Clinical trial NCT03659916: Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Progressive Familial Intrahepatic Cholestasis
Keywords: Pediatric
Cholestasis
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2018-09-06
Enrollment: 116
Sex: ALL
Minimum age (years): 0
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


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 Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of intolerable symptoms after completing at least 12 weeks of treatment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

Primary outcomes:
measure: US: Change in Pruritus
timeFrame: From baseline over 72 weeks
measure: EU and rest of world: Change in serum bile acids
timeFrame: From baseline up to week 72
Secondary outcomes:
measure: 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.
timeFrame: 72 weeks
measure: US: Change from baseline in serum bile acids after 72 weeks of treatment.
timeFrame: 72 weeks
measure: All regions: 3. Change from baseline in serum bile acids at Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, 72, and 76
timeFrame: Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, 72, and 76
measure: All regions: Proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument.
timeFrame: 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
measure: All regions: Proportion of individual AM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument
timeFrame: 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
measure: All regions: Proportion of individual PM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument
timeFrame: 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
measure: All regions. All-cause mortality
timeFrame: From baseline to weeks 24, 48, and 72
measure: All regions: Number of patients undergoing biliary diversion surgery
timeFrame: From baseline to weeks 24, 48, and 72
measure: All regions: Number of patients undergoing liver transplantation
timeFrame: From baseline to weeks 24, 48, and 72
measure: All regions: Change in growth
timeFrame: From baseline to weeks 24, 48, and 72
measure: All regions: Change in AST to platelet ratio idex (APRI) score
timeFrame: From baseline to week 72
measure: All regions: Change in Fib-4 score
timeFrame: From baseline to week 72
measure: All regions: Change in pediatric end-stage liver disease (PELD)/model for end-stage liver disease (MELD) score
timeFrame: From baseline to week 72
measure: All regions: Change in use of antipruritic medication
timeFrame: From baseline to weeks 24, 48, and 72
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Denver
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Indianapolis
country: United States
facility: Riley Hospital for Children - Riley Children's Specialists
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University Medical Center - Presbyterian Hospital Building
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine - Texas Children's Liver Center
state: Texas
city: Melbourne
country: Australia
facility: The Royal Children's Hospital
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Bron
country: France
facility: University and Pediatric Hospital of Lyon
city: Le Kremlin-Bicêtre
country: France
facility: Universite Paris SUD - Hpitaux Universitaires Paris-Sud - Hopital Bicetre
city: Marseille
country: France
facility: Hospital De La Timone
city: Paris
country: France
facility: Hospital Necker-Enfants Maladies
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Tübingen
country: Germany
facility: Kinderklinik Tubingen, Universitatsklinikum Tubingen
city: Tübingen
country: Germany
facility: Univesitatsklinikum Tubingen Klinik fur Kinder und Jugendmedizin
city: Jerusalem
country: Israel
facility: Shaare-Zedek Mc
city: Petach-Tikva
country: Israel
facility: Schneider Children's Medical Center Of Israel
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
city: Padova
country: Italy
facility: University Hospital Of Padova
city: Torino
country: Italy
facility: Ospedale Regina Margherita
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum (UMC) Utrecht
city: Warsaw
country: Poland
facility: Instytut Pomnik - Centrum Zarowia Dziecka
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Centre
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Solna
country: Sweden
facility: Astrid Lindgren Children's Hospital, Karolinska University Hospital
city: Ankara
country: Turkey
facility: Gazi University
city: Ankara
country: Turkey
facility: Hacettepe University Faculty of Medicine
city: Antalya
country: Turkey
facility: Akdeniz University
city: Istanbul
country: Turkey
facility: Istanbul University Medical Faculty
city: Malatya
country: Turkey
facility: Inonu University Medical Faculty
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: London
country: United Kingdom
facility: Institute of Liver Studies - Kings College Hospital
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: