Clinical trial NCT05035030: Long-term Safety and Efficacy of Odevixibat in Patients With Alagille Syndrome
Official title: An Open Label Study to Evaluate the Long-term Safety and Efficacy of Odevixibat (A4250) in Patients With Alagille Syndrome (ASSERT-EXT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Alagille Syndrome
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2021-09-05
Enrollment: 70
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the long-term safety and effectiveness of odevixibat in participants with Alagille syndrome (ALGS).

The participants of this study will have ALGS a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth and severe itching (pruritis).

The drug used for the study is odevixibat and was authorized for the treatment of cholestatic pruritus in infants with ALGS over 12 months of age by the United States Food and Drug Administration on 13 June 2023.

Detailed description: This Phase 3, open-label, multi-center extension study will have two groups of participants: Cohort 1 (participants who participated in Study A4250-012 \[NCT04674761; ASSERT\] and meet the entry criteria for this study) and Cohort 2 (infants under 12 months of age) with ALGS.

The study will consist of 2 or 3 periods:

1. A 'Treatment period' of 72 weeks (cohort 1) or 12 weeks (cohort 2). Participants will visit the clinic every 4 to 12 weeks and will receive a dose of 120 μg/kg odevixibat daily.
2. An 'Optional extension period' where participants who wish to continue receiving odevixibat after the 'treatment period' will have the opportunity to remain on treatment with visits every 16 weeks until the drug is commercially available. The optional extension is available provided continued use is supported by the risk-benefit profile, the participant has not been previously withdrawn or discontinued from the study, and the study is not terminated by the Sponsor.
3. A 'Safety follow-up period' of 4 weeks (cohort 1) or 2 weeks (cohort 2). The Safety Follow-up Period will not occur for those who remain on treatment in the optional extension period.

Participants will need to complete an e-diary and questionnaires throughout the study (cohort 1 only). Participants will undergo blood samplings, urine collections (cohort 1 only), physical examinations, and clinical evaluations. They may continue some other medications, but the details need to be recorded.

Eligibility criteria: Inclusion Criteria:

Cohort 1 :

1. Completion of the 24-week Treatment Period of Study A4250-012
2. Signed 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 to remain on the study
3. Caregivers (and age-appropriate patients) must be willing and able to use an electronic diary (eDiary) device as required by the study
4. Sexually active males and females must agree to use a reliable contraceptive method with ≤1% failure rate (such as hormonal contraception, intra-uterine device, or complete abstinence) from signed informed consent through 90 days after last dose of study drug.

Cohort 2 :

1. Infant with clinically confirmed ALGS , ≤11 months of age at Study Day 1
2. Body weight ≥2 kg at Study Day 1
3. Gestational age ≥36 weeks. For children born with gestational age between 32 and 36 weeks, a postmenstrual age of ≥36 weeks is required .
4. Signed parent/legal guardian informed consent.

Exclusion Criteria:

Cohort 1 :

1. Decompensated liver disease, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
2. Patients who were not compliant with study drug treatment or procedures in Study A4250-012
3. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the safety of the patient, or interfere with the patient participating in or completing the study
4. Known hypersensitivity to any components of odevixibat

Cohort 2 :

1. 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. Progressive familial intrahepatic cholestasis (PFIC)
   3. Benign recurrent intrahepatic cholestasis
2. 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
3. Patient with past medical history or ongoing chronic diarrhea requiring intravenous fluid or nutritional intervention for treatment of the diarrhea and/or its sequelae
4. Patient has a confirmed past diagnosis of infection with human immunodeficiency virus or other present and active, clinically significant chronic infection
5. Recent infection requiring hospitalization or treatment with parenteral anti-infective within 4 weeks of Study Day 1 or completion of oral anti-infective treatment within 2 weeks prior to the Screening Visit
6. Cancer diagnosis (except for basal cell carcinoma)
7. Chronic kidney disease with an impaired renal function and a glomerular filtration rate \<70 mL/min/1.73 m2
8. Patient with surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months prior to the Screening Visit
9. Patient has had a liver transplant, or a liver transplant is planned within 6 months of Study Day 1
10. Decompensated liver disease, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
11. International normalized ratio (INR) \>1.4 (the patient may be treated with Vitamin K, and if INR is ≤1.4 at resampling the patient may be enrolled)
12. Serum alanine aminotransferase (ALT) \>10 × upper limit of normal (ULN) at Screening
13. Serum ALT \>15 × ULN at any time point during the last 6 months unless an alternate etiology was confirmed for the elevation
14. Total bilirubin \>15 × ULN at Screening
15. Patient suffers from uncontrolled, recalcitrant pruritic condition other than ALGS. Examples include, but not limited to, refractory atopic dermatitis or other primary pruritic skin diseases.
16. Patient exposed to alcohol or substance abuse in utero
17. Bile acid or lipid binding resins and medications that slow gastrointestinal motility
18. Patient has had investigational exposure to a drug, biologic agent, or medical device within 30 days prior to the Screening Visit, or 5 half-lives of the study agent, whichever is longer
19. Any other conditions or abnormalities which, in the opinion of the investigator may compromise the safety of the patient, or interfere with the patient participating in or completing the study

Primary outcomes:
measure: Change from baseline in pruritus
timeFrame: Baseline to week 72 (cohort 1).
measure: Percentage of participants with Treatment Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline to week 12 (cohort 2).
measure: Percentage of participants with clinically significant changes from baseline in Physical Examination
timeFrame: Baseline to week 12 (cohort 2).
measure: Percentage of participants with clinically significant changes in Laboratory Parameters
timeFrame: Baseline to week 12 (cohort 2).
measure: Percentage of participants with clinically significant changes from baseline in Vital Signs.
timeFrame: Baseline to week 12 (cohort 2).
measure: Change from baseline in concomitant medications.
timeFrame: Baseline to week 12 (cohort 2).
measure: Change from baseline in fat-soluble vitamin levels.
timeFrame: Baseline to week 12 (cohort 2).
Secondary outcomes:
measure: Change from baseline in serum bile acids levels
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in patient reported and observer reported itching and scratching severity scores
timeFrame: Baseline to week 72 (cohort 1).
measure: Percentage of participants achieving a clinically meaningful decrease in pruritus (pruritus responders)
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in sleep parameters.
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in Pediatric Quality of Life Inventory (PedsQL) scores.
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in in Global Symptom Relief: Patient Global Impression of Improvement (PGIC) score.
timeFrame: Baseline to Weeks 4, 12, 24, 48 and 72 (cohort 1).
measure: Change from baseline in in Global Symptom Relief: Clinical Global Impression of Improvement (CGIC) score.
timeFrame: Baseline to Weeks 4, 12, 24, 48 and 72 (cohort 1).
measure: Change from baseline in in Global Symptom Relief: Caregiver Global Impression of Change (CaGIC) score
timeFrame: Baseline to Weeks 4, 12, 24, 48 and 72 (cohort 1).
measure: Change from baseline in serum bile acid levels.
timeFrame: Baseline through week 72 (cohort 1).
measure: Percentage of participants with Treatment Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline to week 72 (cohort 1).
measure: Number of participants with change from baseline in physical examination
timeFrame: Baseline to week 72 (cohort 1).
measure: Number of participants with change from baseline in vital signs
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in concomitant medications
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in laboratory test results Pharmacokinetic (PK) Cmax [Time Frame: Day 1, Week 4, Week 8, and Week 12]
timeFrame: Baseline to week 72 (cohort 1).
measure: Change from baseline in plasma concentration of study drug
timeFrame: Day 1, Week 4, Week 8, and Week 12 (cohort 1).
measure: Pharmacodynamic Parameters: Change in serum bile acids levels
timeFrame: Baseline to Week 12 (cohort 2).
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF
state: California
city: San Francisco
country: United States
facility: University of California San Francisco (UCSF)
state: California
city: Indianapolis
country: United States
facility: Riley Hospital for Children at IU Health
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Missouri
city: Bronx
country: United States
facility: The Childrens Hospital at Montefiore Albert Einstein School of Medicine
state: New York
city: New York
country: United States
facility: Hassenfeld Children's Hospital at NYU Langone
state: New York
city: Durham
country: United States
facility: Atrium Health Carolinas Medical
state: North Carolina
city: San Antonio
country: United States
facility: Texas Liver Institute
state: Texas
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc Bruxelles
city: Bron
country: France
facility: Hôpital Femme Mère Enfant de Lyon
city: Lille
country: France
facility: Antenne pediatrique du CIC-Hopital Jeanne De Flandre
city: Paris
country: France
facility: Hopital Necker Enfants Malades
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Hannover
country: Germany
facility: Medizinische Hochschul
city: Tübingen
country: Germany
facility: Universitatsklinik fur Kinder-und Jugendmedizin Tubingen
city: Florence
country: Italy
facility: AOU Meyer
city: Padova
country: Italy
facility: Azienda Ospedale University
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Center
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Utrecht
country: Netherlands
facility: University Medical Center
city: Warszawa
country: Poland
facility: Instytut Pomnik-Centrum Zdrowia Dzieck
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty Hospital
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust King's College Hospital Paediatric Research
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: