Clinical Trial Results:
A 26-week, Randomized, Open-label, Parallel-group Comparison of SAR341402 Mix 70/30 to NovoMix®30 in Adult Patients with Diabetes Mellitus Using Pre-mix Insulin Analogs
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Summary
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EudraCT number |
2017-000092-84 |
Trial protocol |
PL |
Global end of trial date |
08 Mar 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Mar 2022
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First version publication date |
08 Mar 2022
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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 |
EFC15082
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
U1111-1202-0910 | ||
Other trial identifiers |
STUDY NAME: GEMELLI M | ||
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Sponsors
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Sponsor organisation name |
Sanofi-aventis Recherche & Développement
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Sponsor organisation address |
1 avenue Pierre Brossolette, Chilly Mazarin Cedex, France, 91380
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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 |
16 Apr 2021
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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 |
08 Mar 2021
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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 |
To demonstrate non-inferiority of SAR341402 Mix 70/30 in comparison to NovoMix 30 on glycated hemoglobin A1c (HbA1c) change from Baseline to Week 26 in subjects with Type 1 and Type 2 diabetes mellitus (T1DM and T2DM).
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
Oral antihyperglycemic therapy in subjects with T2DM - if applicable - was to be continued at a stable dose throughout the study. | ||
Evidence for comparator |
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Actual start date of recruitment |
03 Jul 2019
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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 |
Poland: 50
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Country: Number of subjects enrolled |
India: 210
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Country: Number of subjects enrolled |
Philippines: 35
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Country: Number of subjects enrolled |
Russian Federation: 32
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Country: Number of subjects enrolled |
Ukraine: 75
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Worldwide total number of subjects |
402
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EEA total number of subjects |
50
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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) |
300
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From 65 to 84 years |
102
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85 years and over |
0
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Recruitment
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Recruitment details |
Study was conducted at 54 active centres in 5 countries. A total of 509 subjects were screened; of which 107 subjects had screen failure. Screen failure was mainly due to HbA1c level outside of eligibility range and incomplete Baseline 7-point self-measured plasma glucose profile. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Assigned to treatment in 1:1 ratio (SAR341402 Mix 70/30:NovoMix 30) by using an interactive response technology system. Randomisation: stratified by geographical region (Indian; non-Indian), type of diabetes (T1DM; T2DM), HbA1c obtained at screening visit (less than [<]8.0%; greater than or equal to [>=] 8.0%) and prior use of NovoMix 30 (Yes; No). | |||||||||||||||||||||||||||
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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 |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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SAR341402 Mix 70/30 | |||||||||||||||||||||||||||
Arm description |
Subject received SAR341402 Mix 70/30 100 units per millilitre (U/mL) subcutaneous (SC) injection for up to Week 26. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
SAR341402 Mix 70/30
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
SAR341402 Mix 70/30, 100 U/mL, twice daily as self-administered SC injection. Dose was adjusted based on investigator's clinical judgement to achieve preprandial plasma glucose between 4.4 and 7.2 millimoles per litre (mmol/L; 80 to 130 milligrams per decilitre [mg/dL]) and a 2-hour postprandial plasma glucose of <10 mmol/L (<180 mg/dL).
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Arm title
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NovoMix 30 | |||||||||||||||||||||||||||
Arm description |
Subject received NovoMix 30 100 U/mL SC injection for up to Week 26. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
NovoMix 30
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
NovoMix 30, 100 U/mL, twice daily as self-administered SC injection. Dose was adjusted based on investigator's clinical judgement to achieve preprandial plasma glucose between 4.4 and 7.2 mmol/L (80 to 130 mg/dL) and a 2-hour postprandial plasma glucose of <10 mmol/L (<180 mg/dL).
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Baseline characteristics reporting groups
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Reporting group title |
SAR341402 Mix 70/30
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Reporting group description |
Subject received SAR341402 Mix 70/30 100 units per millilitre (U/mL) subcutaneous (SC) injection for up to Week 26. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
NovoMix 30
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Reporting group description |
Subject received NovoMix 30 100 U/mL SC injection for up to Week 26. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
SAR341402 Mix 70/30
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Reporting group description |
Subject received SAR341402 Mix 70/30 100 units per millilitre (U/mL) subcutaneous (SC) injection for up to Week 26. | ||
Reporting group title |
NovoMix 30
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Reporting group description |
Subject received NovoMix 30 100 U/mL SC injection for up to Week 26. | ||
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End point title |
Change From Baseline to Week 26 in Glycated Hemoglobin A1c (HbA1c) | ||||||||||||
End point description |
Combined least square (LS) means and standard errors (SE) were estimated by analysis of covariance (ANCOVA) model based on data obtained from return-to-baseline multiple imputations for missing data. Analysis was performed on intent-to-treat (ITT) population, which included all randomised subjects (irrespective of compliance with study protocol and procedures) analysed according to treatment group allocated by randomisation, and included all values up to Week 26 (regardless of adherence to treatment).
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End point type |
Primary
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End point timeframe |
Baseline to Week 26
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Statistical analysis title |
SAR341402 Mix 70/30 versus NovoMix 30 | ||||||||||||
Statistical analysis description |
Analysis was performed using ANCOVA with treatment group (SAR341402 Mix 70/30, NovoMix 30), the randomisation strata of geographical region (Indian, non-Indian), type of diabetes (T1DM, T2DM) and prior use of NovoMix 30 (Yes, No) as fixed categorical effects, as well as the continuous fixed covariate of Baseline HbA1c value.
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Comparison groups |
SAR341402 Mix 70/30 v NovoMix 30
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Number of subjects included in analysis |
402
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
LS Mean difference | ||||||||||||
Point estimate |
0.08
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.139 | ||||||||||||
upper limit |
0.303 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.113
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| Notes [1] - Non-inferiority of SAR341402 Mix 70/30 over NovoMix 30 was demonstrated if upper bound of the 2‑sided 95% confidence interval of difference between SAR341402 Mix 70/30 and NovoMix 30 on ITT population was <0.3%. |
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End point title |
Percentage of Subjects With Treatment-induced, Treatment-boosted and Treatment-emergent Anti-insulin Aspart Antibodies (AIAs) | |||||||||||||||||||||
End point description |
AIA incidence: 1) Treatment-induced AIAs:subjects who developed AIA following investigational medicinal product (IMP) administration (subjects with at least 1 positive AIA sample at any time during on-treatment period, in those subjects without pre-existing AIA or with missing baseline sample). 2) Treatment-boosted AIAs:subjects with pre-existing AIAs that were boosted to significant higher titer following IMP administration (subjects with at least 1 AIA sample with at least 4-fold increase in titers compared to baseline value at any time during on-treatment period). 3) Treatment-emergent AIA:subjects with treatment-induced/treatment-boosted AIAs. AIA population: all subjects who received at least 1 dose of IMP; had at least 1 AIA sample for analysis during on-treatment period, analysed according to treatment actually received. Here, ‘n’=subjects included in the AIA population for each specified category.
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End point type |
Secondary
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End point timeframe |
From first injection of IMP up to last injection of IMP (i.e., Week 26) + 2 days follow-up after last IMP injection
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Number of Subjects With at Least One Hypoglycemic Event | |||||||||||||||||||||
End point description |
Severe hypoglycemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the subject was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of less than or equal to (<=) 3.9 mmol/L (70 mg/dL) or plasma glucose level of <3.0 mmol/L (54 mg/dL). Analysis was performed on safety population which included all subjects who took at least 1 dose of IMP and were analysed according to the treatment actually received.
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End point type |
Secondary
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End point timeframe |
From first injection of IMP up to last injection of IMP (i.e., Week 26) + 2 days follow-up after last IMP injection
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Number of Hypoglycemia Events Per Subject-Year | ||||||||||||||||||||||||
End point description |
Severe hypoglycemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the subject was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (70 mg/dL) or plasma glucose level of <3.0 mmol/L (54 mg/dL). Number of hypoglycemia events (any, severe and documented [both thresholds]) per subject-year of exposure were reported. Analysis was performed on safety population.
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End point type |
Secondary
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End point timeframe |
From first injection of IMP up to last injection of IMP (i.e., Week 26) + 2 days follow-up after last IMP injection
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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 |
All treatment-emergent adverse events (TEAEs) were collected from the first injection of IMP up to last injection of IMP (i.e., Week 26) + 2 days follow-up after last IMP injection, regardless of seriousness or relationship to investigational product
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Adverse event reporting additional description |
Reported AEs and deaths were TEAEs, that is AEs that developed/worsened or became serious and deaths that occurred during 'on-treatment period’ (time from the first injection of IMP up to last injection of IMP [i.e., Week 26] + 2 days follow-up after the last injection of IMP). Analysis was performed on safety population.
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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 |
23.1
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Reporting groups
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Reporting group title |
SAR341402 Mix 70/30
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Reporting group description |
Subject received SAR341402 Mix 70/30 100 U/mL SC injection for up to Week 26. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
NovoMix 30
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Reporting group description |
Subject received NovoMix 30 100 U/mL SC injection for up to Week 26. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: Since there was no non-serious adverse event with a frequency threshold greater than 5%, no data were available to present in this section. |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 Nov 2019 |
Following changes were done:
• Exploratory pharmacokinetic substudy added at the request of the Indian Health Authority in a subset of approximately 14 Indian subjects with T2DM.
• Screening period extended by up to a maximum of 3 days after the 2-week period.
• Addition of 2 tertiary/exploratory endpoints to assess a) the number of subjects with neutralising anti insulin aspart antibody (NAb) at baseline and specific time-points and b) the clinical effects of NAb on efficacy (HbA1c) and insulin dose.
• Clarification of exclusion criteria with regards to use of systemic immunosuppressive agents and glucocorticoids.
• Clarification of the process for “direct-to-patient” regulating the delivery of IMP to subjects via a Sponsor’s courier in case of emergency.
• Clarification of the counter measures in case of hypoglycemia and the use of subject’s personal glucose monitoring devices in occasional circumstances.
• Clarification of the reporting of hypoglycemia on the electronic case report form; removal of asymptomatic overdose among standard AEs.
• Removal of the requirement of fasting state for blood sampling for antibody measurements.
• Addition of the events of potential loss of efficacy to the list of events to be adjudicated by allergic reaction assessment committee (ARAC) to be consistent with the ARAC charter.
• Update of the time of retention of study records from 15 to 25 years.
• Addition of injectable combined hormonal contraception and barrier contraception as permitted contraception. |
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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. | |||
| Upon request of Indian Health Authority an exploratory PK substudy was conducted in a subset of 13 additional Indian subjects with T2DM. Substudy results were exploratory and are not included in main study results. | |||
