Type 2 Diabetes Mellitus
Conditions
Brief summary
The primary objective is to demonstrate the superiority of Sotagliflozin 400 milligrams (mg) versus placebo with respect to hemoglobin A1c (Hb1Ac) reduction in participants with type 2 diabetes (T2D) who have inadequate glycemic control on diet and exercise only or with a stable antidiabetes regimen.
Detailed description
Study duration per participant is approximately 110 weeks (Screening period of up to 2 weeks, 2 week single-blind run-in period), a 26-week double-blind core treatment period, a 78-week double-blind extension period, and a 2- week post treatment follow up period. Dual-energy X-ray absorptiometry (DXA) scans will be performed to assess Bone Mineral Density and Fat vs. Lean body mass at baseline and Weeks 26, 52, and 104.
Interventions
DRUGPlacebo
Pharmaceutical form: Tablet; Route of administration: Oral
DRUGSotagliflozin
Pharmaceutical form: Tablet; Route of administration: Oral
Sponsors
Sanofi
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Participants with T2D managed with diet and exercise only or with a stable antidiabetes regimen (in monotherapy or combination therapy that can include oral antidiabetes medications, insulin, or glucagon-like peptide-1 agonists) for more than 12 weeks. * Participants has given written informed consent to participate in the study in accordance with local regulations.
Exclusion criteria
* Age \<55 years. * Women who have been postmenopausal (or undergone bilateral oophorectomy) for less than 5 years. * Type 1 diabetes mellitus. * Body mass index (BMI) ≤20 or \>45 kilogram per meter square kg/m\^2 or bodyweight that exceeds the weight limits of the DXA scanner. * Hemoglobin A1C (HbA1c) \<7.0% or HbA1c \>11.0%. * Use of a selective sodium-glucose cotransporter type 2 (SGLT2) inhibitor or thiazolidinedione within 24 months. * Bone mineral density (BMD) T- score \<-2.0 at any site (ie, lumbar spine, total hip, or femoral neck). * History of fracture within 12 months (except for fractures of the hand/fingers, foot/toes, facial bones, and skull). * Treatment with medications known to affect bone mass or modify the risk of fractures within 36 months (eg, bisphosphonates, selective estrogen receptor modulators, calcitonin, teriparatide, denosumab, strontium ranelate, growth hormone, aromatase inhibitors, androgen deprivation therapy, carbamazepine, phenytoin, and phenobarbital). Use of hormonal replacement that includes systemic or transdermal estrogen or testosterone is excluded unless is stable for at least 24 months prior to Screening. * Lower extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) identified during the Screening period, and still requiring treatment at randomization. * Uncontrolled high blood pressure, severe anemia, severe cardiovascular problems, such as heart failure, active cancer, or other conditions that the Investigator believes with result in a short life expectancy. * Renal disease as defined by an estimated glomerular filtration rate (eGFR) \<30 milliliter per minute (mL/min)/1.73 meter square (m\^2) at the Screening Visit by the 4 variable Modification of Diet in Renal Disease equation. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | Baseline to Week 26 | An analysis of covariance (ANCOVA) model is used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Bone Mineral Density (BMD) of Total Hip at Week 26 | Baseline to Week 26 | An ANCOVA model is used for analysis. |
| Percent Change From Baseline in Bone Mineral Density (BMD) of Femoral Neck at Week 26 | Baseline to Week 26 | An ANCOVA model is used for analysis. |
| Change From Baseline in Body Weight at Week 26 | Baseline to Week 26 | An ANCOVA model is used for analysis. |
| Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Week 26 | Baseline to Week 26 | An ANCOVA model is used for analysis. |
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 | Baseline to Week 12 | An ANCOVA model is used for analysis. |
| Percentage of Participants With Hemoglobin A1c (HbA1c) <7.0% at Week 26 | Week 26 | — |
| Percentage of Participants With Adverse Events (AEs) | up to 106 weeks | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Baseline to Week 26 | An ANCOVA model is used for analysis. |
Countries
Australia, Canada, Mexico, New Zealand, Russia, South Korea, Taiwan, United States
Participant flow
Recruitment details
Participants took part in the study at 53 investigative sites in the United States, Australia, Canada, Korea, Republic of Mexico, New Zealand, Russian Federation, and Taiwan from 19 February 2018 to 30 May 2020.
Pre-assignment details
Participants with a diagnosis of Type 2 Diabetes Mellitus (DM), were enrolled in 1 of 3 treatment groups: Placebo, Sotagliflozin 200 milligrams (mg) or Sotagliflozin 400 mg.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Following a 2 week run-in period, participants were randomized to matching placebo to sotagliflozin administered as 2 tablets, once daily, before the first meal of the day, for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 106 weeks. | 126 |
| Sotagliflozin 200 mg Following a 2 week run-in period, participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day, for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 104 weeks. | 125 |
| Sotagliflozin 400 mg Following a 2 week run-in period, participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day, for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 104 weeks. | 125 |
| Total | 376 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 | 1 |
| Overall Study | At the Participant's own Request | 7 | 7 | 8 |
| Overall Study | Lost to Follow-up | 3 | 2 | 1 |
| Overall Study | Poor Compliance to Protocol | 0 | 1 | 0 |
| Overall Study | Reason not Specified | 0 | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 101 | 102 | 106 |
Baseline characteristics
| Characteristic | Total | Sotagliflozin 400 mg | Sotagliflozin 200 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 6.5 | 66.5 years STANDARD_DEVIATION 6.9 | 66.1 years STANDARD_DEVIATION 6.7 | 66.3 years STANDARD_DEVIATION 5.7 |
| BMD T-score: Femoral Neck | -0.60 t-score STANDARD_DEVIATION 0.93 | -0.46 t-score STANDARD_DEVIATION 1.03 | -0.66 t-score STANDARD_DEVIATION 0.88 | -0.69 t-score STANDARD_DEVIATION 0.86 |
| BMD T-score: Total Hip | 0.12 t-score STANDARD_DEVIATION 1.04 | 0.24 t-score STANDARD_DEVIATION 1.17 | 0.00 t-score STANDARD_DEVIATION 0.9 | 0.13 t-score STANDARD_DEVIATION 1.01 |
| Bone Mineral Density (BMD) T-score: Lumbar Spine | 0.76 t-score STANDARD_DEVIATION 1.82 | 0.88 t-score STANDARD_DEVIATION 1.71 | 0.70 t-score STANDARD_DEVIATION 1.74 | 0.69 t-score STANDARD_DEVIATION 2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 67 Participants | 23 Participants | 21 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 308 Participants | 102 Participants | 104 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Hemoglobin A1c (HbA1c) | 8.34 percentage of HbA1c STANDARD_DEVIATION 0.94 | 8.32 percentage of HbA1c STANDARD_DEVIATION 0.95 | 8.32 percentage of HbA1c STANDARD_DEVIATION 0.96 | 8.38 percentage of HbA1c STANDARD_DEVIATION 0.91 |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 75 Participants | 24 Participants | 25 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 6 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 6 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 263 Participants | 88 Participants | 87 Participants | 88 Participants |
| Region of Enrollment Austria | 13 participants | 3 participants | 8 participants | 2 participants |
| Region of Enrollment Canada | 57 participants | 20 participants | 17 participants | 20 participants |
| Region of Enrollment Mexico | 47 participants | 17 participants | 14 participants | 16 participants |
| Region of Enrollment New Zealand | 29 participants | 11 participants | 9 participants | 9 participants |
| Region of Enrollment Russia | 50 participants | 19 participants | 14 participants | 17 participants |
| Region of Enrollment South Korea | 24 participants | 7 participants | 9 participants | 8 participants |
| Region of Enrollment Taiwan | 28 participants | 7 participants | 9 participants | 12 participants |
| Region of Enrollment United States | 128 participants | 41 participants | 45 participants | 42 participants |
| Sex: Female, Male Female | 167 Participants | 55 Participants | 56 Participants | 56 Participants |
| Sex: Female, Male Male | 209 Participants | 70 Participants | 69 Participants | 70 Participants |
| Systolic Blood Pressure (SBP) | 133.06 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.88 | 134.65 millimeter of mercury (mmHg) STANDARD_DEVIATION 14.74 | 131.48 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.69 | 133.04 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 125 | 0 / 125 | 0 / 125 |
| other Total, other adverse events | 66 / 125 | 67 / 125 | 68 / 125 |
| serious Total, serious adverse events | 20 / 125 | 10 / 125 | 9 / 125 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26
An analysis of covariance (ANCOVA) model is used for analysis.
Time frame: Baseline to Week 26
Population: Intent-to-treat (ITT) population included all randomized participants, irrespective of compliance with the study protocol and procedures. Missing data are imputed using washout imputation method under the missing not at random framework.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | -0.22 percentage of HbA1c | Standard Error 0.08 |
| Sotagliflozin 200 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | -0.66 percentage of HbA1c | Standard Error 0.077 |
| Sotagliflozin 400 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | -0.67 percentage of HbA1c | Standard Error 0.079 |
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline HbA1c as a covariate.p-value: <0.000195% CI: [-0.649, -0.25]ANCOVA
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline HbA1c as a covariate.p-value: <0.000195% CI: [-0.634, -0.235]ANCOVA
Secondary
Change From Baseline in Body Weight at Week 26
An ANCOVA model is used for analysis.
Time frame: Baseline to Week 26
Population: ITT population included all randomized participants, irrespective of compliance with the study protocol and procedures. Missing data are imputed using washout imputation method under the missing not at random framework.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight at Week 26 | -0.46 kilogram (kg) | Standard Error 0.261 |
| Sotagliflozin 200 mg | Change From Baseline in Body Weight at Week 26 | -2.37 kilogram (kg) | Standard Error 0.258 |
| Sotagliflozin 400 mg | Change From Baseline in Body Weight at Week 26 | -2.16 kilogram (kg) | Standard Error 0.264 |
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline body weight as a covariate.p-value: <0.000195% CI: [-2.568, -1.252]ANCOVA
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline body weight as a covariate.p-value: <0.000195% CI: [-2.36, -1.046]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
An ANCOVA model is used for analysis.
Time frame: Baseline to Week 26
Population: ITT population included all randomized participants, irrespective of compliance with the study protocol and procedures. Missing data are imputed using washout imputation method under the missing not at random framework.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -7.274 milligram per deciliter (mg/dL) | Standard Error 3.6064 |
| Sotagliflozin 200 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -26.165 milligram per deciliter (mg/dL) | Standard Error 3.4656 |
| Sotagliflozin 400 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -28.607 milligram per deciliter (mg/dL) | Standard Error 3.5912 |
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, baseline fasting plasma glucose as a covariate.p-value: <0.000195% CI: [-27.8605, -9.9205]ANCOVA
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, baseline fasting plasma glucose as a covariate.p-value: <0.000195% CI: [-30.3294, -12.336]ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) at Week 12
An ANCOVA model is used for analysis.
Time frame: Baseline to Week 12
Population: ITT population included all randomized participants, irrespective of compliance with the study protocol and procedures. Missing data are imputed using washout imputation method under the missing not at random framework.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 | -0.80 millimeter of mercury (mmHg) | Standard Error 1.149 |
| Sotagliflozin 200 mg | Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 | -1.61 millimeter of mercury (mmHg) | Standard Error 1.13 |
| Sotagliflozin 400 mg | Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 | -1.97 millimeter of mercury (mmHg) | Standard Error 1.165 |
Comparison: The change from baseline to Week 12 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline SBP as a covariate.p-value: 0.586495% CI: [-3.705, 2.095]ANCOVA
Comparison: The change from baseline to Week 12 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline SBP as a covariate.p-value: 0.431595% CI: [-4.058, 1.734]ANCOVA
Secondary
Percentage of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
Time frame: up to 106 weeks
Population: Safety population included all randomized participants who had received at least one dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events (AEs) | 80.0 percentage of participants |
| Sotagliflozin 200 mg | Percentage of Participants With Adverse Events (AEs) | 82.4 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With Adverse Events (AEs) | 82.4 percentage of participants |
Secondary
Percentage of Participants With Hemoglobin A1c (HbA1c) <7.0% at Week 26
Time frame: Week 26
Population: ITT population included all randomized participants, irrespective of compliance with the study protocol and procedures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Hemoglobin A1c (HbA1c) <7.0% at Week 26 | 9.5 percentage of participants |
| Sotagliflozin 200 mg | Percentage of Participants With Hemoglobin A1c (HbA1c) <7.0% at Week 26 | 20.0 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With Hemoglobin A1c (HbA1c) <7.0% at Week 26 | 21.6 percentage of participants |
Comparison: Percentage difference between treatment groups from randomization strata of HbA1c (≤8.5, \>8.5%) at screening and randomization strata of sex (male, female) using Cochran-Mantel-Haenszel weights.p-value: 0.017295% CI: [1.78, 19.23]Cochran-Mantel-Haenszel
Comparison: Percentage difference between treatment groups from randomization strata of HbA1c (≤8.5, \>8.5%) at screening and randomization strata of sex (male, female) using Cochran-Mantel-Haenszel weights.p-value: 0.007695% CI: [3.23, 20.86]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Bone Mineral Density (BMD) of Femoral Neck at Week 26
An ANCOVA model is used for analysis.
Time frame: Baseline to Week 26
Population: Safety population included all randomized participants who had received at least one dose of IMP. Missing data are imputed using a pattern-based imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Bone Mineral Density (BMD) of Femoral Neck at Week 26 | -0.94 percent change | Standard Error 0.379 |
| Sotagliflozin 200 mg | Percent Change From Baseline in Bone Mineral Density (BMD) of Femoral Neck at Week 26 | -0.20 percent change | Standard Error 0.332 |
| Sotagliflozin 400 mg | Percent Change From Baseline in Bone Mineral Density (BMD) of Femoral Neck at Week 26 | -0.62 percent change | Standard Error 0.338 |
Comparison: Percent change from baseline to Week 26 was analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline BMD as a covariate.p-value: 0.10595% CI: [-0.157, 1.654]ANCOVA
Comparison: Percent change from baseline to Week 26 was analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline BMD as a covariate.p-value: 0.480495% CI: [-0.577, 1.226]ANCOVA
Secondary
Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Week 26
An ANCOVA model is used for analysis.
Time frame: Baseline to Week 26
Population: Safety population included all randomized participants who had received at least one dose of investigational medicinal product (IMP). Missing data are imputed using a pattern-based imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Week 26 | 0.37 percent change | Standard Error 0.327 |
| Sotagliflozin 200 mg | Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Week 26 | 0.13 percent change | Standard Error 0.323 |
| Sotagliflozin 400 mg | Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Week 26 | 0.22 percent change | Standard Error 0.327 |
Comparison: Percent change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline BMD as a covariate.p-value: 0.570795% CI: [-1.07, 0.59]ANCOVA
Comparison: Percent change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline BMD as a covariate.p-value: 0.724795% CI: [-0.969, 0.674]ANCOVA
Secondary
Percent Change From Baseline in Bone Mineral Density (BMD) of Total Hip at Week 26
An ANCOVA model is used for analysis.
Time frame: Baseline to Week 26
Population: Safety population included all randomized participants who had received at least one dose of IMP. Missing data are imputed using a pattern-based imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Bone Mineral Density (BMD) of Total Hip at Week 26 | -0.36 percent change | Standard Error 0.259 |
| Sotagliflozin 200 mg | Percent Change From Baseline in Bone Mineral Density (BMD) of Total Hip at Week 26 | -0.22 percent change | Standard Error 0.22 |
| Sotagliflozin 400 mg | Percent Change From Baseline in Bone Mineral Density (BMD) of Total Hip at Week 26 | -0.16 percent change | Standard Error 0.223 |
Comparison: Percent change from baseline to Week 26 was analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline lumbar spine as a covariate.p-value: 0.645495% CI: [-0.462, 0.745]ANCOVA
Comparison: Percent change from baseline to Week 26 was analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of sex (male, female), and country as fixed effects, and baseline lumbar spine as a covariate.p-value: 0.528995% CI: [-0.41, 0.798]ANCOVA