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The purpose of this study was to investigate the effects of initiation of sacubitril/valsartan vs enalapril treatment on objective measures of both waking activity and sleep in subjects with heart failure with reduced ejection fraction.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Enalapril | Active Comparator | Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level. Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level. |
|
| Sacubitril/Valsartan | Experimental | Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level. Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| sacubitril/valsartan (LCZ696) | Drug | sacubitril/valsartan tablet taken orally. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline | The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio > 1 indicates an increase in mean activity counts from baseline to week 8. | Baseline, week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1 | Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). | Baseline, Week 1 |
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Key Inclusion Criteria:
(Reduced ejection is defined as left ventricular EF ≤ 40%. LVEF ≤40% may be determined via any local measurement within the past 6 months prior to signing consent, using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography provided no subsequent study documenting an EF of >40%. If the EF measurement is expressed as a value range, the average of the range endpoint values should be used as the EF).
Key Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Fort Payne | Alabama | 35967 | United States | ||
| Novartis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32978755 | Derived | Khandwalla RM, Grant D, Birkeland K, Heywood JT, Fombu E, Owens RL, Steinhubl SR; AWAKE-H. F. Study Investigators. The AWAKE-HF Study: Sacubitril/Valsartan Impact on Daily Physical Activity and Sleep in Heart Failure. Am J Cardiovasc Drugs. 2021 Mar;21(2):241-254. doi: 10.1007/s40256-020-00440-y. Epub 2020 Sep 26. |
| Label | URL |
|---|---|
| A Plain Language Trial Summary is available on novartisclinicaltrials.com | View source |
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140 subjects from 23 sites in the US were randomized. The study consisted of a 2-week baseline period , followed by an 8-week double-blind treatment period ( randomized to sacubitril/valsartan or enalapril, in a 1:1 ratio), followed by an 8-week open label extension period during which all patients were treated with sacubitril/valsartan.
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| ID | Title | Description |
|---|---|---|
| FG000 | Enalapril | Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level. Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level. |
| Title | Milestones | Reasons Not Completed | ||||
|---|---|---|---|---|---|---|
| Double-blind Period |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 13, 2018 | Mar 14, 2019 |
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| enalapril | Drug | Enalapril tablet taken orally. |
|
| matching placebo sacubitril/valsartan (LCZ696) | Drug | matching placebo sacubitril/valsartan tablet taken orally |
|
| matching placebo enalapril | Drug | matching placebo enalapril tablet taken orally |
|
| Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). | Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16 |
| Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). | Baseline, Week 8 |
| Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). | Baseline, Week 1 |
| Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). | Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16 |
| Beverly Hills |
| California |
| 90211 |
| United States |
| Novartis Investigative Site | Stockton | California | 95204 | United States |
| Novartis Investigative Site | West Hills | California | 91307 | United States |
| Novartis Investigative Site | Doral | Florida | 33126 | United States |
| Novartis Investigative Site | Inverness | Florida | 34452 | United States |
| Novartis Investigative Site | Ormond Beach | Florida | 32174 | United States |
| Novartis Investigative Site | Port Orange | Florida | 32127 | United States |
| Novartis Investigative Site | Lutherville | Maryland | 21093 | United States |
| Novartis Investigative Site | East Brunswick | New Jersey | 08816 | United States |
| Novartis Investigative Site | Ridgewood | New Jersey | 07450 | United States |
| Novartis Investigative Site | Columbia | South Carolina | 29203 | United States |
| Novartis Investigative Site | Greenville | South Carolina | 29615 | United States |
| Novartis Investigative Site | Lancaster | South Carolina | 29720 | United States |
| Novartis Investigative Site | Allen | Texas | 75002-3688 | United States |
| Novartis Investigative Site | McKinney | Texas | 75013 | United States |
| Novartis Investigative Site | New Braunfels | Texas | 78130 | United States |
| Novartis Investigative Site | San Antonio | Texas | 78229 | United States |
| Novartis Investigative Site | San Marcos | Texas | 78666 | United States |
| Novartis Investigative Site | Sherman | Texas | 75092 | United States |
| Novartis Investigative Site | Tomball | Texas | 77375 | United States |
| Novartis Investigative Site | Midlothian | Virginia | 23114 | United States |
| Novartis Investigative Site | Tacoma | Washington | 98405 | United States |
| FG001 | Sacubitril/Valsartan | Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level. Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level. |
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| NOT COMPLETED |
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| Open-label Period |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Enalapril | Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan |
| BG001 | Sacubitril/Valsartan | Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| 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 | Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline | The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio > 1 indicates an increase in mean activity counts from baseline to week 8. | Full Analysis Set | Posted | Geometric Mean | 95% Confidence Interval | Ratio | Baseline, week 8 |
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| Secondary | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1 | Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). | Full Analysis Set | Posted | Least Squares Mean | Standard Error | counts | Baseline, Week 1 |
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| Secondary | Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 | Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). | Full Analysis Set | Posted | Mean | Standard Deviation | counts | Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16 |
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| Secondary | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). | Full Analysis Set | Posted | Least Squares Mean | Standard Error | counts/minute | Baseline, Week 8 |
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| Secondary | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). | Full Analysis Set | Posted | Least Squares Mean | Standard Error | counts/minute | Baseline, Week 1 |
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| Secondary | Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 | Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer). | Full Analysis Set | Posted | Mean | Standard Deviation | counts/minute | Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16 |
|
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8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
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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 | Enalapril (Randomized Treatment Period) | Week 1 to Week 8: Enalapril | 1 | 70 | 4 | 70 | 26 | 70 |
| EG001 | Sacubitril/Valsartan (Randomized Treatment Period) | Week 1 to Week 8: Sacubitril/Valsartan | 0 | 69 | 5 | 69 | 8 | 69 |
| EG002 | Enalapril (Open-Label Extension Period) | Week 9 - 16: Sacubitril/Valsartan | 0 | 62 | 4 | 62 | 11 | 62 |
| EG003 | Sacubitril/Valsartan (Open-Label Extension Period) | Week 9 - 16: Sacubitril/Valsartan | 0 | 64 | 3 | 64 | 11 | 64 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Angina pectoris | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cardiac failure congestive | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Ischaemic cardiomyopathy | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Complication associated with device | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Non-cardiac chest pain | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cerebrovascular accident | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
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| Incoherent | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Peripheral arterial occlusive disease | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Peripheral coldness | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
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The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | Novartis.email@novartis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 10, 2018 | Mar 14, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D054143 | Heart Failure, Systolic |
| D004108 | Dilatation, Pathologic |
| D017379 | Hypertrophy, Left Ventricular |
| D006333 | Heart Failure |
| D009043 | Motor Activity |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D020763 | Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006332 | Cardiomegaly |
| D006984 | Hypertrophy |
| D001519 | Behavior |
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| ID | Term |
|---|---|
| C000717211 | sacubitril |
| D000068756 | Valsartan |
| C549068 | sacubitril and valsartan sodium hydrate drug combination |
| D004656 | Enalapril |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D014633 | Valine |
| D000597 | Amino Acids, Branched-Chain |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000601 | Amino Acids, Essential |
| D004151 | Dipeptides |
| D009842 | Oligopeptides |
| D010455 | Peptides |
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| Physician Decision |
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| Male |
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| Black |
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| Asian |
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| Native American |
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| Pacific Islander |
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| Other |
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| Unknown |
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