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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

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

5

- Primary Cohort: A total of 3 subjects were diagnosed with nt-PFIC 2 and subsequently classified into the primary cohort. The mean (standard deviation [SD]) age was 7.7 (3.21) years and ranged from 4 to 10 years of age. One subject was male and 2 subjects were female. - Supplemental Cohort: A total of 2 subjects were diagnosed with PFIC 1 and subsequently classified into the supplemental cohort. The mean (SD) age was 8.0 (4.24) years and ranged from 5 to 11 years of age. One subject was male and the other subject was female. - All Cohorts: For all cohorts, 3 subjects were classified into the primary cohort and the remaining 2 subjects were classified into the supplemental cohort. The mean (SD) age was 7.8 (3.11) years and ranged from 4 to 11 years of age. Two subjects were male and 3 subjects were female.

Of the 5 subjects (3 subjects in the primary cohort and 2 subjects in the supplemental cohort) who were enrolled in the study, all subjects completed the study.

Interim analysis for Week 26: - A total of 4/5 subjects (80.0%) experienced at least 1 TEAE up to the time of the interim analysis. The most frequently reported TEAE was upper respiratory tract infection (4 subjects [80.0%]). All TEAEs were mild or moderate in severity (2 subjects [40.0%] each had mild TEAEs and moderate TEAEs, respectively); no subjects had a severe TEAE. - One subject (20.0%) in the primary cohort experienced drug-related TEAEs of diarrhoea and dermatitis. - No deaths, serious TEAEs, or TEAEs leading to study drug discontinuation were reported. - No AECIs related to LSV deficiency events were reported. One subject in the primary cohort experienced AECIs related to liver parameter disruption (alanine aminotransferase increased and aspartate aminotransferase increased). Both events were moderate in severity and were not considered to be related to the study drug by the investigator. - No remarkable findings or clinical concerns were noted with respect to clinical laboratory tests, vital signs, weight, height, BMI, and ECGs. - Overall, TAK-625 was well-tolerated in subjects with PFIC. Interim analysis for Week 48: - All 5 subjects (100%) experienced at least 1 treatment-emergent adverse events (TEAE) up to the time of the interim analysis for Week 48. The most frequently reported TEAE was upper respiratory tract infection (4 subjects [80.0%]). All TEAEs were mild or moderate in severity (at the maximum severity, 3 subjects [60.0%] had mild TEAEs and 2 subjects [40.0%] had moderate TEAEs); no subjects had a severe TEAE. - One subject (20.0%) in the primary cohort experienced drug-related TEAEs of diarrhoea and dermatitis. - No deaths, serious TEAEs, or TEAEs leading to study drug discontinuation were reported. - No AECIs related to lipid soluble vitamin deficiency events were reported. A total of 2 subjects experienced AECIs related to liver parameter disruption: 1 subject in the primary cohort experienced ALT increased and AST increased, and 1 subject in the supplemental cohort experienced blood bilirubin increased. ALT increased and AST increased were both moderate in severity and blood bilirubin increased was mild in severity. All of these events were not considered to be related to the study drug by the investigator. The outcomes of ALT increased and AST increased were both 'recovered/resolved', and the outcome of blood bilirubin increased was 'not recovered/not resolved' at the time of the interim analysis for Week 48. - No remarkable findings or clinical concerns were noted with respect to clinical laboratory tests, vital signs, weight, height, body mass index, and electrocardiograms. - Overall, TAK-625 was well-tolerated in subjects with PFIC. Final Analysis: - All 5 subjects (100%) experienced at least one treatment-emergent adverse events (TEAE) during the study. The most frequently reported TEAE was upper respiratory tract infection (5 subjects [100%]). All TEAEs were mild or moderate in severity (at the maximum severity, 2 subjects [40.0%] had mild TEAEs and 3 subjects [60.0%] had moderate TEAEs); no subjects had a severe TEAE. - One subject (20.0%) in the primary cohort experienced drug-related TEAEs of diarrhoea and dermatitis. - No deaths, serious TEAEs, or TEAEs leading to study drug discontinuation were reported. - No AECIs related to lipid soluble vitamin deficiency events were reported. A total of 3 subjects experienced AECIs related to liver parameter disruption: One subject in the primary cohort experienced liver function test increased, another subject in the primary cohort experienced ALT increased and AST increased, and one subject in the supplemental cohort experienced blood bilirubin increased. Liver function test increased was mild in severity, ALT increased and AST increased were both moderate in severity, and blood bilirubin increased was mild in severity. All of these events were not considered to be related to the study drug by the investigator. The outcome of liver function test increased was 'not recovered/not resolved', those of ALT increased and AST increased were both 'recovered/resolved', and that of blood bilirubin increased was 'not recovered/not resolved' at the time of the final analysis. - No remarkable findings or clinical concerns were noted with respect to clinical laboratory tests, vital signs, weight, height, body mass index, and electrocardiograms, except that one subject experienced an AECI related to liver parameter disruption (liver function test increased), one subject experienced AECIs related to liver parameter disruption (ALT increased and AST increased), and one subject experienced an AECI related to liver parameter disruption (blood bilirubin increased); all of these AECIs were not considered to be related to the study drug by the investigator. - Overall, TAK-625 was well-tolerated in subjects with PFIC. CONCLUSION: Interim analysis for Week 26: In this study, the efficacy, PK, and safety of TAK-625 administered (600 microg/kg, BID) in Japanese subjects with PFIC were evaluated. TAK-625 was initially administered to subjects at a dose of 150 microg/kg, BID. The dosage was then incrementally increased on a weekly basis in the following order: 300 microg/kg, 450 microg/kg, and finally 600 microg/kg, all administered BID. The safety results indicated that TAK-625 was well-tolerated in subjects with PFIC for 26 weeks, up to the time of the interim analysis. Overall, results of this study showed that TAK-625 was an effective and well-tolerated treatment for Japanese subjects with PFIC. Interim analysis for Week 48: In this study, the efficacy, PK, and safety of TAK-625 administered (600 microg/kg, twice daily [BID]) in Japanese subjects with PFIC were evaluated. TAK-625 was initially administered to subjects at a dose of 150 microg/kg, BID. The dosage was then incrementally increased on a weekly basis in the following order: 300 microg/kg, 450 microg/kg, and finally 600 microg/kg, all administered BID. All 5 subjects received the study treatment at 600 microg/kg, BID at the time of the interim analysis for Week 26, and these dosages were maintained at Week 48. All of these subjects were still in the treatment period at the time of the interim analysis for Week 48. Furthermore, the safety results indicated that TAK-625 was well-tolerated in subjects with PFIC for 48 weeks, up to the time of the interim analysis. Overall, results of this study showed that TAK-625 was an effective and well-tolerated treatment for Japanese subjects with PFIC when administered in the long term. Final Analysis: In this study, the efficacy, pharmacokinetics, and safety of TAK-625 administered (600 microg/kg, BID) in Japanese subjects with PFIC were evaluated. TAK-625 was initially administered to subjects at a dose of 150 microg/kg, BID. The dosage was then incrementally increased on a weekly basis in the following order: 300 microg/kg, 450 microg/kg, and finally 600 microg/kg, all administered BID. Furthermore, the safety results indicated that TAK-625 was well-tolerated in subjects with PFIC during the study.

- Primary Endpoint: -- Decreases in the average morning ItchRO (Obs) severity scores between baseline and the average of Week 15 through Week 26 were observed for the primary and all cohorts, with mean changes of -1.514 (95% CI: -3.6541, 0.6255) and -0.989 (95% CI: -2.1838, 0.2048) respectively. In the supplemental cohort, the average morning ItchRO (Obs) severity score remained at the baseline level. - Key Secondary Endpoints: -- Decreases in the average morning ItchRO (Obs) frequency scores between baseline and the average of Week 15 through Week 26 were observed for the primary, supplemental, and all cohorts, with mean changes of -0.740 (95% CI: -4.8063, 3.3254), -0.735 (95% CI: -6.0922, 4.6213), and -0.738 (95% CI: -1.4256, -0.0503) respectively. The decrease in the average morning ItchRO (Obs) frequency scores in the primary and all cohorts were less than that of the average morning ItchRO (Obs) severity scores. This could have potentially been influenced by missing data, a result of the eDiary settings. -- Decreases in the total sBA level between baseline and Week 26 were observed for the primary and all cohorts, with mean changes of -149.900 (95% CI: -561.4008, 261.6008) micromol/L and -97.240 (95% CI: -268.3678, 73.8878) micromol/L respectively. In the supplemental cohort, the total sBA level remained at the baseline level. - Other Secondary Endpoints: -- The proportion of sBA responders from baseline through Week 26 was 33.3% (1/3 subjects), 0% (0/2 subjects), and 20.0% (1/5 subjects) in the primary, supplemental, and all cohorts, respectively. -- Decreases in the weekly average ItchRO (Obs) severity scores between baseline and the average of Week 15 through Week 26 were observed for the primary and all cohorts, with mean changes of -1.629 (95% CI: -3.5064, 0.2481) and -1.079 (95% CI: -2.2608, 0.1026) respectively. In the supplemental cohort, the weekly average ItchRO (Obs) severity score remained at the baseline level. CONCLUSION: Interim analysis for Week 26: In the efficacy evaluation, there were decreases from baseline in the average morning ItchRO (Obs) severity scores (primary endpoint) and the total sBA level (key secondary endpoint) during the treatment periods up to Week 26.

Overall, results of this study showed that TAK-625 was an effective and well-tolerated treatment for Japanese subjects with PFIC when administered in the long term.

No

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).

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220356

Shikamura Mitsuhiro

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Contact for Clinical Trial Information

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

+81-6-6204-2111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

Jan. 10, 2023

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

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:
a) 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.
b) The participant has a PFIC phenotype without a known mutation or with another known mutation not described above.
c) 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).

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.

Both

Progressive Familial Intrahepatic Cholestasis (PFIC)

Primary cohort: 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.

Supplemental cohort: 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.

1. Change in the Average Morning Itch Reported Outcome (ItchRO) (Observer Instrument [Obs]) Severity Score Between Baseline and Average of Week 15 through Week 26
Time Frame: 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).

1. Change in the Average Morning ItchRO (Obs) Frequency Score Between Baseline and Average of Week 15 through Week 26
Time Frame: 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).

2. Change From Baseline in Total Serum Bile Acid (sBA) Levels to Week 26
Time Frame: 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.

3. Percentage of Participants (Responders) Who Experienced an sBA Control From Baseline through Week 26
Time Frame: Baseline through Week 26
Responders to sBA control were defined as participants who achieved a decrease to less than (<) 102 micro mol/L, a decrease of greater than (>) 75 percent (%), or normalization at any timepoint from baseline through Week 26.

4. Change in the ItchRO (Obs) Weekly Average Severity Between Baseline and the Average of Week 15 through Week 26
Time Frame: 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).

+81-29-853-3749

Oct. 28, 2022

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