Trial Outcomes & Findings for Study on the Effects of Sacubitril/Valsartan on Physical Activity and Sleep in Heart Failure With Reduced Ejection Fraction Patients. (NCT NCT02970669)

Last Updated: 2021-10-07

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

140 participants

Primary outcome timeframe

Baseline, week 8

Results posted on

2021-10-07

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.
Double-blind Period STARTED	70	70
Double-blind Period COMPLETED	62	64
Double-blind Period NOT COMPLETED	8	6
Open-label Period STARTED	62	64
Open-label Period COMPLETED	58	62
Open-label Period NOT COMPLETED	4	2

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Double-blind Period Adverse Event	4	0
Double-blind Period Death	1	0
Double-blind Period Study terminated by sponsor	1	2
Double-blind Period Physician Decision	0	2
Double-blind Period Withdrawal by Subject	2	2
Open-label Period Withdrawal by Subject	2	2
Open-label Period Adverse Event	1	0
Open-label Period Physician Decision	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Total n=140 Participants Total of all reporting groups	Sacubitril/Valsartan n=70 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Enalapril n=70 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Age, Continuous	63.3 years n=5 Participants	62.3 years n=7 Participants	64.2 years n=5 Participants
Sex: Female, Male Female	32 Participants n=5 Participants	18 Participants n=7 Participants	14 Participants n=5 Participants
Sex: Female, Male Male	108 Participants n=5 Participants	52 Participants n=7 Participants	56 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	108 Participants n=5 Participants	48 Participants n=7 Participants	60 Participants n=5 Participants
Race/Ethnicity, Customized Black	21 Participants n=5 Participants	13 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized Asian	5 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Native American	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Other	3 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, week 8

Population: Full Analysis Set

Outcome measures

Outcome measures
Measure	Enalapril n=60 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Sacubitril/Valsartan n=64 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline	1.0411 Ratio Interval 0.9938 to 1.0906	0.9844 Ratio Interval 0.9411 to 1.0297

SECONDARY outcome

Timeframe: Baseline, Week 1

Population: Full Analysis Set

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).

Outcome measures

Outcome measures
Measure	Enalapril n=54 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Sacubitril/Valsartan n=59 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1	171.3 counts Standard Error 440.9	464.9 counts Standard Error 421.8

SECONDARY outcome

Timeframe: Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16

Population: Full Analysis Set

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).

Outcome measures

Outcome measures
Measure	Enalapril n=62 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Sacubitril/Valsartan n=64 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 Week 9 (change from Baseline)	-198.8 counts Standard Deviation 5245.5	-402.9 counts Standard Deviation 5857.0
Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16 Week 16 (change from Baseline)	-455.1 counts Standard Deviation 4966.7	46.9 counts Standard Deviation 4811.2

SECONDARY outcome

Timeframe: Baseline, Week 8

Population: Full Analysis Set

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).

Outcome measures

Outcome measures
Measure	Enalapril n=64 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Sacubitril/Valsartan n=65 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8	0.339 counts/minute Standard Error 0.752	2.377 counts/minute Standard Error 0.746

SECONDARY outcome

Timeframe: Baseline, Week 1

Population: Full Analysis Set

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).

Outcome measures

Outcome measures
Measure	Enalapril n=59 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Sacubitril/Valsartan n=63 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1	0.169 counts/minute Standard Error 0.696	2.647 counts/minute Standard Error 0.674

SECONDARY outcome

Timeframe: Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16

Population: Full Analysis Set

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).

Outcome measures

Outcome measures
Measure	Enalapril n=62 Participants Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan	Sacubitril/Valsartan n=64 Participants Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 Week 9 (change from Baseline)	2.158 counts/minute Standard Deviation 5.150	3.230 counts/minute Standard Deviation 7.269
Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16 Week 16 (change from Baseline)	1.066 counts/minute Standard Deviation 5.367	1.489 counts/minute Standard Deviation 5.642

Adverse Events

Enalapril (Randomized Treatment Period)

Serious events: 4 serious events

Other events: 26 other events

Deaths: 1 deaths

Sacubitril/Valsartan (Randomized Treatment Period)

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

Enalapril (Open-Label Extension Period)

Serious events: 4 serious events

Other events: 11 other events

Deaths: 0 deaths

Sacubitril/Valsartan (Open-Label Extension Period)

Serious events: 3 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Enalapril (Randomized Treatment Period) n=70 participants at risk Week 1 to Week 8: Enalapril	Sacubitril/Valsartan (Randomized Treatment Period) n=69 participants at risk Week 1 to Week 8: Sacubitril/Valsartan	Enalapril (Open-Label Extension Period) n=62 participants at risk Week 9 - 16: Sacubitril/Valsartan	Sacubitril/Valsartan (Open-Label Extension Period) n=64 participants at risk Week 9 - 16: Sacubitril/Valsartan
Gastrointestinal disorders Diarrhoea	8.6% 6/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	3.2% 2/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Gastrointestinal disorders Vomiting	5.7% 4/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
General disorders Fatigue	12.9% 9/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	7.8% 5/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Nervous system disorders Dizziness	17.1% 12/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	7.2% 5/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	8.1% 5/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	6.2% 4/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Vascular disorders Hypotension	5.7% 4/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	6.5% 4/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	6.2% 4/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Enalapril (Randomized Treatment Period) n=70 participants at risk Week 1 to Week 8: Enalapril	Sacubitril/Valsartan (Randomized Treatment Period) n=69 participants at risk Week 1 to Week 8: Sacubitril/Valsartan	Enalapril (Open-Label Extension Period) n=62 participants at risk Week 9 - 16: Sacubitril/Valsartan	Sacubitril/Valsartan (Open-Label Extension Period) n=64 participants at risk Week 9 - 16: Sacubitril/Valsartan
Cardiac disorders Angina pectoris	1.4% 1/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Cardiac disorders Cardiac failure congestive	1.4% 1/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Cardiac disorders Ischaemic cardiomyopathy	1.4% 1/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
General disorders Complication associated with device	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
General disorders Non-cardiac chest pain	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Infections and infestations Pneumonia	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Infections and infestations Sepsis	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Infections and infestations Urinary tract infection	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Metabolism and nutrition disorders Dehydration	1.4% 1/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Nervous system disorders Cerebrovascular accident	1.4% 1/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Nervous system disorders Incoherent	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.4% 1/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.6% 1/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)
Vascular disorders Peripheral coldness	0.00% 0/70 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	1.4% 1/69 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/62 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)	0.00% 0/64 • 8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)