Clinical Trial Results:
The effect of lixisenatide in type 1 diabetes
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Summary
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EudraCT number |
2013-002259-14 |
Trial protocol |
GB |
Global end of trial date |
03 May 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Feb 2018
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First version publication date |
09 Feb 2018
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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 |
TRG12-05
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Additional study identifiers
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ISRCTN number |
ISRCTN00290196 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Oxford
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Sponsor organisation address |
Joint Research Office, Churchill Hospital, Oxford, United Kingdom, OX3 7LE
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Public contact |
Dr Irene Kennedy, Diabetes Trials Unit, University of Oxford, +44 (0)1865857257, trg@dtu.ox.ac.uk
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Scientific contact |
Dr Irene Kennedy, Diabetes Trials Unit, University of Oxford, +44 (0)1865857257, trg@dtu.ox.ac.uk
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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 |
03 May 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 May 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
03 May 2016
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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 primary objective of the main trial is to determine whether adding lixisenatide to basal bolus insulin (combination of long acting insulin once a day called basal with short acting insulin with meals, called bolus) significantly improves glycaemic (blood sugar) control during the 3 hour post prandial period (i.e. following a meal) compared to basal bolus insulin and a 'dummy' or placebo injection.
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Protection of trial subjects |
The trial was conducted in conformance with Good Clinical Practice (GCP) standards and applicable local statutes and regulations regarding ethical committee review, informed consent and the protection of human subjects participating in biomedical research. The following additional measures, defined for this individual trial, were in-place for the protection of the trial subjects:
- The main trial was preceded by a preliminary safety trial which assessed the amount of meal-time insulin dose reduction that avoided hypoglycaemic episodes while maintaining blood glucose levels within an acceptable range when dual treatment with GLP-1 receptor agonist and insulin was started.
- To avoid hypoglycaemia in trial participants, their usual dose of insulin was reduced at the beginning of treatment periods, and titrated to maintain blood glucose within the protocol-defined range.
- In the event that a participant experienced severe hypoglycaemia (an event requiring third-party assistance) at any point during the trial, Investigational Medicinal Product (IMP) would be discontinued permanently.
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Background therapy |
Inclusion criteria for the trial specify participants must be taking a stable insulin dose (within 20%) over 3 months prior to recruitment. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 May 2014
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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 |
United Kingdom: 27
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Worldwide total number of subjects |
27
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EEA total number of subjects |
27
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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) |
26
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was single-centre, carried out at the Clinical Research Unit (CRU), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), UK, between 2nd May 2014 (First Patient First Visit) and 3rd May 2016 (Last Patient Last Visit) | ||||||||||||||||||
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Pre-assignment
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Screening details |
Participants aged 18-70 years inclusive providing written informed consent were eligible if they were diagnosed with stable type 1 diabetes for at least 12 months (Stable insulin dose (within 20%) over 3 months prior to recruitment), used a Basal-Bolus insulin regimen, HbA1c between 6.5% and 10.0% (inclusive) and BMI < 35 Kg/m2. | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
38 [1] | ||||||||||||||||||
Number of subjects completed |
27 | ||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Participants failed to meet eligibility criteria.: 11 | ||||||||||||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of participants starting the pre-assignment period are those who provided Informed Consent and were screened. The number enrolled is the number eligible who then went on to be enrolled i.e. randomised. The difference is due to those individuals who failed screening. |
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Period 1
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Period 1 title |
Main trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | ||||||||||||||||||
Blinding implementation details |
Participants were randomised to one of two treatment arms in a double blind cross-over trial. An independent statistician generated the randomization code list and this was added in a concealed fashion to the Trial Management System (TMS). It was blinded to all personnel apart from: The independent statistician who generated it; the IT team member who uploaded it onto the TMS; the IMP packaging team and the pharmacy team who managed the 24-hour emergency unblinding service.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Lixisenatide followed by matching placebo | ||||||||||||||||||
Arm description |
Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||||||||||||||||||
Arm type |
Cross-over design | ||||||||||||||||||
Investigational medicinal product name |
Lixisenatide
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Investigational medicinal product code |
AVE0010
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Other name |
Lyxumia
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Lixisenatide 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by lixisenatide 20μg/day injected for a further 2 weeks then a 28-day washout period.
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Investigational medicinal product name |
Matching placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Matching placebo 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by matching placebo 20μg/day injected for a further 2 weeks then a 28-day washout period leading to the closeout visit.
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Arm title
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Matching placebo followed by lixisenatide | ||||||||||||||||||
Arm description |
Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||||||||||||||||||
Arm type |
Cross-over design | ||||||||||||||||||
Investigational medicinal product name |
Matching placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Matching placebo 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by matching placebo 20μg/day injected for a further 2 weeks then a 28-day washout period leading to the closeout visit.
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Investigational medicinal product name |
Lixisenatide
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Investigational medicinal product code |
AVE0010
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Other name |
Lyxumia
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Lixisenatide 10μg/day injected subcutaneously between 8-10am for 2 weeks followed by lixisenatide 20μg/day injected for a further 2 weeks then a 28-day washout period.
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Baseline characteristics reporting groups
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Reporting group title |
Lixisenatide followed by matching placebo
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Reporting group description |
Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Matching placebo followed by lixisenatide
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Reporting group description |
Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Data for one participant was removed from the full analysis population for Arm 2 (matching placebo followed by lixisenatide) due to pregnancy post-randomisation. Twenty-six participants were therefore included in the initial full analysis data-set.
Data for two of the remaining twenty-six participants was subsequently also excluded from the primary analysis because one participant dropped out of the study visits after the first treatment period and one participant was missing baseline primary endpoint data. This meant that determination of treatment affect was not possible for these two individuals' data.
The primary end-point results analysis data presented in this report relates to the remaining 24 of the 27 participants randomised.
The Safety Population (SP) consists of all randomised individuals who received at least one dose of the study medication, hence adverse event information in this report is presented for all 27 participants randomised.
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End points reporting groups
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Reporting group title |
Lixisenatide followed by matching placebo
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Reporting group description |
Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||
Reporting group title |
Matching placebo followed by lixisenatide
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Reporting group description |
Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||
Subject analysis set title |
Full analysis population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Data for one participant was removed from the full analysis population for Arm 2 (matching placebo followed by lixisenatide) due to pregnancy post-randomisation. Twenty-six participants were therefore included in the initial full analysis data-set.
Data for two of the remaining twenty-six participants was subsequently also excluded from the primary analysis because one participant dropped out of the study visits after the first treatment period and one participant was missing baseline primary endpoint data. This meant that determination of treatment affect was not possible for these two individuals' data.
The primary end-point results analysis data presented in this report relates to the remaining 24 of the 27 participants randomised.
The Safety Population (SP) consists of all randomised individuals who received at least one dose of the study medication, hence adverse event information in this report is presented for all 27 participants randomised.
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End point title |
The change in the percentage of Continuous Glucose Monitoring (CGM) readings between 4 and 10 mmol/l (inclusive) during the 3 hour post-prandial period, before and after treatment with lixisenatide compared to matching placebo. | ||||||||||||
End point description |
The primary end-point is to determine whether adding lixisenatide to basal bolus insulin significantly improves glycaemic control during the 3 hour post prandial period compared to basal bolus insulin and a placebo injection.
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End point type |
Primary
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End point timeframe |
Up to 4 months.
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| Notes [1] - One participant only completed period 1 and a second was missing baseline primary endpoint data. [2] - Data for one participant was removed from the analysis data-set due to pregnancy post-randomisation. |
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Statistical analysis title |
The Within-subject differences | ||||||||||||
Statistical analysis description |
The analysis was based on the means and standard deviations of the within-subject difference to reflect the resultant treatment effect and the paired nature of the design. The treatment effect was estimated based on an average of within-subject differences, after testing for the assumptions of no carryover or period effect, and that the within-subject differences were normally distributed. The estimated treatment effects are presented in means and standard deviations with 95% interval ranges.
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Comparison groups |
Matching placebo followed by lixisenatide v Lixisenatide followed by matching placebo
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Number of subjects included in analysis |
24
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||
upper limit |
- | ||||||||||||
Variability estimate |
Standard deviation
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| Notes [3] - Efficacy study. |
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Adverse events information
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Timeframe for reporting adverse events |
Safety was assessed from screening through to each participant's closout visit. The closeout visit took place a minimum of 28 days after last dose of trial medication.
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Adverse event reporting additional description |
All Adverse Events were documented within 24 hours of awareness with sponsor notified of Serious Adverse Events or pregnancy within 24 hours of awareness using sponsor-supplied forms.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Events not coded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
N/A
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Reporting groups
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Reporting group title |
Lixisenatide followed by matching placebo
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Reporting group description |
Lixisenatide treatment period (4 weeks) followed by a washout period (4 weeks) then matching placebo treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Matching placebo followed by lixisenatide
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Reporting group description |
Matching placebo treatment period (4 weeks) followed by a washout period (4 weeks) then lixisenatide treatment period (4 weeks) followed by a final washout period (4 weeks). Participants were asked to inject the trial medication using an injection pen once each morning (between 8-10 am) in addition to their prescribed insulin medication. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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19 Mar 2014 |
Substantial amendment 1.0 - summary of changes:
- Amend the type of Continuous Glucose Monitoring device used during the trial.
- Extend the Body Mass Index eligibility criterion from < or = 27 kg/m2 to < 30 kg/m2.
- Clarify how the Part A trial results will be analysed.
- Ensure that visit procedures are consistent and will permit the collection of eligibility data at screening.
- To seek permission to store surplus blood samples collected during the Part B trial for up to 5 years following the end of the trial, after which time they will be destroyed.
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09 Jul 2014 |
Substantial amendment 2.0 - Summary of changes:
- To increase the Body Mass Index (BMI) eligibility criterion from < 30 kg/m2 to < 35 kg/m2.
- To remove the following inclusion criterion: 'Insulin treatment since diabetes'.
- To amend the blood collection tubes used for the following tests during the trial: Glucose-dependant insulinotropic peptide or gastric inhibitory peptide (GIP), Glucagon-Like-Peptide1 (GLP1), Glucagon and the counter-regulatory hormones, adrenaline, noradrenaline, cortisol and pancreatic polypeptide.
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05 Dec 2014 |
Substantial amendment 3.0 - Summary of changes:
- To increase the upper age limit eligibility criterion from aged 18-65 years to 18-70 years.
- To increase the upper glycated haemoglobin (HbA1c) eligibility criterion limit from 7.0 - 9.0% inclusive to 7.0 - 10.0% inclusive.
- To increase the upper C-peptide value (C-peptide negative group only) eligibility criterion from Random or fasting C-peptide <0.02 nmol/l to <0.1 nmol/l.
- Include a breath test procedure to measure gastric emptying.
- Clarify that the ancillary study procedures are optional and take place once during the trial. To also document separate Informed Consent for the ancillary study procedures.
- Revise the length of some of the Part B trial visits.
- Update the Gastric Inhibitory Peptide (GIP) and Glucagon Like Peptide-1 (GLP-1) assay names.
- To update other trial documents in-line with the above protocol updates (Participant Information Leaflet, Informed Consent Form, Protocol summary and the advertising poster).
- To notify that an updated version of existing Investigator Brochure is now issued (Edition 11 dated 21 April 2014). |
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21 Aug 2015 |
Substantial amendment 4.0 - Summary of changes:
- To decrease the lower glycated haemoglobin (HbA1c) limit eligibility criterion from 7.0 - 10.0% inclusive to 6.5 - 10.0% inclusive.
- To Update to the existing single-centre clinical site team (addition of one further research clinician).
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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. | |||
| The study closed to recruitment on 5th January 2016. This deadline was fixed in-line with the expiry date of the study medication. At this point a total of 27 participants were randomised onto the main study compared to the target of 30. | |||
