Type 1 Diabetes Mellitus-Type 2 Diabetes Mellitus Clinical Trial
— GEMELLI1Official title:
Six-month, Randomized, Open-label, Parallel-group Comparison of SAR341402 to NovoLog®/NovoRapid® in Adult Patients With Diabetes Mellitus Also Using Insulin Glargine, With a 6-month Safety Extension Period
| Verified date | March 2022 |
| Source | Sanofi |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
Primary Objective: To demonstrate non-inferiority of SAR341402 versus NovoLog/NovoRapid in glycated hemoglobin A1c (HbA1c) change from baseline to Week 26 in participants with type 1 or type 2 diabetes mellitus (T1DM or T2DM) also using Lantus®. Secondary Objectives: - To assess the immunogenicity of SAR341402 and NovoLog/NovoRapid in terms of positive/negative status and anti-insulin antibody (AIA) titers during the course of the study. - To assess the relationship of AIAs with efficacy and safety. - To assess the efficacy of SAR341402 and NovoLog/NovoRapid in terms of proportion of participants reaching HbA1c lesser than (<) 7.0% and change in HbA1c, fasting plasma glucose (FPG), and self-measured plasma glucose (SMPG) profiles from baseline to Week 26 and Week 52 (only Week 52 for HbA1c). - To assess safety of SAR341402 and NovoLog/NovoRapid.
| Status | Completed |
| Enrollment | 597 |
| Est. completion date | January 12, 2019 |
| Est. primary completion date | July 16, 2018 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion criteria : - Participants with T1DM or T2DM (T2DM US only) diagnosed for at least 12 months, who have been treated with a multiple daily injection regimen with - NovoLog/NovoRapid or insulin lispro (100 U/mL) in the last 6 months prior to screening visit AND - insulin glargine (100 U/mL) in the last 6 months prior to screening visit OR insulin detemir (Levemir®) in the last 12 months prior to screening visit. Exclusion criteria: - At screening visit, age under legal age of adulthood. - HbA1c <7.0% or greater than (>) 10% at screening. - Less than 1 year on continuous insulin treatment. - Use of insulin pump in the last 3 months before screening visit. - Participants with incomplete baseline 7-point SMPG profile, defined as participants who do not have 7-point profiles with at least 5 points on at least 2 days in the week before randomization Visit 3. - Participants with T1DM: Use of glucose lowering agents other than insulin including use of non-insulin injectable peptides in the last 3 months prior to screening. - Participants with T2DM: - Use of glucagon-like peptide-1 (GLP-1) receptor agonists in the last 3 months before screening visit. - Use of oral antidiabetic drugs (OADs) not on stable dose in the last 3 months before screening visit (sulfonylureas was discontinued at baseline). - At screening visit, body mass index (BMI) greater than or equal to (>=) 35 kilogram per meter square (kg/m^2) in participants with T1DM and >=40 kg/m^2 in participants with T2DM. - Use of insulin other than: - insulin glargine 100 U/mL and NovoLog/NovoRapid or insulin lispro 100 U/mL as part of a multiple injection regimen in the last 6 months before screening visit, OR - insulin detemir 100 U/mL in the 12 months before screening visit and NovoLog/NovoRapid or insulin lispro 100 U/mL in the last 6 months before screening visit as part of a multiple injection regimen. - Status post pancreatectomy. - Status post pancreas and/or islet cell transplantation. - Hospitalization for recurrent diabetic ketoacidosis in the last 3 months before screening visit. - History of severe hypoglycemia requiring Emergency Room admission or hospitalization in the last 3 months before screening visit. - Unstable proliferative diabetic retinopathy or any other rapidly progressive diabetic retinopathy or macular edema likely to require treatment (eg, laser, surgical treatment or injectable drugs) during the study period. - Pregnant or breastfeeding women. - Women of childbearing potential not protected by highly effective method(s) of birth control. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial. |
| Country | Name | City | State |
|---|---|---|---|
| Finland | Investigational Site Number 2460006 | Jyväskylä | |
| Finland | Investigational Site Number 2460002 | Kuopio | |
| Finland | Investigational Site Number 2460004 | Pori | |
| Finland | Investigational Site Number 2460003 | Seinäjoki | |
| Germany | Investigational Site Number 2760001 | Berlin | |
| Germany | Investigational Site Number 2760006 | Essen | |
| Germany | Investigational Site Number 2760004 | Heidelberg | |
| Germany | Investigational Site Number 2760005 | Oldenburg In Holstein | |
| Germany | Investigational Site Number 2760002 | Pirna | |
| Hungary | Investigational Site Number 3480012 | Balatonfüred | |
| Hungary | Investigational Site Number 3480001 | Budapest | |
| Hungary | Investigational Site Number 3480004 | Budapest | |
| Hungary | Investigational Site Number 3480005 | Budapest | |
| Hungary | Investigational Site Number 3480008 | Budapest | |
| Hungary | Investigational Site Number 3480011 | Budapest | |
| Hungary | Investigational Site Number 3480007 | Debrecen | |
| Hungary | Investigational Site Number 3480003 | Nagykanizsa | |
| Hungary | Investigational Site Number 3480010 | Nyíregyháza | |
| Hungary | Investigational Site Number 3480009 | Szentendre | |
| Japan | Investigational Site Number 3920009 | Fukuyama-Shi | |
| Japan | Investigational Site Number 3920008 | Higashiosaka-Shi | |
| Japan | Investigational Site Number 3920007 | Kashiwara-Shi | |
| Japan | Investigational Site Number 3920001 | Koriyama-Shi | |
| Japan | Investigational Site Number 3920005 | Kumamoto-Shi | |
| Japan | Investigational Site Number 3920003 | Mito-Shi | |
| Japan | Investigational Site Number 3920010 | Osaka-Shi | |
| Japan | Investigational Site Number 3920002 | Sagamihara-Shi | |
| Japan | Investigational Site Number 3920004 | Shinjuku-Ku | |
| Japan | Investigational Site Number 3920006 | Ushiku-Shi | |
| Poland | Investigational Site Number 6160004 | Bialystok | |
| Poland | Investigational Site Number 6160003 | Krakow | |
| Poland | Investigational Site Number 6160005 | Krakow | |
| Poland | Investigational Site Number 6160007 | Lublin | |
| Poland | Investigational Site Number 6160006 | Nowy Sacz | |
| Poland | Investigational Site Number 6160001 | Poznan | |
| Poland | Investigational Site Number 6160002 | Warszawa | |
| Russian Federation | Investigational Site Number 6430002 | Samara | |
| Russian Federation | Investigational Site Number 6430003 | Saratov | |
| Russian Federation | Investigational Site Number 6430001 | St. Petersburg | |
| Russian Federation | Investigational Site Number 6430004 | Tomsk | |
| United States | Investigational Site Number 8400038 | Arlington Heights | Illinois |
| United States | Investigational Site Number 8400007 | Atlanta | Georgia |
| United States | Investigational Site Number 8400037 | Aurora | Colorado |
| United States | Investigational Site Number 8400044 | Austin | Texas |
| United States | Investigational Site Number 8400029 | Bend | Oregon |
| United States | Investigational Site Number 8400039 | Bridgeport | West Virginia |
| United States | Investigational Site Number 8400033 | Chattanooga | Tennessee |
| United States | Investigational Site Number 8400022 | Columbus | Georgia |
| United States | Investigational Site Number 8400012 | Concord | California |
| United States | Investigational Site Number 8400009 | Dallas | Texas |
| United States | Investigational Site Number 8400021 | Dallas | Texas |
| United States | Investigational Site Number 8400035 | Dallas | Texas |
| United States | Investigational Site Number 8400005 | Des Moines | Iowa |
| United States | Investigational Site Number 8400018 | Englewood | Colorado |
| United States | Investigational Site Number 8400002 | Escondido | California |
| United States | Investigational Site Number 8400023 | Fargo | North Dakota |
| United States | Investigational Site Number 8400019 | Flint | Michigan |
| United States | Investigational Site Number 8400030 | Fresno | California |
| United States | Investigational Site Number 8400004 | Greenbrae | California |
| United States | Investigational Site Number 8400024 | Henderson | Nevada |
| United States | Investigational Site Number 8400001 | Houston | Texas |
| United States | Investigational Site Number 8400017 | Houston | Texas |
| United States | Investigational Site Number 8400020 | Houston | Texas |
| United States | Investigational Site Number 8400014 | La Jolla | California |
| United States | Investigational Site Number 8400040 | Little Rock | Arkansas |
| United States | Investigational Site Number 8400043 | Los Angeles | California |
| United States | Investigational Site Number 8400016 | Mesquite | Texas |
| United States | Investigational Site Number 8400041 | Metairie | Louisiana |
| United States | Investigational Site Number 8400025 | Morehead City | North Carolina |
| United States | Investigational Site Number 8400031 | New Port Richey | Florida |
| United States | Investigational Site Number 8400028 | New York | New York |
| United States | Investigational Site Number 8400027 | Ocoee | Florida |
| United States | Investigational Site Number 8400003 | Omaha | Nebraska |
| United States | Investigational Site Number 8400036 | Pomona | California |
| United States | Investigational Site Number 8400008 | Renton | Washington |
| United States | Investigational Site Number 8400015 | Rockville | Maryland |
| United States | Investigational Site Number 8400032 | Roswell | Georgia |
| United States | Investigational Site Number 8400034 | Salt Lake City | Utah |
| United States | Investigational Site Number 8400011 | Santa Barbara | California |
| United States | Investigational Site Number 8400013 | Ventura | California |
| United States | Investigational Site Number 8400042 | Waltham | Massachusetts |
| United States | Investigational Site Number 8400010 | Wilmington | North Carolina |
| Lead Sponsor | Collaborator |
|---|---|
| Sanofi |
United States, Finland, Germany, Hungary, Japan, Poland, Russian Federation,
Garg SK, Wernicke-Panten K, Wardecki M, Kramer D, Delalande F, Franek E, Sadeharju K, Monchamp T, Miossec P, Mukherjee B, Shah VN. Safety, Immunogenicity, and Glycemic Control of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart in People with Diabetes Also Using Insulin Glargine: 12-Month Results from the GEMELLI 1 Trial. Diabetes Technol Ther. 2020 Jul;22(7):516-526. doi: 10.1089/dia.2020.0008. Epub 2020 Mar 31. — View Citation
Garg SK, Wernicke-Panten K, Wardecki M, Kramer D, Delalande F, Franek E, Sadeharju K, Monchamp T, Mukherjee B, Shah VN. Efficacy and Safety of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart in People with Diabetes Treated for 26 Weeks with Multiple Daily Injections in Combination with Insulin Glargine: A Randomized Open-Label Trial (GEMELLI 1). Diabetes Technol Ther. 2020 Feb;22(2):85-95. doi: 10.1089/dia.2019.0382. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Change in Glycated Hemoglobin A1c From Baseline to Week 26 and Week 52: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog | All values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c at Week 26 and Week 52 was calculated by subtracting baseline value from Week 26 and Week 52 value, respectively. Missing changes at Week 26 and Week 52 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA model on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26 and Week 52 | |
| Other | Number of Participants With at Least One Hypoglycemic Event: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the participant 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). | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Other | Number of Participants With Adverse Events: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog | Any untoward medical occurrence in a participant who received IMP was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during the main 6-month or 12-month on-treatment periods. | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Other | Percentage of Participants With Treatment-Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies (AIAs): Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog | AIA incidence were categorized as: treatment-induced, treatment-boosted AIAs, and treatment-emergent AIA. 1) Participants with treatment-induced AIAs were those who developed AIA following IMP administration (participants with at least one positive AIA sample at any time during on-treatment period, in those participants without pre-existing AIA or with missing baseline sample. 2) Participants with treatment-boosted AIAs were those with pre-existing AIAs that were boosted to a significant higher titer following IMP administration (participants with at least one AIA sample with at least a 4-fold increase in titers compared to baseline value at any time during on-treatment period). 3) Participants with treatment-emergent AIA were defined as participants with treatment-induced, or treatment-boosted AIAs. Data was summarized separately for each treatment arm in each subgroup (based on the prior use of NovoLog/NovoRapid or Humalog/Liprolog). | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Other | Change in Daily Insulin Dose From Baseline to Day 1, Week 26 and Week 52 | Change in daily insulin dose (basal, mealtime and total) was calculated by subtracting baseline value from Day1, Week 26 and Week 52 values respectively. Baseline was defined as the median of daily doses available in the week prior to the first injection of IMP (corresponding to doses of the pre-study insulin), value at Day 1 as the median of daily doses available in the week after the first injection of IMP (first doses of IMP), and value at Week 26 and Week 52 as the median of daily doses available in the week prior to each visit. | Baseline, Day 1, Week 26 and Week 52 | |
| Primary | Change in Glycated Hemoglobin A1c (HbA1c) From Baseline to Week 26 | All values up to Week 26 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Missing changes at Week 26 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted least square (LS) means and standard errors (SE) were obtained using an analysis of covariance (ANCOVA) model on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26 | |
| Secondary | Change in HbA1c From Baseline to Week 52 | All values up to Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c was calculated by subtracting baseline value from Week 52 value. Missing changes at Week 52 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA model on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 52 | |
| Secondary | Percentage of Participants With HbA1c <7% at Week 26 and Week 52 | Participants who had no available assessment at Week 26 and Week 52 were considered as non-responders. | Week 26 and Week 52 | |
| Secondary | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 and Week 52 | All values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in FPG at Week 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26, and Week 52 | |
| Secondary | Change in the Mean 24-hour Plasma Glucose Concentration From Baseline to Week 26 and Week 52 | Mean 24-hour plasma glucose concentration was calculated based on 7-point self-measured plasma glucose (SMPG) profiles with plasma glucose measurements before and 2-hours after each main meal and at bedtime. Mean 24-hour plasma glucose concentration was calculated for each profile and then averaged across profiles performed in the week before a visit. All calculated values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in mean 24-hour plasma glucose concentration at Weeks 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a return-to-baseline multiple imputation method (values imputed as participant baseline plus an error). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26, and Week 52 | |
| Secondary | Change in Postprandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 and Week 52 | Plasma glucose excursions were calculated at breakfast, lunch and dinner for each 7-point SMPG profile, as 2-hour PPG minus plasma glucose value obtained 30 minutes prior to start of the meal. Values of plasma glucose excursions at each visit were then calculated as the average across profiles performed in the week before the visit. All calculated values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in PPG excursions at Weeks 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a return-to-baseline multiple imputation method (values imputed as participant baseline plus an error). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26, and Week 52 | |
| Secondary | Change in 7-Point SMPG Profiles From Baseline to Week 26 and Week 52 Per Time Point | 7-point SMPG profiles were measured at the following 7 points at each visit (Baseline, Week 26, and Week 52): before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, and bedtime. For each time point, the value at each visit was calculated as the average of values obtained for the same time point across profiles performed in the week before the visit. | Baseline, Week 26, and Week 52 | |
| Secondary | Number of Participants With at Least One Hypoglycemic Event | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the participant 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). | From first injection of investigational medicinal product (IMP) up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Secondary | Number of Hypoglycemia Events Per Participant-Year | Number of hypoglycemia events (any, severe and documented [both thresholds]) per participant-year of exposure were reported. Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the participant 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). | From first injection of investigational medicinal product (IMP) up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Secondary | Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions | Participants with at least one treatment-emergent adverse event linked to hypersensitivity reaction and injection site reaction regardless of relationship to IMP during the main 6-month and the 12-month on-treatment periods was assessed and reported. | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Secondary | Percentage of Participants With at Least One Positive Anti-Insulin Aspart Antibodies (AIA) Sample | Participants with at least one positive AIA sample at baseline or at any time during the on-treatment period (Prevalence). | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | |
| Secondary | Percentage of Participants With Treatment-Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies (AIAs) | AIA incidence were categorized as: treatment-induced, treatment-boosted AIAs, and treatment-emergent AIA. 1) Participants with treatment-induced AIAs were those who developed AIA following IMP administration (participants with at least one positive AIA sample at any time during on-treatment period, in those participants without pre-existing AIA or with missing baseline sample). 2) Participants with treatment-boosted AIAs were those with pre-existing AIAs that were boosted to a significant higher titer following IMP administration (participants with at least one AIA sample with at least a 4-fold increase in titers compared to baseline value at any time during on-treatment period). 3) Participants with treatment-emergent AIA were defined as participants with treatment-induced, or treatment-boosted AIAs. | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 |