Clinical Trial Results:
A Multicenter, Open Label, Single- and Multiple-Dose, Dose Finding Study to Assess the Effects of Obeticholic Acid in Pediatric Subjects with Biliary Atresia
Summary
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EudraCT number |
2014-004693-42 |
Trial protocol |
GB DE NL BE FI FR PL ES IT |
Global end of trial date |
09 Mar 2023
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Results information
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Results version number |
v2(current) |
This version publication date |
30 May 2024
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First version publication date |
24 Sep 2023
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
747-206
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05321524 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Intercept Pharmaceuticals, Inc.
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Sponsor organisation address |
305 Madison Avenue, Morristown, New Jersey, United States, 07960
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Public contact |
Intercept Pharmaceuticals, Inc., Intercept Pharmaceuticals, Inc., +1 844 782-4278, medinfo@interceptpharma.com
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Scientific contact |
Medical Information, Medical Information, +1 844 782-4278, medinfo@interceptpharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001304-PIP02-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Mar 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Mar 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
- Safety and tolerability
- Pharmacokinetics (PK) of Obeticholic acid (OCA) and its conjugates
o Single dose (SD) Phase: To assess the PK of low dose OCA and its conjugates and to determine the appropriate dose of OCA in the multiple dose (MD) Phase
o MD Phase: To assess the PK of a range of OCA doses and its conjugates after a single dose and at steady state
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Protection of trial subjects |
The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonisation (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the Sponsor’s policies.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jul 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 4
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Germany: 3
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Worldwide total number of subjects |
8
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EEA total number of subjects |
7
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
4
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Adolescents (12-17 years) |
4
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This was an open label, SD and MD, dose-finding study that evaluated the safety, tolerability, PK, and pharmacodynamics (PD) of a range of OCA doses pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE). | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 8 participants were enrolled from 3 countries (Belgium, Germany, and the United Kingdom). | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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SD MD Control Low Dose Cohort | ||||||||||||||||||||||||||||||
Arm description |
Participants entered the OLE phase and continued to receive OCA from the SD MD phase for up to 2 years to assess the effects of long-term OCA treatment. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Obeticholic acid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants were treated with adult equivalent OCA doses based on body weight..
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Arm title
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SD MD Low Dose Cohort | ||||||||||||||||||||||||||||||
Arm description |
Participants entered OLE phase and received SD MD low dose of OCA. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Obeticholic acid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were treated with adult equivalent OCA doses of 1.5 milligrams (mg), 5 mg, and 10 mg daily (Low, Medium, or High OCA dose cohorts, respectively) based on body weight.
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Baseline characteristics reporting groups
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Reporting group title |
SD MD Control Low Dose Cohort
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Reporting group description |
Participants entered the OLE phase and continued to receive OCA from the SD MD phase for up to 2 years to assess the effects of long-term OCA treatment. | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SD MD Low Dose Cohort
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Reporting group description |
Participants entered OLE phase and received SD MD low dose of OCA. | ||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
SD MD Control Low Dose Cohort
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Reporting group description |
Participants entered the OLE phase and continued to receive OCA from the SD MD phase for up to 2 years to assess the effects of long-term OCA treatment. | ||
Reporting group title |
SD MD Low Dose Cohort
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Reporting group description |
Participants entered OLE phase and received SD MD low dose of OCA. |
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End point title |
Number of participants reporting serious treatment emergent adverse events (serious TEAEs) and non-serious TEAEs [1] | ||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
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End point type |
Primary
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End point timeframe |
Up to 17 Weeks
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analyses were not executed as pre-specified as the study was early terminated. |
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No statistical analyses for this end point |
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End point title |
Number of participants with clinically significant changes in electrocardiogram (ECG), physical exam, clinical laboratory results, and vital signs. [2] | ||||||||||||
End point description |
Blood samples were planned to be collected for the analysis of clinically significant changes in ECG, physical exam, clinical laboratory results, and vital signs. 99999 indicates that the study was terminated after extensive efforts to improve recruitment and it was not feasible to enroll the requisite number of participants to generate data needed to meet the study objectives. European Medicine Agency (EMA) Paediatric Committee agreed with the Sponsor to terminate the study.
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End point type |
Primary
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End point timeframe |
Up to 17 Weeks
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analyses were not executed as pre-specified as the study was early terminated. |
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No statistical analyses for this end point |
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End point title |
Plasma concentrations of OCA [3] | ||||||||||||
End point description |
Blood samples were planned to be collected for the analysis of plasma concentrations of OCA. 99999 indicates that the study was terminated after extensive efforts to improve recruitment and it was not feasible to enroll the requisite number of participants to generate data needed to meet the study objectives. EMA Paediatric Committee agreed with the Sponsor to terminate the study.
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End point type |
Primary
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End point timeframe |
Up to Day 63
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analyses were not executed as pre-specified as the study was early terminated. |
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No statistical analyses for this end point |
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End point title |
Number of participants with clinically significant changes in clinical chemistry | ||||||||||||
End point description |
Blood samples were planned to be collected at indicated timepoints for the analysis of clinical chemistry parameters including alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and total and direct (conjugated) bilirubin. 99999 indicates that the study was terminated after extensive efforts to improve recruitment and it was not feasible to enroll the requisite number of participants to generate data needed to meet the study objectives. EMA Paediatric Committee agreed with the Sponsor to terminate the study.
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End point type |
Secondary
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End point timeframe |
Up to 17 Weeks
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No statistical analyses for this end point |
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End point title |
Plasma concentrations of C4 | ||||||||||||
End point description |
Serum samples were planned to be collected for the analysis of plasma concentrations of C 24. 99999 indicates that the study was terminated after extensive efforts to improve recruitment and it was not feasible to enroll the requisite number of participants to generate data needed to meet the study objectives. EMA Paediatric Committee agreed with the Sponsor to terminate the study.
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End point type |
Secondary
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End point timeframe |
Up to Day 63
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No statistical analyses for this end point |
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End point title |
Plasma concentrations of bile acids | ||||||||||||
End point description |
Serum samples were planned to be collected for the analysis of plasma concentrations of bile acids. 99999 indicates that the study was terminated after extensive efforts to improve recruitment and it was not feasible to enroll the requisite number of participants to generate data needed to meet the study objectives. EMA Paediatric Committee agreed with the Sponsor to terminate the study.
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End point type |
Secondary
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End point timeframe |
Up to Day 63
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to 17 Weeks
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Adverse event reporting additional description |
Treatment emergent adverse events and serious treatment adverse events were collected in Safety Population. Safety population included all participants who received OCA with their current standard of care treatment.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25
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Reporting groups
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Reporting group title |
SD MD Low Dose Cohort
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Reporting group description |
Subjects received SD MD low dose of OCA. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SD MD Control Low Dose Cohort
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Reporting group description |
Participants continued to receive OCA from the SD MD phase. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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20 Apr 2015 |
The protocol has been amended to implement an open label extension (OLE). |
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17 Jun 2015 |
Based on feedback from regulatory authorities, the stopping criteria and subsequent regulatory action has been clarified and defined. |
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17 Jul 2015 |
Based on feedback from regulatory authorities, acceptable methods of contraception have been clarified and defined. Additionally, exclusion criteria for females of child-bearing
potential has been added. |
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07 Sep 2015 |
Protocol 2 has been prepared to: Change the terminology of the OCA drug formulation that will be used for the younger and smaller children from “oral suspension” to “pediatric formulation” since an oral suspension will not be used. The pediatric formulation is currently under development and therefore a generic term is more appropriate at this time; Clarify the timing and process for initiating enrollment of the younger group of children (<2 years); Clarify that standard of care medications for the treatment of biliary atresia (eg, UDCA) need to be stable for at least 1 month prior to Day 1; Clarify that the collection of a blood sample is intended for all participants at each visit per Table 1 and Table 2 who meet the minimum enrollment weight restriction on Day 0 of ≥20 kilograms (kg). Initially, the protocol indicated that blood would only be drawn for participants who weighed ≥20 kg at the time of each visit. participants who have slight weight loss resulting in a weight <20 kg should still provide a blood sample at each respective visit. Originally, the minimum weight requirement was defined based on the ability to dose the participants appropriately without having a pediatric formulation available, and was not based on any safety concerns for participants who weighed <20 kg; Updated the Table of Procedures (Table 2 and Table 3) for the OLE phase to include the procedures required for participants who enroll into the OLE phase at a time other than the end of the SD MD phase (Day 64); Clarify that participants who enroll in the OLE phase ≥3 weeks to ≤3 months and >3 months will be dispensed OCA on Day 1, but will be instructed to wait for a telephone contact by the principle investigator (PI) or designee before starting dosing; Clarify in the Procedure Section the list of procedures required for participants who enroll in the OLE phase at a time other than the end of the SD MD phase (Day 64); Delete dose charts in Appendix B as it is not necessary to include. |
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18 Apr 2016 |
OCA 0.1 mg mini-tablet formulation has become available for dosing of participants aged <2 years. Protocol Version 3 includes details regarding this formulation and dosing instructions. Further, the weight restrictions on participant enrollment have been clarified. Other major changes include addition of exploratory objectives: (1) accessibility and swallowability and (2) palatability. |
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07 Apr 2017 |
The pathophysiology of biliary atresia is known to include portal hypertension, cholestasis, and/or hepatic impairment (cirrhosis). The presence and magnitude of these disease features are likely to have a substantial impact on the plasma and/or liver concentrations of OCA. Although there are no safety concerns, as a precautionary measure, additional time has been added to receive single-dose pharmacokinetics (PK) data for all participants being treated with OCA prior to the start of the MD phase. This additional time is intended to allow for a decision regarding whether each participant should proceed into the MD phase or be discontinued from the study. Exclusion criteria for participants with aspartate aminotransferase (AST) to platelet ratio index Aspartate aminotransferase to platelet ratio index (APRI) >0.95 was added to make sure participants are unnecessarily exposed to high levels of OCA. Participants would be allowed to rescreen. Based on PK data from the initial participants enrolled into the low dose arm of this protocol, which showed a positive relationship between single-dose total OCA area under the concentration-time curve from time 0 to 24 hours (AUC0-24h) exposure and the APRI calculated at the screening visit, APRI will also be used as a preliminary predictor of exposure. Visit window extensions for Days 7 and 14 have been incorporated to receive and evaluate single-dose PK data for participants prior to entering the MD phase due to disease features (ie, portal hypertension) playing a significant role in OCA PK exposure. Additional visits have been added for Control participants enrolling into the OLE, to evaluate baseline characteristics prior to assigning participants to an appropriate dose group. |
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18 Dec 2017 |
There are not known or accepted clinical parameters to evaluate the efficacy of therapies such as OCA in participants with post-hepatoportoenterostomy (HPE) biliary atresia. There is a mechanistic rationale for OCA as a candidate for the treatment of post-HPE biliary atresia based on its farnesoid X receptor (FXR) mediated hepatoprotective properties including improvement in choleresis, inhibition of the progression to fibrosis, reversal of established fibrosis, and the ability of OCA to counteract hepatic inflammation. Modifications have been made to transition the intent of the 747-206 trial from proof of concept to a clinical pharmacology and proof of mechanism study that assesses safety, PK, and pharmacodynamics (PD). Efficacy will be evaluated in subsequent studies.
Additionally, based on participant PK data received to date, there has been difficulty in predicting OCA exposure due to varying levels of disease manifestations, including portal hypertension, and therefore OCA exposure has shown to be higher than anticipated in certain participants. No adverse events or safety concerns existed with the higher exposures seen, in fact some measurements of transaminases improved with OCA dosing. However, this finding required a re-assessment of the study design to minimize the potential risk of high OCA exposure. |
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25 Jan 2019 |
Previous iterations of the study protocol allowed the use of contraceptives that did not meet the criteria of a failure rate of less than 1% per year. The current protocol revision updates the entry criteria to limit the acceptable methods of contraceptives to be compliant with a failure rate of less than 1% per year. Additionally, protocol version 5 lacked clarity on the combination of tablets to achieve the most appropriate weight adjusted dose. The current protocol revision includes dosing charts describing the combination of tablets to achieve the most accurate target dose as well as an alternate dose minimizing the number of tablets while remaining accurate to maximize participant compliance. |
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06 May 2021 |
The three most important modifications to the protocol include a reduction of the sample size by elimination of several dose cohorts in both the Single-Dose (SD) and Multiple-Dose (MD) Phases, a reduction in the duration of the MD Phase from 8 to 4 weeks, and a reintroduction of an OLE Phase following the MD Phase. Other changes include updating the Introduction, including the literature review and clinical history with OCA, changing the eligibility criteria (inclusion and exclusion criteria) to enroll more stable participants, and updating the Drug-induced Liver Injury (DILI) Algorithm and safety tables according to advisory board suggestions. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |