Phase 3 Study of A4250 in Children with PFIC (PEDFIC 1)

  • Research type

    Research Study

  • Full title

    A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study to Demonstrate Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1)

  • IRAS ID

    237501

  • Contact name

    Tassos Grammatikopoulos

  • Contact email

    t.grammatikopoulos@nhs.net

  • Sponsor organisation

    Albireo AB

  • Eudract number

    2017-002338-21

  • Duration of Study in the UK

    1 years, 8 months, 17 days

  • Research summary

    Research Summary:
    Progressive Familial Intrahepatic Cholestasis (PFIC) is a chronic liver disease with impaired bile flow and patients’ also experience a severe itch. PFIC exists worldwide and both girls and boys are equally affected.
    Approximately half of PFIC patients undergo liver transplants. Many patients also undergo Partial External Biliary Diversion, which is a surgery to divert/drain bile away form the liver to try and improve persistent, treatment resistant itching.
    Currently, the treatment is palliative and there is no medical treatment approved for use in PFIC.
    A4250 is a research medicine that is being developed to treat patients with PFIC. A4250 is believed to reduce the absorption of bile acids from the intestine and lower bile acid levels in the blood. A4250 has so far been tested on healthy volunteers and in a study in children with any of several cholestatic (impaired bile flow) liver diseases, including some with PFIC.
    This is a Phase 3, double-blind study. Participants will be assigned randomly to receive the study medicine in 1 of 3 groups:
    • Group A: A4250 at a dose of 40 microgrammes (mcg) per kilogramme (kg) of body weight per day
    • Group B: A4250 at a dose of 120 mcg per kg of body weight per day
    • Group C: Matching placebo capsules to take daily

    There are 3 stages to this study: Screening Period, Treatment Period, and Follow Up. Approximately 60 participants will take part in the study at about 50 clinics in 15 countries. The study will last for approx. 9 months.

    Participants will need to have a number of different tests to determine if the study drug works and what side effects there might be, including: physical examinations, blood and urine tests and vital sign checks.

    Potential participants should be aged between 6 months and 18 years and have a confirmed diagnosis of PFIC type 1 or 2.

    Summary of Results:
    A Study to Investigate the Effectiveness and Safety of A4250 in Children with PFIC Types 1 or 2 (PEDFIC 1)

    Official Study Title: A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study to Demonstrate Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2

    Study Acronym: PEDFIC 1

    Medicine Studied: Odevixibat (A4250) Protocol Number: A4250-005 EU Trial Number: 2017-002338-21

    Dates of Trial: 16 May 2018 to 28 July 2020

    Important note: This summary shows only the results of this study. Other studies may find different results. Researchers and health authorities look at the results of many studies to understand which products work and how they work. It takes lots of people in many studies all around the world to advance science.

    To learn more about this study, visit the websites listed at the end of this summary.

    What was studied?

    Progressive Familial Intrahepatic Cholestasis (PFIC)

    PFIC stands for Progressive (gets worse over time) Familial (runs in families) Intrahepatic (occurs inside the liver) Cholestasis (poor bile flow) (PFIC).

    PFIC is a long lasting (chronic) liver disease that occurs when the cells in the liver cannot release bile. Bile is a fluid produced by the liver to carry away the waste and break down fats during digestion (process of breaking down food that you eat so that your body can use it). When bile flow from the liver is slow or stopped, it is called cholestasis. PFIC can make people feel very itchy

    Study Medicine

    Odevixibat or A4250 is believed to reduce the absorption (process of soaking up substances) of bile acids from the intestine, which lowers bile acid levels in the blood. It is being studied to treat participants with PFIC as they have higher levels of bile acid in the blood. Prior to conducting this study, odevixibat was tested in healthy participants and in a study which had participants with cholestatic liver disease, including some with PFIC.

    Study Purpose

    The main questions the researchers wanted to answer in this study was how odevixibat affects:

    • How much bile acid is in the blood
    • How itchy you feel
    • How you grow
    • How you sleep
    • Your quality of life

    To answer this, the researchers looked at:

    • How many participants had a decrease in amount of bile acid in the blood of at least 70 percent (%) or reached a bile level of less than or equal to 70 micromoles per litre after taking the study medicine for 24 weeks
    • How many participants had improvement in itching, as measured by scratching • How sleep changed because of odevixibat • How growth was impacted because of odevixibat • How quality of life was impacted because of odevixibat

    This summary gives the results of the main questions the researchers wanted to answer.

    Who was in the study?

    There were 62 participants from 14 countries in this study: 35 participants from Europe (France, Germany, Italy, Netherlands, Poland, and the United Kingdom), 8 from the United States, and 19 from the rest of the world (Australia, Canada, Israel, Saudi Arabia, and Turkey).

    Participants could take part in this study if they had:

    • A genetic test that confirmed PFIC 1 or PFIC 2
    • Bile acids levels that were more than 100 micromoles per litre
    • Severe itching

    Half of the participants were boys and half were girls. Most of the participants in the study (84%) were younger than 8 years; the rest (16%) were older than 8 years.

    What happened during this study?

    This was a Phase 3 study. In a Phase 3 study, a new treatment is tested in participants to determine if it works, and if it is safe. In this study, researchers compared two different dose levels of odevixibat with placebo. A placebo does not have any medicine in it but looks just like the medicine being tested.

    This study was also “double-blinded.” This means that both the participants and the doctors did not know who took odevixibat and who took placebo. This was done to make sure that the results were not influenced (“biased”) by knowing which treatment they were on.

    Participants first completed a screening period to find out if they could be a part of the study. The participants were then put into 3 groups (two groups received doses of odevixibat and one group placebo) and were picked for each treatment by chance alone. Doing this makes the groups more even to compare.

    • Group 1: Participants took placebo
    • Group 2: Participants took 40 micrograms per kilogram of odevixibat; the total dose was based on body weight
    • Group 3: Participants took 120 micrograms per kilogram of odevixibat; the total dose was based on body weight

    In this study, all participants took capsules (either odevixibat or matching placebo) by mouth. For participants who could not swallow the capsule, it was opened and sprinkled in a small amount of yoghurt, apple sauce, or fruit purée.

    The first dose was given to all participants on Day 1. All participants had 7 study visits, which took place every 2 to 6 weeks. A final follow-up visit took place after the last dose of odevixibat (end of treatment).

    What were the study results?

    The data shown in this summary are the average results from the study; individual participants could be different from the average results. To learn more about this study and the other questions the researchers asked, visit the websites listed at the end of this summary.

    How many participants had a decrease in amount of bile acid in the blood of at least 70% during this study or reached a bile level of less than or equal to 70 micromoles per litre of bile after taking the study medicine for 24 weeks?

    To answer this question, researchers measured the fasting serum bile acid levels (which means the sample of blood was taken on an empty stomach, after not eating for at least 4 hours). Blood samples were collected at the start of the study (baseline), at each study visit, and at the end of the study.

    How many participants had improvement in itching after taking the study medicine for 24 weeks?

    To answer this question, researchers used a tool called the Albireo ObsRO (Observer Reported Outcome) Instrument to measure scratching as a reflection of itching. Observers were asked to score the level of scratching the participant had and put the score into a diary given to them by their doctor. They had to do this once in the morning and once in the evening every day the participant took the study medicine. There were 5 levels to score the scratching. Level 0 was no scratching and Level 4 was really bad scratching. Level 1 was the minimum score needed to enter in this study. Scratching was considered to get better (improve) if the last score in the study was at least the same as or less than Level 1 or went down by at least one level from the first score in the study.

    How did sleep change because of odevixibat at the end of the study (last 4 weeks) as compared to the start of the study?

    To answer this question, researchers used the Albireo ObsRO (Observer Reported Outcome) Instrument to measure different sleep parameters. To see the effect of odevixibat on sleep, researchers looked at:

    • Percentage of days
    o Participants needed the help of a caregiver/parent for putting them to sleep o Participants required soothing o Participants slept with caregiver o Participants saw blood because of scratching o Participant took medications to help them sleep • How tired participants felt during the day • Number of times a participant woke up during night sleep

    Participants in Group 2 (40 micrograms per kilogram of odevixibat) and Group 3 (120 micrograms per kilogram of odevixibat) showed an improvement at the end of the study (the last 4 weeks) in the percentage of days needing help falling asleep, requiring soothing, or sleeping with the caregiver.

    Participants in Group 1 (placebo) did not show any improvement from the start of the study in any sleep parameter. Also, it was observed that participants in both the odevixibat groups showed great improvement in how tired they felt during the day compared with those who took placebo.

    There was no difference between the three groups for any of the other sleep parameters.

    How was growth impacted by odevixibat at Week 24 compared to the start of the study?

    To answer this question, researchers wrote down the height, weight, and body mass index (BMI [a factor used for indicating nutritional status in children/adults]) for all participants at the start and end of the study. Participants in Group 2 (40 micrograms per kilogram of odevixibat) showed the most improvement in height and weight at Week 24 as compared to the start of the study. The change in BMI at Week 24 was the same across Groups 1, 2, and 3.

    How was quality of life impacted by odevixibat at Week 24 compared with the start of the study?

    To answer this question, researchers looked at two different areas of quality of life. The first was quality of life for the participants themselves and the second was for the families or caregivers of participants with health issues. The second module could be filled by the participants, parent, or caregiver. A questionnaire called the Paediatric Quality of Life Inventory (PedsQL) was used. Participants or families/caregivers had to answer several questions about different ‘domains’ of daily life. These domains were physical activities, emotional well-being, social interactions, logical reasoning, communication, and worry.

    Quality of life improved for participants, families, and caregivers across all areas from the start of the study to Week 24 in participants from Group 2 (40 micrograms per kilogram of odevixibat) and Group 3 (120 micrograms per kilogram of odevixibat) when compared with Group 1 (placebo).

    What side effects did the study participants have?

    This summary only considers the results of this one study. Researchers need to compare the results of many studies to understand which medical problems could be related to a study treatment.

    Side effects are unwanted medical problems (such as a headache) that can happen during a study. Medical problems could have been caused by odevixibat, by another drug the participant was taking or due to current/other diseases. Sometimes the cause of a medical problem is not known. By comparing medical problems across many treatment groups in many studies, doctors try to understand the side effects of an experimental medicine.

    Side effects considered “serious” include those that are life-threatening or cause death, cause lasting problems, or where the participant needs hospital care. In some studies participants may stop study treatment because of a side effect or a serious side effect.

    The websites listed at the end of this summary have more information about the medical problems that happened in this study.

    How many participants left the study treatment due to side effects?

    One participant out of 62 stopped the study treatment because of a side effect of diarrhoea.

    How many participants had serious side effects related to odevixibat?

    No participants died during this study or had serious side effects related to odevixibat during this study.

    What were the most common non-serious side effects related to odevixibat?

    The most common non-serious side effects related to odevixibat that occurred in participants in any group are reported below.

    How was this study useful for participants and researchers?

    This study helped researchers learn more about how bile acid levels and severe itching were affected by the drug odevixibat.

    In order to make a drug that works and is safe, researchers perform many studies to see how the drug functions inside the body. Different studies of the same drug may show different results. One should not rely solely on the results of this study alone to make health decisions. This summary explains only the results of one study. For more information on this study or other studies on PFIC and odevixibat, please speak to your doctor or refer to the websites listed below.

    Where can I learn more about this study?

    If you have questions about the results of this study, please speak with your doctor. If you were a participant for this study, please contact the staff at your study site.

    You can find more details on this study at the following websites:

    https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C6b8ddc50fb554a8cdfaa08da33522a6c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637878725238443684%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=3OGHGnwp4jrJlp32KV%2BV2sNwHID4UesA0%2FkBqGo%2FpZg%3D&reserved=0 Please search NCT03566238.
    https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C6b8ddc50fb554a8cdfaa08da33522a6c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637878725238443684%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=vX%2BSeQ0OrSdjIgZ8TFqX2ZcaHGF45wJnFof8ZRzcR2Q%3D&reserved=0 Please search 2017-002338-21

    Sponsor of this study: Albireo AB can be contacted at medinfo@albireopharma.com

    Date of this summary: 10 February 2022

  • REC name

    London - Dulwich Research Ethics Committee

  • REC reference

    18/LO/0398

  • Date of REC Opinion

    4 Jun 2018

  • REC opinion

    Further Information Favourable Opinion