ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12611000847910

Ethics application status

Approved

Date submitted

27/07/2011

Date registered

10/08/2011

Date last updated

7/07/2022

Date data sharing statement initially provided

27/02/2020

Date results provided

27/02/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

Diet Exercise and ARmodafinil for treatment resistant sleep apnea (DEAR)

Scientific title

Factorial trial for treating sleepy overweight or obese sleep apnea patients who cannot use standard treatments comparing hypocaloric diet with high protein/ low glycemic index diet for fat mass reduction and simultaneously comparing armodafinil with placebo for improving simulated driving ability and neuro-behavioural functioning.

Secondary ID [1]

Nil

Universal Trial Number (UTN)

Trial acronym

DEAR

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Sleep Apnea

Obesity

Condition category

Condition code

Respiratory

Sleep apnoea

Diet and Nutrition

Obesity

Injuries and Accidents

Other injuries and accidents

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a factorial trial which means we are testing two types of intervention in the same patients starting at the same time. This means that all patients will be in both the Drug trial and the Lifestyle trial at the same time until the final 3 months of the trial when they will only be on the diet. This is also a parallel study design which means once a patient has been randomly allocated to their intervention groups they will not crossover to the other intervention program. At baseline patients will see an exercise physiologist and dietitian for approximately 1.5 hours in an individual consultation. They will then participate in individual sessions conducted by the exercise physiologist/dietitian running for 1.5-2 hours at 2 weeks, 1 month and 4.5 month timepoints. Patients will also recieve a phonecall from exercise physiologist/dietitian at 1.5 months to review their progress. Further approx 1 hour individual consultations at 6, 9 and 12 months to review their progress with the dietitian and exercise physiologist. The Drug Trial is a Superiority Trial (i.e. is the drug better than the placebo?): 3x50mg tablets (ie 150mg) of Armodafinil or placebo once in the morning for 9 months. The Lifestyle Trial is an Equivalence Trial (i.e. are these two diets similarly effective interventions?): Participants will also be randomly allocated for 12 months to either a low GI/high protein diet or a standard low calorie diet as a part of an individualized lifestyle modification program also providing exercise and lifestyle recommendations.

Intervention code [1]

Lifestyle

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

Diet: low GI/high protein diet compared with standard low calorie diet. The program will be individualized.
Drug: Control group placebo- 3 x 50mg (ie 150mg) sugar pill tablets in the morning for 9 months will be the control for 3 x 50mg (ie 150mg) Armodafinil.

Control group

Placebo

Outcomes

Primary outcome [1]

Primary outcome for pharmaceutical trial: Improvement in simulated driving ability quantified by standard deviation in lane position as measured by the AusEd driving simulator in the last 30 minutes of a 90 minute drive.

Timepoint [1]

Baseline, 3 months, 6 months and 9 months.

Primary outcome [2]

Primary outcome for diet trial: loss of fat mass (grams) as measured by a DXA scan at 12 months.

Timepoint [2]

Baseline, 6 months and 12 months.

Secondary outcome [1]

Pharmaceutical trial will have 3 secondary outcomes of equal importance:
A) Sleepiness related quality of life as measured by the functional outcomes of sleepiness questionnaire (FOSQ)

Timepoint [1]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [2]

Pharmaceutical trial will have 3 secondary outcomes of equal importance:
B) Sleepiness related quality of life as measured by Epworth Sleepiness Scale (ESS).

Timepoint [2]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [3]

Pharmaceutical trial will have 3 secondary outcomes of equal importance:
C) Loss of fat mass (grams) as measured by a DXA scan.

Timepoint [3]

baseline, 6 months and 12 months

Secondary outcome [4]

Diet trial will have 4 secondary outcomes of equal importance:
A) weight (kg)

Timepoint [4]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [5]

Diet trial will have 4 secondary outcomes of equal importance:
B) waist circumference (cm)

Timepoint [5]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [6]

Diet trial will have 4 secondary outcomes of equal importance:
C) Sleep apnea severity as measured by the apnea hypopnea index on an overnight polysomnogram

Timepoint [6]

Baseline, 6 months and 12 months

Secondary outcome [7]

Diet trial will have 4 secondary outcomes of equal importance:
D) Impact of Weight on Quality of Life Questionnaire (IWQOL)

Timepoint [7]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [8]

Tertiary outcome: Reduction in the Framingham cardiovascular disease risk score

Timepoint [8]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [9]

Tertiary outcome: lipid profile (LDL, HDL, triglycerides) via fasting blood test

Timepoint [9]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [10]

Tertiary outcome: HOMA index in all participants and HBA1c for those participants who are diabetic at baseline via fasting blood test.

Timepoint [10]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [11]

Tertiary outcome: Activity counts via actiwatch and activity questionnaire

Timepoint [11]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [12]

Tertiary outcome: Resting blood pressure

Timepoint [12]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [13]

Explanatory/efficacy outcome: Energy intake, macronutrient percentage contributions, fat intake, fibre intake, glycaemic load (where measurable). These will be measured by 3 day food and activity diaries preceeding visits and analysed using FoodWorks Software.

Timepoint [13]

Baseline, 3 months, 6 months, 9 months and 12 months

Secondary outcome [14]

Explanatory/efficacy outcome: Pharmacogenomics. The Val158Met polymorphism of COMT has been reported to explain the effectiveness of modafinil due to it's effects in the dopaminergic system. We will genotype all patients using high Resolution melt analysis for the val/val met/met or met/val polymorphisms with the hypothesis that val/val subtypes will have superior response to met/met types with met/val types intermediate.

Timepoint [14]

Genotyping at baseline will be compared to outcomes relevant to the pharmaceutical intervention

Secondary outcome [15]

Tertiary outcome: Working memory measured by the n-back (2-back version). The n-back is a computerised memory task where participants monitor a series of stimuli (in this case letters apearing at different locations on the computer screen) and respond when a stimulus is presented that is the same as the one presented "n" times previously. In this case the participant must press a button on the computer keyboard if the letter that appears on the screen is in the same location as the one 2 times previously.

Timepoint [15]

Baseline, 3 months, 6 months and 9 months.

Secondary outcome [16]

Tertiary outcome: mean reaction time and number of lapses (<500ms reaction time) on the psychomotor vigilance task

Timepoint [16]

Baseline, 3 months, 6 months and 9 months.

Secondary outcome [17]

Tertiary outcome: Other measurements of driving performance on the AusEd driving simulator including number of crashes, standard deviation in speed variability and secondary reaction time.

Timepoint [17]

Baseline, 3 months, 6 months and 9 months.

Secondary outcome [18]

Tertiary outcome: Bioimpedence analysis to calculate fat mass in the event of patient dropout or data loss of DXA.

Timepoint [18]

Baseline, 3 months, 6 months, 9 months and 12 months.

Eligibility

Key inclusion criteria

1. Males & Females aged 18-70 years.
2. General or central obesity. BMI:>=27 but less than 40kg/m2 or waist circumference >=80cm for women and >=94cm for men.
3. Moderate-severe and symptomatic OSA (Apnea Hypopnea Index (AHI) >= 15/hr with concomitant daytime sleepiness ESS>=10 or clinical report of disturbing daytime sleepiness).
4. Ambulatory and community-dwelling.
5. Hold a current drivers license.
6. Must have rejected CPAP and MAS within the past 2 years. Otherwise patients will be encouraged to recommence a standard mechanical treatment.

Minimum age

18 Years

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Pregnancy or lactation- the effects of this drug on pregnant women or their unborn or breastfed children is unknown and the obesity reduction program is NOT suitable for pregnant or lactating women. CAUTION: Fertile women should be warned that this class of medication is known to interfere with contraceptive pills and they should employ additional contraceptive strategies.
2. Severe hypertension (SBP>=180 and/or DBP>=110).
3. Patients with moderate-severe skin allergies and/or eczema should not be enrolled due to side effects of this drug class being reported in these patients.
4. Shift workers who rotate to night shift.
5. Unstable Angina / Heart Failure (NYHA Class III and IV)/ Stroke.
6. Current use of device based treatment (CPAP, MAS or positional treatment) OR upper airway surgery with 6 months.
7. Cognitive impairment / Psychiatric disorder / Physically unable to participate.
8. Severe OSA (minimum oxygen saturation < 65% or RDI > 100) or excessively sleepy patients at increased risk for driving-related accidents requiring immediate treatment.
9. More than 20% of AHI with central apneas.
10. Previous use of Modafinil or Armodafinil
11. Alcohol or Caffeine dependence as patients undergo multiple 24 hours periods in our sleep laboratory without access to these.
12. Cytochrome P450 affecting drugs
13. Patients with severe tonsillar enlargement or nasal obstruction will be referred to an ENT surgeon for surgical intervention before an additional attempt at CPAP or MAS use.
14. Severe Haemophobics as we must take blood as a safety check in this study.
15. Participation in a drug trial or lifestyle modification program within the preceding three months.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Only eligible adults providing written informed consent, according to the protocol approved by the local ethics committee, will be enrolled into the trial. OSA patients will be enrolled sequentially according to two pre-allocated randomisation lists stratified at the cut-line between Class 1 and 2 obesity (Class 1 30-35 BMI; Class 2 35-40 BMI) and randomised to a 2 x 2 factorial design in either: 1. Armodafinil (3x50mg tablets (ie 150mg): morning) OR an identical placebo for 9 months. 2. Standard low calorie diet, lifestyle and exercise program OR a low GI and High protein diet, lifestyle and exercise program. Allocation concealment in the drug trial will be achieved by numbered containers of the drug that have been prepared according to entry numbers into the trial. This list has been generated by an independent statistician and investigators in the trial will not have access to this list until the end of the trial. Allocation concealment in the diet trial will be achieved via sealed opaque envelopes prepared by the trial epidemiologist who will play no role in the recruitment of patients.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

computerised random sequence generator.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Factorial

Other design features

Researchers and patients will not be blinded to lifestyle treatment allocation in this open-label trial as blinding is not feasible in these types of interventions.
All researchers and patients will be blinded to drug allocation.

Phase

Phase 2 / Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

22/06/2012

Actual

6/07/2012

Date of last participant enrolment

Anticipated

Actual

8/10/2014

Date of last data collection

Anticipated

Actual

9/10/2015

Sample size

Target

130

Accrual to date

Final

113

Recruitment in Australia

Recruitment state(s)

NSW

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Other Collaborative groups

Name

Woolcock Institute for Medical Research

Address

PO Box M77 Missenden Rd
Camperdown 2050
NSW

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

SSWAHS Human Ethics Review Committee

Ethics committee address [1]

c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Rd
CAMPERDOWN NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/03/2011

Approval date [1]

29/05/2012

Ethics approval number [1]

HREC/11/RPAH/119 X11-0088 Protocol version 4.

Summary

Brief summary

This is a clinical trial for patients with sleep apnea who cannot use the standard treatments: continuous positive airway pressure machines or mandibular advancement splints. In this study we are testing two types of treatments at the same time, one a drug-based treatment and one a diet and exercise treatment, in combination we hope these will reduce sleep apnea and control its daytime symptoms. Patients will be randomly assigned to one of two types of diet for 12 months, a standard low calorie diet versus a diet which is high in protein and low in glycemic index (Low GI). Both of these groups will participate in the same lifestyle program promoting activity, exercise and healthier choices.
The drug based treatment is testing a drug called Armodafinil for 9 months. Armodafinil is a drug that promotes wakefulness but does not improve your sleep apnea directly. So we think that it may improve other secondary outcomes including ability to concentrate, particularly whilst driving. We will be comparing Armodafinil to an inert placebo which does not have any active ingredient.

Trial website

Trial related presentations / publications

None

Public notes

Contacts

Principal investigator

Name

Prof Ron Grunstein

Address

Woolcock Institute for Medical Research
PO Box M77 Missenden Rd
Camperdown
NSW 2050
Australia

Country

Australia

Phone

+61 2 9114 0000

Fax

[email protected]

Contact person for public queries

Name

Julia Chapman

Address

Woolcock Institute of Medical Research
Postal Address: PO Box M77
Missenden Road
NSW 2050
Physical Address: 431 Glebe Point Rd
Glebe NSW 2037

Country

Australia

Phone

+61 2 9114 0449

Fax

+61 2 9114 0011

[email protected]

Contact person for scientific queries

Name

Nathaniel Marshall

Address

Woolcock Institute of Medical Research
Postal Address: PO Box M77
Missenden Road
NSW 2050
Physical Address: 431 Glebe Point Rd
Glebe NSW 2037

Country

Australia

Phone

+61 2 9351 0829

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Individual participant underlying published results only.

When will data be available (start and end dates)?

Data will be made available upon request, after publication, with no end date determined.

Available to whom?

Data will be made available upon request, after publication and will be determined upon negotiation with researchers who provided a methodologically sound proposal.

Available for what types of analyses?

Any purpose.

How or where can data be obtained?

Secure data transfer and signed data access agreement. Contact: [email protected]

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Agreement between electronic and paper Epworth Sleepiness Scale responses in obstructive sleep apnoea: Secondary analysis of a randomised controlled trial undertaken in a specialised tertiary care clinic.	2018	https://dx.doi.org/10.1136/bmjopen-2017-019255
Embase	Does armodafinil improve driving task performance and weight loss in sleep apnea? A randomized trial.	2018	https://dx.doi.org/10.1164/rccm.201712-2439OC
Embase	Intra-individual stability of NREM sleep quantitative EEG measures in obstructive sleep apnea.	2019	https://dx.doi.org/10.1111/jsr.12838
Embase	The effect of armodafinil on sleep spindles in obstructive sleep apnea: Secondary analyses of a randomised placebo-controlled trial.	2020	https://dx.doi.org/10.1111/jsr.13181
Embase	The effect of armodafinil on sleep spindles in obstructive sleep apnea: Secondary analysis of a randomized placebo-controlled trial.	2020	https://dx.doi.org/10.1093/sleep/zsaa056.668
Embase	Does craniofacial morphology relate to sleep apnea severity reduction following weight loss intervention? A patient-level meta-analysis.	2021	https://dx.doi.org/10.1093/sleep/zsaa207

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically