E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
In patients with progressive familial intrahepatic cholestasis (PFIC),impairment of the egress of bile acids from the liver leads to cholestasis, hepatocellular injury and damage, and progressive liver disease that may ultimately lead to the need for liver transplantation. Itch is a common symptom associated with cholestasis, it can occur at all stages of cholestatic liver disease, with or without jaundice.
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E.1.1.1 | Medical condition in easily understood language |
PFIC is a long-term debilitating and life-threatening disease due to liver and heart problems.
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10076033 |
E.1.2 | Term | Progressive familial intrahepatic cholestasis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of maralixibat versus placebo on the severity of pruritus in participants with PFIC2. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of maralixibat vs placebo on total serum bile acid (sBA) levels in participants with PFIC2 • To evaluate the efficacy of maralixibat vs placebo on the severity of pruritus in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) • To evaluate the efficacy of maralixibat vs placebo on total sBA levels inparticipants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) • To evaluate the efficacy of maralixibat vs placebo on the proportion of responders for the ItchRO(Obs) pruritus score in participants with PFIC2 and participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) • To evaluate the efficacy of maralixibat vsplacebo on the sBA responder rate in participants with PFIC2 and participants with PFIC (PFIC1, PFIC2,PFIC3, PFIC4, PFIC5, and PFIC6) • To evaluate the safety, tolerability, and pharmacokinetics of maralixibat vsplacebo in all participants who receive at least 1 dose of study medication (safety population)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Informed consent and assent (as applicable) per Institutional Review Board/Ethics Committee (IRB/EC) 2.Male or female subjects with a body weight ≥ 5 kg, who are ≥12 months and < 18 years of age at time of baseline 3.Cholestasis as manifested by total sBA ≥ 3× ULN (applies to primary cohort only) 4.An average AM ItchRO(Obs) score ≥ 1.5 during 4 consecutive weeks of the screening period, leading to the baseline visit (Visit 1) 5.Completion of at least 21 valid* morning ItchRO(Obs) entries during 4 consecutive weeks of the screening period, leading to the baseline visit (Visit 1) (*valid = completed and not answered as “I don’t know”; maximum allowed invalid reports = 7, no more than 2 invalid reports during the last 7 days before randomization) 6.6.Diagnosis of PFIC based on: Chronic cholestasis as manifested by persistent (>6 months) pruritus in addition to biochemical abnormalities and/or pathological evidence of progressive liver disease and Primary Cohort: Subjects with genetic testing results consistent with biallelic disease-causing variation in ABCB11 (PFIC2), based on standard of care genotyping Supplemental Cohort: i.Subjects with genetic testing results consistent with biallelic disease-causing variation in ATP8B1 (PFIC1), ABCB4 (PFIC3), or TJP2 (PFIC4), based on standard of care genotyping ii.Subjects with PFIC phenotype without a known mutation or with another known mutation not described above or with intermittent cholestasis as menifested by fluctuating sBA levels iii.Subjects with PFIC after internal or external biliary diversion surgery or for whom internal or external biliary diversion surgery was reversed 7.Male and females of non-childbearing potential. Males and non-pregnant, non-lactating females of childbearing potential who are sexually active must agree to use acceptable methods of contraception during the study and 30 days following the last dose of the study medication. Females of childbearing potential must have a negative pregnancy test result 8.Access to email or phone for scheduled remote visits 9.Ability to read and understand the questionnaires (both caregivers and subjects above the age of assent) 10.Access to consistent caregiver(s) during the study 11.Subject and caregiver willingness to comply with all study visits and requirements
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E.4 | Principal exclusion criteria |
1.Predicted complete absence of bile salt excretion pump (BSEP) function based on the type of ABCB11 mutation (PFIC2), as determined by a standard of care genotyping (applies to primary cohort only). Subjects can enter the study in the Supplemental Cohort (under inclusion criteria 6.ii or 6.iii) 2. Recurrent intrahepatic cholestasis, indicated by a history of sBA levels <3x ULN or intermittent pruritus (applies to primary cohort only) 3.Current or recent history (<1 year) of atopic dermatitis or other non-cholestatic diseases associated with pruritus 4. History of surgical disruption of the enterohepatic circulation (applies to primary cohort only) 5.Chronic diarrhea requiring intravenous fluid or nutritional intervention for the diarrhea and/or its sequelae at screening or during the 6 months prior to screening 6.Previous or need for imminent liver transplant 7.Decompensated cirrhosis (international normalized ratio [INR] > 1.5, albumin < 30 g/L, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy) 8.ALT or total serum bilirubin (TSB) > 15× ULN at screening 9. Presence of other liver disease 10. Presence of any other disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine (e.g., inflammatory bowel disease), per Investigator discretion 11.Possibly malignant liver mass on imaging, including screening ultrasound 12.Known diagnosis of human immunodeficiency virus (HIV) infection 13.Any prior cancer diagnosis (except for in situ carcinoma) within 5 years before of the screening visit (Visit 0) 14.Any known history of alcohol or substance abuse 15.Administration of bile acids or lipid binding resins, or phenylbuthyrates during the screening period 16.criterion has been deleted as of Amendment 3 17.Administration of any investigational drug, biologic, or medical device during the screening period 18.Previous use of an ileal bile acid transporter inhibitor (IBATi) 19.History of non-adherence to medical regimens, unreliability, medical condition, mental instability or cognitive impairment that, in the opinion of the Investigator or Sponsor medical monitor, could compromise the validity of informed consent, compromise the safety of the subject, or lead to nonadherence with the study protocol or inability to conduct the study procedures 20.Known hypersensitivity to maralixibat or any of its excipients
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E.5 End points |
E.5.1 | Primary end point(s) |
•Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 through Week 26 using 4-week average morning ItchRO(Obs) severity scores |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary, secondary, and exploratory efficacy endpoints will be evaluated in the primary cohort, overall supplemental cohort, all cohorts combined, and the PFIC1 and PFIC3 sub-cohorts (separately) given sufficient sample size. The safety and tolerability, and other endpoints will be evaluated in the primary cohort, and all cohorts combined.
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E.5.2 | Secondary end point(s) |
• Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 • Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 through Week 26 in participants with PFIC • Proportion of ItchRO(Obs) responders from Week 15 to Week 26 o For the purpose of determining response, the average value from the three 4-week periods (Weeks 15-18, 19-22, and 23-26) will be computed and used. • Proportion of sBA responders from Week 18 to Week 26 o For the purpose of determining response, the average value from Weeks 18, 22, and 26 values will be computed and used |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These are measured throughout the trial by means of the subject eDiary and clinician scales and questionnaires. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
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E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Canada |
Colombia |
Lebanon |
Mexico |
Singapore |
United States |
Austria |
France |
Poland |
Germany |
Italy |
Belgium |
Hungary |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 16 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 14 |