AWAKE-HF: Study on the Effects of Sacubitril/Valsartan on Physical Activity and Sleep in Heart Failure With Reduced Ejection Fraction Patients.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02970669
• Collaborator: (none)
• Enrollment: 140
• Locations: 23
• Arms: 2
• Actual Duration (Months): 15
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure, Reduced Ejection Fraction	Drug: sacubitril/valsartan (LCZ696); Drug: enalapril; Drug: matching placebo sacubitril/valsartan (LCZ696); Drug: matching placebo enalapril	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study and 8-week Open Label Extension to Evaluate the Effect of Initiation of Sacubitril/Valsartan on Objective Measures of Waking Activity and Sleep, as Health-related Quality of Life Functions in Subjects With Heart Failure and Reduced Ejection Fraction (AWAKE-HF).
• Actual Study Start Date: Dec 16, 2016
• Actual Primary Completion Date: Mar 19, 2018
• Actual Study Completion Date: Mar 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: sacubitril/valsartan (LCZ696); sacubitril/valsartan tablet taken orally.; Drug: enalapril; Enalapril tablet taken orally.; Drug: matching placebo sacubitril/valsartan (LCZ696); matching placebo sacubitril/valsartan tablet taken orally
Experimental: 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.	Drug: sacubitril/valsartan (LCZ696); sacubitril/valsartan tablet taken orally.; Drug: matching placebo enalapril; matching placebo enalapril tablet taken orally

Outcome Measures

Primary Outcome Measures

1. Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline [Baseline, week 8]

   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.

Secondary Outcome Measures

1. Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1 [Baseline, 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).

2. Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 [Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), 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).

3. Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8 [Baseline, 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).

4. Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1 [Baseline, 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).

5. Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 [Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed.

• Men and women between 18 and 80 years of age

• Subjects diagnosed with NYHA class II or III heart failure and with reduced ejection (HFrEF).

(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).

• Subjects must be a candidate for treatment with sacubitril/valsartan as per USPI.

• Subjects must be living in a traditional residence, apartment, or non-communal adult home where they can move about freely and frequently and are primarily responsible for scheduling their sleep and daily activities.

Key Exclusion Criteria:

• Subjects with a history of hypersensitivity to any of the study drugs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs.

• Subjects with a history of angioedema drug related or otherwise

• Subjects with symptomatic hypotension or systolic blood pressure <100 mmHg at screening or <95 mmHg at randomization

• Subjects with any conditions in skin or upper extremities which would limit the ability to tolerate a wrist-worn actigraphy device on the non-dominant arm for 24 hours/day for the duration of the study.

• Subjects who are non-ambulatory or use mobility assistive devices such as motorized devices, wheelchairs, or walkers. The use of canes for stability while ambulating is acceptable.

• Subjects with physical activity impairment primarily due to conditions other than heart failure such as:

• Exertional angina inflammatory or degenerative joint disease -gout

• peripheral vascular disease

• neurologic disease affecting activity or mobility

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Fort Payne	Alabama	United States	35967
2	Novartis Investigative Site	Beverly Hills	California	United States	90211
3	Novartis Investigative Site	Stockton	California	United States	95204
4	Novartis Investigative Site	West Hills	California	United States	91307
5	Novartis Investigative Site	Doral	Florida	United States	33126
6	Novartis Investigative Site	Inverness	Florida	United States	34452
7	Novartis Investigative Site	Ormond Beach	Florida	United States	32174
8	Novartis Investigative Site	Port Orange	Florida	United States	32127
9	Novartis Investigative Site	Lutherville	Maryland	United States	21093
10	Novartis Investigative Site	East Brunswick	New Jersey	United States	08816
11	Novartis Investigative Site	Ridgewood	New Jersey	United States	07450
12	Novartis Investigative Site	Columbia	South Carolina	United States	29203
13	Novartis Investigative Site	Greenville	South Carolina	United States	29615
14	Novartis Investigative Site	Lancaster	South Carolina	United States	29720
15	Novartis Investigative Site	Allen	Texas	United States	75002-3688
16	Novartis Investigative Site	McKinney	Texas	United States	75013
17	Novartis Investigative Site	New Braunfels	Texas	United States	78130
18	Novartis Investigative Site	San Antonio	Texas	United States	78229
19	Novartis Investigative Site	San Marcos	Texas	United States	78666
20	Novartis Investigative Site	Sherman	Texas	United States	75092
21	Novartis Investigative Site	Tomball	Texas	United States	77375
22	Novartis Investigative Site	Midlothian	Virginia	United States	23114
23	Novartis Investigative Site	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 13, 2018
• Statistical Analysis Plan - Apr 10, 2018

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02970669
• Other Study ID Numbers: CLCZ696BUS14
• First Posted: Nov 22, 2016
• Last Update Posted: Oct 7, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Novartis Pharmaceuticals: Heart failure with reduced left ventricular ejection fraction (LVEF); Cardiac dysfunction; Heart muscle dysfunction; Left ventricular (LV) dilation; Left ventricular hypertrophy; HF; AHF; CHF; acute heart failure; chronic heart failure; congestive heart failure; congestive cardiac failure; Heart failure; HReEF; Physical Activity; Actigraphy; Home sleep test; wake
• Additional relevant MeSH terms: Heart Failure; Heart Failure, Systolic; Valsartan; Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	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.	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.
Period Title: Double-blind Period
STARTED	70	70
COMPLETED	62	64
NOT COMPLETED	8	6
Period Title: Double-blind Period
STARTED	62	64
COMPLETED	58	62
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Enalapril	Sacubitril/Valsartan	Total
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Total of all reporting groups
Overall Participants	70	70	140
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	64.2	62.3	63.3
Sex: Female, Male (Count of Participants)
Female	14 20%	18 25.7%	32 22.9%
Male	56 80%	52 74.3%	108 77.1%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	60 85.7%	48 68.6%	108 77.1%
Black	8 11.4%	13 18.6%	21 15%
Asian	1 1.4%	4 5.7%	5 3.6%
Native American	0 0%	1 1.4%	1 0.7%
Pacific Islander	0 0%	1 1.4%	1 0.7%
Other	1 1.4%	2 2.9%	3 2.1%
Unknown	0 0%	1 1.4%	1 0.7%

Outcome Measures

1. Primary Outcome

Title	Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline
Description	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.
Time Frame	Baseline, week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Measure Participants	60	64
Geometric Mean (95% Confidence Interval) [Ratio]	1.0411	0.9844

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0895
	Comments
	Method	ANCOVA
	Comments	model for a log-scaled response with treatment group as a class variable and the baseline value in logarithmic scale as a continuous covariate.
Method of Estimation	Estimation Parameter	Ratio of Geometric Means (SacVal/Ena)
	Estimated Value	0.9456
	Confidence Interval	(2-Sided) 95%; 0.8863 to 1.0088
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1
Description	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).
Time Frame	Baseline, Week 1

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Measure Participants	54	59
Least Squares Mean (Standard Error) [counts]	171.3 (440.9)	464.9 (421.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6316
	Comments
	Method	ANCOVA
	Comments	model with treatment group as a class variable and the baseline value as a continuous covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	293.6
	Confidence Interval	(2-Sided) 95%; -916.5 to 1503.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16
Description	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).
Time Frame	Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Measure Participants	62	64
Week 9 (change from Baseline)	-198.8 (5245.5)	-402.9 (5857.0)
Week 16 (change from Baseline)	-455.1 (4966.7)	46.9 (4811.2)

4. Secondary Outcome

Title	Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8
Description	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).
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Measure Participants	64	65
Least Squares Mean (Standard Error) [counts/minute]	0.339 (0.752)	2.377 (0.746)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0570
	Comments
	Method	ANCOVA
	Comments	model with treatment group as a class variable and the baseline value as a continuous covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.038
	Confidence Interval	(2-Sided) 95%; -0.062 to 4.138
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1
Description	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).
Time Frame	Baseline, Week 1

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Measure Participants	59	63
Least Squares Mean (Standard Error) [counts/minute]	0.169 (0.696)	2.647 (0.674)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0121
	Comments
	Method	ANCOVA
	Comments	model with treatment group as a class variable and the baseline value as a continuous covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.478
	Confidence Interval	(2-Sided) 95%; 0.553 to 4.403
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16
Description	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).
Time Frame	Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril	Sacubitril/Valsartan
Arm/Group Description	Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Measure Participants	62	64
Week 9 (change from Baseline)	2.158 (5.150)	3.230 (7.269)
Week 16 (change from Baseline)	1.066 (5.367)	1.489 (5.642)

Adverse Events

Time Frame	8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Arm/Group Title	Enalapril (Randomized Treatment Period)		Sacubitril/Valsartan (Randomized Treatment Period)		Enalapril (Open-Label Extension Period)		Sacubitril/Valsartan (Open-Label Extension Period)
Arm/Group Description	Week 1 to Week 8: Enalapril		Week 1 to Week 8: Sacubitril/Valsartan		Week 9 - 16: Sacubitril/Valsartan		Week 9 - 16: Sacubitril/Valsartan
All Cause Mortality
	Enalapril (Randomized Treatment Period)		Sacubitril/Valsartan (Randomized Treatment Period)		Enalapril (Open-Label Extension Period)		Sacubitril/Valsartan (Open-Label Extension Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/70 (1.4%)		0/69 (0%)		0/62 (0%)		0/64 (0%)
Serious Adverse Events
	Enalapril (Randomized Treatment Period)		Sacubitril/Valsartan (Randomized Treatment Period)		Enalapril (Open-Label Extension Period)		Sacubitril/Valsartan (Open-Label Extension Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/70 (5.7%)		5/69 (7.2%)		4/62 (6.5%)		3/64 (4.7%)
Cardiac disorders
Angina pectoris	1/70 (1.4%)		1/69 (1.4%)		1/62 (1.6%)		0/64 (0%)
Cardiac failure congestive	1/70 (1.4%)		0/69 (0%)		1/62 (1.6%)		0/64 (0%)
Ischaemic cardiomyopathy	1/70 (1.4%)		0/69 (0%)		0/62 (0%)		0/64 (0%)
General disorders
Complication associated with device	0/70 (0%)		0/69 (0%)		1/62 (1.6%)		0/64 (0%)
Non-cardiac chest pain	0/70 (0%)		1/69 (1.4%)		0/62 (0%)		0/64 (0%)
Infections and infestations
Pneumonia	0/70 (0%)		0/69 (0%)		0/62 (0%)		1/64 (1.6%)
Sepsis	0/70 (0%)		1/69 (1.4%)		0/62 (0%)		0/64 (0%)
Urinary tract infection	0/70 (0%)		0/69 (0%)		1/62 (1.6%)		1/64 (1.6%)
Metabolism and nutrition disorders
Dehydration	1/70 (1.4%)		0/69 (0%)		0/62 (0%)		0/64 (0%)
Nervous system disorders
Cerebrovascular accident	1/70 (1.4%)		0/69 (0%)		0/62 (0%)		0/64 (0%)
Incoherent	0/70 (0%)		0/69 (0%)		0/62 (0%)		1/64 (1.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/70 (0%)		0/69 (0%)		0/62 (0%)		1/64 (1.6%)
Chronic obstructive pulmonary disease	0/70 (0%)		0/69 (0%)		1/62 (1.6%)		0/64 (0%)
Respiratory failure	1/70 (1.4%)		0/69 (0%)		0/62 (0%)		0/64 (0%)
Vascular disorders
Peripheral arterial occlusive disease	0/70 (0%)		1/69 (1.4%)		0/62 (0%)		1/64 (1.6%)
Peripheral coldness	0/70 (0%)		1/69 (1.4%)		0/62 (0%)		0/64 (0%)
Other (Not Including Serious) Adverse Events
	Enalapril (Randomized Treatment Period)		Sacubitril/Valsartan (Randomized Treatment Period)		Enalapril (Open-Label Extension Period)		Sacubitril/Valsartan (Open-Label Extension Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/70 (37.1%)		8/69 (11.6%)		11/62 (17.7%)		11/64 (17.2%)
Gastrointestinal disorders
Diarrhoea	6/70 (8.6%)		1/69 (1.4%)		2/62 (3.2%)		1/64 (1.6%)
Vomiting	4/70 (5.7%)		0/69 (0%)		1/62 (1.6%)		0/64 (0%)
General disorders
Fatigue	9/70 (12.9%)		1/69 (1.4%)		1/62 (1.6%)		5/64 (7.8%)
Nervous system disorders
Dizziness	12/70 (17.1%)		5/69 (7.2%)		5/62 (8.1%)		4/64 (6.3%)
Vascular disorders
Hypotension	4/70 (5.7%)		1/69 (1.4%)		4/62 (6.5%)		4/64 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.