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Efficacy and Safety of Maralixibat (SHP625) in the Treatment of Participants With Progressive Familial Intrahepatic Cholestasis (PFIC)

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ClinicalTrials.gov Identifier: NCT03353454
Recruitment Status : Not yet recruiting
First Posted : November 27, 2017
Last Update Posted : May 10, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
The purpose of this study is to determine if the investigational treatment (maralixibat) is safe and effective in children and adolescents with Progressive Familial Intrahepatic Cholestasis (PFIC).

Condition or disease Intervention/treatment Phase
Cholestasis Drug: Maralixibat Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Efficacy and Safety of Maralixibat (SHP625) in the Treatment of Subjects With Progressive Familial Intrahepatic Cholestasis (PFIC)
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : June 15, 2020
Estimated Study Completion Date : June 15, 2020


Arm Intervention/treatment
Experimental: Maralixibat (SHP625)
Participants will be randomized to Maralixibat oral solution (up to 600 microgram per kilogram [mcg/kg]) orally twice daily for 26 weeks.
Drug: Maralixibat
Maralixibat oral solution (up to 600 microgram per kilogram [mcg/kg]) orally twice daily for 26 weeks.
Other Name: SHP625

Placebo Comparator: Placebo
Participants will recieve placebo matched to maralixibat oral solution twice daily for 26 weeks.
Drug: Placebo
Placebo matching to maralixibat orally twice daily for 26 weeks.




Primary Outcome Measures :
  1. Treatment Response as measured by the Observer Itch Reported Outcome (ItchRO(Obs) ™) [ Time Frame: Baseline up to Week 26 ]
    Compare the percentage of patients on active treatment vs. placebo who meet response criteria which is defined as improvement in average Observer Itch Reported Outcome (ItchRO(Obs) severity decrease from baseline on at least 2 of the last 3 study visits.


Secondary Outcome Measures :
  1. Normalization or Reduction From Baseline in Serum Bile Acids (sBA) [ Time Frame: Baseline, Week 26 ]
    Compare the percentage of patients on active treatment vs. placebo with normalization or significant reduction from baseline in serum bile acids

  2. Disappearance of Pruritus as Measured by Observer Itch Reported Outcome (ItchRO(Obs) [ Time Frame: Baseline up to Week 26 ]
    Compare the percentage of patients on active treatment vs. placebo of participants who experience disappearance of pruritus as measured by ItchRO(Obs)

  3. Change in Patient Itch Reported Outcome Instrument (ItchRO[Pt]) [ Time Frame: Baseline, Week 26 ]
    Change in ItchRO(pt) ™, as completed by participants of appropriate age, will be compared between active treatment and placebo

  4. Improvement in Height [ Time Frame: Baseline up to Week 26 ]
    Proportion of participants on active treatment vs. placebo with a height z-score change from baseline >0.

  5. Improvement in Weight [ Time Frame: Baseline up to Week 26 ]
    Proportion of participants on active treatment vs. placebo with a weight z-score change from baseline >0.

  6. Change From Baseline in Nutritional Status as Measured by Mid-arm Circumference [ Time Frame: Baseline, Week 26 ]
    Compare the change in nutritional status as measured by mid-arm circumference in participants on active treatment vs. placebo

  7. Change From Baseline in Nutritional Status as Measured by Triceps Skin Fold [ Time Frame: Baseline, Week 26 ]
    Compare the change in nutritional status as measured by triceps skin fold in participants on active treatment vs. placebo

  8. Mean Change From Baseline in Clinician Scratch Scale (CSS) [ Time Frame: Baseline, Week 26 ]
    Compare the change in Clinician Scratch Scale score in participants on active treatment vs. placebo.

  9. Change From Baseline in Quality of Life as Measured by Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: Baseline, Week 26 ]
    Compare the change from baseline of PedsQL in participants on active treatment vs. placebo.

  10. Change From Baseline in Quality of Sleep as Measured by Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: Baseline, Week 26 ]
    Compare the change from baseline of CSHQ in participants on active treatment vs. placebo.

  11. Normalization or meaningful reduction from baseline of Alanine aminotransferase (ALT) [ Time Frame: Baseline up to Week 26 ]
    Proportion of participants whose ALT normalizes on treatment or has decreased ≥50%.

  12. Normalization or meaningful decrease from baseline of Total Bilirubin [ Time Frame: Baseline up to Week 26 ]
    Proportion of participants whose total bilirubin normalizes on treatment or has decreased ≥50%.

  13. Change From Baseline in Biomarkers of Bile Acid Synthesis [ Time Frame: Baseline, Week 26 ]
    Change from baseline in biomarkers of bile acid synthesis (serum 7 alpha-hydroxy-4-cholesten-3-one [C4])

  14. Evaluate the safety of SHP625 [ Time Frame: Baseline, week 26 ]
    Adverse events, changes in vital signs, laboratory, and other safety parameters will be compared between participants on active treatment vs. placebo

  15. Plasma Levels of Maralixibat Over Time [ Time Frame: Pre-dose through Week 26 ]
    Systemic concentrations of maralixibat in plasma



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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Informed consent and assent (as applicable for participants less than or equal to (<=) 18 years per Institutional Review Board/Ethics Committee (IRB)/Ethics Committee (EC) as appropriate.
  • Male or female participants between the ages of 12 months and 18 years inclusive (primary cohort) or birth to 18 years inclusive (exploratory cohort) at time of consent, with a body weight greater than or equal to (>=) 5 kilogram (kg).
  • Cholestasis as manifested by total sBA greater than (>) 3 × upper limit of normal (ULN)
  • A weekly average ItchRO(Obs) score >= 1.5 during the week leading to the baseline visit
  • Diagnosis of PFIC based on:

    a. Primary cohort: i. Participants with 2 documented mutant alleles in ABCB11 (PFIC2); participants without bile salt export pump (BSEP) function (biallelic truncating mutations in ABCB11) will not be enrolled into the primary cohort. b. Exploratory cohort: i. Participants with PFIC1/3/4 or PFIC2 with biallelic truncating mutationsiii.Infants from birth to <12 months of age with PFIC ii. Participants with PFIC after internal or external (eg, PEBD) biliary diversion surgery with unsatisfactory pruritus control or where biliary diversion was reversed.

Key Exclusion Criteria:

  • Chronic diarrhea requiring intravenous fluid or nutritional intervention for the diarrhea and/or its sequelae.
  • History of surgical disruption of the enterohepatic circulation (applies to primary cohort only).
  • Liver transplant
  • Decompensated cirrhosis (international normalized ratio [INR] >1.5, albumin <30 gram per liter [g/L, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy).
  • ALT >15× ULN at screening.
  • History or presence of other liver disease.
  • History or 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 (example [eg], inflammatory bowel disease), per investigator discretion.
  • Liver mass on imaging
  • Known diagnosis of human immunodeficiency virus (HIV) infection.
  • Any prior cancer diagnosis except for in situ carcinoma or cancers treated within 5 years of the screening visit (Visit 0) with no evidence of recurrence.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03353454


Contacts
Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

Sponsors and Collaborators
Shire
Investigators
Study Director: Shire Study Physician Shire

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT03353454     History of Changes
Other Study ID Numbers: SHP625-306
2017-003138-99 ( EudraCT Number )
First Posted: November 27, 2017    Key Record Dates
Last Update Posted: May 10, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shire:
Cholestasis
Maralixibat
Mutation

Additional relevant MeSH terms:
Cholestasis
Cholestasis, Intrahepatic
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Liver Diseases