Clinical trial NCT04102345
Conditions: Sleep
Keywords: aromatherapy diagnostic sleep study zolpidem
Sponsor: HealthPartners Institute
Start date: 2019-09-04; Completion date: 2020-11-10
Enrollment: 58 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this pragmatic, clinical study the investigators propose that lavender aromatherapy is comparable to Zolpidem (Ambien) in improving the quality of diagnostic sleep studies.

Detailed description:

Arms: arm 1: 1-2 drops of Lavender (essential oil) in approximately 120 ml of distilled water is added to a diffuser 10 minutes before light out. The diffuser runs for approximately 2 hours before automatically being shut off. A low mist option is used on the diffuser. arm 2: Pre-prescribed, physician directed use of zolpidem. There is no dose exclusionary criteria for the zolpidem. This study does not have any dose specifications, anyone on zolpidem may be eligible.
Interventions: intervention 1: Lavender Aromatherapy intervention 2: Zolpidem
Intervention descriptions: intervention 1: Commercially available lavender essential oil and diffuser. intervention 2: Physician directed, pre-prescribed. Study team does not prescribe zolpidem.

Protocol documents:
Prot_SAP_000.pdf: 
12/31/2019 
Lavender vs Zolpidem Sleep Quality During Diagnostic Polysomnography 
IRB: A19-156 
NCT: 04102345  
Clinical Study Protocol  and Statistical Analysis Plan
Amendment 1 Date: 31 December 2019 
Sponsor  
HealthPartners Institute 
This study will be conducted in compliance with the protocol, IND regulations and other applicable 
regulatory requirements. 
Confidential Information 
No use or disclosure of this document is permitted without prior written authorization from 
HealthPartners Institute 


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Participant Contact Project Narrative 
1.
Summary
A common problem associated with sleep studies (polysomnogram or PSGs) is “first night effect” (FNE), with
disruption of sleep, resulting in insufficient time to make a diagnosis or achieve effective therapy 1. Current
practice is to prescribe sleep aids or sleep medications to prevent FNE. Zolpidem (Ambien) is the most
commonly prescribed medication, but has several significant side effects, limiting its usefulness 2. Hence, it is
important to find an alternative that is safer, more acceptable and personable to patients. In this study we
propose to prospectively evaluate sleep related outcomes with lavender aromatherapy compared to those with
pre-medication prior to diagnostic or split night polysomnography (PSG).
2.
Study aims
Overall Objective: To determine if lavender aromatherapy is as effective as pre-prescribed zolpidem in
improving PSG quality, and reducing the need for repeating PSGs for a diagnostic or split night sleep study.
Primary Outcome: 
x
Sleep efficiency
Secondary Outcomes: 
x
A successful split night PSG or a diagnostic PSG and wake after sleep onset (WASO)
Exploratory Outcomes: 
x
Total sleep time (TST), sleep onset latency, REM sleep onset latency, Stage 3/4 sleep
percentage, Arousal index, side effects
3.
Background, Rationale, Significance
FNE is well described in both normal and pathological conditions in the literature 1. The main characteristics of
the first night effect are shorter total sleep time and REM sleep time, lower sleep efficiency, longer REM sleep
latency, and decreased slow wave sleep 1. This reduced sleep quality is probably due to multiple factors:
discomfort caused by electrodes, limitation of movements, and the unfamiliar environment of the sleep
laboratory. To improve recordings, the sleep lab offers individualization of the environment such as controlling
temperature, personal pillows and sound proofing. Despite these factors, there is a percentage of studies
reported (33-46%) that result in the need to either repeat the study or have the patient return to the lab for
titrating study 2,3. This results in increased cost as well as poorer patient experience 4.  Pre-medication with non-
benzodiazepines sleep aids has been shown to decrease the likelihood of FNE 2,3, however with side effects such
as falls and post-study confusion, it is important to find an alternative that is safer, more acceptable and
personable to patients 5.
Aromatherapy encompasses the therapeutic use of aromatic essential oils. These are ‘non-oily, highly fragrant
essences extracted from plants by distillation, which evaporate readily’ 6. Essential oils are usually presented as
massage oils or lotions, in herbal packets under a pillow, or in an ambient vapor machine. The mechanisms by
which they are thought to function by are: olfaction, topical absorption and/or ingestion through the oral cavity
7. Jimbo et al, proposes the action of aromatherapy begins from a smell molecule combined with a receptor
particular to each specific odor 8.  The smell molecule passes along the nasal cavity and adheres to the olfactory
epithelium.  The stimulus is then transmitted from the olfactory bulb to the higher sensory centers in the
cerebral cortex 9
Lavender (Lavender angustifolia) aromatherapy has a long history of being commonly used for promoting sleep 
10-17 with almost no side effects. Specifically relevant to this study, Goel and colleagues studied the effects of
lavender using PSG in young men and women in 2005. When compared to the controls, participants in the
lavender arm showed improvement in slow wave sleep, % sleep time, along with gender differentiated effects
on stage 2, REM sleep and wake after sleep onset latency 18.  In addition, the prospective study conducted by the
neuroscience research department with residents in memory care, showed an improvement of total sleep by 42


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minutes and increase in sleep efficiency by 6.31% with lavender 19 (manuscript submitted).  In this study, we 
hypothesize that lavender will improve sleep quality and reduce the need for repeat PSGs, as effectively as 
zolpidem.  
Aromatherapy is currently being utilized in many Regions Hospital departments with a positive patient response 
and experience.  In addition, the study conducted by the neuroscience research evaluating aromatherapy with 
total joint patients at Regions hospital showed; patients that chose aromatherapy report better patient 
satisfaction scores in regard to the control of pain.  In line with the triple aim, we think that this study will 
provide an opportunity to reduce total cost of care by reducing the number of failed diagnostic PSGs 
(affordability), resulting in earlier initiation of treatment (health), with improved patient experience 
(experience). In addition, lavender provides a better safety profile than any sedatives that are currently being 
used for diagnostic sleep studies.  
4.
Approach
a.
Study design
We propose to do a pragmatic clinical study by recruiting patients who are scheduled for their first in
center diagnostic or split night sleep study (PSG).  The overall goal for this study is to show that lavender
is as effective as Zolpidem (non-inferiority analysis) with regard to improvement of sleep quality and
usability of diagnostic PSGs with sleep efficiency as the primary outcome.
b.
Population
Briefly, we will use a convenience sample (non-random selection) to recruit patients (refer to pre-screen
form for recruiting patients). We plan to enroll about 144 patients, 120 who were prescribed sleep
medications and 24 who agree to use lavender aromatherapy. Study would be considered complete if
the enrollment was 24 or more in both groups. Patients who are not prescribed any sleep
medication/aids or chose not to use them, will be offered lavender aromatherapy as an alternative. The
sleep aids are prescribed by the referring doctor.  We will consent both patients who are prescribed/use
zolpidem during their diagnostic or split/night sleep study and those that chose lavender. At the
Maplewood center, there are 45-50 sleep studies scheduled per week. We estimate that there are 15-20
patients per week that are eligible for the study.
Inclusion Criteria
x
Age >=18 years
x
In-center diagnostic or split night sleep study (PSG)
c.
Data collection process
i.
Process steps for identification of patients or records
Refer to Figure 1. Briefly, when the patient checks in for the sleep study, the research team
reviews the chart to identify if the patient is potentially eligible for the study. The pre-screen
algorithm will be used.  The patients can qualify for the study
i.
If the patient is prescribed zolpidem (Ambien) by the referring doctor for the sleep study
or
ii.
If the patient has not been prescribed any sleep aid.
ii.
Recruitment
Refer to Figure 1
If the patient is eligible;
x
scenario (i), they will be offered to participate in the study  as part of the zolpidem group or
x
Scenario (ii), they will be offered to participate in the study as part of the Lavender group.


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In either scenarios, the patient will be consented. Consent will be collected from both groups to 
ensure we can use their sleep study results. 
Figure 1: Process Steps 
iii.
Data sources
x
EPIC – Chart review
x
Questionnaires
x
Polysomnogram (PSG) – Sleep Study
Refer to data dictionary for details regarding data that will be collected from each of the 
sources. 
Table 1: Terms and Definitions – for Sleep Study 
Term 
Definitions 
Total Recording Time 
(TRT) 
Total amount of time during which the patient is in bed with recording equipment 
activated 
Total Sleep Time (TST)
Total amount of sleep time scored during the total recording time; includes time from 
sleep onset to sleep offset and is distributed throughout the sleep time as minutes of 
Stage N1 sleep, Stage N2 sleep, Stage N3, and rapid eye movement (REM) sleep. 
Sleep efficiency 
Refers to percentage of total time in bed actually spent in sleep. It is calculated as sum of 
Stage N1, Stage N2, Stage N3, and REM sleep, divided by the total time in bed and 
multiplied by 100
Sleep Latency 
Time in minutes from ‘lights off’ that marks the starting of total recording time to the first 
epoch scored as sleep 
Wake after Sleep Onset 
(WASO) 
Periods of wakefulness occurring after defined sleep onset 
Apnea-Hypopnea Index
Number of apnea and hypopnea events per hour of sleep. 
Total Arousals 
# of transient phenomenon that may lead to wakefulness or only briefly interrupt sleep
Arousal index 
Total number of arousals x 60/TST (min) 
Sleep R Latency 
Rapid eye movement latency is the time from the sleep onset to the first epoch of REM 
sleep 
N1 Time 
Stage N1 Sleep Time 
N2 Time 
Stage N2 Sleep Time 
N3 Time 
Stage N3 Sleep Time 
REM Time 
Stage REM Sleep Time 
% N1
Minutes of N1 sleep stage × 100/TST 


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% N2 
Minutes of N2 sleep stage × 100/TST 
% N3 
Minutes of N3 sleep stage × 100/TST 
% REM 
Minutes of REM sleep stage × 100/TST 
Limb Movements 
Repetitive limb movements that may disrupt sleep 
Lights On 
Time that recording of sleep is terminated 
Lights Off 
Time at which the patient is allowed to fall asleep and marks the start of data that will be 
staged and analyzed. 
iv.
Process steps for data acquisition
At this visit, study staff will review the consent form with the patient. All of their questions will
be answered and they will be asked to demonstrate their understanding of participation. If they
would like to participate, they will sign the consent form. As scheduled, the patient will undergo
all the scheduled standard procedures for the diagnostic/split night study. Data will be extracted
and entered into REDCap by the study staff. No data outside of standard of care will be
collected.
d.
Intervention, treatments
Intervention: Aromatherapy with Lavender using a diffuser. To be eligible for this intervention, the
participant should not be prescribed any sleep aid. We will be using commercially available lavender
essential oil and diffusers. The study staff will fill the diffuser with water sufficient to run for about two
hours and recommended drops of oil will be added about 10 min before the lights are turned off. The
diffusers automatically turn off (mode – two hour shut off) when the water level falls below trigger in
about two hours.
Comparator: Oral Zolpidem. To be eligible for this group, the participant was prescribed zolpidem for
the sleep study by referring doctor, i.e., pre-prescribed physician-directed use of zolpidem. For this
group, the subjects will take the prescribed medication prior to the sleep study, as directed by the
physician.
Consent will be collected from both groups to ensure we can use their sleep study results.
e.
Outcomes/endpoint and other variable definitions, and instruments used
Sleep Efficiency: Refers to percentage of total time in bed actually spent in sleep. It is calculated as sum
of Stage N1, Stage N2, Stage N3, and REM sleep, divided by the total time in bed and multiplied by 100
A successful split night PSG or a diagnostic PSG: Is a binary outcome (yes/no) based on chart review. The
outcome will be inferred from documentation in the chart either in notes or PSG report showing a
successful split night or if a diagnosis is made or if a repeat PSG is ordered.
Wake after sleep onset (WASO): Periods of wakefulness occurring after defined sleep onset
Side effects: For both the interventions, the side effects will be inferred from post sleep study
questionnaire. The side effects will be described and compiled as a binary outcome (yes/no). This will be
used to report the safety profile of the two interventions as an exploratory outcome.
Please refer to attached data dictionary for details.
f.
Statistical analysis plan
Outcome measures will be graphed and visually assessed to determine if the planned analyses are
appropriate for the distribution of the outcomes. Descriptive statistics (means, standard deviations,


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frequencies, etc.) will be calculated overall and by group for the population demographic variables. We 
will then compare these characteristics between the two groups using t-tests, Wilcoxon, chi-square, and 
Fisher’s exact tests, as appropriate. Missing data will be considered to be missing at random and those 
subjects will be excluded from analysis. If a large proportion of data is missing (>10%), we will compare 
baseline characteristics between subjects with missing and non-missing data. No adjustment for 
multiple comparisons will be done.  
All statistical analyses will be performed in SAS Version 9.4. This analysis plan was written by and will be 
executed by Lauren Erickson. 
Primary Outcomes:  
Non-inferiority of sleep efficacy when using lavender versus zolpidem will be assessed using a one-sided, 
two-sample t-test. A noninferiority margin of 6% will be used for sleep efficiency (see power calculation 
for justification). The null hypothesis of inequality (difference is greater than or equal to 6%) is rejected 
in favor of the alternative hypothesis of equality (difference is less than margin) if the 1-sided p-value is 
less than 0.025. Due to the inflated probability of a type 1 error with unequal sample sizes, we will 
perform a sensitivity analysis in which a random sample of 24 active control participants will be 
compared to the lavender group. 
Secondary Outcomes:  
The secondary outcomes, rate of successful split night PSG and wake after sleep onset (WASO) latency 
will be analyzed similarly to the primary outcome. The noninferiority margins for successful split night 
PSG and WASO are 13.5% and 16 minutes, respectively, and are based on data from the three Lettieri 
studies2,3,20. 
Exploratory Outcomes:  
This is a descriptive aim. All values will be summarized using means and standard deviations or 
frequencies and percentages, as appropriate.  
g.
Power analysis or statement of precision
We reviewed 3 previous studies by Lettieri2,3,20 in which the pooled average sleep efficiency was 88.3%
for treatment groups versus 79.0% for controls. The absolute defference in sleep efficiency was 9.3% (CI:
6% - 12.3%). We, therefore, will define the lower bound of our confidence interval, 6%, as the operative
noninferiority margin.
It is estimated based on clinical experience that five times as many people have a sleep aid prescription
upon arrival to the sleep clinic. This was accounted for in the power calculation. Therefore, group sizes
of 24 (treatment) and 120 (control) achieve 80% power to detect non-inferirority using a one-sided two-
sample t-test. The noninferiority margin is 6%, the true difference between the means is assumed to be
0, the alpha level is 2.5% and the data are assumed to be drawn from populations with standard
deviations of 8.4 and 13.3.
This power calculation was conducted using the Non-Inferiority Test of the Difference of Two Means
function in PASS.
h.
Strengths and limitations
There is potential for bias due to non-randomized nature of study. We will compare baseline
characteristics to determine if the groups are inherently different.
5.
Setting/Environment/Organizational feasibility


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This study will be conducted at the Maplewood Regions Hospital Sleep Laboratory. This location is appropriate, 
as the sleep studies are scheduled at this location. We think that this will not disturb the standard practice at the 
lab as it adds about 5 to 10 min to normal care. The staff time for research is compensated and is supported by 
the department leaders. 
6.
Risks and Benefits
There are minimal psychological or physical risks from participating in this study. The largest risk is the
possibility of an allergic reaction or sensitivity to lavender. The risk of uncovering a previously unidentified
allergy is low.
7.
Data Confidentiality and Privacy
This study involves almost no risk. There is possibility of a confidential breach of the collected data, which
may result in risk for reputation and social risk. To minimize the risk of data breach, the records of the study
will be kept private. In any sort of report we might publish, we will not include any information that will make
it possible to identify the participant. Research records will be locked up or stored on a secure server with
password protection and only researchers on this study will be able to use the records.
8.
Timeline
Jan – April 2018 (Study Development) 
x
Prepare and Submit Application to Conduct Research/IRB
May – Nov 2019
x
Recruitment, Enroll Patients
x
Data Collection
Dec 2019– Mar 2020
x
Analyze and interpret data
x
Prepare abstract and manuscript
9.
Dissemination/Sharing Results/Integration and Impact
We will disseminate results through presentation at internal Sleep meetings, and medical exective committee
meetings for red fund. We also plan to publish the results in  conferences and peer-reviewed journal for sleep.
10. References
1.
Agnew Jr H, Webb WB, Williams RL. The First Night Effect: An Eeg Studyof Sleep. Psychophysiology.
1966;2(3):263-266.
2.
Lettieri CJ, Eliasson AH, Andrada T, Khramtsov A, Kristo DA. Does zolpidem enhance the yield of
polysomnography? Journal of Clinical Sleep Medicine. 2005;1(02):129-131.
3.
Lettieri CJ, Quast TN, Eliasson AH, Andrada T. Eszopiclone improves overnight polysomnography and continuous
positive airway pressure titration: a prospective, randomized, placebo-controlled trial. Sleep. 2008;31(9):1310-
1316.
4.
Brown LK. Quantum physics and polysomnography: can we prevent the act of measuring sleep from changing
sleep? Journal of Clinical Sleep Medicine. 2005;1(02):133-135.
5.
LLC s-aUS. Labeling-Package Insert - Ambien. 2018; FDA Label. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019908s042lbl.pdf. Accessed Sep 26 2018, 2018.
6.
Tisserand R. Aromatherapy : to heal and tend the body. Santa Fe, N.M.: Lotus Press; 1988.
7.
Buckle J. Clinical aromatherapy and touch: complementary therapies for nursing practice. Critical care nurse.
1998;18(5):54-61.
8.
Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K. Effect of aromatherapy on patients with Alzheimer's
disease. Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society. 2009;9(4):173-179.


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9.
Axel R. The molecular logic of smell. Scientific American. 1995;273(4):154-159.
10.
Buckle J. Clinical aromatherapy: Essential oils in practice. Elsevier Health Sciences; 2014.
11.
Holmes C, Ballard C. Aromatherapy in dementia. Advances in psychiatric treatment. 2004;10(4):296-300.
12.
Forrester LT, Maayan N, Orrell M, Spector AE, Buchan LD, Soares-Weiser K. Aromatherapy for dementia.
Cochrane Database Syst Rev. 2014;2:CD003150.
13.
Henry J, Rusius C, Davies M, Veazey-French T. Lavender for night sedation of people with dementia.
International Journal of Aromatherapy. 1994;5(2):28-30.
14.
Wolfe N, Herzberg J. LETTER TO THE EDITOR. Can Aromatherapy Oils Promote Sleep in Severely Demented
Patients? International journal of geriatric psychiatry. 1996;11(10):926-927.
15.
Goel N, Kim H, Lao RP. An olfactory stimulus modifies nighttime sleep in young men and women. Chronobiology
International. 2005;22(5):889-904.
16.
Lillehei AS, Halcon LL. A systematic review of the effect of inhaled essential oils on sleep. J Altern Complement
Med. 2014;20(6):441-451.
17.
Lillehei AS, Halcón LL, Savik K, Reis R. Effect of Inhaled Lavender and Sleep Hygiene on Self-Reported Sleep
Issues: A Randomized Controlled Trial. The Journal of Alternative and Complementary Medicine. 2015;21(7):430-
438.
18.
Goel N, Kim H, Lao RP. An olfactory stimulus modifies nighttime sleep in young men and women. Chronobiology
international. 2005;22(5):889-904.
19.
Leah R Hanson PhD BK, MBBS, PhD, Amanda Cagan BA, Katie Rinehimer, Logan Stuck MS, Thomas Flottemesch
PhD, Jayne Clairmont BS, Linda Sackett-Lundeen, Erhard Haus, MD. Lavender Essential Oil Improved Sleep in
Residents of a Memory Care Assisted Living Facility2018.
20.
Lettieri CJ, Collen JF, Eliasson AH, Quast TM. Sedative use during continuous positive airway pressure titration
improves subsequent compliance: a randomized, double-blind, placebo-controlled trial. Chest.
2009;136(5):1263-1268.