The Impact of Venlafaxine on Apnea Hypopnea Index in Obstructive Sleep Apnea

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT02714400
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Actual Duration (Months): 4
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

The investigators hypothesis is that obstructive sleep apnea (OSA) patients with a low arousal threshold may wake up too early during a respiratory event, before upper airway muscles can be activated to achieve stable ventilation. Thus, strategies to manipulate the respiratory arousal threshold could potentially improve the quality of sleep and sleep disordered breathing. Agents that raise arousal threshold are therefore likely to benefit some patients with OSA. The overall goal of this project is to determine the importance of the arousal threshold in OSA, determine which patients might benefit from a raised arousal threshold, and test this hypothesis by using pharmacological manipulation of the arousal threshold to achieve this goal.

Condition or Disease	Intervention/Treatment	Phase
Obstructive Sleep Apnea	Drug: Venlafaxine; Drug: Placebo	Phase 4

Detailed Description

This study is a randomized double-blinded crossover pilot study. The investigators will test whether Venlafaxine has important effects on the apnea hypopnea index. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) for the treatment of depression and anxiety. Venlafaxine increases serum serotonin level, which may affect arousal threshold. Furthermore, higher serotonin level theoretically may improve muscle tone, including upper airway muscle. Therefore, the investigators hypothesize that venlafaxine may decrease arousal threshold and improve muscle tone, leading to improvement of OSA.

Eligible participants will undergo overnight polysomonography as described below and will receive either Venlafaxine(50 mg 2 hour prior to sleep) or placebo (in random order) followed roughly 7 days later with placebo or donepezil. This aim will allow us to test the impact of Venlafaxine on the apnea hypopnea index.

The change in apnea hypopnea index will be compared in the Venlafaxine groups with the placebo group.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Impact of Venlafaxine on Apnea Hypopnea Index in Patients With Obstructive Sleep Apnea
• Actual Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Venlafaxine 50mg of Venlafaxine before sleep	Drug: Venlafaxine; Venlafaxine 50mg before sleep
Placebo Comparator: Placebo One piece of placebo before sleep	Drug: Placebo; One piece of placebo before sleep

Outcome Measures

Primary Outcome Measures

1. The Apnea Hypopnea Index [Baseline and 7-day follow up]

   The Apnea hypopnea index is an index used to indicate the severity of sleep apnea. It is represented by the number of apnea and hypopnea events per hour of sleep. The change from baseline in apnea hypopnea index after a single dose of Venlafaxine will be evaluated using overnight polysomnography. An apnea hypopnea index less than five events per hour is considered within normal limits.

2. Nadir Oxygen Level During Sleep [Baseline and 7-day follow up]

   Change from baseline in nadir oxygen level during sleep after a single dose of Venlafaxine will be evaluated using overnight polysomnography. A lower blood oxygen saturation during sleep is associated with a more severe obstructive sleep apnea.

Secondary Outcome Measures

1. Loop Gain [Baseline and 7-day follow up]

   Loop gain 1 is used to describe the stability of ventilatory control. The change from baseline in loop gain after a single dose of Venlafaxine will be estimated.

2. Arousal Threshold [Baseline and 7-day follow up]

   Change from baseline in respiratory arousal threshold after single dose of Venlafaxine will be estimated.

3. Sleep Efficiency [Baseline and 7-day follow up]

   Change from baseline in sleep efficiency after single dose of Venlafaxine will be estimated using overnight polysomnography.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ages 18-70 years

• sleep study (with apnea hypopnea index>5)

• Diagnosis of obstructive sleep apnea

Exclusion Criteria:

• Any known cardiac (apart from treated hypertension), pulmonary (including uncontrolled asthma), renal, neurologic (including epilepsy), neuromuscular, or hepatic disease.

• Susceptible to stomach ulcers.

• co-administration of MAO inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing the MAO inhibitor); initiation of MAO inhibitor intended to treat psychiatric disorders within 7 days of discontinuing venlafaxine; initiation in patients receiving linezolid or intravenous methylene blue

• Pregnant women.

• History of hypersensitivity to Afrin, Lidocaine (all Aims) or venlafaxine

• History of bleeding diathesis and/or gastrointestinal bleeding.

• Glaucoma and Urinary Retention

• Use of any medications that may affect sleep or breathing.

• Use of any medications that have known interaction with venlafaxine and the interaction may significantly increase the risk of the subject or decrease the therapeutic effect of the medication.

• A psychiatric disorder, other than mild depression; e.g. schizophrenia, bipolar disorder, major depression, panic or anxiety disorders.

• Substantial cigarette (>5/day), alcohol (>3oz/day) or use of illicit drugs.

• More than 10 cups of beverages with caffeine (coffee, tea, soda/pop) per day.

• Desaturations to below 70% lasting greater than 10 seconds in duration per event

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92093

Sponsors and Collaborators

• University of California, San Diego

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Carter SG, Berger MS, Carberry JC, Bilston LE, Butler JE, Tong BK, Martins RT, Fisher LP, McKenzie DK, Grunstein RR, Eckert DJ. Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea. Sleep. 2016 Apr 1;39(4):757-66. doi: 10.5665/sleep.5622.
• Deacon NL, Jen R, Li Y, Malhotra A. Treatment of Obstructive Sleep Apnea. Prospects for Personalized Combined Modality Therapy. Ann Am Thorac Soc. 2016 Jan;13(1):101-8. doi: 10.1513/AnnalsATS.201508-537FR. Review.
• Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013 Oct 15;188(8):996-1004. doi: 10.1164/rccm.201303-0448OC.
• Eckert DJ, Younes MK. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. J Appl Physiol (1985). 2014 Feb 1;116(3):302-13. doi: 10.1152/japplphysiol.00649.2013. Epub 2013 Aug 29. Review.
• Edwards BA, Eckert DJ, McSharry DG, Sands SA, Desai A, Kehlmann G, Bakker JP, Genta PR, Owens RL, White DP, Wellman A, Malhotra A. Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2014 Dec 1;190(11):1293-300. doi: 10.1164/rccm.201404-0718OC.

• Responsible Party: Robert L. Owens, Assistant Professor, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02714400
• Other Study ID Numbers: UCSD141272ARM5-1
• First Posted: Mar 21, 2016
• Last Update Posted: Apr 17, 2020
• Last Verified: Apr 1, 2020

• Keywords provided by Robert L. Owens, Assistant Professor, University of California, San Diego: Obstructive Sleep Apnea; Arousal threshold; Venlafaxine
• Additional relevant MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Venlafaxine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Venlafaxine First, Placebo Second	Placebo First, Venlafaxine Second
Arm/Group Description	50mg of Venlafaxine before sleep first night 1 Pill of Placebo before sleep second night	1 Pill of Placebo before sleep first night 50mg of Venlafaxine before sleep second night
Period Title: First Intervention (1 Day)
STARTED	12	8
COMPLETED	12	8
NOT COMPLETED	0	0
Period Title: First Intervention (1 Day)
STARTED	12	8
COMPLETED	12	8
NOT COMPLETED	0	0
Period Title: First Intervention (1 Day)
STARTED	12	8
COMPLETED	12	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Analyzed Participants
Arm/Group Description	All participants who were randomized, completed both study nights, and were included in the analysis.
Overall Participants	20
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.8 (8.1)
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	The Apnea Hypopnea Index
Description	The Apnea hypopnea index is an index used to indicate the severity of sleep apnea. It is represented by the number of apnea and hypopnea events per hour of sleep. The change from baseline in apnea hypopnea index after a single dose of Venlafaxine will be evaluated using overnight polysomnography. An apnea hypopnea index less than five events per hour is considered within normal limits.
Time Frame	Baseline and 7-day follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Venlafaxine	Placebo
Arm/Group Description	50mg of Venlafaxine before sleep Venlafaxine: Venlafaxine 50mg before sleep	One piece of placebo before sleep Placebo: One piece of placebo before sleep
Measure Participants	20	20
Mean (Standard Deviation) [Events per Hour of Sleep]	40.5 (16.5)	46.1 (21.9)

2. Primary Outcome

Title	Nadir Oxygen Level During Sleep
Description	Change from baseline in nadir oxygen level during sleep after a single dose of Venlafaxine will be evaluated using overnight polysomnography. A lower blood oxygen saturation during sleep is associated with a more severe obstructive sleep apnea.
Time Frame	Baseline and 7-day follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Venlafaxine	Placebo
Arm/Group Description	50mg of Venlafaxine before sleep Venlafaxine: Venlafaxine 50mg before sleep	One piece of placebo before sleep Placebo: One piece of placebo before sleep
Measure Participants	20	20
Median (Inter-Quartile Range) [Percent Oxygen Saturation]	82.0	81.5

3. Secondary Outcome

Title	Loop Gain
Description	Loop gain 1 is used to describe the stability of ventilatory control. The change from baseline in loop gain after a single dose of Venlafaxine will be estimated.
Time Frame	Baseline and 7-day follow up

Outcome Measure Data

Analysis Population Description

In one subject loop gain could not be quantified.

Arm/Group Title	Venlafaxine	Placebo
Arm/Group Description	50mg of Venlafaxine before sleep Venlafaxine: Venlafaxine 50mg before sleep	One piece of placebo before sleep Placebo: One piece of placebo before sleep
Measure Participants	19	19
Mean (Standard Deviation) [Dimensionless]	0.58 (0.15)	0.56 (0.14)

4. Secondary Outcome

Title	Arousal Threshold
Description	Change from baseline in respiratory arousal threshold after single dose of Venlafaxine will be estimated.
Time Frame	Baseline and 7-day follow up

Outcome Measure Data

Analysis Population Description

In one subject arousal threshold could not be quantified.

Arm/Group Title	Venlafaxine	Placebo
Arm/Group Description	50mg of Venlafaxine before sleep Venlafaxine: Venlafaxine 50mg before sleep	One piece of placebo before sleep Placebo: One piece of placebo before sleep
Measure Participants	19	19
Median (Inter-Quartile Range) [Percent V-eupnea]	115.6	118.6

5. Secondary Outcome

Title	Sleep Efficiency
Description	Change from baseline in sleep efficiency after single dose of Venlafaxine will be estimated using overnight polysomnography.
Time Frame	Baseline and 7-day follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Venlafaxine	Placebo
Arm/Group Description	50mg of Venlafaxine before sleep Venlafaxine: Venlafaxine 50mg before sleep	One piece of placebo before sleep Placebo: One piece of placebo before sleep
Measure Participants	20	20
Mean (Standard Deviation) [Percent Time in Bed]	63.1 (16.7)	72.5 (15.5)

Adverse Events

Arm/Group Title	Venlafaxine		Placebo
Arm/Group Description	50mg of Venlafaxine before sleep Venlafaxine: Venlafaxine 50mg before sleep		One piece of placebo before sleep Placebo: One piece of placebo before sleep
All Cause Mortality
	Venlafaxine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Venlafaxine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Venlafaxine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		1/20 (5%)
Gastrointestinal disorders
Nausea	2/20 (10%)	2	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.