IMWELL: Ranolazine Among Unrevascularized Chronic Stable Angina Patients

• Sponsor: North Florida Foundation for Research and Education (Other)
• Overall Status: Completed
• CT.gov ID: NCT02265796
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 50
• Location: 1
• Arms: 2
• Duration (Months): 24
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This is a prospective, double-blind, placebo-controlled, randomized, single-center (North Florida- South Georgia VA Medical Center) study. The study objective is to determine if ranolazine improves angina symptoms at 4 months compared with placebo among stable coronary artery disease patients who have demonstrable myocardial ischemia, but who do not undergo revascularization

Condition or Disease	Intervention/Treatment	Phase
Angina	Drug: Ranolazine; Drug: Sugar pill	Phase 2

Detailed Description

This is a prospective, double-blind, placebo-controlled, randomized, single-center (North Florida- South Georgia VA Medical Center) study. The study objective is to determine if ranolazine improves angina symptoms at 4 months compared with placebo among stable coronary artery disease patients who have demonstrable myocardial ischemia, but who do not undergo revascularization.

Baseline Procedure:

Assessments performed exclusively to determine eligibility for this study would be done only after obtaining informed consent. Assessments performed for clinical indications (not exclusively to determine study eligibility) may be used for baseline values even if the studies were done before informed consent was obtained. The assessment will include:

• Informed Consent

• Review subject eligibility criteria

• FFR value calculated at the time of cardiac catheterization

• Review previous and concomitant medications

• Frequency of symptoms and quality of life prior to study according to Seattle Angina Questionnaire (SAQ)

Screening Visit:

The assessments to determine eligibility are:

• Review of eligibility criteria

• Review of cardiac catheterization and FFR

• Review of medications taken in the past 30 days Subjects that meet eligibility criteria will be randomized to receive either the active drug, Ranolazine or a matching placebo (non-active drug). Staff and subjects will not know if the subject will be receiving the active drug or the placebo.

Drug schedule will be as follows:

• 1st dose of one tablet (500mg) will begin the evening of Day 1

• On Days 2-7, one tablet (500mg) two times a day (12-hours apart).

• On Day 8, increase dose of study drug to two tablets (1000mg) twice a day; once in the morning and once in the evening, 12 hours apart. This dose will continue for the duration of the study. The study drug can be taken with or without food.

Telephone Follow-up:

One week phone calls will be made to determine well being, adverse events, answer questions and remind subjects to increase the study medication dose.

Month 4 Follow-up:

• Frequency of symptoms and quality of life according to Seattle Angina Questionnaire (SAQ)

• Assessment of well-being

• Any hospitalizations or the need for revascularization

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Improvement of Subjective Well-Being by Ranolazine Among Unrevascularized Chronic Stable Coronary Artery Disease Patients
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ranolazine Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Drug: Ranolazine; Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks; Other Names: Ranexa
Placebo Comparator: Sugar pill Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Drug: Sugar pill; 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Seattle Angina Questionnaire Score Change From Baseline to 16 Weeks [Change in baseline to 16 weeks]

   The SAQ quantifies patients' physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life.Each of the 5 dimensions are scored by assigning eachresponse an ordinal value, beginning with 1 for the response that implies the lowest level of functioning, and summing across items within each of the 5 scales. Scale scores then transformed to 0-100 range by subtracting the lowest possible scale score, dividing by the range1 / 3 Seattle Angina Questionnaire (SAQ)of the scale and multiplying by 100. No overall scale score is generated. Factors and Each scale is transformed to a score of 0 to 100, where higher scores indicate better function (eg, less physical limitation, less angina, and better quality of life). .

Secondary Outcome Measures

1. Subjective Well Being [Compare from baseline to month 4]

   overall feeling of well being determined from rating of excellent, good, fair or poor at baseline compared to same at month 4

2. Ischemia Driven Revascularization or Hospitalization [4 month]

   Number of participants who reported adverse events for ischemia driven revascularization or hospitalization

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients >= 18 years of age referred for cardiac catheterization for evaluation of cardiac symptoms ( angina, fatigue, or shortness of breath)

• At least 1 indeterminate stenosis (20-80%),

• Fractional flow reserve (FFR) <=0.8 and PCI deferred

Exclusion Criteria:

• Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) during the index procedure or anticipated within the next month

• acute coronary syndrome or cardiogenic shock

• QTc > 500 milliseconds

• use of strong inhibitors of CTP3A (i.e. ketoconazole, itraconazole, clarithromycin,nefazodone, nelfinavir, ritonavir, indinavir and saquinavir)

• use of inducers of CYP3A (i.e. rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort)

• liver cirrhosis

• sever renal insufficiency (i.e. creatinine clearance < 30mL/min/1.73 m2)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	North Florida/South Georgia Veterans Health System	Gainesville	Florida	United States	32608

Sponsors and Collaborators

• North Florida Foundation for Research and Education
• Gilead Sciences

Investigators

• Principal Investigator: Anthony A Bavry, MD, MPH, NorthFlorida/South Georgia Veterans Health System, Gainesville, FL 32608

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bavry AA, Park KE, Choi CY, Mahmoud AN, Wen X, Elgendy IY. Improvement of Subjective Well-Being by Ranolazine in Patients with Chronic Angina and Known Myocardial Ischemia (IMWELL Study). Cardiol Ther. 2017 Jun;6(1):81-88. doi: 10.1007/s40119-016-0081-3. Epub 2017 Jan 2. Erratum in: Cardiol Ther. 2017 Jun;6(1):89.

• Responsible Party: Anthony A Bavry, Interventional Cardiologist, North Florida Foundation for Research and Education
• ClinicalTrials.gov Identifier: NCT02265796
• Other Study ID Numbers: 149-2013
• First Posted: Oct 16, 2014
• Last Update Posted: Aug 22, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Anthony A Bavry, Interventional Cardiologist, North Florida Foundation for Research and Education: deferred percutaneous coronary intervention; fractional flow reserve
• Additional relevant MeSH terms: Angina Pectoris; Ranolazine

Study Results

Participant Flow

Recruitment Details	recruitment period first subject enrolled 9/24/2014 to last subject enrolled 12/12/2015

Arm/Group Title	Ranolazine	Sugar Pill
Arm/Group Description	Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Ranolazine: Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Sugar pill: 1. 500mg tablet two times per day for 7 days then, 2. 500mg tablet (1000mg) two times per day for 15 weeks
Period Title: Overall Study
STARTED	25	25
COMPLETED	22	24
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Ranolazine	Sugar Pill	Total
Arm/Group Description	Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Ranolazine: Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Sugar pill: 1. 500mg tablet two times per day for 7 days then, 2. 500mg tablet (1000mg) two times per day for 15 weeks	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 40%	12 48%	22 44%
>=65 years	15 60%	13 52%	28 56%
Sex: Female, Male (Count of Participants)
Female	1 4%	0 0%	1 2%
Male	24 96%	25 100%	49 98%
Region of Enrollment (participants) [Number]
United States	25 100%	25 100%	50 100%
Hypertension (Count of Participants)
Count of Participants [Participants]	25 100%	25 100%	50 100%
Hyperlipidemia (Count of Participants)
Count of Participants [Participants]	16 64%	17 68%	33 66%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	14 56%	16 64%	30 60%
on Insulin (Count of Participants)
Count of Participants [Participants]	5 20%	7 28%	12 24%
history of Percutaneous Coronary Intervention (Count of Participants)
Count of Participants [Participants]	19 76%	14 56%	33 66%
history of Coronary Artery Bypass Graft surgery (Count of Participants)
Count of Participants [Participants]	8 32%	6 24%	14 28%

Outcome Measures

1. Primary Outcome

Title	Seattle Angina Questionnaire Score Change From Baseline to 16 Weeks
Description	The SAQ quantifies patients' physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life.Each of the 5 dimensions are scored by assigning eachresponse an ordinal value, beginning with 1 for the response that implies the lowest level of functioning, and summing across items within each of the 5 scales. Scale scores then transformed to 0-100 range by subtracting the lowest possible scale score, dividing by the range1 / 3 Seattle Angina Questionnaire (SAQ)of the scale and multiplying by 100. No overall scale score is generated. Factors and Each scale is transformed to a score of 0 to 100, where higher scores indicate better function (eg, less physical limitation, less angina, and better quality of life). .
Time Frame	Change in baseline to 16 weeks

Outcome Measure Data

Analysis Population Description

by intention to treat, 46 subjects had baseline and follow up SAQ data completed at 16 weeks

Arm/Group Title	Ranolazine	Sugar Pill
Arm/Group Description	Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Ranolazine: Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Sugar pill: 1. 500mg tablet two times per day for 7 days then, 2. 500mg tablet (1000mg) two times per day for 15 weeks
Measure Participants	22	24
Physical Limitation baseline	48 (25)	50 (20)
Physical Limitation 16 weeks	40 (19)	60 (24)
Physical Limitation group difference	-7 (27)	6 (20)
Angina Stability baseline	39 (28)	37 (28)
Angina Stablility 16 weeks	58 (26)	55 (27)
Angia Stability group difference	19 (36)	18 (32)
Angina Frequency baseline	65 (24)	64 (23)
Angina Frequency 16 weeks	81 (23)	80 (24)
Angina Frequency group difference	16 (36)	15 (27)
Treatment Satisfaction baseline	80 (19)	85 (18)
Treatment Statisfaction 16 weeks	77 (26)	82 (22)
Treatment Satisfaciton group difference	-4 (26)	-3 (26)
Quality of Life baseline	37 (24)	45 (27)
Quality of Life 16 weeks	56 (29)	63 (18)
Quality of Life group difference	21 (32)	18 (31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine, Sugar Pill
	Comments	between group comparison for all SAQ domains
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	the reported p value is for all between group comparisons of the SAQ domains.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments	within group comparison of change from baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	reported p value is for the physical limitation, angina frequency and treatment satisfaction domains
	Method	paired t test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments	within group comparison of change from baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	reported p value is for the angina stability and quality of life domains
	Method	paired t test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill
	Comments	within group comparison of change from baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	reported p value is for the physical limitation and treatment satisfaction domains
	Method	paired t test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill
	Comments	within group comparison of change from baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	reported p value is for the angina stability, angina frequency and quality of life domains
	Method	paired t test
	Comments

2. Secondary Outcome

Title	Subjective Well Being
Description	overall feeling of well being determined from rating of excellent, good, fair or poor at baseline compared to same at month 4
Time Frame	Compare from baseline to month 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine	Sugar Pill
Arm/Group Description	Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Ranolazine: Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Sugar pill: 1. 500mg tablet two times per day for 7 days then, 2. 500mg tablet (1000mg) two times per day for 15 weeks
Measure Participants	22	24
excellent/good	9 36%	6 24%
fair/poor	12 48%	16 64%
missing	1 4%	2 8%
excellent/good	11 44%	10 40%
fair/poor	10 40%	10 40%
missing	1 4%	4 16%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine, Sugar Pill
	Comments	between group comparison for the "excellent/good"
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranolazine, Sugar Pill
	Comments	Between group analysis for "fair/poor"
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.80
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments	within group analysis of change from baseline for excellent/good
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	McNemar
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments	within group comparison of change from baseline for fair/poor
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	McNemar
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill
	Comments	within group analysis of change from baseline for excellent/good
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	McNemar
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sugar Pill
	Comments	within group comparison of change from baseline for fair/poor
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	McNemar
	Comments

3. Secondary Outcome

Title	Ischemia Driven Revascularization or Hospitalization
Description	Number of participants who reported adverse events for ischemia driven revascularization or hospitalization
Time Frame	4 month

Outcome Measure Data

Analysis Population Description

the incidence of ischemia driven hospitalization or catheterization was assessed for all subjects.

Arm/Group Title	Ranolazine	Sugar Pill
Arm/Group Description	Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Ranolazine: Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks	Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Sugar pill: 1. 500mg tablet two times per day for 7 days then, 2. 500mg tablet (1000mg) two times per day for 15 weeks
Measure Participants	25	25
Count of Participants [Participants]	3 12%	5 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine, Sugar Pill
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Baseline to 16 weeks
Adverse Event Reporting Description	adverse events assessed at 1 week, 4 week and 16 week phone call follow-up.
Arm/Group Title	Ranolazine		Sugar Pill
Arm/Group Description	Ranolazine 500 mg tablets 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Ranolazine: Ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks		Sugar pill that looks like the drug ranolazine 500mg tablet 500mg tablet two times per day for 7 days then, 500mg tablet (1000mg) two times per day for 15 weeks Sugar pill: 1. 500mg tablet two times per day for 7 days then, 2. 500mg tablet (1000mg) two times per day for 15 weeks
All Cause Mortality
	Ranolazine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		0/25 (0%)
Serious Adverse Events
	Ranolazine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/25 (20%)		4/25 (16%)
Cardiac disorders
death	1/25 (4%)	1	0/25 (0%)	0
bradycardia, symptomatic	1/25 (4%)	1	0/25 (0%)	0
Unstable Angina	0/25 (0%)	0	1/25 (4%)	1
Myocardial Infarctoin	1/25 (4%)	1	0/25 (0%)	0
chest pain	1/25 (4%)	1	0/25 (0%)	0
coronary artery disease	0/25 (0%)	0	1/25 (4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
lung mass	0/25 (0%)	0	1/25 (4%)	1
Renal and urinary disorders
Hematuria	1/25 (4%)	1	0/25 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/25 (0%)	0	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Ranolazine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/25 (68%)		15/25 (60%)
Gastrointestinal disorders
Diarrhea	0/25 (0%)	0	2/25 (8%)	2
Constipation	2/25 (8%)	2	0/25 (0%)	0
Nausea	1/25 (4%)	1	1/25 (4%)	1
Black stools	0/25 (0%)	0	1/25 (4%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	2/25 (8%)	2	3/25 (12%)	3
Leg cramps	0/25 (0%)	0	1/25 (4%)	1
Fall	1/25 (4%)	1	1/25 (4%)	1
Nervous system disorders
dizziness	5/25 (20%)	5	1/25 (4%)	1
Fainting	3/25 (12%)	3	2/25 (8%)	2
Lethargy	1/25 (4%)	1	0/25 (0%)	0
Confusion	0/25 (0%)	0	1/25 (4%)	1
Psychiatric disorders
anxiety	0/25 (0%)	0	1/25 (4%)	1
Renal and urinary disorders
worsening renal function	1/25 (4%)	1	0/25 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchitis	1/25 (4%)	1	0/25 (0%)	0
productive cough	0/25 (0%)	0	1/25 (4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.