Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2 diabetes mellitus, T2DM, Ranolazine, Ranexa, HbA1c
Brief summary
This study enrolled participants with inadequately controlled type 2 diabetes mellitus (T2DM) despite non-insulin antidiabetic therapy in addition to diet and exercise, and would have benefited from additional control of blood glucose levels. The study assessed the metabolic effects of ranolazine, including its effect in lowering glycosylated hemoglobin A1c (HbA1c), and lowering glucose while fasting, and following a meal (postprandial). Participants were randomized in a 1:1 ratio to receive ranolazine or placebo, and were stratified by HbA1c ≤ 7.5% or \> 7.5%. Enrollment was to include no more than two-thirds of participants with baseline HbA1c ≤ 7.5%. Other than glucose values, efficacy endpoint results remained blinded during the study; for safety purposes, the investigator was to be alerted of severe hyperglycemia or hypoglycemia. Participants were instructed to maintain logs of their physical activity/exercise (Subject Activity Assessment) and study drug dosing (Dosing Log).
Interventions
DRUGRanolazine
Ranolazine ER 1000 mg (two 500 mg tablets) administered orally twice daily
DRUGPlacebo
Placebo to match ranolazine administered orally twice daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participant with T2DM on stable non-insulin antidiabetic therapy in addition to diet and exercise * Body mass index (BMI) ≥ 25 kg/m\^2 and ≤ 40 kg/m\^2 * HbA1c 7 - 11% * Ability and willingness to maintain a complete and accurate Subject Activity Log during the course of the trial * Female of child-bearing potential must have agreed to use effective methods of contraception * Ability to understand and willing to sign written informed consent
Exclusion criteria
* Type 1 Diabetes Mellitus (T1DM) * T2DM with history of or current insulin therapy. Prior use during pregnancy or gestational diabetes was acceptable. * History of ketoacidosis or ketosis-prone diabetes * Clinically significant complications of diabetes that in the judgment of the investigator would have made participant unsuitable to participate in this trial * History of a severe episode of hypoglycemia * Change in non-insulin antidiabetic therapy in addition to diet and exercise \< 2 months prior to screening * Any clinically significant cardiovascular event \< 2 months prior to screening * Clinically significant, inadequately controlled or unstable hypertension * Hospitalization \< 2 months prior to screening * Major surgery \< 3 months prior to screening * Weight loss medication (prescription or non-prescription) \< 2 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | Baseline to Week 12 | HbA1c is a blood test to measure blood sugar control over the prior 3-month period. The last observation carried forward (LOCF) method was used: the last observed post-baseline measurements prior to Week 12 carried forward for participants with no available Week 12 values. Participants were summarized according to the actual treatment received regardless of the allocated treatment. |
| Change From Baseline in 2-hour Postprandial Serum Glucose at Week 12 Following a Standardized Meal | Baseline to Week 12 | 2-hour postprandial serum glucose was defined as the average of serum glucose measurement at 120 minutes and 125 minutes following a standardized meal. The LOCF method was used. Participants were summarized according to the actual treatment received regardless of the allocated treatment. |
| Change From Baseline in Fasting Serum Glucose at Week 12 | Baseline to Week 12 | Serum glucose was measured following an overnight fast. The LOCF method was used. Participants were summarized according to the actual treatment received regardless of the allocated treatment. |
Countries
United States
Participant flow
Recruitment details
Participants with type 2 diabetes mellitus (T2DM) were enrolled in a total of 9 study sites in the United States. The first participant was screened on 22 June 2010. The last participant observation was on 15 November 2010.
Pre-assignment details
The Safety Analysis Set (n = 80) includes participants who were randomized in the study and received at least one dose of study drug. The Full Analysis Set (n = 79) includes participants who were randomized in the study and received at least one dose of study drug, and had at least one post-baseline efficacy measurement.
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine Participants were randomized to receive ranolazine for 12 weeks. | 39 |
| Placebo Participants were randomized to receive placebo to match ranolazine for 12 weeks. | 41 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 6 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Ranolazine | Total | Placebo |
|---|---|---|---|
| 2-hour Postprandial Glucose | 253.1 mg/dL STANDARD_DEVIATION 57.37 | 262.5 mg/dL STANDARD_DEVIATION 74.57 | 271.5 mg/dL STANDARD_DEVIATION 87.67 |
| Age Continuous | 58 years STANDARD_DEVIATION 10.1 | 58 years STANDARD_DEVIATION 9.5 | 58 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 53 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 27 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting Serum Glucose | 153.7 mg/dL STANDARD_DEVIATION 43.05 | 163.4 mg/dL STANDARD_DEVIATION 48.6 | 172.7 mg/dL STANDARD_DEVIATION 52.2 |
| Glycosylated hemoglobin (HbA1c) | 8.41 percent HbA1c in blood STANDARD_DEVIATION 1.078 | 8.46 percent HbA1c in blood STANDARD_DEVIATION 1.117 | 8.51 percent HbA1c in blood STANDARD_DEVIATION 1.163 |
| Race/Ethnicity, Customized Black | 5 participants | 6 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White | 33 participants | 72 participants | 39 participants |
| Sex: Female, Male Female | 16 Participants | 32 Participants | 16 Participants |
| Sex: Female, Male Male | 23 Participants | 48 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 39 | 15 / 41 |
| serious Total, serious adverse events | 0 / 39 | 1 / 41 |
Outcome results
Primary
Change From Baseline in 2-hour Postprandial Serum Glucose at Week 12 Following a Standardized Meal
2-hour postprandial serum glucose was defined as the average of serum glucose measurement at 120 minutes and 125 minutes following a standardized meal. The LOCF method was used. Participants were summarized according to the actual treatment received regardless of the allocated treatment.
Time frame: Baseline to Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change From Baseline in 2-hour Postprandial Serum Glucose at Week 12 Following a Standardized Meal | -26.6 mg/dL | Standard Error 9.88 |
| Placebo | Change From Baseline in 2-hour Postprandial Serum Glucose at Week 12 Following a Standardized Meal | -11.2 mg/dL | Standard Error 9.63 |
p-value: 0.23495% CI: [-41, 10.2]ANCOVA
Primary
Change From Baseline in Fasting Serum Glucose at Week 12
Serum glucose was measured following an overnight fast. The LOCF method was used. Participants were summarized according to the actual treatment received regardless of the allocated treatment.
Time frame: Baseline to Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change From Baseline in Fasting Serum Glucose at Week 12 | 2.0 mg/dL | Standard Error 7.21 |
| Placebo | Change From Baseline in Fasting Serum Glucose at Week 12 | 4.5 mg/dL | Standard Error 6.83 |
p-value: 0.79495% CI: [-21.1, 16.2]ANCOVA
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12
HbA1c is a blood test to measure blood sugar control over the prior 3-month period. The last observation carried forward (LOCF) method was used: the last observed post-baseline measurements prior to Week 12 carried forward for participants with no available Week 12 values. Participants were summarized according to the actual treatment received regardless of the allocated treatment.
Time frame: Baseline to Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | -0.61 percent of HbA1c in blood | Standard Error 0.142 |
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | -0.08 percent of HbA1c in blood | Standard Error 0.142 |
Comparison: Assuming a common standard deviation of 1.1%, 60 evaluable participants would provide 93% power to detect a statistically significant -1.0% difference in change from baseline HbA1c at Week 12 between ranolazine and placebo (2-sided alpha = 0.05). 80 participants were randomized to ensure at least 60 evaluable participants.p-value: 0.0195% CI: [-0.93, -0.13]ANCOVA