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| Name | Class |
|---|---|
| American Heart Association | OTHER |
| National Institutes of Health (NIH) | NIH |
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The ultimate goal is to improve our understanding of the pathophysiology and resistance to effective treatment of sleep disordered breathing in patients with heart failure, with a focus on selecting patients that will benefit specifically from acetazolamide treatment.
The study addresses three primary hypotheses: 1) Acetazolamide treatment will reduce the apnea-hypopnea index and improve markers of heart-failure severity in heart-failure patients with sleep apnea. 2) Acetazolamide will provide the greatest improvement in patients with the most severe ventilatory control instability (strongest chemoreflex response to carbon dioxide; highest loop gain). 3) Acetazolamide will act primarily via stabilizing ventilatory control (reducing loop gain), rather than via improvement to upper airway anatomy, pulmonary congestion, and cardiac function.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acetazolamide | Experimental |
| |
| Sugar pill | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetazolamide | Drug | 4 mg/kg, once daily before bed, for 7 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | The frequency of apneas and hypopneas (apnea-hypopnea index) was assessed. The primary measure was the value for non-REM supine sleep. A higher value indicates more severe sleep apnea. A value above 15 indicates the presence of moderate-to-severe sleep apnea. | 1 week |
| Measure | Description | Time Frame |
|---|---|---|
| Ventilatory Chemoreflex Sensitivity, "Loop Gain" Using Carbon Dioxide Pulses | Chemoreflex "loop gain" was assessed according to Sands SA et al AJRCCM 2017 Jan 15;195(2):237-246. Loop gain is a unitless ratio measure that describes the magnitude of the increase in ventilation that occurs in response to a prior reduction in ventilation ("disturbance") and has units of L/min per L/min. A larger value indicates a more sensitive and unstable control system predisposing to oscillatory breathing. Loop gain was measured on the time scale of 1 min (i.e. response to a 1 cycle/min sinusoidal disturbance, referred to as "LG1"). The procedure involved brief administration of 7% carbon dioxide in air for 0.5 min ("pulses"); tests were repeated every 3 min for 30 min while measuring ventilation and carbon dioxide levels at the nose with patients awake and supine. measured using 0.5 min pulses of carbon dioxide. |
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Inclusion Criteria (Heart failure patients)
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrew Wellman, MD, PhD | Brigham and Women's Hospital | Principal Investigator |
| Atul Malhotra, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Acetazolamide First, Then Placebo | Acetazolamide: 4 mg/kg, once daily before bed, for 7 days 1 week washout Placebo: 4 mg/kg, once daily before bed, for 7 days |
| FG001 | Placebo First, Then Acetazolamide | Placebo: 4 mg/kg, once daily before bed, for 7 days 1 week washout Acetazolamide: 4 mg/kg, once daily before bed, for 7 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (7 Days) |
| |||||||||||||
| Washout (7 Days) |
| |||||||||||||
| Second Intervention (7 Days) |
|
All patients randomized
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| ID | Title | Description |
|---|---|---|
| BG000 | All Patients | All patients randomized |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) | The frequency of apneas and hypopneas (apnea-hypopnea index) was assessed. The primary measure was the value for non-REM supine sleep. A higher value indicates more severe sleep apnea. A value above 15 indicates the presence of moderate-to-severe sleep apnea. | All participants who were randomized and completed the relevant study arm. Data are for non-REM supine sleep. | Posted | Mean | Standard Deviation | events per hour | 1 week |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Acetazolamide | Acetazolamide (active arm) | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall without injury | General disorders | Systematic Assessment | Fall without injury during 7 days using study medication |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Scott Sands | Brigham and Women's Hospital | 617 278 0911 | sasands@bwh.harvard.edu |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000086 | Acetazolamide |
| ID | Term |
|---|---|
| D013830 | Thiadiazoles |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
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| Placebo | Drug | 4 mg/kg, once daily before bed, for 7 days |
|
| 1 week |
| Sympathetic Activity (Urinary Norepinephrine) | Urinary norepinephrine levels overnight | 1 week |
| Left-atrial Volume | Left-atrial volume index, echocardiography, bi-plane method. Lower values were considered a favorable outcome. We considered values ≤28 mL/m^2 to indicate normal left atrial volume. Values indicating graded left atrial enlargement were described as follows: mild (29-33 mL/m^2), moderate (34-39 mL/m^2), severe (≥40 mL/m^2). | 1 week |
| Brain Natriuretic Peptide (NT-proBNP) | Brain natriuretic peptide (NT-proBNP) in morning | 1 week |
| Pittsburgh Sleep Quality Index | Pittsburgh Sleep Quality Index is a measure of self-reported sleep quality containing 19 questions that make up 7 component scores that are added to provide a total score. Total scores range from 0-21 (units on a scale) with higher scores representing reduced sleep quality. A score of 5 or more is interpreted as reduced sleep quality. The total score is reported. | 1 week |
| NOT COMPLETED |
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| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
| Secondary | Ventilatory Chemoreflex Sensitivity, "Loop Gain" Using Carbon Dioxide Pulses | Chemoreflex "loop gain" was assessed according to Sands SA et al AJRCCM 2017 Jan 15;195(2):237-246. Loop gain is a unitless ratio measure that describes the magnitude of the increase in ventilation that occurs in response to a prior reduction in ventilation ("disturbance") and has units of L/min per L/min. A larger value indicates a more sensitive and unstable control system predisposing to oscillatory breathing. Loop gain was measured on the time scale of 1 min (i.e. response to a 1 cycle/min sinusoidal disturbance, referred to as "LG1"). The procedure involved brief administration of 7% carbon dioxide in air for 0.5 min ("pulses"); tests were repeated every 3 min for 30 min while measuring ventilation and carbon dioxide levels at the nose with patients awake and supine. measured using 0.5 min pulses of carbon dioxide. | All participants who completed the relevant arm. Morning data are reported. | Posted | Mean | Standard Deviation | unitless | 1 week |
|
|
|
| Secondary | Sympathetic Activity (Urinary Norepinephrine) | Urinary norepinephrine levels overnight | All participants who completed the relevant study arm | Posted | Mean | Standard Deviation | ug/g-creatinine | 1 week |
|
|
|
| Secondary | Left-atrial Volume | Left-atrial volume index, echocardiography, bi-plane method. Lower values were considered a favorable outcome. We considered values ≤28 mL/m^2 to indicate normal left atrial volume. Values indicating graded left atrial enlargement were described as follows: mild (29-33 mL/m^2), moderate (34-39 mL/m^2), severe (≥40 mL/m^2). | echocardiography could not be performed on one study due to rescheduling issues | Posted | Mean | Standard Deviation | mL/m^2 | 1 week |
|
|
|
| Secondary | Brain Natriuretic Peptide (NT-proBNP) | Brain natriuretic peptide (NT-proBNP) in morning | All participants who completed the relevant arm | Posted | Mean | Standard Deviation | pg/ml | 1 week |
|
|
|
| Secondary | Pittsburgh Sleep Quality Index | Pittsburgh Sleep Quality Index is a measure of self-reported sleep quality containing 19 questions that make up 7 component scores that are added to provide a total score. Total scores range from 0-21 (units on a scale) with higher scores representing reduced sleep quality. A score of 5 or more is interpreted as reduced sleep quality. The total score is reported. | All participants who participated in the relevant study arm. | Posted | Mean | Standard Deviation | units on a scale | 1 week |
|
|
|
| 28 |
| 0 |
| 28 |
| 17 |
| 28 |
| EG001 | Placebo | Placebo arm | 0 | 28 | 0 | 28 | 6 | 28 |
|
| Nocturia | Renal and urinary disorders | Systematic Assessment | Self-reported incident nocturia during 7 days using study medication |
|
| Taste Disturbance | Metabolism and nutrition disorders | Systematic Assessment | Self-reported incident taste disturbances during 7 days using study medication |
|
| Paresthesias | Nervous system disorders | Systematic Assessment | Self-reported incident paresthesias during 7 days using study medication |
|
| Fatigue | General disorders | Systematic Assessment | Self-reported incident fatigue during 7 days using study medication |
|
| Lightheadedness upon standing | Vascular disorders | Systematic Assessment | Self-reported incident lightheadedness upon standing during 7 days using study medication |
|
| Headache | General disorders | Systematic Assessment | Self-reported incident headache during 7 days while using study medication |
|
| Gastrointestinal discomfort | Gastrointestinal disorders | Self-reported incident gastrointestinal discomfort during the 7 days while using study medication |
|
| Dry eyes | Eye disorders | Systematic Assessment | Self-reported incident dry eyes during 7 days while using study medication |
|
| Reduced exercise tolerance | General disorders | Systematic Assessment | Self-reported incident reduction in exercise tolerance during the 7 days while using study medication |
|
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| D001393 |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |