morning scores divided by the number of days from Week 15 to Week 26.
Time Frame
Baseline, from Week 15 to Week 26
Secondary Outcome Measure Information:
Title
Change in the Average Morning ItchRO (Obs) Frequency Score between Baseline and Average of Week 15 through Week 26
Description
Change in the average morning ItchRO (Obs) frequency score between baseline and average of Week 15 through Week 26 will be reported. Pruritus will be assessed using the Itch caregiver/patient reported outcome (Patient Reported Outcome; PRO) measure (ItchRO) twice a day (once in the morning and once in the evening). Caregivers will rate the frequency of pruritus using 6 choices (0= None, 1= A little bit of the time, 2= Some of the time, 3= Most of the time, 4= Almost all of the time/constantly, I don't know) to describe their pruritus condition. 'I don't know' will be categorized as missing data. Average morning frequency score of Week 15 through Week 26 will be calculated from the sum of daily morning scores divided by the number of days from Week 15 to Week 26.
Time Frame
Baseline, from Week 15 to Week 26
Title
Change of Total sBA Levels from Baseline to Week 26
Description
Change of total sBA levels from baseline to Week 26 will be reported.
Time Frame
From baseline to Week 26
Title
Percentage of Participants who Achieve sBA Well Control from Baseline through Week 26
Description
Percentage of participants who achieve sBA well control from baseline through Week 26 will be reported. The sBA well control defines as a reduction to <102 micro mol/L, or a reduction of >75%, or normalization.
Time Frame
From baseline to Week 26
Title
Change in the ItchRO (Obs) Weekly Average Severity between Baseline and Average of Week 15 through Week 26
Description
Change in the ItchRO (Obs) weekly average severity between baseline and average of Week 15 through Week 26 will be reported. Pruritus will be assessed using the Itch caregiver/patient reported outcome (Patient Reported Outcome; PRO) measure (ItchRO) twice a day (once in the morning and once in the evening). Caregivers will rate the severity of pruritus using 5 choices (0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe, I don't know) to describe their pruritus condition. 'I don't know' will be categorized as missing data. Weekly average severity of Week 15 through Week 26 will be calculated from the sum of all daily scores, based on daily maximum of morning and evening severity scores, divided by the number of days from Week 15 to Week 26.
Time Frame
Baseline, from Week 15 to Week 26

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The participant is Japanese male or female with a body weight >=3.0 kg and who is >=1 month of age at the time of informed consent. The participant has a cholestasis as manifested by total serum bile acid (sBA) >=3^ upper limit of the normal range (ULN) (applies to the primary cohort only). The participant has an average morning ItchRO (Obs) score >=1.5 during 4 consecutive weeks of the screening period, leading to the baseline visit (Week 0/Visit 2). Since it is difficult to evaluate pruritus in infants, participants <12 months of age at screening whose pruritus is unavoidably difficult to be evaluated are not necessarily required to meet the above score. The caregiver has completed at least 21 valid* morning ItchRO (Obs) entries during 4 consecutive weeks of the screening period, leading to the baseline visit (Week 0/Visit 2) (*valid=completed and not answered as "I don't know"; the maximum allowed invalidreports=7, no more than 2 invalid reports during the last 7 days before the baseline visit [Week 0/Visit 2]). The participant has a diagnosis of progressive familial intrahepatic cholestasis (PFIC) based on: Chronic cholestasis as manifested by persistent (>6 months*) pruritus in addition to biochemical abnormalities and/or pathological evidence of progressive liver disease. (* =<6 months is acceptable for participants <12 months of age). AND For Primary cohort: a) The participant has a genetic testing result consistent with disease-causing variation in ABCB11 (PFIC2), based on a genotyping. For Supplemental cohort: The participant has a genetic testing results consistent with disease causing variation in ATP8B1 (PFIC1), ABCB4 (PFIC3), or tight junction protein 2 gene (TJP2) (PFIC4), based on a genotyping. The participant has a PFIC phenotype without a known mutation or with another known mutation not described above. The PFIC participant has internal or external biliary diversion surgery history, and the internal or external biliary diversion surgery was reversed. The participant (whenever possible) and caregiver are able to be contacted by phone for scheduled remote visits (participant contacts [phone calls]). Both a caregiver and participant above the age of assent are capable of reading and understanding the questionnaires. The same caregiver should be contacted during this study. The ItchRO (Obs) should be completed by the same caregiver for consistency during this study, even if the participant is an adult (over 18 years old). Exclusion Criteria: The diagnosed with PFIC2 due to ABCB11 mutation that predicts complete absence of BSEP function due to the type of ABCB11 mutation (t-PFIC2), based on a genotyping (applies to the primary cohort only). The participant has a diagnosis of benign recurrent intrahepatic cholestasis indicated by a history of intermittent cholestasis with no disease progression. The participant has a current or recent history (<1 year) of atopic dermatitis or other non-cholestatic diseases associated with pruritus. The participant has a previous history of surgical interruption of the enterohepatic circulation (applies to the primary cohort only). The participant with chronic diarrhea requiring intravenous (IV) fluid or nutritional intervention and/or its sequelae at screening or during the 6 months prior to screening. The participant has a history of liver transplant or currently requires imminent liver transplant. The participant with decompensated cirrhosis (international normalized ratio [INR] >1.5, and/or albumin <30 g/L, history, or presence of clinically significant ascites, and/or variceal hemorrhage, and/or encephalopathy). The participant has an alanine aminotransferase (ALT) or total serum bilirubin (TSB) level >15^ ULN at screening. The participant has other liver disease. The participant has any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, including bile salt metabolism in the intestine (eg, inflammatory bowel disease), per investigator discretion. The participant has a possible malignant liver mass in imaging, including screening ultrasound. The participant has received bile acid, lipid binding resins or ileal bile acid transporter (IBAT) inhibitors within 28 days prior to screening and throughout the trial. The participant who has received sodium phenylbutyrate for less than 6 months at the initiation of screening.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
University of Tsukuba Hospital
City
Tsukuba
State/Province
Ibaraki
Country
Japan
Facility Name
Yokohamashi Tobu Hospital
City
Yokohama
State/Province
Kanagawa
Country
Japan
Facility Name
Tsuyama Chuo Hospital
City
Tsuyama
State/Province
Okayama
Country
Japan
Facility Name
Osaka University Hospital
City
Suita
State/Province
Osaka
Country
Japan
Facility Name
Juntendo University Hospital
City
Bunkyo-ku
State/Province
Tokyo
Country
Japan
Facility Name
Kyushu University Hospital
City
Fukuoka
Country
Japan
Facility Name
Kyoto University Hospital
City
Kyoto
Country
Japan
Facility Name
Saitama Prefectural Children's Medical Center
City
Saitama
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites).
Links:
URL
https://clinicaltrials.takeda.com/study-detail/5c64837a6d7c464c
Description
To obtain more information on the study, click here/on this link

Learn more about this trial

A Study of TAK-625 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC)

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