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Ranolazine Monotherapy in Subjects With Type 2 Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT01472185
Recruitment Status : Completed
First Posted : November 16, 2011
Results First Posted : October 15, 2014
Last Update Posted : October 24, 2014
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: Ranolazine
Drug: Placebo
Behavioral: Diet
Behavioral: Exercise
Enrollment 465
Recruitment Details Participants were enrolled at a total of 113 study sites in the United States, South Africa, Europe, and Russia. The first participant was screened on 15 November 2011. The last participant observation occurred on 21 October 2013.
Pre-assignment Details 605 participants entered the qualifying period; 465 were randomized, and 464 were randomized and treated (Safety Analysis Set). Of these, 8 were excluded due to major eligibility criteria protocol violation or had baseline but no on-treatment data; thus, 456 were included in the Full Analysis Set.
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Period Title: Overall Study
Started 232 233
Completed 198 199
Not Completed 34 34
Reason Not Completed
Randomized but Not Treated             0             1
Adverse Event Other than Hyperglycemia             3             10
Hyperglycemia             5             2
Investigator’s Discretion             3             1
Lost to Follow-up             4             1
Protocol Violation             5             1
Subject Noncompliance             8             15
Subject Withdrew Consent             6             3
Arm/Group Title Placebo Ranolazine Total
Hide Arm/Group Description

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Total of all reporting groups
Overall Number of Baseline Participants 232 232 464
Hide Baseline Analysis Population Description
Baseline characteristics are reported for the Safety Analysis Set following randomization. The Safety Analysis Set includes randomized participants who received at least one dose of study treatment, analyzed based on actual treatment received.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 232 participants 232 participants 464 participants
56  (9.3) 55  (9.5) 56  (9.4)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 232 participants 232 participants 464 participants
< 65 years 197 199 396
≥ 65 years 35 33 68
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 232 participants 232 participants 464 participants
Female
113
  48.7%
123
  53.0%
236
  50.9%
Male
119
  51.3%
109
  47.0%
228
  49.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 232 participants 232 participants 464 participants
Hispanic or Latino
31
  13.4%
29
  12.5%
60
  12.9%
Not Hispanic or Latino
201
  86.6%
202
  87.1%
403
  86.9%
Unknown or Not Reported
0
   0.0%
1
   0.4%
1
   0.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 232 participants 232 participants 464 participants
Asian 10 9 19
Black or African-American 10 9 19
White 209 213 422
Other 2 1 3
Not Permitted 1 0 1
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 232 participants 232 participants 464 participants
Serbia 0 2 2
United States 62 56 118
Hungary 12 9 21
Slovakia 8 13 21
Poland 7 11 18
Ukraine 39 36 75
Romania 10 11 21
South Africa 11 13 24
Russian Federation 83 82 165
[1]
Measure Description: All randomized participants were analyzed for region of enrollment (placebo, n = 232; ranolazine, n = 233).
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 232 participants 232 participants 464 participants
32.8  (4.85) 32.8  (4.75) 32.8  (4.80)
Glycosylated hemoglobin (HbA1c)  
Mean (Standard Deviation)
Unit of measure:  Percent HbA1c in blood
Number Analyzed 232 participants 232 participants 464 participants
8.01  (0.727) 8.06  (0.732) 8.04  (0.729)
Fasting Serum Glucose  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 232 participants 232 participants 464 participants
171.5  (34.45) 172.1  (34.32) 171.8  (34.35)
Duration of Diabetes  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 232 participants 232 participants 464 participants
3.0  (4.00) 3.0  (4.29) 3.0  (4.14)
Estimated glomerular filtration rate (eGFR)  
Mean (Standard Deviation)
Unit of measure:  mL/min/1.73m^2
Number Analyzed 232 participants 232 participants 464 participants
83.3  (18.40) 84.5  (18.80) 83.9  (18.59)
1.Primary Outcome
Title Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
Hide Description The average (mean) change from baseline in HbA1c at Week 24 was analyzed.
Time Frame Baseline; Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set (randomized participants who received ≥ 1 dose of study treatment with a baseline and at least one postbaseline measurement of HbA1c, excluding subjects with major eligibility violations and analyzed based on the randomized treatment regardless of actual treatment received) with available data were analyzed.
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description:

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Overall Number of Participants Analyzed 195 199
Mean (Standard Deviation)
Unit of Measure: percent of HbA1c in blood
HbA1c at Week 24 7.70  (1.183) 7.26  (1.101)
Change from baseline in HbA1c at Week 24 -0.27  (1.027) -0.80  (1.020)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ranolazine
Comments Assuming a common standard deviation of 1.2%, an effective sample size of 400 would provide at least 90% power to detect a statistically significant treatment difference of -0.5% (ranolazine vs. placebo) for the reduction of HbA1c from baseline at Week 24 based on a 2-sided alpha of 0.05 and 1:1 randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments P-value is from a mixed effects model including terms for baseline HbA1c value, treatment group, visit week, and treatment by visit week interaction. Unstructured covariance matrix was used.
Method Mixed Effects Model Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter difference in least squares mean (LSM)
Estimated Value -0.56
Confidence Interval (2-Sided) 95%
-0.76 to -0.36
Estimation Comments The estimation (LSM) is of the placebo-corrected change from baseline.
2.Secondary Outcome
Title Change From Baseline in Fasting Serum Glucose at Week 24
Hide Description The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed.
Time Frame Baseline; Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set with available data were analyzed.
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description:

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Overall Number of Participants Analyzed 191 197
Mean (Standard Deviation)
Unit of Measure: mg/dL
1  (42.2) -7  (37.5)
3.Secondary Outcome
Title Percentage of Participants With HbA1c < 7% at Week 24
Hide Description [Not Specified]
Time Frame Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants in the Full Analysis Set with Baseline HbA1c ≥ 7% and available data were analyzed.
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description:

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Overall Number of Participants Analyzed 195 199
Measure Type: Number
Unit of Measure: percentage of participants
25.6 41.2
4.Secondary Outcome
Title Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24
Hide Description

The average (mean) change from baseline in 2-hour postprandial serum glucose at Week 24 was analyzed.

Mixed Meal Tolerance Test (MMTT) Full Analysis Set: randomized participants who received at least one dose of study treatment with a baseline and at least one postbaseline measurement of serum glucose at time [T] = 120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations and analyzed based on the randomized treatment regardless of actual treatment received.

Time Frame Baseline; Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants in the Mixed Meal Tolerance Test (MMTT) Full Analysis Set with available data were analyzed.
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description:

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Overall Number of Participants Analyzed 178 185
Mean (Standard Deviation)
Unit of Measure: mg/dL
2  (65.1) -19  (53.8)
5.Secondary Outcome
Title Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24
Hide Description The average (mean) change from baseline in incremental change of 2-hour postprandial serum glucose at Week 24 was analyzed.
Time Frame Baseline; Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants in the Mixed Meal Tolerance Test (MMTT) Full Analysis Set with available data were analyzed.
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description:

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Overall Number of Participants Analyzed 173 180
Mean (Standard Deviation)
Unit of Measure: mg/dL
-1  (47.7) -12  (37.9)
Time Frame Up to 24 Weeks plus 30 days
Adverse Event Reporting Description Safety Analysis Set: randomized participants who received at least one dose of study treatment, analyzed based on actual treatment received.
 
Arm/Group Title Placebo Ranolazine
Hide Arm/Group Description

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Placebo to match ranolazine (Days 1–7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.

Treatment Period: Ranolazine tablets (Days 1–7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.

Participants were required to maintain their diet and exercise regimen.

All-Cause Mortality
Placebo Ranolazine
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Ranolazine
Affected / at Risk (%) Affected / at Risk (%)
Total   7/232 (3.02%)   6/232 (2.59%) 
Cardiac disorders     
Angina unstable  1  1/232 (0.43%)  0/232 (0.00%) 
Atrial fibrillation  1  0/232 (0.00%)  1/232 (0.43%) 
Atrioventricular block second degree  1  1/232 (0.43%)  0/232 (0.00%) 
Myocardial ischaemia  1  0/232 (0.00%)  1/232 (0.43%) 
Sinoatrial block  1  1/232 (0.43%)  0/232 (0.00%) 
Infections and infestations     
Infected dermal cyst  1  0/232 (0.00%)  1/232 (0.43%) 
Injury, poisoning and procedural complications     
Lower limb fracture  1  1/232 (0.43%)  0/232 (0.00%) 
Upper limb fracture  1  1/232 (0.43%)  0/232 (0.00%) 
Metabolism and nutrition disorders     
Hyperglycaemia  1  0/232 (0.00%)  1/232 (0.43%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Non-small cell lung cancer stage iv  1  1/232 (0.43%)  0/232 (0.00%) 
Uterine cancer  1  1/232 (0.43%)  0/232 (0.00%) 
Nervous system disorders     
Carotid artery stenosis  1  1/232 (0.43%)  0/232 (0.00%) 
Dizziness  1  0/232 (0.00%)  1/232 (0.43%) 
Renal and urinary disorders     
Renal failure acute  1  0/232 (0.00%)  1/232 (0.43%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/232 (0.43%)  0/232 (0.00%) 
Bronchitis chronic  1  1/232 (0.43%)  0/232 (0.00%) 
Vascular disorders     
Hypertension  1  1/232 (0.43%)  0/232 (0.00%) 
Superior vena cava syndrome  1  1/232 (0.43%)  0/232 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Ranolazine
Affected / at Risk (%) Affected / at Risk (%)
Total   31/232 (13.36%)   28/232 (12.07%) 
Metabolism and nutrition disorders     
Hyperglycaemia  1  23/232 (9.91%)  18/232 (7.76%) 
Nervous system disorders     
Headache  1  10/232 (4.31%)  12/232 (5.17%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

  • The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
  • The study has been completed at all study sites for at least 2 years
Results Point of Contact
Name/Title: Clinical Trial Disclosures
Organization: Gilead Sciences, Inc.
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01472185     History of Changes
Other Study ID Numbers: GS-US-259-0131
First Submitted: November 11, 2011
First Posted: November 16, 2011
Results First Submitted: October 8, 2014
Results First Posted: October 15, 2014
Last Update Posted: October 24, 2014