Trial Outcomes & Findings for Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea (NCT NCT04639193)

Last Updated: 2024-05-29

Results Overview

The AHI is a measure of sleep apnea severity and based on the American Academy of Sleep Medicine (AASM)-recommended criteria is defined as the number of apneas (no breathing for 10+ seconds) and hypopneas (reduced breathing for 10+ seconds associated with a \>=3% desaturation or cortical arousal) per hour of sleep. To avoid confounding by sleep stages and positions across study nights the primary focus was on the AHI during supine non rapid eye movement (NREM) sleep. For comparability with other studies, we also explored the AASM-acceptable "AHI4", which defines hypopneas as reduced breathing for 10+ seconds associated with a \>=4% desaturation.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

20 participants

Primary outcome timeframe

3 nights

Results posted on

2024-05-29

Participant Flow

Of 88 subjects who were assessed for eligibility, 20 were randomized. The other 68 were excluded due to not meeting eligibility criteria or not being interested.

Participant milestones

Participant milestones
Measure	Placebo, Then Dual-Therapy, Then Triple-Therapy Subjects started with a 3-day PLACEBO regimen: * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory. After a wash-out period of 4+ days, subjects then crossed over to a 3-day EXPERIMENTAL DUAL-regimen: * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory. After a wash-out period of 4+ days, subjects then underwent an OPEN-LABEL TRIPLE-regimen: Day 1: Acetazolamide 250mg at bedtime at home. Day 2: Acetazolamide 500mg at bedtime at home. Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory Acetazolamide: Acetazolamide tablet (encapsulated) Eszopiclone: Eszopiclone tablet (encapsulated) Placebo: Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone Venlafaxine: Venlafaxine capsule	Dual-Therapy, Then Placebo, Then Triple-Therapy Subjects started with a 3-day EXPERIMENTAL DUAL-regimen: * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory. After a wash-out period of 4+ days, subjects then crossed over to a 3-day PLACEBO regimen: * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory. After a wash-out period of 4+ days, subjects then underwent an OPEN-LABEL TRIPLE-regimen: Day 1: Acetazolamide 250mg at bedtime at home. Day 2: Acetazolamide 500mg at bedtime at home. Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory Acetazolamide: Acetazolamide tablet (encapsulated) Eszopiclone: Eszopiclone tablet (encapsulated) Placebo: Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone Venlafaxine: Venlafaxine capsule
First Intervention STARTED	10	10
First Intervention COMPLETED	10	10
First Intervention NOT COMPLETED	0	0
Second Intervention STARTED	10	10
Second Intervention COMPLETED	10	10
Second Intervention NOT COMPLETED	0	0
Third Intervention STARTED	9	9
Third Intervention COMPLETED	9	9
Third Intervention NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants Who Were Enrolled Into the Trial n=20 Participants All 20 participants who were randomized, completed the dual-therapy and placebo phases (blinded/random order) 18 of these 20 participants went on to also complete the the open label triple therapy phase
Age, Continuous	49 years n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants
Race (NIH/OMB) More than one race	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Region of Enrollment United States	20 participants n=5 Participants
Body Mass Index	29.1 kg/m^2 n=5 Participants
Apnea Hypopnea Index (AHI) AHI (supine, NREM)	32.8 events/hour of sleep n=5 Participants
Apnea Hypopnea Index (AHI) AHI (overall)	39.2 events/hour of sleep n=5 Participants
Apnea Hypopnea Index (AHI) AHI4 (overall)	21.8 events/hour of sleep n=5 Participants
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Vpasssive, transformed	69.9 % Veupnea n=5 Participants
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Vactive	92.1 % Veupnea n=5 Participants
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Arousal Threshold, transformed	142 % Veupnea n=5 Participants
Pathophysiological Trait: Loop Gain	0.56 dimensionless n=5 Participants

PRIMARY outcome

Timeframe: 3 nights

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Apnea Hypopnea Index (AHI) AHI (supine, NREM)	17.1 events/hour of sleep Interval 9.4 to 37.7	32.7 events/hour of sleep Interval 23.8 to 51.8	26 events/hour of sleep Interval 9.2 to 40.0
Apnea Hypopnea Index (AHI) AHI (overall)	23.6 events/hour of sleep Interval 15.2 to 38.3	37.4 events/hour of sleep Interval 30.4 to 50.0	25.8 events/hour of sleep Interval 9.9 to 43.3
Apnea Hypopnea Index (AHI) AHI4 (overall)	14.1 events/hour of sleep Interval 7.9 to 27.3	20.3 events/hour of sleep Interval 13.3 to 37.9	9 events/hour of sleep Interval 4.5 to 14.7

SECONDARY outcome

Timeframe: 3 nights

The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
SpO2 Nadir	83.5 Percent Oxygen Saturation Interval 79.8 to 87.2	84 Percent Oxygen Saturation Interval 82.0 to 85.2	86 Percent Oxygen Saturation Interval 82.5 to 87.5

SECONDARY outcome

Timeframe: 3 nights

Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm.

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Vpasssive, transformed	69.5 % Veupnea Interval 58.7 to 78.2	67.4 % Veupnea Interval 59.4 to 73.2	70.4 % Veupnea Interval 61.7 to 75.3
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Vactive	96.2 % Veupnea Interval 79.0 to 99.1	92.1 % Veupnea Interval 83.9 to 97.7	94.4 % Veupnea Interval 83.9 to 99.6
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Arousal Threshold, transformed	140.1 % Veupnea Interval 126.7 to 161.5	149.8 % Veupnea Interval 137.9 to 162.2	137.2 % Veupnea Interval 125.0 to 155.7

SECONDARY outcome

Timeframe: 3 nights

Loop Gain 1 was quantified from polysomnography data using a validated algorithm. This metric measures the increase in respiratory drive relative to a preceding drop in ventilation and thus is dimensionless (typical range is approximately 0.2 to 1.5, with values \>0.7 being considered high loop gain, indicating ventilatory instability)

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Pathophysiological Trait: Loop Gain	0.54 dimensionless Interval 0.49 to 0.59	0.57 dimensionless Interval 0.51 to 0.69	0.49 dimensionless Interval 0.44 to 0.6

SECONDARY outcome

Timeframe: 3 nights

Full responders were defined as a drop in AHI\>50% to \<10/h.

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Percent Responders Based on AHI in supine NREM sleep	5 Participants	0 Participants	4 Participants
Percent Responders Based on AHI overall	1 Participants	1 Participants	4 Participants

SECONDARY outcome

Timeframe: 3 nights

Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Blood Pressure Systolic Blood Pressure	112.5 mmHg Interval 107.8 to 119.8	116.5 mmHg Interval 109.8 to 124.5	116 mmHg Interval 110.2 to 120.8
Blood Pressure Diastolic Blood Pressure	72 mmHg Interval 67.8 to 78.2	74 mmHg Interval 68.5 to 82.0	70.5 mmHg Interval 63.2 to 79.5

SECONDARY outcome

Timeframe: 3 nights

Subjective sleepiness was assessed using the Stanford Sleepiness Scale (SSS) in the morning following the overnight sleep study. The score ranges from 1 to 7, with greater values indicating more sleepiness.

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Subjective Sleepiness: Stanford Sleepiness Scale (SSS)	2 units on a scale Interval 1.0 to 2.2	2 units on a scale Interval 1.0 to 3.0	2 units on a scale Interval 1.0 to 3.8

SECONDARY outcome

Timeframe: 3 nights

Sleep quality was assessed based on a modified 8-question PROMIS Sleep Disturbance (SDA 8b) questionnaire in the morning following the overnight sleep study. The raw score ranges from 8 to 40 and is translated into a T-score, a standardized score with a mean of 50 and a standard deviation of 10. Greater T-scores indicate greater sleep disturbance.

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance	53 t-score Interval 49.0 to 56.3	53.9 t-score Interval 49.9 to 57.8	53 t-score Interval 48.8 to 55.6

SECONDARY outcome

Timeframe: 3 nights

Vigilance was assessed using the 10-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study. Primary focus was on "response speed" 1/reaction time (1/RT) and lapses (reaction time \>500ms).

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Psychomotor Vigilance: Response Speed	3 1/seconds Interval 2.8 to 3.3	3.1 1/seconds Interval 2.8 to 3.4	2.9 1/seconds Interval 2.8 to 3.3

SECONDARY outcome

Timeframe: 3 nights

Outcome measures

Outcome measures
Measure	Dual-Therapy n=20 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 Participants * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 Participants * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
Psychomotor Vigilance: Lapses	3 Number of lapses Interval 0.0 to 8.2	3 Number of lapses Interval 1.0 to 6.2	5 Number of lapses Interval 2.2 to 9.8

Adverse Events

Dual-Therapy

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Triple-Therapy

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr Chris Schmickl

University of California San Diego

Phone: 8582462154

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Dual-Therapy n=20 participants at risk * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.	Placebo n=20 participants at risk * Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home. * Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home. * Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.	Triple-Therapy n=18 participants at risk * Day 1: Acetazolamide 250mg at bedtime at home. * Day 2: Acetazolamide 500mg at bedtime at home. * Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory.
General disorders Bad Dreams	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Renal and urinary disorders Cloudy Urine	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Nervous system disorders Dizziness	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Abnormal Taste when Drinking Carbonated Beverages	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Fatigue	10.0% 2/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Gastrointestinal disorders Gastrointestinal Upset	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	33.3% 6/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Musculoskeletal and connective tissue disorders Hand Pain	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Headache	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	11.1% 2/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Gastrointestinal disorders Heartburn	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Hot Flashes	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Itchiness	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Metallic Taste	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Gastrointestinal disorders Nausea	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Nervous system disorders Paresthesia	15.0% 3/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	11.1% 2/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Renal and urinary disorders Polyuria	10.0% 2/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Skin and subcutaneous tissue disorders Rash	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Musculoskeletal and connective tissue disorders Shoulder Cramp	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
General disorders Sleepiness	25.0% 5/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	20.0% 4/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	44.4% 8/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
Gastrointestinal disorders Vomiting	0.00% 0/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.0% 1/20 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.	5.6% 1/18 • During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.