Progressive Familial Intrahepatic Cholestasis (PFIC)
Conditions
Keywords
Cholestasis, Maralixibat, Mutation, PFIC, PFIC2, Bile Duct Diseases, Liver Diseases, Biliary Tract Diseases, Digestive System Diseases, Pediatric
Brief summary
The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric participants with Progressive Familial Intrahepatic Cholestasis (PFIC).
Detailed description
This study was conducted at multiple sites in North America, Europe, Asia and South America.
Interventions
DRUGMaralixibat
Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks.
OTHERPlacebo
Placebo matching to maralixibat orally twice daily for 26 weeks.
Sponsors
Mirum Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
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. Diagnosis of PFIC based on the following: * 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 manifested 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 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.
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 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 phenylbutyrates 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort | MMRM model was used with inputs of the average changes from baseline (BL) to Weeks 1-6, 7-10, 11-14, 15-18, 19-22, 23-26, and other covariates. The average change from BL over Weeks 15-26 is calculated in the model and presented as a single number. | The primary efficacy endpoint is the mean change in the average morning ItchRO(Obs) severity score between baseline and Weeks 15-26, using 4-week average morning ItchRO(Obs) severity scores (Mixed Model Repeated Measures). The baseline average morning ItchRO(Obs) severity score is defined as the 4-week average morning ItchRO(Obs) severity score prior to the first dose of the study medication. ItchRo(Obs) Severity Score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in the Average Morning ItchRO(Obs) Severity Score in Participants With PFIC (PFIC1, Nt-PFIC2, PFIC3, PFIC4 and PFIC6) | Between Baseline and Week 15 through Week 26 | Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 through Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). ItchRo(Obs) Severity Score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better. |
| Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | Between Baseline and average of Weeks 18, 22 and 26 | Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) |
| Proportion of ItchRO(Obs) Responders in the Primary Cohort | Week 15 to Week 26 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26) | Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants with PFIC2 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26). The number in the Subject Analysis Set refers to the number of responders. ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 or an average severity score of ≤1.0. |
| Mean Change in Total sBA Level in the Primary Cohort. | Baseline and average of Weeks 18, 22 and 26 | Mean change in total sBA level between baseline and average of Weeks 18, 22 and 26. |
| Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | From Week 15 to Week 26 | Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). The number in the Subject Analysis Set refers to the number of responders. ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 OR an average severity score of ≤1.0. |
| Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | Week 18 to Week 26 | Proportion of sBA responders from Week 18 to Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). The number in the Subject Analysis Set refers to the number of responders. sBA responders are defined as a subject having an average sBA level of \<102 umol/L (applies only if baseline sBA level was ≥102 umol/L), or a ≤-75% average percent change from baseline. |
| Proportion of sBA Responders in the Primary Cohort | Average value from Weeks 18, 22 and 26 | Proportion of sBA responders from Week 18 to Week 26 in participants with PFIC2, using the average value from Weeks 18, 22 and 26 values. The number in the Subject Analysis Set refers to the number of responders. sBA responders are defined as a subject having an average sBA level of \<102 umol/L (applies only if baseline sBA level was ≥102 umol/L), OR a ≤-75% average percent change from baseline. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, Colombia, France, Germany, Hungary, Italy, Lebanon, Mexico, Poland, Singapore, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 93 participants were enrolled at 29 sites in 16 countries (Argentina, Austria, Belgium, Brazil, Canada, Colombia, France, Germany, Italy, Lebanon, Mexico, Poland, Singapore, Turkey, United Kingdom, and United States).
Pre-assignment details
The screening period starts when informed consent (or assent as applicable) is signed. The duration of the screening period is up to 6 weeks during which all procedures listed for the screening visit must be completed. A total of 125 patients were screened for the study. 32 of these patients were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Maralixibat After a screening period of up to 6 weeks, subjects were randomized 1:1 to receive either maralixibat or placebo. The Dose Escalation period (4-6 weeks) was followed by a stable dosing period (20-22 weeks) and a 7 days Safety Follow-up period for subjects discontinuing early and for subjects not enrolling into the extension Study MRX-503. | 47 |
| Placebo Participants received a corresponding placebo. | 46 |
| Total | 93 |
Baseline characteristics
| Characteristic | Maralixibat | Placebo | Total |
|---|---|---|---|
| Age, Categorical All subjects <=18 years | 47 Participants | 46 Participants | 93 Participants |
| Age, Categorical All subjects >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical All subjects Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical PFIC cohort <=18 years | 33 Participants | 31 Participants | 64 Participants |
| Age, Categorical PFIC cohort >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical PFIC cohort Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Primary Cohort <=18 years | 14 Participants | 17 Participants | 31 Participants |
| Age, Categorical Primary Cohort >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Primary Cohort Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous All subjects | 4.8 years STANDARD_DEVIATION 4.15 | 4.7 years STANDARD_DEVIATION 3.57 | 4.7 years STANDARD_DEVIATION 3.85 |
| Age, Continuous PFIC Cohort | 4.9 years STANDARD_DEVIATION 4.1 | 4.4 years STANDARD_DEVIATION 3.61 | 4.6 years STANDARD_DEVIATION 3.85 |
| Age, Continuous Primary Cohort | 6.3 years STANDARD_DEVIATION 5.24 | 4.2 years STANDARD_DEVIATION 3.56 | 5.1 years STANDARD_DEVIATION 4.45 |
| Ethnicity (NIH/OMB) All subjects Hispanic or Latino | 18 Participants | 17 Participants | 35 Participants |
| Ethnicity (NIH/OMB) All subjects Not Hispanic or Latino | 28 Participants | 27 Participants | 55 Participants |
| Ethnicity (NIH/OMB) All subjects Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) PFIC Cohort Hispanic or Latino | 16 Participants | 13 Participants | 29 Participants |
| Ethnicity (NIH/OMB) PFIC Cohort Not Hispanic or Latino | 17 Participants | 16 Participants | 33 Participants |
| Ethnicity (NIH/OMB) PFIC Cohort Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Primary Cohort Hispanic or Latino | 9 Participants | 7 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Primary Cohort Not Hispanic or Latino | 5 Participants | 9 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Primary Cohort Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) All subjects American Indian or Alaska Native | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) All subjects Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) All subjects Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) All subjects More than one race | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) All subjects Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) All subjects Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) All subjects White | 36 Participants | 34 Participants | 70 Participants |
| Race (NIH/OMB) PFIC Cohort American Indian or Alaska Native | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) PFIC Cohort Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) PFIC Cohort Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) PFIC Cohort More than one race | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) PFIC Cohort Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) PFIC Cohort Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) PFIC Cohort White | 24 Participants | 19 Participants | 43 Participants |
| Race (NIH/OMB) Primary Cohort American Indian or Alaska Native | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Primary Cohort Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Primary Cohort Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Primary Cohort More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Primary Cohort Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Primary Cohort Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Primary Cohort White | 9 Participants | 9 Participants | 18 Participants |
| Region of Enrollment Argentina | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Austria | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Belgium | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Brazil | 7 participants | 3 participants | 10 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Colombia | 2 participants | 4 participants | 6 participants |
| Region of Enrollment France | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Germany | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Italy | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Lebanon | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Mexico | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Poland | 4 participants | 2 participants | 6 participants |
| Region of Enrollment Singapore | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Turkey | 1 participants | 1 participants | 2 participants |
| Region of Enrollment United Kingdom | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 9 participants | 13 participants | 22 participants |
| Sex: Female, Male All subjects Female | 27 Participants | 24 Participants | 51 Participants |
| Sex: Female, Male All subjects Male | 20 Participants | 22 Participants | 42 Participants |
| Sex: Female, Male PFIC Cohort Female | 16 Participants | 18 Participants | 34 Participants |
| Sex: Female, Male PFIC Cohort Male | 17 Participants | 13 Participants | 30 Participants |
| Sex: Female, Male Primary Cohort Female | 7 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Primary Cohort Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 46 |
| other Total, other adverse events | 47 / 47 | 43 / 46 |
| serious Total, serious adverse events | 5 / 47 | 3 / 46 |
Outcome results
Primary
Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort
The primary efficacy endpoint is the mean change in the average morning ItchRO(Obs) severity score between baseline and Weeks 15-26, using 4-week average morning ItchRO(Obs) severity scores (Mixed Model Repeated Measures). The baseline average morning ItchRO(Obs) severity score is defined as the 4-week average morning ItchRO(Obs) severity score prior to the first dose of the study medication. ItchRo(Obs) Severity Score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better.
Time frame: MMRM model was used with inputs of the average changes from baseline (BL) to Weeks 1-6, 7-10, 11-14, 15-18, 19-22, 23-26, and other covariates. The average change from BL over Weeks 15-26 is calculated in the model and presented as a single number.
Population: Primary Cohort, defined as participants with genetic testing results consistent with biallelic disease causing variation in ABCB11 (PFIC2, also referred to as BSEP deficiency), based on standard-of-care genotyping, excluding those PFIC2 participants predicted to have complete absence of BSEP function (PFIC2 participants with heterozygosis, biliary diversion, having low or fluctuating sBA levels).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Primary Cohort Maralixibat | Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort | -1.718 Score on a scale |
| Primary Cohort Placebo | Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort | -0.628 Score on a scale |
Comparison: The difference between maralixibat and placebo treatment groups in the mean change in the average ItchRO(Obs) severity score between baseline and Weeks 15-26p-value: =0.006395% CI: [-1.845, -0.334]Mixed Models Analysis
Secondary
Mean Change in the Average Morning ItchRO(Obs) Severity Score in Participants With PFIC (PFIC1, Nt-PFIC2, PFIC3, PFIC4 and PFIC6)
Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 through Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). ItchRo(Obs) Severity Score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better.
Time frame: Between Baseline and Week 15 through Week 26
Population: Primary cohort plus PFIC1, PFIC3, PFIC4, PFIC6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Primary Cohort Maralixibat | Mean Change in the Average Morning ItchRO(Obs) Severity Score in Participants With PFIC (PFIC1, Nt-PFIC2, PFIC3, PFIC4 and PFIC6) | -1.811 score on a scale |
| Primary Cohort Placebo | Mean Change in the Average Morning ItchRO(Obs) Severity Score in Participants With PFIC (PFIC1, Nt-PFIC2, PFIC3, PFIC4 and PFIC6) | -0.610 score on a scale |
p-value: <0.000195% CI: [-1.727, -0.674]Mixed Models Analysis
Secondary
Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
Time frame: Between Baseline and average of Weeks 18, 22 and 26
Population: Primary cohort plus PFIC1, PFIC3, PFIC4 and PFIC6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Primary Cohort Maralixibat | Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | -157.489 μmol/L |
| Primary Cohort Placebo | Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | 2.913 μmol/L |
p-value: <0.000195% CI: [-220.836, -99.97]Mixed Models Analysis
Secondary
Mean Change in Total sBA Level in the Primary Cohort.
Mean change in total sBA level between baseline and average of Weeks 18, 22 and 26.
Time frame: Baseline and average of Weeks 18, 22 and 26
Population: Primary Cohort, defined as participants with genetic testing results consistent with biallelic disease causing variation in ABCB11 (PFIC2, also referred to as BSEP deficiency), based on standard-of-care genotyping, excluding those PFIC2 participants predicted to have complete absence of BSEP function (PFIC2 participants with heterozygosis, biliary diversion, having low or fluctuating sBA levels). Two maralixibat participants did not have baseline sBA values and were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Primary Cohort Maralixibat | Mean Change in Total sBA Level in the Primary Cohort. | -175.536 μmol/L |
| Primary Cohort Placebo | Mean Change in Total sBA Level in the Primary Cohort. | 11.187 μmol/L |
p-value: =0.001395% CI: [-293.454, -79.992]Mixed Models Analysis
Secondary
Proportion of ItchRO(Obs) Responders in the Primary Cohort
Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants with PFIC2 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26). The number in the Subject Analysis Set refers to the number of responders. ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 or an average severity score of ≤1.0.
Time frame: Week 15 to Week 26 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26)
Population: Primary Cohort, defined as participants with genetic testing results consistent with biallelic disease causing variation in ABCB11 (PFIC2, also referred to as BSEP deficiency), based on standard-of-care genotyping, excluding those PFIC2 participants predicted to have complete absence of BSEP function (PFIC2 participants with heterozygosis, biliary diversion, having low or fluctuating sBA levels).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primary Cohort Maralixibat | Proportion of ItchRO(Obs) Responders in the Primary Cohort | 8 Number of responders |
| Primary Cohort Placebo | Proportion of ItchRO(Obs) Responders in the Primary Cohort | 4 Number of responders |
p-value: =0.0736Bernard's exact test
Secondary
Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). The number in the Subject Analysis Set refers to the number of responders. ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 OR an average severity score of ≤1.0.
Time frame: From Week 15 to Week 26
Population: Primary cohort plus PFIC1, PFIC3, PFIC4 and PFIC6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primary Cohort Maralixibat | Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | 21 Number of responders |
| Primary Cohort Placebo | Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | 8 Number of responders |
p-value: =0.0023Bernard's exact test
Secondary
Proportion of sBA Responders in the Primary Cohort
Proportion of sBA responders from Week 18 to Week 26 in participants with PFIC2, using the average value from Weeks 18, 22 and 26 values. The number in the Subject Analysis Set refers to the number of responders. sBA responders are defined as a subject having an average sBA level of \<102 umol/L (applies only if baseline sBA level was ≥102 umol/L), OR a ≤-75% average percent change from baseline.
Time frame: Average value from Weeks 18, 22 and 26
Population: Primary Cohort, defined as participants with genetic testing results consistent with biallelic disease causing variation in ABCB11 (PFIC2, also referred to as BSEP deficiency), based on standard-of-care genotyping, excluding those PFIC2 participants predicted to have complete absence of BSEP function (PFIC2 participants with heterozygosis, biliary diversion, having low or fluctuating sBA levels).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primary Cohort Maralixibat | Proportion of sBA Responders in the Primary Cohort | 5 Number of responders |
| Primary Cohort Placebo | Proportion of sBA Responders in the Primary Cohort | 1 Number of responders |
p-value: =0.041Bernard's exact test
Secondary
Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
Proportion of sBA responders from Week 18 to Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). The number in the Subject Analysis Set refers to the number of responders. sBA responders are defined as a subject having an average sBA level of \<102 umol/L (applies only if baseline sBA level was ≥102 umol/L), or a ≤-75% average percent change from baseline.
Time frame: Week 18 to Week 26
Population: Primary cohort plus PFIC1, PFIC3, PFIC4 and PFIC6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primary Cohort Maralixibat | Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | 15 Number of responders |
| Primary Cohort Placebo | Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6) | 2 Number of responders |
p-value: =0.0004Bernard's exact test