Progressive Familial Intrahepatic Cholestasis (PFIC)
Conditions
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.
Interventions
DRUGTAK-625
TAK-625 orally, twice daily (BID)
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 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). 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. 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. (\* =\<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: 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Average Morning Itch Reported Outcome (ItchRO) (Observer Instrument [Obs]) Severity Score Between Baseline and the Average of Week 15 Through Week 26 | Baseline to Week 15 through Week 26 | The ItchRO (Obs) scale measures severity of pruritus. The score on ItchRO (Obs) scale ranged from 0 to 4, where 0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe. A higher score indicated more severe pruritus. Average baseline morning ItchRO (Obs) scores were calculated as sum of the morning scores divided by number of morning scores for the 4-week (28 days) time periods (that is \[i.e.\], Day -28 to Day -1). Average morning ItchRO (Obs) scores Week 15 through Week 26 were calculated as the sum of the morning scores divided by the number of morning scores from Week 15 to Week 26. Change was calculated as: Average value of Weeks 15 to 26 - Average value of Baseline (Day -28 to Day -1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Average Morning ItchRO (Obs) Frequency Score Between Baseline and the Average of Week 15 Through Week 26 | Baseline to Week 15 through Week 26 | The ItchRO (Obs) scale measures frequency of pruritus. The score on ItchRO (Obs) scale ranged from 0 to 4, where 0=None observed or reported, 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' was categorized as missing data. A higher score indicated more severe pruritus. Baseline average morning ItchRO (Obs) frequency scores were calculated as the sum of the morning frequency scores divided by the number of morning severity scores for the 4-week (28 days) time periods. (i.e., Day -28 to Day -1). Average morning ItchRO (Obs) frequency scores of Week 15 through Week 26 were calculated as the sum of the morning frequency scores divided by the number of mornings frequency scores from Week 15 to Week 26. Change was calculated as: Average value of Weeks 15 to 26 - Average value of Baseline (Day -28 to Day -1). |
| Change From Baseline in Total Serum Bile Acid (sBA) Levels to Week 26 | Baseline to Week 26 | Change from baseline was calculated as: Post-baseline observed value - Baseline (before first dosing) observed value. Change from baseline in total sBA levels to Week 26 was reported. |
| Percentage of Participants (Responders) Who Experienced an sBA Control From Baseline Through Week 26 | Baseline through Week 26 | Responders to sBA control were defined as participants who achieved a decrease to less than (\<) 102 mcmol/L, a decrease of greater than (\>) 75 percentage (%), or normalization at any timepoint from baseline through Week 26. |
| Change in the ItchRO (Obs) Weekly Average Severity Between Baseline and the Average of Week 15 Through Week 26 | Baseline to Week 15 through Week 26 | ItchRO (Obs) scale measures severity of pruritus, score ranged from 0 to 4, where 0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe. A higher score indicated more severe pruritus. Weekly average severity was calculated based on daily maximum severity scores from both morning and evening. Average baseline morning and evening ItchRO (Obs) scores were calculated as sum of morning or evening scores divided by number of morning or evening scores for 4-week (28 days) time periods (i.e., Day -28 to Day -1). Average morning and evening ItchRO (Obs) scores Week 15 to Week 26 were calculated as sum of morning or evening scores divided by number of morning or evening scores from Week 15 to Week 26. Change was calculated as: Average value of Weeks 15 to 26 - Average value of Baseline (Day -28 to Day -1). |
Countries
Japan
Contacts
STUDY_DIRECTORStudy Director
Takeda
Participant flow
Recruitment details
Participants took part in the study at 8 sites in Japan from 10 January 2023 to 22 July 2025.
Pre-assignment details
Participants diagnosed with progressive familial intrahepatic cholestasis 2 (PFIC2) due to adenosine triphosphate (ATP) binding cassette subfamily B member 11 (ABCB11) mutation that predicted residual bile salt excretion pump (BSEP) function (non-truncating \[nt\]-PFIC2) were enrolled in Primary Cohort, and participants with other PFIC subtypes or post-surgical were enrolled in Supplemental Cohort, to receive TAK-625 twice daily (BID).
Participants by arm
| Arm | Count |
|---|---|
| Primary Cohort: TAK-625 Participants diagnosed with PFIC2 due to ABCB11 mutation that predicted residual BSEP function received TAK-625 orally, BID. In dose escalation period, dose was increased weekly, 150 mcg/kg, 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg for up to 4 weeks (Weeks 1 to 4) or extended to 6 weeks depending on the safety or tolerability concerns. After the dose escalation period, each participant continued dosing with TAK-625 600 mcg/kg, orally, BID dose level in the stable dosing period until Week 26. | 3 |
| Supplemental Cohort: TAK-625 Participants diagnosed with other PFIC subtypes or post-surgical received TAK-625 orally, BID. In dose escalation period, dose was increased weekly, 150 mcg/kg, 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg for up to 4 weeks (Weeks 1 to 4) or extended to 6 weeks depending on the safety or tolerability concerns. After the dose escalation period, each participant continued dosing with TAK-625 600 mcg/kg, orally, BID dose level in the stable dosing period until Week 26. | 2 |
| Total | 5 |
Baseline characteristics
| Characteristic | Primary Cohort: TAK-625 | Supplemental Cohort: TAK-625 | Total |
|---|---|---|---|
| Age, Continuous | 7.7 years STANDARD_DEVIATION 3.21 | 8.0 years STANDARD_DEVIATION 4.24 | 7.8 years STANDARD_DEVIATION 3.11 |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 2 |
Outcome results
Primary
Change in the Average Morning Itch Reported Outcome (ItchRO) (Observer Instrument [Obs]) Severity Score Between Baseline and the Average of Week 15 Through Week 26
The ItchRO (Obs) scale measures severity of pruritus. The score on ItchRO (Obs) scale ranged from 0 to 4, where 0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe. A higher score indicated more severe pruritus. Average baseline morning ItchRO (Obs) scores were calculated as sum of the morning scores divided by number of morning scores for the 4-week (28 days) time periods (that is \[i.e.\], Day -28 to Day -1). Average morning ItchRO (Obs) scores Week 15 through Week 26 were calculated as the sum of the morning scores divided by the number of morning scores from Week 15 to Week 26. Change was calculated as: Average value of Weeks 15 to 26 - Average value of Baseline (Day -28 to Day -1).
Time frame: Baseline to Week 15 through Week 26
Population: ITT included all participants who received at least one dose of study drug. As per-planned analysis, the cohort-wise (primary and supplemental) data were analyzed, collected, and reported in this study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Primary Cohort: TAK-625 | Change in the Average Morning Itch Reported Outcome (ItchRO) (Observer Instrument [Obs]) Severity Score Between Baseline and the Average of Week 15 Through Week 26 | -1.514 score on a scale |
| Supplemental Cohort: TAK-625 | Change in the Average Morning Itch Reported Outcome (ItchRO) (Observer Instrument [Obs]) Severity Score Between Baseline and the Average of Week 15 Through Week 26 | -0.202 score on a scale |
Secondary
Change From Baseline in Total Serum Bile Acid (sBA) Levels to Week 26
Change from baseline was calculated as: Post-baseline observed value - Baseline (before first dosing) observed value. Change from baseline in total sBA levels to Week 26 was reported.
Time frame: Baseline to Week 26
Population: ITT included all participants who received at least one dose of study drug. As per-planned analysis, the cohort-wise (primary and supplemental) data were analyzed, collected, and reported in this study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Primary Cohort: TAK-625 | Change From Baseline in Total Serum Bile Acid (sBA) Levels to Week 26 | -149.900 micromoles per liter (mcmol/L) |
| Supplemental Cohort: TAK-625 | Change From Baseline in Total Serum Bile Acid (sBA) Levels to Week 26 | -18.250 micromoles per liter (mcmol/L) |
Secondary
Change in the Average Morning ItchRO (Obs) Frequency Score Between Baseline and the Average of Week 15 Through Week 26
The ItchRO (Obs) scale measures frequency of pruritus. The score on ItchRO (Obs) scale ranged from 0 to 4, where 0=None observed or reported, 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' was categorized as missing data. A higher score indicated more severe pruritus. Baseline average morning ItchRO (Obs) frequency scores were calculated as the sum of the morning frequency scores divided by the number of morning severity scores for the 4-week (28 days) time periods. (i.e., Day -28 to Day -1). Average morning ItchRO (Obs) frequency scores of Week 15 through Week 26 were calculated as the sum of the morning frequency scores divided by the number of mornings frequency scores from Week 15 to Week 26. Change was calculated as: Average value of Weeks 15 to 26 - Average value of Baseline (Day -28 to Day -1).
Time frame: Baseline to Week 15 through Week 26
Population: ITT included all participants who received at least one dose of study drug. Here, overall number of participants analyzed signified those participants who were evaluable for this outcome measure. As per-planned analysis, the cohort-wise (primary and supplemental) data were analyzed, collected, and reported in this study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Primary Cohort: TAK-625 | Change in the Average Morning ItchRO (Obs) Frequency Score Between Baseline and the Average of Week 15 Through Week 26 | -0.740 score on a scale |
| Supplemental Cohort: TAK-625 | Change in the Average Morning ItchRO (Obs) Frequency Score Between Baseline and the Average of Week 15 Through Week 26 | -0.735 score on a scale |
Secondary
Change in the ItchRO (Obs) Weekly Average Severity Between Baseline and the Average of Week 15 Through Week 26
ItchRO (Obs) scale measures severity of pruritus, score ranged from 0 to 4, where 0=None observed or reported, 1=Mild, 2=Moderate, 3=Severe, 4=Very severe. A higher score indicated more severe pruritus. Weekly average severity was calculated based on daily maximum severity scores from both morning and evening. Average baseline morning and evening ItchRO (Obs) scores were calculated as sum of morning or evening scores divided by number of morning or evening scores for 4-week (28 days) time periods (i.e., Day -28 to Day -1). Average morning and evening ItchRO (Obs) scores Week 15 to Week 26 were calculated as sum of morning or evening scores divided by number of morning or evening scores from Week 15 to Week 26. Change was calculated as: Average value of Weeks 15 to 26 - Average value of Baseline (Day -28 to Day -1).
Time frame: Baseline to Week 15 through Week 26
Population: ITT included all participants who received at least one dose of study drug. As per-planned analysis, the cohort-wise (primary and supplemental) data were analyzed, collected, and reported in this study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Primary Cohort: TAK-625 | Change in the ItchRO (Obs) Weekly Average Severity Between Baseline and the Average of Week 15 Through Week 26 | -1.629 score on a scale |
| Supplemental Cohort: TAK-625 | Change in the ItchRO (Obs) Weekly Average Severity Between Baseline and the Average of Week 15 Through Week 26 | -0.254 score on a scale |
Secondary
Percentage of Participants (Responders) Who Experienced an sBA Control From Baseline Through Week 26
Responders to sBA control were defined as participants who achieved a decrease to less than (\<) 102 mcmol/L, a decrease of greater than (\>) 75 percent (%), or normalization at any timepoint from baseline through Week 26.
Time frame: Baseline through Week 26
Population: ITT included all participants who received at least one dose of study drug. As per-planned analysis, the cohort-wise (primary and supplemental) data were analyzed, collected, and reported in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primary Cohort: TAK-625 | Percentage of Participants (Responders) Who Experienced an sBA Control From Baseline Through Week 26 | 33.3 percentage of participants |
| Supplemental Cohort: TAK-625 | Percentage of Participants (Responders) Who Experienced an sBA Control From Baseline Through Week 26 | 0.0 percentage of participants |