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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Progressive Familial Intrahepatic Cholestasis (PFIC)

Intervention / Treatment
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* Drug: TAK-625


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-625, Primary cohort<br>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. | Drug: TAK-625<br>* TAK-625 orally, twice daily (BID)<br>* Other names: Maralixibat chloride;|
| Experimental: TAK-625, Supplemental cohort<br>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. | Drug: TAK-625<br>* TAK-625 orally, twice daily (BID)<br>* Other names: Maralixibat chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, from Week 15 to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 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. | From baseline to Week 26 | 
| 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. | From baseline to Week 26 | 
| 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. | Baseline, from Week 15 to Week 26 |