A Phase 3 Study of Ranolazine in Subjects With Type 2 Dia... | NCT01555164

NCT01555164

ID	Type	Description	Link
2012-001259-37	EudraCT Number

Status Module

Oversight Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Ranolazine+metformin	Experimental	Qualifying Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening). Treatment Period: Participants will receive ranolazine 500 mg + metformin 500 mg + placebo to match metformin twice daily on Days 1 through 7, followed by ranolazine 1000 mg + metformin 500 mg + placebo to match metformin twice daily from Day 8 through Week 24. Participants are required to maintain their diet and exercise regimen.	Drug: Ranolazine Drug: Metformin Drug: Placebo to match metformin Behavioral: Diet Behavioral: Exercise
Placebo+metformin	Placebo Comparator	Qualifying Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening). Treatment Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily through Week 24. Participants are required to maintain their diet and exercise regimen.	Drug: Placebo to match ranolazine Drug: Metformin Behavioral: Diet Behavioral: Exercise

Name	Type	Description	Arm Group Labels	Other Names
Ranolazine	Drug	Ranolazine tablet(s) administered orally	Ranolazine+metformin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24	The average (mean) change from baseline in HbA1c at Week 24 was analyzed.	Baseline; Week 24

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Fasting Serum Glucose at Week 24	The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed.	Baseline; Week 24
Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Documented history of T2DM
Metformin therapy at a stable total daily dose ≥ 1500 mg and ≤ 2550 mg in addition to diet and exercise for ≥ 8 weeks prior to Screening
Body mass index (BMI) 25 to 45 kg/m^2, inclusive, at Screening
HbA1c within specified ranges at Screening and at the end of the Qualifying Period based on current metformin dose
C-peptide ≥ 0.8 ng/mL at Screening
Fasting serum glucose (FSG) ≥ 130 mg/dL (7.2 mmol/L) and ≤ 240 mg/dL (13.3 mmol/L) at Screening and at the end of the Qualifying Period

Exclusion Criteria:

Type 1 diabetes mellitus
History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma
History of severe hypoglycemia
Any clinically significant cardiovascular or cerebrovascular event ≤ 3 months prior to Screening
History of congestive heart failure
Corrected QT interval (QTc) > 500 msec by ECG at Screening, a personal or family history of QTc prolongation, congenital long QT syndrome, or individuals who are receiving drugs that prolong the QTc interval, such as Class Ia or Class III antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, ziprasidone)
Serum creatinine concentration ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females at Screening
Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) > 3 x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) > 3 x ULN and/or serum total bilirubin > 2.0 mg/dL
Use of any non-insulin antihyperglycemic therapy (other than metformin) for more than 14 days (consecutive or not) during the 12 weeks (24 weeks for thiazolidinediones) prior to Screening and/or use of any antihyperglycemic therapy other than metformin, at any dose, at any time during the 4 weeks prior to randomization
Treatment with chronic insulin within 24 weeks prior to Screening (except for one temporary period of daily insulin injections no longer than 7 days)
Treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or P-glycoprotein (P-gp) inhibitors within 14 days prior to randomization
Treatment with CYP3A inducers or P-gp inducers within 14 days prior to randomization
Treatment with simvastatin or lovastatin at a dose > 20 mg or > 40 mg daily, respectively, within 14 days prior to randomization

Name	Affiliation	Role
Patrick Yue, MD	Gilead Sciences	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Fundamental Research LLC		Gulf Shores	Alabama	36542	United States
KLR Business Group DBA Arkansas Clinical Research

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

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 T=120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations; analyzed based on the randomized treatment regardless of actual treatment received.

Arm/Group Information

ID	Title	Description
BG000	Placebo+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.
BG001	Ranolazine+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Ranolazine 500 mg (1 x 500 mg tablet) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00056± 8.9 BG00156± 9.3 BG00256± 9.1

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00098 BG001121 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00053 BG00137 BG002

Race/Ethnicity, Customized

Number

participants

Title

Denominators

Categories

American Indian or Alaska Native

Title	Measurements
	BG0002 BG0010 BG002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG00082 BG00167 BG002

Body Mass Index (BMI)

Mean

Standard Deviation

kg/m^2

Title

Denominators

Categories

Title	Measurements
	BG00031.2± 4.46 BG00131.6± 4.95 BG002

Estimated glomerular filtration rate (eGFR)

Mean

Standard Deviation

mL/min/1.73m^2

Title

Denominators

Categories

Title	Measurements
	BG00090.8± 20.01 BG00189.9± 21.82 BG002

Glycosylated hemoglobin (HbA1c)

Mean

Standard Deviation

percent HbA1c in blood

Title

Denominators

Categories

Title	Measurements
	BG0008.09± 0.729 BG0018.10± 0.692 BG002

Fasting Serum Glucose (FSG)

Mean

Standard Deviation

mg/dL

Title

Denominators

Categories

Title	Measurements
	BG000170.0± 35.97 BG001168.8± 32.86 BG002

Duration of Diabetes

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG0006.7± 5.31 BG0016.4± 5.37 BG002

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

Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24

The average (mean) change from baseline in HbA1c at Week 24 was analyzed.

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 participants with major eligibility violations, and analyzed based on randomized treatment, regardless of actual treatment received) with available data were analyzed.

Mean

Standard Deviation

percent of HbA1c in blood

Baseline; Week 24

ID	Title	Description
OG000	Placebo+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.
OG001	Ranolazine+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Ranolazine 500 mg (1 x 500 mg tablet) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.

Units	Counts
Participants	OG000174 OG001179

Title

Denominators

Categories

HbA1c at Week 24

Title	Measurements
	OG0007.86± 1.003 OG0017.72± 1.069

Change from baseline in HbA1c at Week 24

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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 -0.4% (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.	Mixed Effects Model Analysis		0.306	P-value from a mixed-effect model including terms for baseline HbA1c value, treatment group, visit week, and treatment by visit week interaction. Unstructured covariance matrix was used.	difference in least squares mean (LSM)	-0.11			2-Sided	95	-0.31	0.10			The estimation (LSM) is of the placebo-corrected change from baseline.

Secondary

Change From Baseline in Fasting Serum Glucose at Week 24

The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed.

Participants in the Full Analysis Set with available data were analyzed.

Mean

Standard Deviation

mg/dL

Baseline; Week 24

ID	Title	Description
OG000	Placebo+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.
OG001	Ranolazine+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Ranolazine 500 mg (1 x 500 mg tablet) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.

Secondary

Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24

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

Participants in the MMTT Full Analysis Set with available data were analyzed.

Mean

Standard Deviation

mg/dL

Baseline; Week 24

ID	Title	Description
OG000	Placebo+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.
OG001	Ranolazine+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Ranolazine 500 mg (1 x 500 mg tablet) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.			2	222	14	222
EG001	Ranolazine+Metformin	Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Ranolazine 500 mg (1 x 500 mg tablet) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.			3	220	18	220

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Coronary artery disease	Cardiac disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected222 at risk EG0010 affected220 at risk
Myocardial infarction	Cardiac disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected222 at risk EG0010 affected220 at risk
Impaired gastric emptying	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected222 at risk EG0011 affected220 at risk
Vomiting	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected222 at risk EG0011 affected220 at risk
Lower limb fracture	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0000 affected222 at risk EG0011 affected220 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected222 at risk EG0011 affected220 at risk
Spinal osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected222 at risk EG0011 affected220 at risk
Lumbar spinal stenosis	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected222 at risk EG0011 affected220 at risk

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases

ID	Term
D000083	Acetanilides
D000813	Anilides
D000577	Amides
D009930	Organic Chemicals
D000814	Aniline Compounds
D000588	Amines
D010879	Piperazines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D001645	Biguanides
D006146	Guanidines
D000578	Amidines
D009747	Nutritional Physiological Phenomena
D000066888	Diet, Food, and Nutrition
D010829	Physiological Phenomena
D009043	Motor Activity
D009068	Movement
D009142	Musculoskeletal Physiological Phenomena
D055687	Musculoskeletal and Neural Physiological Phenomena

ID	Term
D000069458	Ranolazine
D008687	Metformin
D004032	Diet
D015444	Exercise