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

Phase 3CompletedNCT03659916

Albireo, an Ipsen Company116 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

116

Conditions

Progressive Familial Intrahepatic Cholestasis

Interventions

A4250 (odevixibat)DRUG

A4250 is a small molecule and selective inhibitor of IBAT

Eligibility

Sex: ALLMin age: 0 MonthsMax age: 100 Years

Medical Language ↔ Plain English

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 Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of intolerable symptoms after completing at least 12 weeks of treatment 2.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.

Locations (41)

Outcomes

Primary Outcomes

Change From Baseline in Serum Bile Acids

Blood samples for analysis of fasting total serum bile acids were drawn at specified timepoints. Participants were to fast (water intake only) for at least 4 hours prior to the collection of samples for serum bile acids. Exceptions were made for infants \<12 months of age if unable to fast for the full 4 hours. Baseline for Cohort 1 placebo/odevixibat and Cohort 2 groups was defined as the average of last 2 values before the first dose of study treatment in the study. Baseline for Cohort 1 odevixibat/odevixibat group was defined as average of last 2 values before the first dose of study treatment in study A4250-005 (NCT03566238).

Time frame: Baseline and Week 72

Proportion of Positive Pruritus Assessments at the Participant Level Over 72-Week Using the Albireo Observer-Reported Outcome (ObsRo) Instrument

A positive pruritus assessment was defined as a scratching score of \<=1 or at least a 1-point drop from baseline on the Albireo ObsRO instrument. The proportion of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant.

Time frame: Baseline and Week 72

Secondary Outcomes

Proportion of Positive Pruritus Assessments at the Participant Level Using the Albireo ObsRo Instrument From Weeks 0-4, 0-12, 0-22, 0-24, 0-36, 0-46, 0-48, 0-60, and 0-70

Time frame: Weeks 0-4, Weeks 0-12, Weeks 0-22, Weeks 0-24, Weeks 0-36, Weeks 0-46, Weeks 0-48, Weeks 0-60, and Weeks 0-70

Change From Baseline in Serum Bile Acids at Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, and 72

Data from ClinicalTrials.gov

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Children's Hospital Los Angeles

Los Angeles, California, United States

Children's Hospital Colorado

Denver, Colorado, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Riley Hospital for Children - Riley Children's Specialists

Indianapolis, Indiana, United States

Johns Hopkins School of Medicine

Baltimore, Maryland, United States

Washington University School of Medicine

St Louis, Missouri, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Columbia University Medical Center - Presbyterian Hospital Building

New York, New York, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

...and 31 more locations

Blood samples for analysis of fasting total serum bile acids were drawn at specified timepoints. Participants were to fast (water intake only) for at least 4 hours prior to the collection of samples for serum bile acids. Exceptions were made for infants \<12 months of age if unable to fast for the full 4 hours. Baseline for Cohort 1 placebo/odevixibat, and Cohort 2 groups was defined as the average of last 2 values before the first dose of study treatment in the study. Baseline for Cohort 1 odevixibat/odevixibat group was defined as average of last 2 values before the first dose of study treatment in study A4250-005 (NCT03566238).

Time frame: Baseline and Weeks 4, 12, 22, 24, 36, 46, 48, 60, 70, and 72

Proportion of Positive Pruritus Assessments at the Participant Level Using the Albireo ObsRo Instrument From Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 34-36, 44-46, 47-48, 58-60, 68-70, 71-72, 73-76

Time frame: Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 34-36, 44-46, 47-48, 58-60, 68-70, 71-72, 73-76

Proportion of Positive Pruritus Assessments at the Participant Level Using the Albireo ObsRo Instrument (AM Score)

Time frame: Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 34-36, 44-46, 47-48, 58-60, 68-70, 71-72, and 73-76

Proportion of Positive Pruritus Assessments at the Participant Level Using the Albireo ObsRo Instrument (PM Score)

Time frame: Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 34-36, 44-46, 47-48, 58-60, 68-70, 71-72, and 73-76

Percentage of Responders for Pruritus Assessments Bi-Weekly (AM and PM)

A responder is defined as a participant who reports a decrease in pruritus score from unrounded baseline equivalent to or greater than the threshold of meaningful change estimated from the blinded psychometric analysis. The averaged pruritus score was used to calculate the percentage of participants achieving meaningful reduction at specified Week against the thresholds value of 1.00 based on bi-weekly scores at specified Week obtained from blinded psychometric analysis across all anchors support a threshold of 1.0 point for AM, PM and AM and PM scratching scores. ObsRO instrument was used to assess severity of observed scratching twice a day (AM and PM) with score from 0 to 4 where 0 is no scratching and 4 is worst possible scratching.

Time frame: Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12, 13-14, 15-16, 17-18, 19-20, 21-22, 23-24, 35-36, 47-48, 59-60, and 71-72

Percentage of Responders for Pruritus Assessments Monthly (AM and PM)

A responder is defined as a participant who reports a decrease in pruritus score from unrounded baseline equivalent to or greater than the threshold of meaningful change estimated from the blinded psychometric analysis. The averaged pruritus score was used to calculate the percentage of participants achieving meaningful reduction at specified Week against the thresholds value of 1.00 based on monthly scores at specified Week obtained from blinded psychometric analysis across all anchors support a threshold of 1.0 point for AM, PM and AM and PM scratching scores. ObsRO instrument was used to assess severity of observed scratching twice a day (AM and PM) with score from 0 to 4 where 0 is no scratching and 4 is worst possible scratching.

Time frame: Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 34-36, 45-48, 58-60, and 68-72

Percentage of Participants Achieving a Positive Pruritus Assessment for >50% of the Time Based on the Albireo ObsRO (AM and PM)

The percentage of participants who achieved positive pruritus assessment for more than 50% of the time for Weeks 0-72 is reported. A positive pruritus assessment is defined as a scratching score of \<=1 or at least a 1-point decrease from baseline on the Albireo ObsRO instrument based on rounded baseline and was calculated based on reported eDiary data. At each assessment, the AM score was compared to the baseline AM average, and the PM score was compared to the baseline PM average. All assessments after intercurrent events (premature treatment discontinuation, death, or initiation of rescue treatments such as biliary diversion surgery or liver transplantation) or follow-up assessments (\>= last dose day + 15 days) were excluded from analysis.

Time frame: Week 72

Number of Participants Who Underwent Biliary Diversion Surgery and Liver Transplantation

Participants who underwent biliary diversion surgery and or liver transplantation data has been reported.

Time frame: Baseline and Weeks 24, 48, and 72

Change From Baseline in Height Z-Scores

Growth factors like height was measured by the standardized assessments outlined in the US food and drug administration (FDA) guidance document. Height was measured using certified stadiometer. Change in growth parameters was assessed using linear growth (height) compared to standard growth curve (Z-score) calculated by using the software or methods from the centers for disease control (CDC) website for participants with age \>=2 years old and from the world health organization (WHO) website for participants with age \<2 years old. Participants whose accurate age was not available, Z-score was not calculated. Baseline is the last available assessment prior to first dose of study treatment. A Z-score indicates how many standard deviation's (SD) a participant's measurement (like height), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below average a measurement was.

Time frame: Baseline and Weeks 24, 48, 70 and 72

Change From Baseline in Weight Z-Scores

Growth factors like weight was measured by the standardized assessments outlined in the US FDA guidance document. Weight was measured using certified weight scale. Change in growth parameters was assessed using linear growth (weight) compared to standard growth curve (Z-score), calculated by using the software or methods from the CDC website for participants with age \>=2 years old and from the WHO website for participants with age \<2 years old. Participants whose accurate age was not available, Z-score was not calculated. Baseline is the last available assessment prior to the first dose of study treatment. The Z-score indicates how many SDs a participant's measurement (like weight), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below the average a measurement was.

Time frame: Baseline and Weeks 24, 48, 70 and 72

Change From Baseline in Body Mass Index (BMI) Z-Scores

Growth factors like BMI was measured by the standardized assessments outlined in the US FDA guidance document. BMI was calculated by weight (kg) / height (m)\^2. Change in growth parameters was assessed using linear growth (BMI) compared to standard growth curve (Z-score), calculated by using the software or methods from the CDC website for participants with age \>=2 years old and from the WHO website for participants with age \<2 years old. Participants whose accurate age was not available, Z-score was not calculated. Baseline is the last available assessment prior to the first dose of study treatment. The Z-score indicates how many SDs a participant's measurement (like BMI), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below the average a measurement was.

Time frame: Baseline and Weeks 24, 48, 70 and 72

Number of Participants With Use of Ursodeoxycholic Acid (UDCA) and/or Rifampicin at Weeks 24, 48, and 72

Data for the number of participants with use of UDCA and rifampicin are reported.

Time frame: Weeks 24, 48, and 72

Change From Baseline to Week 72 in Pediatric End-Stage Liver Disease (PELD) Score

The PELD score was calculated for children under 12 years of age, ranged across negative to positive values. The calculation of the PELD score was done by converting the laboratory parameters: total bilirubin in milligram/deciliter (mg/dL), albumin in gram (g)/dL, and creatinine in mg/dL laboratory parameters were converted to units. PELD score was calculated as 4.80\*ln (total bilirubin)+18.57\*ln \[international normalized ratio (INR)\] - 6.87\*ln (albumin) + 4.36 (if participant \<1 year: scores for participants listed for liver transplantation before the participant's first birthday continued to include the value assigned for age (\<1 year) until the participant reached the age of 24 months) + 6.67 (if the participant has growth failure \[\<-2 standard deviation\]). The laboratory values \<1.0 were set to 1.0 for the calculation of the PELD score. Lower scores represent less severe hepatic disease. Baseline is the last available assessment prior to the first dose of study treatment.

Time frame: Baseline and Week 72

Change From Baseline to Week 72 in Model for End-stage Liver Disease (MELD) Score for Children 12 Years of Age or Older

The MELD score was calculated for children 12 years of age or older ranges from 6 to 40. The calculation of the MELD score was done by converting the laboratory parameters in the following units: total bilirubin in mg/dL, albumin in g/dL, and creatinine in mg/dL laboratory parameters were converted to units. MELD score for children 12 years of age or older ranges from 6 to 40 was calculated as 9.57\*ln (creatinine) + 3.78\*ln (total bilirubin) + 11.2 \*ln (INR) + 6.43. Laboratory values \<1.0 were set to 1.0 and serum creatinine values \>4.0 mg/dL were set to 4.0 for calculation of the MELD score. Lower scores represent less severe hepatic disease. Baseline is the last available assessment prior to the first dose of study treatment.

Time frame: Baseline and Week 72

Change From Baseline to Week 72 in Aspartate Aminotransferase (AST) to Platelet Ratio Index (APRI) Score

AST to APRI score was calculated as \[(AST in units per liter {U/L})/ (AST upper limit of normal {ULN} in U/L)\] \* 100/ (platelets in 10\^9/L). The APRI score is a way to assess fibrosis of the liver. The lower the APRI score (\< 0.5), the greater the negative predictive value and ability to rule out cirrhosis; the higher the value (\> 1.5) the greater the positive predictive value and ability to rule in cirrhosis. Lower values indicate less severe hepatic fibrosis. Baseline is the last available assessment prior to the first dose of study treatment.

Time frame: Baseline and Week 72

Change From Baseline to Week 72 in Fibrosis-4 (Fib-4) Score

Fib-4 score was calculated as (age \* AST in U/L)/ (platelets in 10\^9/L \*√ ( alanine aminotransferase \[ALT\] in U/L). The FIB-4 score estimates the amount of scarring in the liver. A FIB-4 score \<1.45 has a negative predictive value of 90% for advanced fibrosis (Ishak fibrosis score 4-6 which includes early bridging fibrosis to cirrhosis). In contrast, a FIB-4 \> 3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. Lower values indicate less severe hepatic fibrosis. Baseline is the last available assessment prior to the first dose of study treatment.

Time frame: Baseline and Week 72