A Study of TAK-625 for the Treatment of Alagille Syndrome (ALGS)

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 Alagille Syndrome (ALGS), 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 9 times from the start of study. After 9 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 Alagille Syndrome

Conditions
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Alagille Syndrome (ALGS)

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 kilograms (kg) and who is >=1 month of age at the time of informed consent. The participant is diagnosed with ALGS. The participant has one or more of the following evidences of cholestasis: Total serum bile acid (sBA) >3^ upper limit of the normal range (ULN) for age. Direct bilirubin (conjugated) >1 mg/dL. Lipid soluble vitamin (LSV) deficiency otherwise unexplainable. Gamma-glutamyl transferase (GGT) >3^ ULN for age. Intractable pruritus explainable only by liver disease. The participant is expected to have a consistent caregiver(s) for the duration of the study. The participant has an access to phone for scheduled calls from study site. Both a caregiver and participant above the age of assent are capable of reading and understanding the questionnaires. Caregivers (and age-appropriate participants) must be willing and able to use an eDiary device during the study. Caregivers (and age-appropriate participants) must complete at least 10 eDiary reports (morning or evening) during each of 2 consecutive weeks of the screening period (maximum possible reports=14 per week), even if the participant is an adult (over 18 years old). Average daily score >2 on the ItchRO questionnaire (maximum possible daily score of 4) for 2 consecutive weeks in the screening period, prior to dosing. A daily score is the higher of the scores for the morning and evening ItchRO. The average daily score is the sum of all daily scores divided by the number of days the ItchRO was completed. 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. Exclusion Criteria: The participant has chronic diarrhea requiring ongoing intravenous (IV) fluid or nutritional intervention. The participant has a previous history of surgical interruption of the enterohepatic circulation. The participant has a previous liver transplant. The participant decompensated cirrhosis (ALT >15^ ULN, international normalized ratio [INR] >1.5 [unresponsive to vitamin K therapy], albumin <3.0 g/dL, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy). The participant has a history or presence of other concomitant liver disease. The participant has a history or presence of 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). The participant has a history or presence of gallstones or kidney stones. The participant has a possible malignant liver mass in imaging, including screening ultrasound. The participant has cancers, except for in situ carcinoma, or cancers treated at least 5 years prior to screening with no evidence of recurrence. The participant has received bile acid/lipid binding resins or 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-625<br>TAK-625 200 mcg per kilogram, orally, once daily for 1 week. After that, TAK-625 400 mcg per kilogram, orally, once daily after Week 1. | Drug: TAK-625<br>* TAK-625 200 mcg or 400 mcg per kilogram, orally, once daily<br>* Other names: Maralixibat chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Fasting Serum Bile Acid (sBA) Levels from Week 18 to Week 22 | Change of fasting sBA levels from Week 18 to Week 22 will be reported. | From Week 18 to Week 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Fasting sBA Levels from Baseline to Week 18 | Change of fasting sBA levels from baseline to Week 18 will be reported. | From baseline to Week 18 | 
| Change of Weekly Average Severity of Pruritus Measured by ItchRO (Obs) from baseline to Week 18 | Change of weekly average severity of pruritus measured by ItchRO (Obs) from baseline to Week 18 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) to describe their pruritus condition. Weekly average severity is a score calculated from the sum of all daily scores, based on daily maximum of morning and evening severity scores, divided by the number of weeks the ItchRO was completed. | From baseline to Week 18 | 
| Change of Weekly Average Morning Severity of Pruritus Measured by ItchRO (Obs) from baseline to Week 18 | Change of weekly average morning severity of pruritus measured by ItchRO (Obs) from baseline to Week 18 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) to describe their pruritus condition. Weekly average morning severity is a score calculated from the sum of all daily morning scores divided by the number of weeks the ItchRO was completed. | From baseline to Week 18 | 
| Change of Weekly Average Severity of Pruritus Measured by ItchRO (Obs) from Week 18 to Week 22 | Change of weekly average severity of pruritus measured by ItchRO (Obs) from Week 18 to Week 22 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) to describe their pruritus condition. Weekly average severity is a score calculated from the sum of all daily scores, based on daily maximum of morning and evening severity scores, divided by the number of weeks the ItchRO was completed. | From Week 18 to Week 22 | 
| Change of Weekly Average Morning Severity of Pruritus Measured by ItchRO (Obs) from Week 18 to Week 22 | Change of weekly average morning severity of pruritus measured by ItchRO (Obs) from Week 18 to Week 22 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) to describe their pruritus condition. Weekly average morning severity is a score calculated from the sum of all daily morning scores divided by the number of weeks the ItchRO was completed. | From Week 18 to Week 22 | 
| Change of Weekly Average Severity of Pruritus Measured by ItchRO (Pt) from baseline to Week 18 | Change of weekly average severity of pruritus measured by ItchRO (Pt) from baseline to Week 18 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). Participants will rate the severity of pruritus using 5 choices (0= Not felt itchy, 1= Felt a little bit itchy, 2= Felt pretty itchy, 3= Felt very itchy, 4= Felt very, very itchy) to describe their pruritus condition. Weekly average severity is a score calculated from the sum of all daily scores, based on daily maximum of morning and evening severity scores, divided by the number of weeks the ItchRO was completed. | From baseline to Week 18 | 
| Change of Weekly Average Morning Severity of Pruritus Measured by ItchRO (Pt) from baseline to Week 18 | Change of weekly average morning severity of pruritus measured by ItchRO (Pt) from baseline to Week 18 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). Participants will rate the severity of pruritus using 5 choices (0= Not felt itchy, 1= Felt a little bit itchy, 2= Felt pretty itchy, 3= Felt very itchy, 4= Felt very, very itchy) to describe their pruritus condition. Weekly average morning severity is a score calculated from the sum of all daily morning scores divided by the number of weeks the ItchRO was completed. | From baseline to Week 18 | 
| Change of Alanine Aminotransferase (ALT) Levels from Baseline to Week 18 | Change of ALT levels from baseline to Week 18 will be reported. | From baseline to Week 18 | 
| Change of Alkaline Phosphatase (ALP) Levels from Baseline to Week 18 | Change of ALP levels from baseline to Week 18 will be reported. | From baseline to Week 18 | 
| Change of Bilirubin (Total and Direct) Levels from Baseline to Week 18 | Change of bilirubin (total and direct) levels from baseline to Week 18 will be reported. | From baseline to Week 18 | 
| Change of Weekly Average Severity of Pruritus Measured by ItchRO (Pt) from Week 18 to Week 22 | Change of weekly average severity of pruritus measured by ItchRO (Pt) from Week 18 to Week 22 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). Participants will rate the severity of pruritus using 5 choices (0= Not felt itchy, 1= Felt a little bit itchy, 2= Felt pretty itchy, 3= Felt very itchy, 4= Felt very, very itchy) to describe their pruritus condition. Weekly average severity is a score calculated from the sum of all daily scores, based on daily maximum of morning and evening severity scores, divided by the number of weeks the ItchRO was completed. | From Week 18 to Week 22 | 
| Change of Weekly Average Morning Severity of Pruritus Measured by ItchRO (Pt) from Week 18 to Week 22 | Change of weekly average morning severity of pruritus measured by ItchRO (Pt) from Week 18 to Week 22 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). Participants will rate the severity of pruritus using 5 choices (0= Not felt itchy, 1= Felt a little bit itchy, 2= Felt pretty itchy, 3= Felt very itchy, 4= Felt very, very itchy) to describe their pruritus condition. Weekly average morning severity is a score calculated from the sum of all daily morning scores divided by the number of weeks the ItchRO was completed. | From Week 18 to Week 22 | 
| Change of Alanine Aminotransferase (ALT) Levels from Week 18 to Week 22 | Change of ALT levels from Week 18 to Week 22 will be reported. | From Week 18 to Week 22 | 
| Change of Alkaline Phosphatase (ALP) Levels from Week 18 to Week 22 | Change of ALP levels From Week 18 to Week 22 will be reported. | From Week 18 to Week 22 | 
| Change of Bilirubin (Total and Direct) Levels from Week 18 to Week 22 | Change of bilirubin (total and direct) levels from Week 18 to Week 22 will be reported. | From Week 18 to Week 22 |