Clinical Trial Results:
A Multicenter, Open-label, Metabolic Balance Study to Evaluate the Effects of Apraglutide on Intestinal Absorption in Adult Subjects with Short Bowel Syndrome, Intestinal Failure (SBS-IF), and Colon-in-continuity (CIC)
Summary
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EudraCT number |
2020-005129-99 |
Trial protocol |
FR BE DK |
Global end of trial date |
06 Jun 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Aug 2024
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First version publication date |
15 Aug 2024
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Other versions |
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 |
TA799-013
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04964986 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
VectivBio AG
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Sponsor organisation address |
Aeschenvorstadt 36, Basel, Switzerland, 4051
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Public contact |
Clinical Trial Information Desk, VectivBio AG, clinicaltrial.enquiries@vectivbio.com
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Scientific contact |
Clinical Trial Information Desk, VectivBio AG, clinicaltrial.enquiries@vectivbio.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
06 Jun 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 |
06 Jun 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objectives of this trial were to evaluate the safety and tolerability of apraglutide and the efficacy of apraglutide in increasing intestinal energy absorption assessed by bomb calorimetry in relation to metabolic balance assessments.
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Protection of trial subjects |
This trial was performed in compliance with:
• Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013).
• The ICH-GCP guidelines (ICH E6 (R2), November 2016).
• European Union Clinical Trials Regulation No. 536/2014.
• Any amendments to these regulations.
• Local laws and regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Jun 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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: 8
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Country: Number of subjects enrolled |
France: 2
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Worldwide total number of subjects |
10
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EEA total number of subjects |
10
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
8
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 10 participants with SBS-IF and CIC were enrolled as planned, eight participants at the Belgium site and two participants at the France site. A total of nine participants were treated and analyzed. | ||||||
Pre-assignment
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Screening details |
- | ||||||
Pre-assignment period milestones
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Number of subjects started |
10 | ||||||
Number of subjects completed |
9 | ||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Enrolled but not treated: 1 | ||||||
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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Arm title
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Apraglutide | ||||||
Arm description |
All participants received, based on their body weight, either 2.5 mg (<50 kg) or 5 mg (≥50 kg) apraglutide once weekly, for 52 weeks. The investigational medicinal product (IMP) was administered subcutaneously (SC). | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Apraglutide
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Investigational medicinal product code |
TA799
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The IMP was administered SC.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One participant was enrolled but not treated. |
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Baseline characteristics reporting groups
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Reporting group title |
Apraglutide
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Reporting group description |
All participants received, based on their body weight, either 2.5 mg (<50 kg) or 5 mg (≥50 kg) apraglutide once weekly, for 52 weeks. The investigational medicinal product (IMP) was administered subcutaneously (SC). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Apraglutide
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Reporting group description |
All participants received, based on their body weight, either 2.5 mg (<50 kg) or 5 mg (≥50 kg) apraglutide once weekly, for 52 weeks. The investigational medicinal product (IMP) was administered subcutaneously (SC). |
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End point title |
Number of Participants who Experienced a Treatment-Emergent Adverse Event (TEAE) [1] | ||||||||||||||||||||
End point description |
Applicable to Protocol V4.0 implemented in Belgium (classed as secondary endpoint in Protocol V3.0 [implemented in France]).
A TEAE was any unfavorable and unintended sign, symptom, or disease temporally associated with apraglutide, whether or not related, that occurred or worsened after the dose of apraglutide. A serious TEAE was defined as any TEAE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. Clinically significant changes from baseline in clinical chemistry, hematology, hemostasis, anti-drug antibodies (ADAs), and urine analysis were reported as adverse events.
Adverse events of special interest (AESI):
• Injection site reaction
• Gastrointestinal obstruction
• Gallbladder, biliary, and pancreatic disease
• Fluid overload
• Colorectal polyps
• Malignancies
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End point type |
Primary
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End point timeframe |
Day 1 up to approximately 55 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: No additional statistical analysis was pre-specified for this endpoint. |
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Notes [2] - The safety analysis set included all participants exposed to trial medication. |
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No statistical analyses for this end point |
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End point title |
Absolute Change in Absorption of Energy Over Metabolic Balance (MB) Periods From Baseline at Week 48 [3] | ||||||||||
End point description |
Applicable to Protocol V3.0 implemented in France (classed as secondary endpoint in Protocol V4.0 [implemented in Belgium]).
The absorption was defined as dietary intake minus output from fecal excretion over a 72-hour MB period at a given analysis time point. Since dietary intake and fecal excretion were measured daily, i.e., up to three measurements may contribute to absorption calculations, the average over all available daily absorption measurements over the 72-hour period were used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
The increase from baseline at Week 48 was statistically significant (p-value=0.041). The p-value was computed based on the paired t-test.
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End point type |
Primary
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End point timeframe |
Baseline and Week 48
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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: Additional statistical analysis presented as free-text due to inability to add this for single arm trials within EudraCT. |
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No statistical analyses for this end point |
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End point title |
Relative Change From Baseline in Actual Weekly Parenteral Support (PS) Volume at Weeks 4, 24, and 52 | ||||||||||||||
End point description |
The sum of daily PS volume (including extra fluids) from weekly PS diary data recorded for the corresponding analysis timepoint was used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4, Week 24, and Week 52
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No statistical analyses for this end point |
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End point title |
Absolute Change From Baseline in Actual Weekly PS Volume at Weeks 24 and 52 | ||||||||||||
End point description |
The sum of daily PS volume (including extra fluids) from weekly PS diary data recorded for the corresponding analysis timepoint was used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
At Week 24 and Week 52, significant decreases (p-values=<0.001 for both) in mean PS volume were reported. The p-values were computed based on the paired t-test.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and Week 52
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No statistical analyses for this end point |
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End point title |
Number of Participants Who Achieved a Reduction of at Least 1 Day Per Week of PS From Baseline at Weeks 24 and 52 | ||||||||||
End point description |
Participants were considered to have a reduction of at least one day per week of PS from Baseline (incl. extra fluids) if the number of days with PS from weekly PS diary data recorded for the corresponding analysis timepoint was smaller compared to the number of days with PS from weekly PS diary data for Baseline.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and Week 52
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No statistical analyses for this end point |
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End point title |
Number of Participants Considered Clinical Responders at Weeks 24 and 52 | ||||||||||
End point description |
Clinical response was defined as a 20% reduction of PS volume from Baseline. The sum of daily PS volume (including extra fluids) from weekly PS diary data recorded for the corresponding analysis timepoint was used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and 52
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No statistical analyses for this end point |
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End point title |
Number of Participants Who Achieved Enteral Autonomy at Weeks 24 and 52 | ||||||||||
End point description |
Enteral autonomy was defined as a participant not receiving PS for hydration or parenteral nutrition (PN) for calories. Participants may have still received minimal fluid to maintain patency of the central line or for specific elemental/micro-nutrient needs (e.g., <100 mL fluid for administration of magnesium).
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Week 24 and Week 52
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No statistical analyses for this end point |
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End point title |
Absolute Change in Total Energy in PN From Baseline at Weeks 24 and 52 | ||||||||||||
End point description |
PN was defined as PS that includes protein, carbohydrate, fat, vitamins, and/or trace elements.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
At Week 24 and Week 52, there was a significant decrease (p-value=0.002 and p-value=<0.001, respectively) in mean total energy from baseline. The p-values were computed based on the paired t-test.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and Week 52
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No statistical analyses for this end point |
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End point title |
Relative Change in Absorption of Energy Over MB Periods From Baseline at Week 48 | ||||||||||
End point description |
The absorption was defined as dietary intake minus output from fecal excretion over a 72-hour MB period at a given analysis time point. Since dietary intake and fecal excretion were measured daily, i.e., up to three measurements may contribute to absorption calculations, the average over all available daily absorption measurements over the 72-hour period were used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 48
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No statistical analyses for this end point |
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End point title |
Absolute Change in Absorption of Macronutrients Over MB Periods From Baseline at Weeks 4 and 48 | ||||||||||||||||||||
End point description |
The absorption was defined as dietary intake minus output from fecal excretion over a 72-hour MB period at a given analysis time point. Since dietary intake and fecal excretion were measured daily, i.e., up to three measurements may contribute to absorption calculations, the average over all available daily absorption measurements over the 72-hour period were used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
Fat absorption increase at Weeks 4 and 48 was not statistically significant (p-value=0.294 and 0.155, respectively). Carbohydrate absorption at Week 4 was not statistically significant (p-value=0.260); however, the increase at Week 48 was statistically significant (p-value=0.024). Protein aborption increase at Weeks 4 and 48 was not statistically significant (p-value=0.096 and 0.075, respectively). P-values were computed based on paired t-test.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4 and Week 48
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No statistical analyses for this end point |
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End point title |
Absolute Change in Urine Volume over MB Periods From Baseline at Week 4 and Week 48 | ||||||||||||
End point description |
Based on average daily urine volume data derived as per balance period calculations.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
At Week 4, there was a non-significant increase from baseline (p-value=0.063). At Week 48, there was a non-significant decrease from baseline (p-value=0.112). The p-values were computed based on the paired t-test.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4 and Week 48
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No statistical analyses for this end point |
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End point title |
Absolute Change in Absorption of Energy Over MB Periods From Baseline at Week 4 | ||||||||
End point description |
The absorption was defined as dietary intake minus output from fecal excretion over a 72-hour MB period at a given analysis time point. Since dietary intake and fecal excretion were measured daily, i.e., up to three measurements may contribute to absorption calculations, the average over all available daily absorption measurements over the 72-hour period were used for analysis.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
The increase from baseline at Week 4 was not statistically significant (p-value= 0.306). The p-value was computed based on the paired t-test.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 4
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No statistical analyses for this end point |
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End point title |
Absolute Change in Urinary Electrolytes over MB Periods From Baseline at Week 4 and Week 48 | ||||||||||||||||||||||||||||||||
End point description |
Since urinary electrolytes data were measured over the 72-hour MB period, the average of all available results was used for analyses for each MB parameter at a given analysis time point.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
No significant changes from baseline were reported at Week 4 or Week 48 for calcium, magnesium, potassium, or creatinine. A significant change from baseline was reported for sodium at Week 4 (p-value=0.004) but not Week 48. A significant change from baseline in urea was reported at Week 48 (p-value-0.009) but not Week 4.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4 and Week 48
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Pittsburgh Sleep Quality Inventory (PSQI) Total Score at Week 24 and Week 52 | ||||||||||||
End point description |
The PSQI is a patient-reported questionnaire used to measure the quality and patterns of sleep, over the past month. The PSQI has seven components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction over the last month. Minimum Score = 0 (better); Maximum Score = 21 (worse). A negative change from baseline represents a reduction in symptoms.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
The decrease in mean PSQI total score at Week 24 was not statistically significant (p-value=0.066); however, the decrease at Week 52 was statistically significant (p-value=0.015). The p-values were computed based on the paired t-test.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and Week 52
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Patient Global Impression of Change (PGIC) at Week 24 and Week 52 | ||||||||||||||
End point description |
PGIC v2.0 is a single-item questionnaire using a 5-point verbal rating scale, to assess overall change in the participants status after taking the IMP. Response options range from 2= very much better to -2= very much worse.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and Week 52
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Notes [4] - Week 24 n = 8. |
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No statistical analyses for this end point |
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End point title |
Patient Global Impression of Treatment Satisfaction (PGI-TS) at Week 24 and Week 52 | ||||||||||||||
End point description |
This form is a single-item questionnaire assessing the participant’s satisfaction with the trial medication over the preceding 7 days. Response options range from -2 to 2, very dissatisfied to very satisfied.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Week 24 and Week 52
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Notes [5] - Week 24 n = 8. |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Patient Global Impression of Satisfaction with Parenteral Support (PGI-SPS) at Week 24 and Week 52 | ||||||||||||
End point description |
This is a single-item questionnaire assessing the participant's satisfaction with PS over the preceding 7 days. Response options range from -2 to 2, very dissatisfied to very satisfied. A reduction from baseline represents a decrease in satisfaction.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Week 24 and Week 52
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Patient Global Impression of Parenteral Support Impact (PGI-PSI) at Week 24 and Week 52 | ||||||||||||||||||||
End point description |
This is a three-item questionnaire assessing the impact of PS on the participant’s sleep, daily activities, and quality of life (QoL) over the past 7 days. All questions have response options ranging from 0 to 4, not at all to extremely. A reduction from baseline represents a decrease in symptoms.
The full analysis set included all participants who received at least one dose of trial treatment and contributed at least one valid post-baseline efficacy point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24 and Week 52
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Notes [6] - Week 52 n = 4. |
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No statistical analyses for this end point |
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End point title |
Trough Apraglutide Plasma Concentration (Ctrough) | ||||||||||||||||||||||||
End point description |
The safety analysis set included all participants exposed to trial medication.
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End point type |
Secondary
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End point timeframe |
Pre-dose on Weeks 2, 4, 12, 24, 32, 40, 48, and 52
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No statistical analyses for this end point |
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End point title |
Mean Plasma Citrulline Level | ||||||||||||||||||||||||||
End point description |
The safety analysis set included all participants exposed to trial medication.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 2, 4, 12, 24, 32, 40, 48, and 52
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Notes [7] - Week 4 n = 8. |
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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 |
Day 1 up to approximately 55 weeks
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Adverse event reporting additional description |
The safety analysis set included all participants exposed to trial medication.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
Apraglutide
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Reporting group description |
All participants received, based on their body weight, either 2.5 mg (<50 kg) or 5 mg (≥50 kg) apraglutide once weekly, for 52 weeks. The IMP was administered SC. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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24 Feb 2020 |
• Corrected inconsistencies and typos
• Corrected the wording of the primary endpoint
• Updates to inclusion and exclusion criteria
• Updated planned trial dates
• Added glutamine to the list of prior medications to be specifically recorded
• Added fecal sample testing for H. pylori at baseline and added vital signs assessment at Visit 3 (Day 0); reduced the time window for the final visit of the treatment period (Visit 17, Week 52) to ±2 days
• Specified that body temperature is to be taken in the axilla for all vital signs assessments
• Additional clinical chemistry parameters to be tested
• Included microbiota questionnaires and measurement of hip and waist circumference
• Updated the number of biopsies required for the experimental trials and clarified the distinction between standard and single-cell ribonucleic acid sequencing
• Specified the parameters to be analyzed for microbiota, and the duration of sample storage and results archiving
• Added details of the considerations on IMP dose reduction and temporary discontinuation of IMP
• Specified that in the case that a vulnerable participant enters the trial, the Principal Investigator is encouraged to consult their local independent ethics committee/institutional review board for guidance |
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03 Sep 2021 |
• Corrected inconsistencies and typos
• Minor wording changes and clarifications
• Sponsor representative changed
• Abbreviations list updated
• Synopsis: clarified definition of short bowel syndrome and deleted PS definition
• Secondary endpoints and Section 5.1.9 PROs updated
• Updated inclusion and exclusion criteria
• Updates to Tables 1 and 2
• Section 2.2: wording added to include definitions of PS, fluids, and other parameters during the trial
• Section 2.2.1: inclusion of wording regarding history of vomiting
• Section 4.5: Added further details on the PS reduction procedure
• Section 4.7 and exclusion criteria: use of somatostatin analogs removed
• Section 4.7.1 & 4.7.2: Definition of use of antibiotics updated. Added routine vaccinations allowed
• Section 5.1.11: ADA follow up procedures post EOT clarified
• Section 5.2.9: Total HCO3- added to blood lab tests at safety evaluation post PS reduction
• Section 6.6.2: Updated the stopping rules
• Section 8: Added section regarding DMC
• Section 10.2.1: Updated that biomarker samples will be stored for 15 years
• Section 16.5: Electrolytes all now analyzed by Atomic absorptiometry |
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07 Feb 2022 |
• General changes to improve clarity and minor formatting issues
• International Coordinating Investigator changed
• Primary objective changed to evaluate the safety and tolerability of apraglutide
• Evaluation of calories added to secondary objectives
• Primary endpoints updated to reflect the change in primary objective by including AEs, AESIs, clinical laboratory assessment and ADA
• Addition of the Week 4 assessment in relative change from baseline in actual weekly PS volume
• Changes to secondary endpoints
• Section 1.5.2.4: Definition of enteral autonomy added
• Inclusion criterion 2 clarified
• Table 1: Addition of definition of MB period
• Table 2: Addition of Bristol Stool Form Scale on Days 2 and 3
• Section 2.1: Additional background added
• Section 2.2: Confirmation that infusion of a small amount of fluid to maintain catheter patency is not considered PS
• Section 2.2.1: Added that investigator can use clinical judgment to demonstrate that the small intestine is <200 cm
• Section 2.2.2: Additional instructions relating to drinking menu and enteral nutrition
• Section 4.5: Clarifications on PS volume reduction criteria and process and clarification on method of calculation baseline urine average |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
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 |