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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-004303-12 | EudraCT Number |
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This study will examine the safety and efficacy of once-weekly omarigliptin in participants 18 to <45 years of age with Type 2 diabetes mellitus and inadequate glycemic control. The study hypothesis is that treatment with omarigliptin compared with placebo provides greater reduction in hemoglobin A1c (A1C) in participants after 24 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Omarigliptin 25 mg | Experimental | Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. |
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| Placebo | Placebo Comparator | Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Omarigliptin | Drug | Omarigliptin 25 mg capsule administered orally once weekly |
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| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in A1C at Week 24 | A1C (%) is used to report average blood glucose levels over prolonged periods of time. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | Baseline and Week 24 |
| Percentage of Participants Who Experienced at Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the all participants as treated (APaT) population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). | Up to Week 27 |
| Percentage of Participants Who Discontinued Study Drug Due to an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in 2-hr PMG at Week 24 | Blood glucose was measured 120 minutes from start of meal. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. |
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Inclusion Criteria:
Has type 2 diabetes mellitus
Currently not on an antihyperglycemic agent (AHA) for at least the past 12 weeks and has not been treated with omarigliptin at any time prior to study participation
Participant is one of the following:
Exclusion Criteria:
History of type 1 diabetes mellitus or a history of ketoacidosis
History of hypersensitivity to dipeptidyl-peptidase-4 (DPP-4) inhibitor
Currently participating in or has participated in a clinical trial in the past 12 weeks
Is on a weight loss program and not in the maintenance phase; has been on a weight loss medication in the past 6 months; or has undergone bariatric surgery within 12 months prior to study participation
Has undergone a surgical procedure within 4 weeks of study participation or has planned major surgery during the study
Is on or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids
Is currently being treated for hyperthyroidism or is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks
Is expecting to undergo hormonal therapy in preparation to donate eggs during the study, including 21 days following the last dose of study drug
History of active liver disease (other than non-alcoholic hepatic steatosis) including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease
Has human immunodeficiency virus (HIV)
Has had new or worsening coronary heart disease or congestive heart failure within the past 3 months, or has any of the following disorders within the past 3 months:
Has poorly controlled hypertension
History of malignancy ≤5 years prior to study participation, except for basal cell or squamous cell skin cancer or in situ cervical cancer
Has a hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
Has a positive urine pregnancy test
Pregnant or breastfeeding, or is expecting to conceive during the study, including 21 days following the last dose of study drug
User of recreational or illicit drugs or has had a recent history of drug abuse. Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking.
Has donated blood products or has had a phlebotomy (>300 mL) within 8 weeks of study participation, or intends to donate blood products during the study or has received, or is anticipated to receive, blood products within 12 weeks of study participation or during the study
Has a clinically significant electrocardiogram abnormality
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28923291 | Derived | Gantz I, Sokolova L, Jain L, Iredale C, O'Neill EA, Wei Z, Lam R, Suryawanshi S, Kaufman KD, Engel SS, Lai E. Use of Prohibited Medication, a Potentially Overlooked Confounder in Clinical Trials: Omarigliptin (Once-weekly DPP-4 Inhibitor) Monotherapy Trial in 18- to 45-year-olds. Clin Ther. 2017 Oct;39(10):2024-2037. doi: 10.1016/j.clinthera.2017.08.009. Epub 2017 Sep 18. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Omarigliptin 25 mg | Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. |
| FG001 | Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Placebo to omarigliptin | Drug | Matching placebo to omarigliptin 25 mg capsule administered orally once weekly |
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| Metformin | Drug | Open-label metformin (dosed daily according to the country-specific product label) was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. |
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| Up to Week 24 |
| Baseline and Week 24 |
| Change in Baseline in FPG at Week 24 | Blood glucose was measured on a fasting basis. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | Baseline and Week 24 |
| Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24 | Percentage of participants was estimated using standard multiple imputation techniques (constrained longitudinal data analysis [cLDA] model). Within-group confidence intervals (CIs) were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | Week 24 |
| Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24 | Percentage of participants was estimated using standard multiple imputation techniques (cLDA). Within-group CIs were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | Week 24 |
| Percentage of Participants Who Required Glycemic Rescue by Week 24 | Participants exceeding pre-specified glycemic thresholds after starting the double-blind treatment period may have received rescue therapy (per protocol) with open-label metformin initiated by the investigator. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). | Up to Week 24 |
Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Omarigliptin 25 mg | Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. |
| BG001 | Placebo | Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Hemoglobin A1c (A1C) | Mean | Standard Deviation | Percent |
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| 2-hour post-meal glucose (2-hr PMG) | Participants with available data at baseline: Omarigliptin, n=98; Placebo, n=101; Total, n=199 | Mean | Standard Deviation | mg/dL |
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| Fasting plasma glucose (FPG) | Mean | Standard Deviation | mg/dL |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Change From Baseline in A1C at Week 24 | A1C (%) is used to report average blood glucose levels over prolonged periods of time. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | Full analysis set (FAS) population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. | Posted | Least Squares Mean | 95% Confidence Interval | Percent | Baseline and Week 24 |
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| Primary | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the all participants as treated (APaT) population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). | APaT population included all randomized participants who received at least one dose of study medication. | Posted | Number | Percentage of participants | Up to Week 27 |
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| Primary | Percentage of Participants Who Discontinued Study Drug Due to an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). | APaT population included all randomized participants who received at least one dose of study medication. | Posted | Number | Percentage of participants | Up to Week 24 |
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| Secondary | Change From Baseline in 2-hr PMG at Week 24 | Blood glucose was measured 120 minutes from start of meal. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. | Posted | Least Squares Mean | 95% Confidence Interval | mg/dL | Baseline and Week 24 |
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| Secondary | Change in Baseline in FPG at Week 24 | Blood glucose was measured on a fasting basis. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. | Posted | Least Squares Mean | 95% Confidence Interval | mg/dL | Baseline and Week 24 |
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| Secondary | Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24 | Percentage of participants was estimated using standard multiple imputation techniques (constrained longitudinal data analysis [cLDA] model). Within-group confidence intervals (CIs) were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. | Posted | Number | 95% Confidence Interval | Percentage of participants | Week 24 |
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| Secondary | Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24 | Percentage of participants was estimated using standard multiple imputation techniques (cLDA). Within-group CIs were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. | FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint. | Posted | Number | 95% Confidence Interval | Percentage of participants | Week 24 |
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| Secondary | Percentage of Participants Who Required Glycemic Rescue by Week 24 | Participants exceeding pre-specified glycemic thresholds after starting the double-blind treatment period may have received rescue therapy (per protocol) with open-label metformin initiated by the investigator. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). | All randomized participants. | Posted | Number | Percentage of participants | Up to Week 24 |
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Up to 27 weeks; Serious adverse events (SAEs) were collected up to 24 weeks during treatment + 3 week follow-up, non-serious adverse events (NSAEs) were collected up to 24 weeks during treatment
SAEs include data after glycemic rescue; NSAEs exclude data after glycemic rescue. Investigations performed by the Sponsor revealed that many participants had used a prohibited antihyperglycemic agent-metformin (i.e., not as rescue medication; see efficacy results description above).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Omarigliptin 25 mg | Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. | 1 | 102 | 10 | 102 | ||
| EG001 | Placebo | Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. | 3 | 101 | 7 | 101 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | MedDRA 18.0 | Systematic Assessment |
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| Pyelonephritis acute | Infections and infestations | MedDRA 18.0 | Systematic Assessment |
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| Vulvovaginal candidiasis | Infections and infestations | MedDRA 18.0 | Systematic Assessment |
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| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA 18.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 18.0 | Systematic Assessment |
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Investigations indicate that the presence of metformin in future biomedical research (FBR) samples from non-rescued participants was due to participant self-administration of metformin outside of the protocol and without investigator knowledge.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D003924 | Diabetes Mellitus, Type 2 |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| ID | Term |
|---|---|
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C587539 | 2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine |
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.
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