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Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction (NEAT-HFpeF)

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ClinicalTrials.gov Identifier: NCT02053493
Recruitment Status : Completed
First Posted : February 3, 2014
Results First Posted : November 28, 2016
Last Update Posted : November 28, 2016
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
University of Vermont
Information provided by (Responsible Party):
Adrian Hernandez, Duke University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Heart Failure
Interventions Drug: Isosorbide Mononitrate
Drug: Placebo
Enrollment 110
Recruitment Details All patients admitted to the participating HFN centers with signs and symptoms suggestive of HFpEF will be screened including their ability to wear the accelerometer belt. Patients meeting eligibility criteria will be approached regarding participation in this study.
Pre-assignment Details All subjects who fulfill all the inclusion criteria and none of the exclusion criteria will undergo the baseline studies and then be randomized.
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
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Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Period Title: Overall Study
Started 51 59
Completed 50 58
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             1             1
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate Total
Hide Arm/Group Description

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Total of all reporting groups
Overall Number of Baseline Participants 51 59 110
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[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 51 participants 59 participants 110 participants
69.8  (8.7) 68.8  (9.7) 69.3  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 59 participants 110 participants
Female
25
  49.0%
38
  64.4%
63
  57.3%
Male
26
  51.0%
21
  35.6%
47
  42.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 51 participants 59 participants 110 participants
51 59 110
1.Primary Outcome
Title Arbitrary Accelerometry Units (AAU) (Phase I)
Hide Description To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Time Frame 5-6 weeks
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 45 56
Mean (Standard Deviation)
Unit of Measure: accelerometry units
9370  (4601) 9538  (6286)
2.Primary Outcome
Title Arbitrary Accelerometry Units (AAU) (Phase II)
Hide Description To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Time Frame 11-12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 42 49
Mean (Standard Deviation)
Unit of Measure: accelerometry units
8824  (3877) 8900  (5457)
3.Secondary Outcome
Title Six Minute Walk Distance (Phase I)
Hide Description To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.
Time Frame Week 7
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 49 57
Mean (Standard Deviation)
Unit of Measure: meters
307.8  (125.5) 327.1  (126.0)
4.Secondary Outcome
Title Six Minute Walk Distance (Phase II)
Hide Description To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.
Time Frame Week 13
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 47 57
Mean (Standard Deviation)
Unit of Measure: meters
321.3  (132.4) 329.7  (132.1)
5.Secondary Outcome
Title Patient Preference for Isosorbide Mononitrate Treatment at the End of Study.
Hide Description Self reported participant preference for study period 1 vs. study period 2.
Time Frame Week 13
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 48 57
Measure Type: Number
Unit of Measure: participants
Phase1 14 14
Phase2 18 24
No Preference 16 19
6.Secondary Outcome
Title Borg Score During 6 Minute Walk Test (Phase I)
Hide Description To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Borg Scale consists of scale range of 0 to 10 (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). Lower values are considered to be better than higher values.
Time Frame Week 7
Hide Outcome Measure Data
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 44 52
Mean (Standard Deviation)
Unit of Measure: units on a scale
4.1  (2.6) 4.0  (2.2)
7.Secondary Outcome
Title Borg Score During 6 Minute Walk Test (Phase II)
Hide Description To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Borg Scale consists of scale range of 0 to 10 (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). Lower values are considered to be better than higher values.
Time Frame Week 13
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 40 49
Mean (Standard Deviation)
Unit of Measure: units on a scale
3.8  (2.3) 3.8  (2.0)
8.Secondary Outcome
Title Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase I)
Hide Description To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).
Time Frame Week 7
Hide Outcome Measure Data
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 50 58
Mean (Standard Deviation)
Unit of Measure: units on a scale
57.3  (23.4) 64.2  (24.2)
9.Secondary Outcome
Title Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase II)
Hide Description To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. • The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).Higher values of the overall KCCQ score are considered to be better than lower values.
Time Frame Week 13
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 49 58
Mean (Standard Deviation)
Unit of Measure: units on a scale
59.1  (23.6) 61.6  (23.5)
10.Secondary Outcome
Title N-terminal Pro-B-type Natriuretic Peptide Level (Phase I)
Hide Description To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo
Time Frame Week 7
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 49 57
Mean (Standard Deviation)
Unit of Measure: pg/mL
513.0  (803.2) 542.4  (710.9)
11.Secondary Outcome
Title N-terminal Pro-B-type Natriuretic Peptide Level (Phase II)
Hide Description To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo
Time Frame Week 13
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 47 54
Mean (Standard Deviation)
Unit of Measure: pg/mL
466.1  (677.4) 573.3  (756.1)
12.Secondary Outcome
Title Improvement in Daily Activity - Hours Active Per Day (Phase I)
Hide Description To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Hours active per day during maximal dose of study drug
Time Frame 5-6 weeks
Hide Outcome Measure Data
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Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 45 56
Mean (Standard Deviation)
Unit of Measure: Hours/day
9.4  (2.4) 9.1  (2.4)
13.Secondary Outcome
Title Improvement in Daily Activity - Hours Active Per Day (Phase II)
Hide Description To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Hours active per day during maximal dose of study drug
Time Frame 11-12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 42 49
Mean (Standard Deviation)
Unit of Measure: Hours/day
9.4  (2.4) 8.8  (2.5)
14.Secondary Outcome
Title Improvement in Daily Activity - Slope of Daily Average (Phase I)
Hide Description To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Slope of daily averaged arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Time Frame 3-6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 47 58
Mean (Standard Deviation)
Unit of Measure: accelerometry units/day
-3.4  (23.1) -1.3  (26.9)
15.Secondary Outcome
Title Improvement in Daily Activity - Slope of Daily Average (Phase II)
Hide Description To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Slope of daily averaged arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Time Frame 9-12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 42 53
Mean (Standard Deviation)
Unit of Measure: accelerometry units/day
2.6  (20.1) -3.9  (16.4)
16.Secondary Outcome
Title Improvement in Daily Activity - Area Under the Curve (Phase I)
Hide Description To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Area under the curve (AUC) of arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement. Area under the curve is defined as ((7*average acceleromtery units/day during 30 mg) + (7*average acceleromtery units/day during 60 mg) + (14*average acceleromtery units/day during 120 mg))/28
Time Frame 3-6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 39 54
Mean (Standard Deviation)
Unit of Measure: accelerometry units
9621.4  (4367.8) 9714.0  (6273.6)
17.Secondary Outcome
Title Improvement in Daily Activity - Area Under the Curve (Phase II)
Hide Description To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Area under the curve (AUC) of arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement. Area under the curve is defined as ((7*average acceleromtery units/day during 30 mg) + (7*average acceleromtery units/day during 60 mg) + (14*average acceleromtery units/day during 120 mg))/28
Time Frame 9-12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with usable data included in the results
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description:

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

Overall Number of Participants Analyzed 38 44
Mean (Standard Deviation)
Unit of Measure: accelerometry units
9146.5  (3695.3) 9325.9  (5668.2)
Time Frame Informed Consent through Week 15 phone visit
Adverse Event Reporting Description

Per protocol, non-serious AEs were not collected; all SAEs were collected except for anticipated, disease-related events in patients with HF with preserved EF.

3 time points summarized: Informed Consent to start of Phase 1 study drug, Phase 1 study drug start to start of Phase 2 study drug, Phase 2 study drug start to Week 15 phone call.

 
Arm/Group Title Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Hide Arm/Group Description

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)

Isosorbide Mononitrate: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN

Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)

Placebo: Dispense phase 1 study drug:

Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo

Dispense phase-2 study drug:

Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

All-Cause Mortality
Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/51 (3.92%)      1/59 (1.69%)    
Gastrointestinal disorders     
Faecaloma  1 [1]  1/51 (1.96%)  1 0/59 (0.00%)  0
Infections and infestations     
Cellulitis  1 [2]  1/51 (1.96%)  1 0/59 (0.00%)  0
Herpes Zoster  1 [3]  0/51 (0.00%)  0 1/59 (1.69%)  1
Renal and urinary disorders     
Urinary retention  1 [1]  1/51 (1.96%)  1 0/59 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
chronic obstructive pulmonary disease  1 [3]  1/51 (1.96%)  1 0/59 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
[1]
Informed consent to start of phase 1 study drug
[2]
Phase 1 study drug start to start of Phase 2 study drug
[3]
Phase 2 study drug start to Week 15 phone call
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Isosorbide Mononitrate Crossover to Placebo Placebo Crossover to Isosorbide Mononitrate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/0      0/0    
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Adrian Hernandez
Organization: Duke Clinical Research Insitute
Phone: 919-668-7515
EMail: Adrian.Hernandez@duke.edu
Layout table for additonal information
Responsible Party: Adrian Hernandez, Duke University
ClinicalTrials.gov Identifier: NCT02053493     History of Changes
Other Study ID Numbers: Pro00050042
4U10HL084904-10 ( U.S. NIH Grant/Contract )
First Submitted: January 3, 2014
First Posted: February 3, 2014
Results First Submitted: February 4, 2016
Results First Posted: November 28, 2016
Last Update Posted: November 28, 2016