Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC

Progressive Familial Intrahepatic Cholestasis Clinical Trial

Official title:

An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of A4250 in Children With Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 2)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03659916
• Other study ID #: A4250-008
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 28, 2018
• Est. completion date: March 31, 2025

Study information

• Verified date: May 2024
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Open Label Extension Study to evaluate long term safety and persistence of effect of A4250 in children with PFIC.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 116
• Est. completion date: March 31, 2025
• Est. primary completion date: February 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Months to 100 Years

Eligibility

Inclusion Criteria Cohort 1:

1. Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of intolerable symptoms after completing at least 12 weeks of treatment

2. Signed informed consent and assent as appropriate

3. Patients expected to have a consistent caregiver for the duration of the study

4. Caregivers (and age appropriate patients) must be willing and able to use an eDiary device as required by the study

Inclusion Criteria Cohort 2:

1. A male or female patient of any age, with a clinical diagnosis of PFIC, including episodic forms (i.e., BRIC), and with a body weight =5 kg at Visit S-1.

2. Patient must have clinical genetic confirmation of PFIC

3. Patients with PFIC, excluding BRIC, must have elevated serum bile acid concentration,specifically measured to be =100 µmol/L, taken as the average of 2 samples at least 7 days apart (Visits S-1 and S-2) prior to the Screening/Inclusion Visit (Visit 1).

4. Patients with PFIC, excluding BRIC, must have history of significant pruritus and a caregiver-reported observed scratching or patient-reported itching (for patients >18 with no caregiver-reported observed scratching) in the eDiary average of =2 (on 0 to 4 scale) in the 2 weeks prior to the Screening/Inclusion Visit (Visit 1).

5. Patients with episodic forms of PFIC (i.e., BRIC) must have an emerging flare characterized by clinically significant pruritus and elevated serum bile acid levels/cholestasis as judged by the investigator.

6. Patient and/or legal guardian must sign informed consent (and assent) 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.

7. Age appropriate patients are expected to have a consistent caregiver for the duration of the study

8. Caregivers and age-appropriate patients (=8 years of age) must be willing and able to use an eDiary device as required by the study

Exclusion Criteria Cohort 1:

1. Decompensated liver disease: coagulopathy, history, or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy

2. Sexually active males and females who are not using a reliable contraceptive method with =1% failure rate (such as hormonal contraception, intra-uterine device, or complete abstinence) throughout the duration of the study and 90 days thereafter

3. Patients not compliant with treatment in study A4250-005

4. Any other conditions or abnormalities which, in the opinion of the investigator or Medical Monitor, may compromise the safety of the patient, or interfere with the patient participating in or completing the study

Exclusion Criteria Cohort 2:

1. Known pathologic variations of the ABCB11 gene that have been demonstrated to result in complete absence of the BSEP protein

2. Patient with past medical history or ongoing presence of other types of liver disease

including, but not limited to, the following:

1. Biliary atresia of any kind

2. Suspected or proven liver cancer or metastasis to the liver on imaging studies

3. Histopathology on liver biopsy is suggestive of alternate non-PFIC related etiology of cholestasis Note: Patients with clinically significant portal hypertension are allowed.

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 has a confirmed past diagnosis of infection with human immunodeficiency virus or other present and active, clinically significant, acute, or chronic infection, or past medical history of any major episode of infection requiring hospitalization or treatment with parenteral anti-infective treatment within 4 weeks of treatment start (Study Day 1) or completion of oral anti-infective treatment within 2 weeks prior to start of Screening Period.

6. Any patient with suspected or confirmed cancers except for basal cell carcinoma, and non-liver cancers treated at least 5 years prior to Screening with no evidence of recurrence.

7. Patient has had a liver transplant, or a liver transplant is planned within 6 months of the Screening/Inclusion Visit.

8. Decompensated liver disease, coagulopathy, history, or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy

9. INR >1.4 (the patient may be treated with Vitamin K intravenously, and if INR is =1.4 at resampling the patient may be included).

10. Serum ALT >10 × upper limit of normal (ULN) at Screening.

11. Serum ALT >15 × ULN at any time point during the last 6 months unless an alternate etiology was confirmed for the elevation.

12. Total bilirubin >10 × ULN at Screening.

13. 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.

14. Any patient who is pregnant or lactating or who is planning to become pregnant within 72 weeks of the Screening/Inclusion Visit.

15. 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).

16. 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.

17. Administration of bile acid or lipid binding resins and medications that slow GI motility.

18. Patient has had investigational exposure to a drug, biologic agent, or medical device within 30 days prior to Screening, or 5 half-lives of the study agent, whichever is longer.

19. Any other conditions or abnormalities which, in the opinion of the investigator or Medical Monitor, may compromise the safety of the patient, or interfere with the patient participating in or completing the study.

Related Conditions & MeSH terms

• Cholestasis
• Cholestasis, Intrahepatic
• Progressive Familial Intrahepatic Cholestasis

Intervention

Drug:
• A4250 (odevixibat)
A4250 is a small molecule and selective inhibitor of IBAT

Locations

Country	Name	City	State
Australia	The Royal Children's Hospital	Melbourne
Belgium	Cliniques Universitaires Saint-Luc	Woluwe-Saint-Lambert
Canada	The Hospital for Sick Children	Toronto
France	University and Pediatric Hospital of Lyon	Bron
France	Universite Paris SUD - Hpitaux Universitaires Paris-Sud - Hopital Bicetre	Le Kremlin-Bicêtre
France	Hospital De La Timone	Marseille
France	Hospital Necker-Enfants Maladies	Paris
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Kinderklinik Tubingen, Universitatsklinikum Tubingen	Tübingen
Germany	Univesitatsklinikum Tubingen Klinik fur Kinder und Jugendmedizin	Tübingen
Israel	Shaare-Zedek Mc	Jerusalem
Israel	Schneider Children's Medical Center Of Israel	Petach-Tikva
Italy	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo
Italy	University Hospital Of Padova	Padova
Italy	Ospedale Regina Margherita	Torino
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Universitair Medisch Centrum (UMC) Utrecht	Utrecht
Poland	Instytut Pomnik - Centrum Zarowia Dziecka	Warsaw
Saudi Arabia	King Faisal Specialist Hospital & Research Centre	Riyadh
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Sweden	Astrid Lindgren Children's Hospital, Karolinska University Hospital	Solna
Turkey	Gazi University	Ankara
Turkey	Hacettepe University Faculty of Medicine	Ankara
Turkey	Akdeniz University	Antalya
Turkey	Istanbul University Medical Faculty	Istanbul
Turkey	Inonu University Medical Faculty	Malatya
United Kingdom	Birmingham Women's and Children's NHS Foundation Trust	Birmingham
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	Institute of Liver Studies - Kings College Hospital	London
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins School of Medicine	Baltimore	Maryland
United States	Children's Hospital Colorado	Denver	Colorado
United States	Baylor College of Medicine - Texas Children's Liver Center	Houston	Texas
United States	Riley Hospital for Children - Riley Children's Specialists	Indianapolis	Indiana
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Columbia University Medical Center - Presbyterian Hospital Building	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Albireo

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Israel,  Italy,  Netherlands,  Poland,  Saudi Arabia,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	US: Change in Pruritus	Change in pruritus as indexed by caregiver-reported (Albireo ObsRO instrument) observed scratching	From baseline over 72 weeks
Primary	EU and rest of world: Change in serum bile acids		From baseline up to week 72
Secondary	EU and rest of world: Proportion of positive pruritus assessments at the patient level over the 72-week treatment period using the Albireo ObsRO instrument.		72 weeks
Secondary	US: Change from baseline in serum bile acids after 72 weeks of treatment.		72 weeks
Secondary	All regions: 3. Change from baseline in serum bile acids at Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, 72, and 76		Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, 72, and 76
Secondary	All regions: Proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument.		weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, 0-70, or the proportion of positive pruritus assessments at each 4-week interval between V1/Screening and V5/Week 24, then by each visit between V5/Week 24 to V12/Week 76
Secondary	All regions: Proportion of individual AM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument		weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, 0-70, or the proportion of positive pruritus assessments at each 4-week interval between V1/Screening and V5/Week 24, then by each visit between V5/Week 24 to V12/Week 76
Secondary	All regions: Proportion of individual PM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument		weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, 0-70, or the proportion of positive pruritus assessments at each 4-week interval between V1/Screening and V5/Week 24, then by each visit between V5/Week 24 to V12/Week 76
Secondary	All regions. All-cause mortality		From baseline to weeks 24, 48, and 72
Secondary	All regions: Number of patients undergoing biliary diversion surgery		From baseline to weeks 24, 48, and 72
Secondary	All regions: Number of patients undergoing liver transplantation		From baseline to weeks 24, 48, and 72
Secondary	All regions: Change in growth	The linear growth deficit compared to the standard growth curve	From baseline to weeks 24, 48, and 72
Secondary	All regions: Change in AST to platelet ratio idex (APRI) score		From baseline to week 72
Secondary	All regions: Change in Fib-4 score		From baseline to week 72
Secondary	All regions: Change in pediatric end-stage liver disease (PELD)/model for end-stage liver disease (MELD) score		From baseline to week 72
Secondary	All regions: Change in use of antipruritic medication		From baseline to weeks 24, 48, and 72