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| ID | Type | Description | Link |
|---|---|---|---|
| HSC20140322H | Other Identifier | University of Texas Health Science Center- San Antonio |
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| Name | Class |
|---|---|
| Janssen Scientific Affairs, LLC | INDUSTRY |
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Specific Aim 1.To examine whether the combination of liraglutide plus canagliflozin can prevent the increase in Hepatic Glucose Production (HGP) following institution of canagliflozin therapy and produce an additive or even synergistic effect to lower the plasma glucose concentration and A1c.
Specific Aim 2: To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive, or even synergistic, effect to promote weight loss and reduction in hepatic and visceral fat content.
Specific Aim 3. To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive or even synergistic effect to reduce systolic/diastolic blood pressure and 24-hour integrated blood pressure.
Specific Aim 1.To examine whether the combination of liraglutide plus canagliflozin can prevent the increase in HGP following institution of canagliflozin therapy and produce an additive or even synergistic effect to lower the plasma glucose concentration and A1c. We will examine this hypothesis by comparing the effect of administration of liraglutide alone, canagliflozin alone, and the combination of liraglutide plus canagliflozin on:(i) the rate of HGP; (ii) decrease in fasting plasma glucose concentration; (iii) counter-regulatory hormone response and (iv) A1c. We anticipate that the addition of liraglutide to canagliflozin will prevent the increase in plasma glucagon concentration, augment insulin secretion, and blunt/block the increase in HGP in response to canagliflozin, resulting in a greater decrease in fasting plasma glucose concentration and A1c than observed with each therapy alone.
Specific Aim 2: To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive, or even synergistic, effect to promote weight loss and reduction in hepatic and visceral fat content.
Specific Aim 3. To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive or even synergistic effect to reduce systolic/diastolic blood pressure and 24-hour integrated blood pressure.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Canagliflozin | Active Comparator | canagliflozin (film-coated tablet), 100 mg/day, increased to 300 mg/day after week two if tolerated without side effects |
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| liraglutide | Active Comparator | liraglutide, 1.2 mg/day, increased to 1.8 mg/day after week two if tolerated without side effects |
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| canagliflozin plus liraglutide | Active Comparator | canagliflozin, 100 mg/day, plus liraglutide, 1.2 mg/day, increased to 300 mg/day and 1.8 mg/day, respectively at week two, if tolerated without side effects |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Canagliflozin | Drug | Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) |
| Measure | Description | Time Frame |
|---|---|---|
| HbA1c at 4 Months | Primary end point of the study is the HbA1c level in response to canagliflozin alone, liraglutide or canagliflozin with liraglutide. | Approximately 4 months |
| Fasting Plasma Glucose (FPG) at 4 Months | Values will be presented as the mean + (Standard Deviation) SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Baseline to Approximately 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| Body Mass Index (BMI) at 4 Months | A measure of BMI at 4 months to examine effects of combination therapy with liraglutide plus canagliflozin. | Approximately 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT) | Values will be presented as the mean + SD. The Matsuda Index is a novel assessment of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT. The index is calculated from plasma glucose (mg/dl) and insulin (mIU/l) concentrations in both fasting state and post-OGTT. The index value obtained is compared to normal physiologic values to assess insulin sensitivity or resistance. The higher the number, the more insulin sensitive and the lower the number the more insulin resistant the subjects are. Insulin secretion will be measured from plasma C-peptide concentration during the OGTT and the Mari Model will be used to measure beta cell glucose sensitivity |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eugenio Cersosimo, MD | The University of Texas Health Science Center at San Antonio | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Texas Health Science Center at San Antonio | San Antonio | Texas | 78229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32745202 | Derived | Ali AM, Mari A, Martinez R, Al-Jobori H, Adams J, Triplitt C, DeFronzo R, Cersosimo E, Abdul-Ghani M. Improved Beta Cell Glucose Sensitivity Plays Predominant Role in the Decrease in HbA1c with Cana and Lira in T2DM. J Clin Endocrinol Metab. 2020 Oct 1;105(10):dgaa494. doi: 10.1210/clinem/dgaa494. | |
| 32220916 | Derived |
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| ID | Title | Description |
|---|---|---|
| FG000 | Canagliflozin | canagliflozin (film-coated tablet), 100 mg/day, increased to 300 mg/day after week two if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 19, 2018 |
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| Liraglutide | Drug | Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
|
|
| Change from Baseline to Approximately 4 months |
| Change in Free Plasma Insulin at the End of the Study From Baseline Value | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | At Approximately 4 months |
| Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Approximately 4 months |
| Change in Total Body Weight at Study End Compared to Baseline | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. The difference between baseline and study end will represent the change in body weight due to change in hepatic, visceral and abdominal subcutaneous fat. | Approximately 4 months |
| Change in 24-hour Blood Pressure at Study End Compared to Baseline. | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Approximately 4 months |
| Ali AM, Martinez R, Al-Jobori H, Adams J, Triplitt C, DeFronzo R, Cersosimo E, Abdul-Ghani M. Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes. Diabetes Care. 2020 Jun;43(6):1234-1241. doi: 10.2337/dc18-2460. Epub 2020 Mar 27. |
| FG001 |
| Liraglutide |
liraglutide, 1.2 mg/day, increased to 1.8 mg/day after week two if tolerated without side effects Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
| FG002 | Canagliflozin Plus Liraglutide | canagliflozin, 100 mg/day, plus liraglutide, 1.2 mg/day, increased to 300 mg/day and 1.8 mg/day, respectively at week two, if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Canagliflozin | canagliflozin (film-coated tablet), 100 mg/day, increased to 300 mg/day after week two if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) |
| BG001 | Liraglutide | liraglutide, 1.2 mg/day, increased to 1.8 mg/day after week two if tolerated without side effects Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
| BG002 | Canagliflozin Plus Liraglutide | canagliflozin, 100 mg/day, plus liraglutide, 1.2 mg/day, increased to 300 mg/day and 1.8 mg/day, respectively at week two, if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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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 | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | HbA1c at 4 Months | Primary end point of the study is the HbA1c level in response to canagliflozin alone, liraglutide or canagliflozin with liraglutide. | Posted | Mean | Standard Deviation | percentage glycated hemoglobin | Approximately 4 months |
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| Primary | Fasting Plasma Glucose (FPG) at 4 Months | Values will be presented as the mean + (Standard Deviation) SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Posted | Mean | Standard Deviation | mg/dl | Baseline to Approximately 4 months |
| ||||||||||||||||||||||||||||||||||
| Secondary | Body Mass Index (BMI) at 4 Months | A measure of BMI at 4 months to examine effects of combination therapy with liraglutide plus canagliflozin. | Posted | Mean | Standard Deviation | kg/m2 | Approximately 4 months |
| ||||||||||||||||||||||||||||||||||
| Other Pre-specified | Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT) | Values will be presented as the mean + SD. The Matsuda Index is a novel assessment of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT. The index is calculated from plasma glucose (mg/dl) and insulin (mIU/l) concentrations in both fasting state and post-OGTT. The index value obtained is compared to normal physiologic values to assess insulin sensitivity or resistance. The higher the number, the more insulin sensitive and the lower the number the more insulin resistant the subjects are. Insulin secretion will be measured from plasma C-peptide concentration during the OGTT and the Mari Model will be used to measure beta cell glucose sensitivity | Posted | Mean | Standard Deviation | index value | Change from Baseline to Approximately 4 months |
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| Other Pre-specified | Change in Free Plasma Insulin at the End of the Study From Baseline Value | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Posted | Mean | Standard Deviation | mg/ml | At Approximately 4 months |
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| Other Pre-specified | Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Posted | Mean | Standard Deviation | mg/ml | Approximately 4 months |
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| Other Pre-specified | Change in Total Body Weight at Study End Compared to Baseline | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. The difference between baseline and study end will represent the change in body weight due to change in hepatic, visceral and abdominal subcutaneous fat. | Posted | Mean | Standard Deviation | kg | Approximately 4 months |
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| Other Pre-specified | Change in 24-hour Blood Pressure at Study End Compared to Baseline. | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. | Posted | Mean | Standard Deviation | mmHg | Approximately 4 months |
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Adverse Events were reported from Baseline to 4 months
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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 | Canagliflozin | canagliflozin (film-coated tablet), 100 mg/day, increased to 300 mg/day after week two if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) | 0 | 15 | 1 | 15 | 13 | 15 |
| EG001 | Liraglutide | liraglutide, 1.2 mg/day, increased to 1.8 mg/day after week two if tolerated without side effects Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. | 0 | 15 | 0 | 15 | 13 | 15 |
| EG002 | Canagliflozin Plus Liraglutide | canagliflozin, 100 mg/day, plus liraglutide, 1.2 mg/day, increased to 300 mg/day and 1.8 mg/day, respectively at week two, if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. | 0 | 15 | 0 | 15 | 12 | 15 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dehydration/Hyperkalemia | General disorders | Non-systematic Assessment | Subject was hospitalized and dehydration and hyperkalemia resolved |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
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| Dry Mouth | Gastrointestinal disorders | Non-systematic Assessment |
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| Abdominal Discomfort | Gastrointestinal disorders | Non-systematic Assessment |
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| Decreased Appetite | Gastrointestinal disorders | Non-systematic Assessment |
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| Gastrointestinal Reflux/Indigestion | Gastrointestinal disorders | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
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| Urinary Frequency increased | Renal and urinary disorders | Non-systematic Assessment |
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| Urinary Tract Infection | Renal and urinary disorders | Non-systematic Assessment |
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| Light-headedness/Dizziness | Nervous system disorders | Non-systematic Assessment |
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| Headache | Nervous system disorders | Non-systematic Assessment |
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| Anxiety | Nervous system disorders | Non-systematic Assessment |
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| Fatigue | General disorders | Non-systematic Assessment |
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| Redness at Injection Site | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Bilateral Leg Cramps | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Cough and nasal congestion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Symptomatic Hypoglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Vaginal Candidiasis | Reproductive system and breast disorders | Non-systematic Assessment |
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| Vaginal itching or foreskin pain | Reproductive system and breast disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eugenio Cersosimo, MD | University of Texas Health San Antonio | 210-358-7220 | cersosimo@uthscsa.edu |
| Mar 19, 2019 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000068896 | Canagliflozin |
| D000069450 | Liraglutide |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005960 | Glucosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D052216 | Glucagon-Like Peptide 1 |
| D004763 | Glucagon-Like Peptides |
| D052336 | Proglucagon |
| D005768 | Gastrointestinal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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| OG002 | Canagliflozin Plus Liraglutide | canagliflozin, 100 mg/day, plus liraglutide, 1.2 mg/day, increased to 300 mg/day and 1.8 mg/day, respectively at week two, if tolerated without side effects Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
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