Clinical Trial Results:
Effect of reparixin on long-term outcomes after pancreatic islet transplantation in type 1 diabetes mellitus patients. A non-interventional, monocentre study to extend up to 3 years the follow-up of patients treated with reparixin under protocol REP0110.
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Summary
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EudraCT number |
2013-002244-86 |
Trial protocol |
IT |
Global end of trial date |
23 Mar 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Dec 2020
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First version publication date |
27 Dec 2020
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Other versions |
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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 |
REP0113
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Dompé Farmaceutici S.p.A.
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Sponsor organisation address |
Via S.Lucia 6, Milan, Italy, 20122
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Public contact |
Clinical Trial Transparency Manager, Dompé Farmaceutici S.p.A., 0039 0258381, info@dompe.it
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Scientific contact |
Clinical Trial Transparency Manager, Dompé Farmaceutici S.p.A., 0039 0258381, info@dompe.it
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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 |
23 Mar 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Mar 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Mar 2015
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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 objective of this extension study is to evaluate whether treatment with reparixin at the time of islet transplantation improves long-term outcome of pancreatic islets allo-transplantation. This study extended the follow-up evaluation of efficacy and safety from 1 to 3 years post-transplant in patients treated with reparixin under protocol REP0110.
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Protection of trial subjects |
The study was conducted in accordance with the Declaration of Helsinki and International
Conference on Harmonisation (ICH) harmonised tripartite guidelines for Good Clinical Practice
(ICH-GCP), and standard operating procedures (SOPs) for clinical investigation and
documentation in force at Dompé.
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Background therapy |
The following immunosuppression regimen was to be used in patients enrolled in the study: Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL. The immunosuppression strategy above could have been changed on the basis of clinical requirements, as per centre practice. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Oct 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
36 Months | ||
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 |
Italy: 3
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Worldwide total number of subjects |
3
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EEA total number of subjects |
3
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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) |
3
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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 |
As per inclusion criteria, only 3 patients were potentially eligible for the extension study. | ||||||||||
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Pre-assignment
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Screening details |
Criteria to be eligible for inclusion into this extended follow-up of the study REP0110 - functioning graft (stimulated serum C-peptide levels >0.3 ng/mL derived from the mixed meal tolerance test [MMTT]) at the last follow-up visit under REP0110 - compliance with the protocol procedures for the duration of the trial - written informed consent | ||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Since the REP0110 study was not blinded, the extension study was conducted in an open fashion.
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Arms
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Arm title
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No intervention patients | ||||||||||
Arm description |
REP0113 is an observational study, hence no products were to be administered. Reparixin was administered in the interventional study REP0110, of which REP0113 is a follow-up. | ||||||||||
Arm type |
no intervention | ||||||||||
Investigational medicinal product name |
Reparixin
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Investigational medicinal product code |
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Other name |
REP
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
REP0113 is an observational study, hence no products were to be administered.
Reparixin was administered in the interventional study REP0110, of which REP0113 is a follow-up.
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Baseline characteristics reporting groups
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Reporting group title |
No intervention patients
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Reporting group description |
REP0113 is an observational study, hence no products were to be administered. Reparixin was administered in the interventional study REP0110, of which REP0113 is a follow-up. | ||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
No intervention patients
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Reporting group description |
REP0113 is an observational study, hence no products were to be administered. Reparixin was administered in the interventional study REP0110, of which REP0113 is a follow-up. | ||
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End point title |
The number of Insulin-independent Patients Following Islet Cell Transplantation [1] | ||||||||||
End point description |
Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
- HbA1c level of less than 7%;
- glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
- glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).
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End point type |
Primary
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End point timeframe |
Months 24, 36 after the last transplant
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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: Based on the inclusion criteria, only 3 patients were enrolled in this follow up trial. Hence, no statistical analysis have been calculated. Moreover, in this trial only patients who were treated with reparixin in the study REP0110 were enrolled, so no analysis between arms/treatments could be accomplished. |
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| Notes [2] - n=3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Total time of insulin independence up to 3 years after the last transplant | ||||||||||||
End point description |
Total time of insulin-independence after the transplant. This was defined as the number
of days between the onset and loss of insulin-independence and was calculated as the
date of loss of insulin-independence minus the date of onset of insulin-independence.
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End point type |
Other pre-specified
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End point timeframe |
Up to 3 years after the last transplant
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Absolute decrease in average daily insulin requirements from pre-transplant levels | ||||||||||||
End point description |
Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 from pre-transplant
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| Notes [3] - n=3 at 24 months n=2 at 36 months |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage decrease in average daily insulin requirements from pre-transplant levels | ||||||||||||
End point description |
Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 from pre-transplant
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| Notes [4] - n=3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Absolute decrease in fasted HbA1c from pre-transplant levels | ||||||||||||
End point description |
The average pre-transplant value was taken as recorded on the CRFs.
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 from pre-transplant levels
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| Notes [5] - n=3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage decrease in Fasted HbA1c from pre-transplant levels | ||||||||||||
End point description |
he average pre-transplant daily insulin requirement was taken as recorded on the CRFs
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 from pre-transplant levels
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| Notes [6] - n=3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
The proportion of patients free of severe hypoglycaemic events | ||||||||||||
End point description |
A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 post-transplant
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| Notes [7] - n=3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time profile (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) | ||||||||||||||||
End point description |
Glucose level reflects the methabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.
Only the value at 120 min after the MMTT administration is reported. See the attachment for data at each timepoint and for each of the two patients.
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End point type |
Other pre-specified
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End point timeframe |
At Months 24 and 36 after the last transplant
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Attachments |
Time profile of glucose |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Time profile (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) | ||||||||||||||||
End point description |
C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the above mentioned timepoints.
Only the value at 120 min after the MMTT administration is reported. See the attachment for data at each timepoint and for each of the two patients.
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 after the last transplant
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Attachments |
Time profile of C-peptide |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Time profile (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) | ||||||||||||||||
End point description |
Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the above mentioned timepoints.
Only the value at 120 min after the MMTT administration is reported. See the attachment for data at each timepoint and for each of the two patients.
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 after the last transplant.
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Attachments |
Time profile of insulin |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Beta-cell function as assessed by beta-score | ||||||||||||
End point description |
The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function.
Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 after the last transplant
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| Notes [8] - n=3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Beta-cell Function as Assessed by Transplant Estimated Function (TEF) | ||||||||||||
End point description |
TEF estimates daily insulin secretion, it is simpler than the beta-score, and its performance against reference indexes of beta-cell secretion is in line with that exhibited by beta-score. TEF can be normalized to the number of transplanted islets and thereby provides a benchmarking tool to evaluate the cost-effectiveness of the transplant.
TEF selects the two pivotal components of the beta-score (daily insulin requirement [DIR] and glycated hemoglobin [A1C]) and links them together through a simple description of how insulin supply influences the patient’s glycemic control.
TEF represents the daily amount of insulin secreted by the beta-cells and can be derived as a linear combination of DIR and A1C:
TEF = a * DIR + b * A1C + c,
where a = -1, b = 1/K, K measures the sensitivity of the glycemic control to the insulin supply, and c is a constant depending on the pretransplant (pretx) DIR and A1C of the patient:
c = -a * DIR(pretx) - b * A1C(pretx)
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End point type |
Other pre-specified
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End point timeframe |
At months 24 and 36 after the last transplant
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| Notes [9] - n= 3 at month 24 n=2 at month 36 |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Throughout the follow up study
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Adverse event reporting additional description |
Only the SAEs were recorded in the study.
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Assessment type |
Systematic | ||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||
Dictionary version |
13.0
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Reporting groups
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Reporting group title |
No intervention patients
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Reporting group description |
Only SAEs were recorded in the study, but no SAEs were reported. | ||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Only SAEs were recorded in the study, but no SAEs were reported. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
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. | |||
| Two the limitations of this trial: 1) the small number of subjects enrolled in the study (3), 2) the fact that these patients came all from the group treated with reparixin. | |||
