A Study of Odevixibat for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC)

JRCT ID: jRCT2061230022

Registered date:16/06/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Progressive Familial Intrahepatic Cholestasis(PFIC)
• Date of first enrollment: 01/06/2023
• Target sample size: 6
• Study type: Interventional
• Intervention(s): Subjects who met the eligibility criteria at the screening test will receive A4250 40 micro g/kg (once daily) of study drug from the next day of Visit 3 (Day 1) for 12 weeks. If no safety problems are observed after 12 weeks (Visit 6), the dose of study drug will be increased to 120 micro g/kg, in principal, and administered for 12 weeks (the study drug will be administered for a total of 24 weeks). After Week 12 (Visit 6), the investigator will select the dose of study drug (either 40 micro g/kg or 120 micro g/kg) according to the subjects safety and tolerability.

Outcome(s)

Primary Outcome

<Dose Adjustment Period>
To evaluate the efficacy of repeated daily doses of A4250 (40 micro g/kg/day in first 12 weeks followed by 40 micro g/kg/day or 120 micro g/kg/day in 12 weeks, 24 weeks in total) in Japanese patients with PFIC Types 1 and 2 (aged from 6 months to <18 years), as determined by the following:
-The proportion of patients experiencing at least a 70% reduction in fasting s-BA concentration from baseline to Week 24 or reaching a level =< 70 micro mol/L after 24 weeks of treatment
-The proportion of improvement in itching assessment over the 24-week treatment period.
To evaluate the safety and tolerability of repeated daily doses of A4250 (40 micro g/kg/day in first 12 weeks followed by 40 micro g/kg/day or 120 micro g/kg/day in 12 weeks, 24 weeks in total) in Japanese patients with PFIC Types 1 and 2 (aged from 6 months to <18 years).

<DoseMaintenance Period>
To evaluate a sustained effect of A4250 on s-BAs and itching score in Japanese patients with PFIC Types 1 and 2 (aged from 6 months to <18 years).
To evaluate the safety and tolerability of 72-weeks repeated daily doses of A4250 (40 micro g/kg/day or 120 micro g/kg/day) in Japanese patients with PFIC Types 1 and 2 (aged from 6 months to <18 years).

Key inclusion & exclusion criteria

• Age minimum: >= 3month old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Patients will be enrolled in the study if they meet all of the following criteria:
1. (Cohort 1) A Japense male or female patient, with diagnosis of PFIC Type 1 or 2 through identification of biallelic pathogenic variants in either the ATP8B1 or ABCB11 genes, between the ages of >=6 months and <18 years at Visit 1 (informed consent) with a body weight above 5 kg.
2. (Cohort 2) Among patients who do not meet item 1 above upon confirmation of gene examination, those with PFIC aged 3 months or older at Visit 1 (informed consent) and weighed above 5 kg.
After the enrollment period of Cohort 1, patients who are eligible for Cohort 1 will be included in Cohort 2.
3. During the screening period, patient must have elevated s-BA concentration, specifically measured to be >=100 micro mol/L, taken as the average of 2 samples at least 7 days apart (Visits 1 and 2) prior to randomization
4. Patient must have history of significant pruritus and a patient or guardian-reported observed scratching in the Patient Diary average of >=2 (on 0 to 4 scale) in the 2 weeks prior to Visit 3. However, if the patient in Cohort 2 is 18 years or older, the patient must have a history of significant pruritus and a patient -reported observed scratching in the Patient Diary with average itching score of >=2 (on 0 to 4 scale) in the 2 weeks prior to Visit 3.
5. Patient and/or legal guardian who can sign informed consent (or assent if the patient is below 15 years old) as appropriate. Patients who turn 18 years of age (or legal age per country) during the study will be required to re-consent in order to remain in the study
6. Patients who are judged by the investigator or subinvestigator to be able to continue treatment with the study drug for at least 24 weeks.
7. Patients will be expected to have a consistent guardian for the duration of the study (Parents and grandparents are preferred as guardians. It is preferable that the same guardian will answer the patient diary and other questionnaires, but parents and grandparents can be changed if it is unavoidable).
For Cohort 2, if the patient is 18 years of age or older at the time of Visit 1 (when informed consent is obtained), setting of the guardian in this study is not mandatory.
8. Guardians and age-appropriate patients (>=8 years of age) and patients who achieve 8 years of age during the study must be willing and able to use an Patient Diary as required by the study

Exclude criteria

Patients who meet any of the following criteria will be excluded from the study:
1. Patient with pathologic variations of the ABCB11 gene that predict complete absence of the BSEP protein
2. Patient with past medical history or ongoing complication of liver disaese other than underlying disease, but not limited to, the following:
a) Biliary atresia of any kind
b) Benign recurrent intrahepatic cholestasis, indicated by any test results of normal s-Bas
c) Suspected or proven liver cancer or metastasis to the liver on imaging studies
d) Histopathology on liver biopsy is suggestive of alternate non-PFIC related etiology of cholestasis
3. Patient with a past medical history or ongoing presence of any other disease or condition known to interfere with the absorption, distribution, metabolism (specifically bile acid metabolism), or excretion of drugs in the intestine, including but not limited to, inflammatory bowel disease
4. Patient with past medical history or ongoing chronic (i.e., >3 months) diarrhea requiring intravenous fluid or nutritional intervention for treatment of the diarrhea and/or its sequelae
5. Patient who has the followings:
a) A confirmed past diagnosis of infection with human immunodeficiency virus
b) Present and active, clinically significant, acute, or chronic infection
c) Past medical history of any major episode of infection requiring hospitalization within 4 weeks of treatment start (study Day 1)
d) Treatment with parenteral anti-infective treatment within 4 weeks of treatment start (study Day 1)
e) Completion of oral anti-infective treatment within 2 weeks prior to start of Screening Period
6. Patient who have diagnosis and treatment history of malignancy within 5 years prior to obtaining concent.
7. Patient with a past medical history of chronic kidney disease with an impaired renal function and a glomerular filtration rate <70 mL/min/1.73 m2 at Screening.
8. Patient with surgical history of endobiliary or extrabiliary fistula within 6 months prior to start of Screening Period.
9. Patient who has a history of liver transplantation or plan to undergo liver transplantation within 6 months after obtaining consent
10. Decompensated liver disease, coagulopathy, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
11. International normalized ratio (INR) >1.4 at Screening
(the patient who is treated with Vitamin K intravenously, and the INR is =<1.4 at resampling may be enrolled)
12. Serum ALT >10^ upper limit of normal (ULN) at Screening
13. Serum ALT >15^ ULN at any time point during the last 6 months and the alternate etiology for the elevation is not confirmed
14. Total bilirubin >10^ ULN at Screening
15. Patient suffers from uncontrolled, recalcitrant pruritic condition other than PFIC. Examples include, but not limited to, refractory atopic dermatitis or other primary pruritic skin diseases
16. Any patient who is pregnant or lactating or who is planning to become pregnan
17. Sexually active males and females who are not using a reliable contraceptive method with =<1% failure rate (such as hormonal contraception, intrauterine device, or complete abstinence) throughout the duration of the study and 90 days thereafter (from signed informed consent through 90 days after last dose of study drug).
18. Patient with a past medical history of alcohol or substance abuse will be excluded. Patient must agree to refrain from illicit drug and alcohol use during the study
19. Administration of bile acid or lipid binding resins and medications that affect GI function (Refer to Appendix 1 - Concomitant Medications Guidelines) at Visit 1 (obtaining concent)
20. Patients who have participated in a clinical trial using the investigational drug within 30 days prior to obtaining consent
21. Patient has had investigational exposure to a drug, biologic agent, or medical device within 30 days prior to Visit 1 (obtaining concent), or 5 half-lives of the other study agent, whichever is longer
22. Patient who has been previously treated with an IBAT inhibitor whose pruritus has not responded to treatment
Of note, if the patient is taking IBAT inhibitors at the time of informed consent, IBAT inhibitors must be discontinued from the date of informed consent.
23. Patient who have changed dosage within 6 months prior to screening if taking sodium phenylbutyrate (excluding patients who have changed dosage due to weitht change)
24. Any other conditions or abnormalities which, in the opinion of the investigator or subinvestigator or the sponsor, may compromise the safety of the patient, or interfere with the patient participating in or completing the study
25. Personnel and family members of the study site or sponsor
26. Patients who are scheduled to undergo surgery during the study period

Related Information

• Primary Sponsor: Achiwa Hiroyuki