Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: * To demonstrate the superiority of Soliqua 100/33 versus Lantus in the hemoglobin A1c (HbA1c) change within the overall population. * To demonstrate the benefit of Soliqua 100/33 versus Lantus in the HbA1c within each ethnic/racial subgroup evaluated (ie, Hispanics of any race, non-Hispanic black/African Americans and non-Hispanic Asians). Secondary Objective: * To assess the effects of Soliqua 100/33 versus Lantus on the secondary efficacy parameters within each ethnic/racial subgroup evaluated. * To assess the change in daily insulin glargine dose within each ethnic/racial subgroup. * To evaluate the safety and tolerability (e.g., gastrointestinal tolerability) of Soliqua 100/33 versus Lantus within each ethnic/racial subgroup.
Detailed description
The study duration was approximately 29 weeks including 2 weeks screening period, 26 weeks open label treatment period, and a 3 days follow-up period.
Interventions
Insulin glargine (100 units per milliliter \[U/mL\]) and lixisenatide (33 micrograms per milliliter \[mcg/mL\]) self administered by a subcutaneous injection using a prefilled pen. Dose was individually titrated to achieve target fasting self-monitoring of plasma glucose (SMPG) of 80 to 100 milligrams per deciliter (mg/dL) (4.4 to 5.6 millimoles per liter \[mmol/L\]) while avoiding hypoglycemia.
Insulin glargine 100 U/mL self-administered by a subcutaneous injection using a prefilled pen. Dose was individually titrated to achieve target fasting SMPG of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia.
Oral Anti diabetics Drugs (OADs) administered orally according to the locally approved label.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Participants with type 2 diabetes mellitus (T2DM) diagnosed at least 1 year prior to the screening visit (signing of informed consent). * Uncontrolled diabetes as demonstrated by a screening centrally measured hemoglobin A1c (HbA1c) between 7.5% and 10% (inclusive). * Participants who were Hispanics of any race, non-Hispanic black/African Americans or non-Hispanic Asians. Note: Decision for ethnic/racial inclusion was made based on the participant's self-identification. Mixed-race participants must select 1 of the above-mentioned categories. If such selection could not be made, the candidate would be ineligible to participate in the study. * Participants who had been treated with any basal insulin (ie, glargine - U100 or U300, detemir, degludec, intermediate-acting \[human Neutral Protamine Hagedorn (NPH\]) for at least 6 months prior to Visit 1. * The basal insulin regimen (ie, type of insulin and time/frequency of the injection) had been stable for at least 3 months prior to Visit 1. * The basal insulin dose had been stable (defined as up to ±20% \[1/5 of the dose\] variability) for at least 2 months prior to Visit 1 within the following dose ranges: * 15 to 50 units/day if HbA1c at Visit 1 is less than or equal to (\<=)8.5%, and * 15 to 40 units/day if HbA1c at Visit 1 is greater than (\>)8.5%. * Participants receiving 1 or 2 of the following OAD drugs: metformin, pioglitazone/rosiglitazone, an sodium-glucose transport protein 2 (SGLT-2) inhibitor or a sulfonylurea (SU), at stable doses for at least 12 weeks prior to Visit 1.
Exclusion criteria
* Age \<18 years of age at Visit 1. * A body mass index (BMI) \<=20 or \>40 kg/m\^2 at Visit 1. * Fasting plasma glucose (FPG) \>200 mg/dL (by central lab measurement) at Visit 1 (1-time repeat measurement before Visit 2 is permitted). * Type 1 DM or any diabetes other than T2DM. * Any use of OAD drugs other than those described in the inclusion criteria (e.g., but not limited to, glucagon like peptide-1 receptor agonist (GLP-1 RA), dipeptidyl peptidase 4 (DPP4) inhibitors) within 12 weeks prior Visit 1. * Use of any other type of insulin except for basal insulin (e.g., prandial or premixed insulin, insulin pump) within 6 months prior to Visit 1. Note: History of short-term treatment (i.e, \<=10 days) with other insulin types due to intercurrent illness was permitted at the discretion of the Investigator. * Known history of discontinuation of treatment with a GLP-1 RA due to safety/tolerability reasons. * Use of systemic glucocorticoids for a total duration of \>7 days within 12 weeks prior to Visit 1. * Initiation/change in type or dose of a weight loss drug within 12 weeks prior to Visit 1. The above information is not intended to contain all considerations relevant to a participants's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 | Baseline, Week 26 | Change in HbA1c was calculated by subtracting baseline value from Week 26 value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 26 | Baseline, Week 26 | The 2-hour PPG test measured blood glucose 2 hours after eating a standardized breakfast meal. |
| Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test at Week 26 | Baseline, Week 26 | — |
| Percentage of Participants Achieving HbA1c Target of <7% at Week 26 | Week 26 | Participants who had no available assessment for HbA1c at Week 26 were considered as non-responders. |
| Change From Baseline in Body Weight at Week 26 | Baseline, Week 26 | Change in body weight was calculated by subtracting baseline value from Week 26 value. |
| Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Baseline to Week 26 | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Documented hypoglycemia with plasma glucose cut-off of \<=70 mg/dL (3.9 mmol/L) was any hypoglycemia documented by a measured plasma glucose \<=70 mg/dL (3.9 mmol/L) and excluding plasma glucose \<54 mg/dL regardless of symptoms. Documented hypoglycemia with plasma glucose cut-off of \<54 mg/dL (3.0 mmol/L) was any hypoglycemia documented by a measured plasma glucose \<54 mg/dL (3.0 mmol/L) regardless of symptoms. |
| Change From Baseline in Daily Insulin Glargine Dose at Week 26 | Baseline, Week 26 | Change in daily dose was calculated by subtracting baseline value from Week 26 value. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 94 sites in United States (US). A total of 534 participants were screened between 20 February 2018 and 01 November 2018, of which 293 participants were screen failures. Screen failures were mainly due to glycated hemoglobin A1c (HbA1c) level less than (\<)7.5% or greater than (\>)10% at the screening visit.
Pre-assignment details
Randomization was stratified by self-reported ethnic/racial group, screening HbA1c values (\<8.5% vs \>=8.5%), background use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors (yes/no), background use of sulfonylureas (yes/no). Assignment to arms was done centrally by an interactive response technology (IRT) in 1:1 ratio (Soliqua 100/33:Lantus).
Participants by arm
| Arm | Count |
|---|---|
| Soliqua 100/33 Soliqua 100/33 (Insulin glargine/lixisenatide) once daily in the morning within 1 hour before breakfast, on top of OAD therapy for 26 weeks. | 116 |
| Lantus Lantus (Insulin glargine) once daily at any time of the day but at about the same time every day on top of OAD therapy for 26 weeks. | 125 |
| Total | 241 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Other than specified | 7 | 5 |
| Overall Study | Poor Compliance to Protocol | 0 | 1 |
| Overall Study | Randomized but not treated | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 91 | 102 |
| Overall Study | Withdrawal by Subject | 7 | 5 |
Baseline characteristics
| Characteristic | Lantus | Total | Soliqua 100/33 |
|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 11.9 | 59.6 years STANDARD_DEVIATION 11.1 | 61.6 years STANDARD_DEVIATION 9.7 |
| Body Mass Index (BMI) | 30.67 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.93 | 30.78 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.83 | 30.90 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.74 |
| Body Weight | 84.84 kilograms (kg) STANDARD_DEVIATION 19.34 | 84.90 kilograms (kg) STANDARD_DEVIATION 17.73 | 84.97 kilograms (kg) STANDARD_DEVIATION 15.89 |
| Duration of Diabetes <10 years | 39 Participants | 65 Participants | 26 Participants |
| Duration of Diabetes >=10 years | 86 Participants | 176 Participants | 90 Participants |
| Glycated Haemoglobin (HbA1c %) | 8.62 percentage of hemoglobin STANDARD_DEVIATION 0.68 | 8.62 percentage of hemoglobin STANDARD_DEVIATION 0.71 | 8.62 percentage of hemoglobin STANDARD_DEVIATION 0.74 |
| Race/Ethnicity, Customized Hispanics of any race | 64 Participants | 124 Participants | 60 Participants |
| Race/Ethnicity, Customized Non-Hispanic Asians | 21 Participants | 38 Participants | 17 Participants |
| Race/Ethnicity, Customized Non-Hispanic black or African Americans | 40 Participants | 79 Participants | 39 Participants |
| Sex: Female, Male Female | 67 Participants | 124 Participants | 57 Participants |
| Sex: Female, Male Male | 58 Participants | 117 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 0 / 125 |
| other Total, other adverse events | 21 / 115 | 20 / 125 |
| serious Total, serious adverse events | 7 / 115 | 4 / 125 |
Outcome results
Primary
Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26
Change in HbA1c was calculated by subtracting baseline value from Week 26 value.
Time frame: Baseline, Week 26
Population: Analysis was performed on intent-to-treat (ITT) population that included all randomized participants. Here, overall number of participants analyzed = participants with available data for the specified outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Soliqua 100/33 | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 | -1.86 percentage of HbA1c | Standard Deviation 0.96 |
| Lantus | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 | -1.07 percentage of HbA1c | Standard Deviation 1.17 |
Secondary
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test at Week 26
Time frame: Baseline, Week 26
Population: Data were not collected, hence planned analysis was not performed due to early termination of the study.
Secondary
Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 26
The 2-hour PPG test measured blood glucose 2 hours after eating a standardized breakfast meal.
Time frame: Baseline, Week 26
Population: Data were not collected, hence planned analysis was not performed due to early termination of the study.
Secondary
Change From Baseline in Body Weight at Week 26
Change in body weight was calculated by subtracting baseline value from Week 26 value.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Soliqua 100/33 | Change From Baseline in Body Weight at Week 26 | 1.69 kilograms (kg) | Standard Deviation 3.74 |
| Lantus | Change From Baseline in Body Weight at Week 26 | 1.52 kilograms (kg) | Standard Deviation 2.92 |
Secondary
Change From Baseline in Daily Insulin Glargine Dose at Week 26
Change in daily dose was calculated by subtracting baseline value from Week 26 value.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Soliqua 100/33 | Change From Baseline in Daily Insulin Glargine Dose at Week 26 | 18.7 International Units (IU) | Standard Deviation 16.4 |
| Lantus | Change From Baseline in Daily Insulin Glargine Dose at Week 26 | 14.1 International Units (IU) | Standard Deviation 16.5 |
Secondary
Percentage of Participants Achieving HbA1c Target of <7% at Week 26
Participants who had no available assessment for HbA1c at Week 26 were considered as non-responders.
Time frame: Week 26
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed = participants with available data for the specified outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Soliqua 100/33 | Percentage of Participants Achieving HbA1c Target of <7% at Week 26 | 52.6 percentage of participants |
| Lantus | Percentage of Participants Achieving HbA1c Target of <7% at Week 26 | 30.8 percentage of participants |
Secondary
Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period
Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Documented hypoglycemia with plasma glucose cut-off of \<=70 mg/dL (3.9 mmol/L) was any hypoglycemia documented by a measured plasma glucose \<=70 mg/dL (3.9 mmol/L) and excluding plasma glucose \<54 mg/dL regardless of symptoms. Documented hypoglycemia with plasma glucose cut-off of \<54 mg/dL (3.0 mmol/L) was any hypoglycemia documented by a measured plasma glucose \<54 mg/dL (3.0 mmol/L) regardless of symptoms.
Time frame: Baseline to Week 26
Population: Analysis was performed on safety population that included all randomized participants who received at least 1 dose of open-label investigational medicinal product (IMP), regardless of the amount of treatment administered. Participants were analyzed according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Soliqua 100/33 | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Any hypoglycemia | 48.7 percentage of participants |
| Soliqua 100/33 | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Severe hypoglycemia | 1.7 percentage of participants |
| Soliqua 100/33 | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Documented hypoglycaemia <=70 mg/dL (3.9 mmol/L) | 43.5 percentage of participants |
| Soliqua 100/33 | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Documented hypoglycaemia <54 mg/dL (3.0 mmol/L) | 12.2 percentage of participants |
| Lantus | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Documented hypoglycaemia <54 mg/dL (3.0 mmol/L) | 18.4 percentage of participants |
| Lantus | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Any hypoglycemia | 52.8 percentage of participants |
| Lantus | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Documented hypoglycaemia <=70 mg/dL (3.9 mmol/L) | 48.8 percentage of participants |
| Lantus | Percentage of Participants With Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Hypoglycemia) During the On-Treatment Period | Severe hypoglycemia | 2.4 percentage of participants |