Type 1 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To demonstrate that morning injection of Toujeo (HOE901-U300) compared to Lantus provides better glycemic control evaluated by Continuous Glucose Monitoring (CGM) in adult participants with type 1 diabetes mellitus. Secondary Objective: To demonstrate that treatment with HOE901-U300 compared to Lantus provides: * Lower incidence rate of nocturnal symptomatic hypoglycemia; * Better glucose control coverage during the last hours of CGM before next basal-insulin dosing; * Less variability in CGM profile.
Detailed description
The maximum study duration per participant was to be of approximately 20 weeks that consisted of an up to a 4-week screening and CGM training period including a 1-2 week baseline (blinded) CGM performance (allowed for re-training), a 14-week open-label, comparative treatment period allowing for dose titration in both basal and meal-time insulin and including a 1-2 week end-of treatment blinded CGM collection with fixed dose of HOE901-U300 and Lantus, and a 2 day post treatment follow-up period.
Interventions
DRUGHOE901-U300 (Insulin Glargine 300 U/ml)
Self-administered by subcutaneous (SC) injection in the morning (between waking up and breakfast) using a pre-filled pen.
DRUGLantus (Insulin Glargine 100 U/ml)
Self-administered by subcutaneous (SC) injection in the morning (between waking up and breakfast using a pre-filled pen.
DRUGMandated back ground therapy
Rapid insulin analogs: e.g., insulin glulisine, insulin lispro or insulin aspart, used by participant at least 30 days before screening. Mealtime insulin was to be continued during the study and titrated towards protocol specified postprandial glucose targets (130-180 mg/dL).
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Adult participants (male and female) with type 1 diabetes mellitus (T1DM). * Signed written informed consent.
Exclusion criteria
* Age \<18 years or \>70 years. * Fasting c-peptide ≥0.3 nmol/L as per source document or central lab test at Visit 1. * Glycated hemoglobin (HbA1c) ≤ 6.5 % or ≥ 10.0% via central lab test at Visit 1. * Participants who experienced none of episode of documented symptomatic and/or severe hypoglycemia (as per the American Diabetes Association (ADA) classification) during the past month prior to screening. * Participants who experienced \>1 episode of severe hypoglycemia resulting in coma/seizures during the last 12 months before screening. * Participants received less than 1 year treatment with basal plus mealtime insulin. * Used any basal insulins other than long-acting insulin analogs (ie, Lantus, Toujeo, Levemir, and Tresiba) in the past 3 months before screening. * Required \>80 U/day basal insulin analogs or not on stable dose (±20% total dose) within 30 days prior to screening. * Used fewer than 2 injections of rapid-acting insulin analog per day within 30 days prior to screening. * Used human regular insulin as mealtime insulin within 30 days prior to screening. * Used an insulin pump during the last 6 months before screening. * History of unstable proliferative diabetic retinopathy or any other rapidly progressive diabetic retinopathy or macular edema likely to required treatment (e.g., laser, surgical treatment, or injectable drugs) during the study period. * Pregnant or breast-feeding women or planned pregnancy during the duration of the study. * Use of any other investigational drug(s) within 1 month or 5 half-lives, whichever was longer prior to screening. * Inappropriate CGM use during screening period evidenced by failure to obtain a minimum of 4 days of usable records by the end of screening. * Noncompliance with self-monitored plasma glucose (SMPG) performance evidenced by failure to demonstrate at least 5 days of 5 point SMPG records by the end of screening. 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 |
|---|---|---|
| Percentage of Time of Mean Glucose Concentration Within the Target Range of 70-180 mg/dL as Obtained From CGM | During Week 15 and/or 16 | The CGM system combined frequent interstitial glucose measurements (every 5 minutes) with ability to analyze glucose levels in real time. Adjusted least square (LS) means and standard error (SE) were obtained from a generalized linear model with identity link including post baseline CGM assessment during Week 15 (and/or Week 16). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Documented Symptomatic Nocturnal Hypoglycemia Event Rate Per Participant-Year | Baseline up to Week 16 | Documented symptomatic nocturnal hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by SMPG \<=70 mg/dL that occurred between 00:00 and 05:59 hours as reported on the hypoglycemia eCRF. |
| Mean Change From Baseline in Glucose Level During Last 4 Hours of CGM Data Collection Prior to the Next Day Basal Insulin Injection During Week 15 and/or Week 16 | Baseline, during Week 15 and/or Week 16 | Adjusted LS means and SE were obtained from mixed model including post baseline CGM assessment during the last 4 hours prior to the next day's basal insulin injection during Week 15 (and/or Week 16). |
| Percentage of Participants With Documented Symptomatic Nocturnal Hypoglycemia | Baseline up to Week 16 | Documented symptomatic nocturnal hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by SMPG \<=70 mg/dL that occurred between 00:00 and 05:59 hours as reported on the hypoglycemia electronic case report form (eCRF). |
| Coefficient of Variation (CV%) in Mean CGM Glucose | During Week 15 and/or Week 16 | CV% was a measure of spread of variability relative to mean of population. For CGM glucose values over 24 hours, CV% was measure of glycemic variability across 24-hour day and calculated for each period (total, within day and between days) as ratio of standard deviation of glucose values to mean of glucose values. |
| Percentage of Time Glucose Concentrations Within the Target Range of 70 to 140 mg/dL During Last 4 Hours of CGM Data Collection Prior to Next Day Basal Insulin Injection | During Week 15 and/or Week 16 | Adjusted LS means and SE were obtained from mixed model including post baseline CGM assessment during the last 4 hours prior to the next day's basal insulin injection during Week 15 (and/or Week 16). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Daily Insulin Dose at Week 16 | Baseline, Week 16 | Change from Baseline at Week 16 for daily basal insulin dose and daily bolus insulin dose was reported. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
The study was conducted at 100 sites in United States. A total of 980 participants were screened between 5 May 2016 and 16 February 2017, of whom 342 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
A total of 638 participants were randomized in HOE901-U300 or Lantus, stratified by baseline HbA1c (\<8 %,\> =8%), frequency of basal insulin injections at Visit 1 (twice vs once daily), current continuous glucose monitoring (CGM) use at Visit 1(yes/no) and mealtime insulin titration algorithm (simple titration vs carbohydrate counting).
Participants by arm
| Arm | Count |
|---|---|
| HOE901-U300 HOE901-U300 (Insulin glargine, 300 U/mL) SC injection once daily up to Week 16 on top of mealtime insulin analogs. Basal insulin doses were individually titrated to reach fasting SMPG levels within the target range of 80 to 100 mg/dL. | 320 |
| Lantus Lantus (Insulin glargine, 100 U/mL) SC injection once daily up to Week 16 on top of mealtime insulin analogs. Basal insulin doses were individually titrated to reach fasting SMPG levels within the target range of 80 to 100 mg/dL. | 318 |
| Total | 638 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Hypoglycemia | 2 | 0 |
| Overall Study | Lack of Efficacy | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Other than Specified | 14 | 25 |
| Overall Study | Poor compliance to protocol | 7 | 4 |
Baseline characteristics
| Characteristic | HOE901-U300 | Lantus | Total |
|---|---|---|---|
| Age, Continuous | 45.5 years STANDARD_DEVIATION 14 | 45.5 years STANDARD_DEVIATION 13.9 | 45.5 years STANDARD_DEVIATION 13.9 |
| Body mass index | 27.50 kg/m^2 STANDARD_DEVIATION 4.88 | 27.65 kg/m^2 STANDARD_DEVIATION 4.92 | 27.57 kg/m^2 STANDARD_DEVIATION 4.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 43 Participants | 42 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 277 Participants | 276 Participants | 553 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 28 Participants | 52 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) White | 281 Participants | 282 Participants | 563 Participants |
| Sex: Female, Male Female | 140 Participants | 138 Participants | 278 Participants |
| Sex: Female, Male Male | 180 Participants | 180 Participants | 360 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 320 | 0 / 318 |
| other Total, other adverse events | 54 / 320 | 54 / 318 |
| serious Total, serious adverse events | 17 / 320 | 14 / 318 |
Outcome results
Primary
Percentage of Time of Mean Glucose Concentration Within the Target Range of 70-180 mg/dL as Obtained From CGM
The CGM system combined frequent interstitial glucose measurements (every 5 minutes) with ability to analyze glucose levels in real time. Adjusted least square (LS) means and standard error (SE) were obtained from a generalized linear model with identity link including post baseline CGM assessment during Week 15 (and/or Week 16).
Time frame: During Week 15 and/or 16
Population: Modified intent-to-treat (mITT) population that included all participants who were randomized and had a post-baseline CGM assessment and enough CGM data values to calculate the primary outcome measure, percent of time in range of 70-180 mg/dL during Week 15 (and/or Week 16).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| HOE901-U300 | Percentage of Time of Mean Glucose Concentration Within the Target Range of 70-180 mg/dL as Obtained From CGM | 55.40 percentage of time | Standard Error 1.08 |
| Lantus | Percentage of Time of Mean Glucose Concentration Within the Target Range of 70-180 mg/dL as Obtained From CGM | 55.18 percentage of time | Standard Error 1.1 |
Comparison: Analysis was performed using generalized linear model with identity link, had percentage of time glucose concentration within target range 70-180 mg/dL as dependent variable, treatment group as an independent variable, adjusting variables including baseline characteristics: duration of diabetes, baseline BMI, age, and randomization strata (HbA1c at screening \[\<8.0% vs ≥8.0%\], frequency of Lantus injection at screening, current CGM use \[yes/no\], and mealtime insulin titration algorithm).p-value: 0.8494Generalized linear model
Secondary
Coefficient of Variation (CV%) in Mean CGM Glucose
CV% was a measure of spread of variability relative to mean of population. For CGM glucose values over 24 hours, CV% was measure of glycemic variability across 24-hour day and calculated for each period (total, within day and between days) as ratio of standard deviation of glucose values to mean of glucose values.
Time frame: During Week 15 and/or Week 16
Population: mITT population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| HOE901-U300 | Coefficient of Variation (CV%) in Mean CGM Glucose | Total CV% | 41.27 percent of mean glucose level | Standard Error 0.63 |
| HOE901-U300 | Coefficient of Variation (CV%) in Mean CGM Glucose | Within-day CV% | 36.99 percent of mean glucose level | Standard Error 0.56 |
| HOE901-U300 | Coefficient of Variation (CV%) in Mean CGM Glucose | Between-days CV% | 17.44 percent of mean glucose level | Standard Error 0.59 |
| Lantus | Coefficient of Variation (CV%) in Mean CGM Glucose | Total CV% | 40.72 percent of mean glucose level | Standard Error 0.64 |
| Lantus | Coefficient of Variation (CV%) in Mean CGM Glucose | Within-day CV% | 36.23 percent of mean glucose level | Standard Error 0.56 |
| Lantus | Coefficient of Variation (CV%) in Mean CGM Glucose | Between-days CV% | 17.53 percent of mean glucose level | Standard Error 0.6 |
Secondary
Documented Symptomatic Nocturnal Hypoglycemia Event Rate Per Participant-Year
Documented symptomatic nocturnal hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by SMPG \<=70 mg/dL that occurred between 00:00 and 05:59 hours as reported on the hypoglycemia eCRF.
Time frame: Baseline up to Week 16
Population: mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HOE901-U300 | Documented Symptomatic Nocturnal Hypoglycemia Event Rate Per Participant-Year | Documented <=70 mg/dL | 11.38 events per participant-year |
| HOE901-U300 | Documented Symptomatic Nocturnal Hypoglycemia Event Rate Per Participant-Year | Documented <54 mg/dL | 4.99 events per participant-year |
| Lantus | Documented Symptomatic Nocturnal Hypoglycemia Event Rate Per Participant-Year | Documented <=70 mg/dL | 11.39 events per participant-year |
| Lantus | Documented Symptomatic Nocturnal Hypoglycemia Event Rate Per Participant-Year | Documented <54 mg/dL | 5.61 events per participant-year |
Secondary
Mean Change From Baseline in Glucose Level During Last 4 Hours of CGM Data Collection Prior to the Next Day Basal Insulin Injection During Week 15 and/or Week 16
Adjusted LS means and SE were obtained from mixed model including post baseline CGM assessment during the last 4 hours prior to the next day's basal insulin injection during Week 15 (and/or Week 16).
Time frame: Baseline, during Week 15 and/or Week 16
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| HOE901-U300 | Mean Change From Baseline in Glucose Level During Last 4 Hours of CGM Data Collection Prior to the Next Day Basal Insulin Injection During Week 15 and/or Week 16 | -1.99 mg/dL | Standard Error 3.68 |
| Lantus | Mean Change From Baseline in Glucose Level During Last 4 Hours of CGM Data Collection Prior to the Next Day Basal Insulin Injection During Week 15 and/or Week 16 | 5.67 mg/dL | Standard Error 3.72 |
Secondary
Percentage of Participants With Documented Symptomatic Nocturnal Hypoglycemia
Documented symptomatic nocturnal hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by SMPG \<=70 mg/dL that occurred between 00:00 and 05:59 hours as reported on the hypoglycemia electronic case report form (eCRF).
Time frame: Baseline up to Week 16
Population: mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HOE901-U300 | Percentage of Participants With Documented Symptomatic Nocturnal Hypoglycemia | Documented <=70mg/dL | 70.8 percentage of participants |
| HOE901-U300 | Percentage of Participants With Documented Symptomatic Nocturnal Hypoglycemia | Documented <54 mg/dL | 50.9 percentage of participants |
| Lantus | Percentage of Participants With Documented Symptomatic Nocturnal Hypoglycemia | Documented <=70mg/dL | 68.3 percentage of participants |
| Lantus | Percentage of Participants With Documented Symptomatic Nocturnal Hypoglycemia | Documented <54 mg/dL | 54.1 percentage of participants |
Secondary
Percentage of Time Glucose Concentrations Within the Target Range of 70 to 140 mg/dL During Last 4 Hours of CGM Data Collection Prior to Next Day Basal Insulin Injection
Adjusted LS means and SE were obtained from mixed model including post baseline CGM assessment during the last 4 hours prior to the next day's basal insulin injection during Week 15 (and/or Week 16).
Time frame: During Week 15 and/or Week 16
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| HOE901-U300 | Percentage of Time Glucose Concentrations Within the Target Range of 70 to 140 mg/dL During Last 4 Hours of CGM Data Collection Prior to Next Day Basal Insulin Injection | 36.49 percentage of time | Standard Error 1.62 |
| Lantus | Percentage of Time Glucose Concentrations Within the Target Range of 70 to 140 mg/dL During Last 4 Hours of CGM Data Collection Prior to Next Day Basal Insulin Injection | 35.07 percentage of time | Standard Error 1.65 |
Other Pre-specified
Change From Baseline in Daily Insulin Dose at Week 16
Change from Baseline at Week 16 for daily basal insulin dose and daily bolus insulin dose was reported.
Time frame: Baseline, Week 16
Population: Safety population: all participants who took at least 1 dose of randomized treatment \& analyzed as-treated (as per treatment actually received) also to whom it was unclear whether they took study medication \& who received more than 1 study treatment during trial. Here, number analyzed: number of participants evaluable for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HOE901-U300 | Change From Baseline in Daily Insulin Dose at Week 16 | Daily basal Insulin Dose | 8.8 International Units | Standard Deviation 11.8 |
| HOE901-U300 | Change From Baseline in Daily Insulin Dose at Week 16 | Daily bolus Insulin Dose | -1.8 International Units | Standard Deviation 11.8 |
| Lantus | Change From Baseline in Daily Insulin Dose at Week 16 | Daily basal Insulin Dose | 7.0 International Units | Standard Deviation 10.1 |
| Lantus | Change From Baseline in Daily Insulin Dose at Week 16 | Daily bolus Insulin Dose | -3.0 International Units | Standard Deviation 11.3 |
Post Hoc
Change From Baseline in Time (Min) of Mean Glucose Concentration Within the Target Range of 70 to 180 mg/dL, by End of Study hbA1c Levels During Week 15 and/or Week 16
Adjusted LS means and SE were obtained from mixed model including post baseline CGM assessments. Data was reported for participants with an end of study HbA1c \<7.5 or HbA1c \>=7.5% over a 24 hour period.
Time frame: Baseline, during Week 15 and/or Week 16
Population: mITT population. Here, number analyzed signifies the number of participants evaluable for each specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| HOE901-U300 | Change From Baseline in Time (Min) of Mean Glucose Concentration Within the Target Range of 70 to 180 mg/dL, by End of Study hbA1c Levels During Week 15 and/or Week 16 | End of study HbA1c <7.5% | 105.84 minutes | Standard Error 25.64 |
| HOE901-U300 | Change From Baseline in Time (Min) of Mean Glucose Concentration Within the Target Range of 70 to 180 mg/dL, by End of Study hbA1c Levels During Week 15 and/or Week 16 | End of study HbA1c >=7.5% | 11.64 minutes | Standard Error 27.26 |
| Lantus | Change From Baseline in Time (Min) of Mean Glucose Concentration Within the Target Range of 70 to 180 mg/dL, by End of Study hbA1c Levels During Week 15 and/or Week 16 | End of study HbA1c <7.5% | 56.07 minutes | Standard Error 25.4 |
| Lantus | Change From Baseline in Time (Min) of Mean Glucose Concentration Within the Target Range of 70 to 180 mg/dL, by End of Study hbA1c Levels During Week 15 and/or Week 16 | End of study HbA1c >=7.5% | 31.95 minutes | Standard Error 27.57 |