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Trial registered on ANZCTR


Registration number
ACTRN12618001493235
Ethics application status
Approved
Date submitted
29/08/2018
Date registered
5/09/2018
Date last updated
26/11/2018
Date data sharing statement initially provided
26/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Do placebos that elicit side effects enhance the placebo effect for sleep compared with conventional placebos that only contain lactose fibres?
Scientific title
Do active placebos enhance the placebo effect for sleep compared with benign placebos? A double-blind randomised controlled trial in healthy adults
Secondary ID [1] 295950 0
None
Universal Trial Number (UTN)
Nil known
Trial acronym
Nil known
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Sleep difficulty 309456 0
Condition category
Condition code
Neurological 308294 308294 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be recruited under the guise of a study testing a new formulation of an antihistaminic drug containing beetroot extract as an antioxidant efficacy booster, but no active treatment is actually delivered. Instead, after one week of baseline measures participants will be randomised to one of three groups: a conventional benign placebo group, an active placebo group, or to a no-treatment control group. Participants randomised to the benign and active placebo groups will be led to believe they are receiving the antihistaminic drug. The no-treatment control group will be told that they will not receive treatment and will instead serve as a control group for the natural course of their sleep difficulty and daily symptoms.

The placebo capsules will be made of gelatine. The benign placebo group will receive four conventional placebo capsules per day for 7 days containing only lactose fibres as filler material. The active placebo group will receive four capsules per day for 7 days containing each 500 mg of the food colour E 162, i.e. beetroot extract and 250 mg oxalic acid to stabilise and guarantee the absorption of the beetroot extract. The intention of the active placebo is to produce beeturia, i.e. a red-ish colouration of the urine to simulate side effects.
Adherence will be assessed using a daily participant diary. Additionally, participants will need to return the capsule container containing all capsules they haven't taken at the end of the study.
Intervention code [1] 312276 0
Treatment: Other
Comparator / control treatment
Benign placebo group and no-treatment group
Control group
Placebo

Outcomes
Primary outcome [1] 307266 0
Insomnia severity assessed using the Insomnia Severity Index (ISI)
Timepoint [1] 307266 0
Baseline (assessed at a single timepoint on the day starting treatment, for the 7 nights period prior to receiving treatment)
Treatment (assessed at a single timepoint on the day after finishing 7 nights of treatment, for the 7 nights period receiving treatment)
Primary outcome [2] 307267 0
Self-reports of urine colouration, using the same 4-point scale as the GASE (0=not present, 1=mild, 2=moderate, 3=severe)
Timepoint [2] 307267 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [1] 351307 0
Sleep quality assessed using the Pittsburgh Sleep Quality Index (PSQI)
Timepoint [1] 351307 0
Baseline (assessed at a single timepoint on the day starting treatment, for the 7 nights period prior to receiving treatment)
Treatment (assessed at a single timepoint on the day after finishing 7 nights of treatment, for the 7 nights period receiving treatment)
Secondary outcome [2] 351308 0
Sleep duration (self-report) using the Consensus Sleep Diary Version C (CSD-C)
Timepoint [2] 351308 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [3] 351309 0
Reports of daily symptoms using the General Assessment of Side Effects (GASE)
Timepoint [3] 351309 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [4] 351310 0
Depression, anxiety, and stress using the Depression Anxiety Stress Scale (DASS-21)
Timepoint [4] 351310 0
Baseline (assessed at a single timepoint on the day starting treatment, for the 7 nights period prior to receiving treatment)
Treatment (assessed at a single timepoint on the day after finishing 7 nights of treatment, for the 7 nights period receiving treatment)
Secondary outcome [5] 351311 0
Quality of life using the World Health Organisation’s quality of life assessment (WHOQOL-BREF)
Timepoint [5] 351311 0
Baseline (assessed at a single timepoint on the day starting treatment, for the 7 nights period prior to receiving treatment)
Treatment (assessed at a single timepoint on the day after finishing 7 nights of treatment, for the 7 nights period receiving treatment)
Secondary outcome [6] 351313 0
Treatment Satisfaction Questionnaire for Medication version II (TSQM-II)
Timepoint [6] 351313 0
Post-treatment (at the end of the seven-night period receiving treatment)
Secondary outcome [7] 351413 0
Sleep duration (objective) using Actigraphy (Philips Actiwatch 2)
Timepoint [7] 351413 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)

Eligibility
Key inclusion criteria
(1) at least 18 years of age
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(1) taking prescription medication (other than the contraceptive pills); (2) pregnancy, trying to conceive, or breastfeeding; (3) received treatment for sleep difficulty in the last three months; (4) antihistamine, beetroot, or lactose allergy, or any other intolerances; (5) abnormal/deficient kidney functioning or any other medical condition

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)
Allocation involved an independent holder of the allocation schedule who was “off-site”
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation (simple randomisation: participants drawing a number from an envelope without replacing the number)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
SAMPLE SIZE CALCULATIONS
Following a power analysis, we will require at least 24 participants finishing the study in each group. The analysis was conducted with the software environment R version 3.4.2 (R Core Team, 2018) and the pwr package using three groups, an effect size of f = .4, a significance level of alpha = .05, and a power of 1-beta = .85. For the power analysis, we referred to an earlier study about the placebo effect in sleep to calculate an appropriate effect size estimate for the placebo effect between the no-treatment group and the placebo groups (Colagiuri et al., 2012). Due to expected attrition, recruitment will go on until we reach the necessary numbers in each group. Participant data will be excluded if they did not answer daily measures at least four nights out of seven for the baseline and intervention week, or if they did not honestly fill out questionnaires (i.e. men reporting menstruation pain, contradicting side effects, or sleep values that are humanly impossible). Adherence is defined as taking at least 2 capsules on at least 5 out of 7 nights. Nonadherence will lead to exclusion from analysis. We will exclude participants from the analysis that reportedly experienced the flu, common cold, or gastroenteritis for more than one day.

BASELINE CHARACTERISTICS
Chi-squared tests and one-way analysis of variance will be used to compare baseline characteristics across the three groups. Baseline characteristics that differ between the three groups with a p-value of < .1 will be included in primary and secondary analyses as covariates.

PRIMARY AND SECONDARY ANALYSES
Changes in outcome measures (ISI, PSQI, CSD-C, Actigraphy, GASE, DASS-21, WHOQOL-BREF, TSQM-II) between the baseline and intervention week will be analysed using analysis of co-variance (ANCOVAs) with orthogonal planned contrasts to analyse differences 1) between the placebo groups and the no-treatment group, 2) between the active and benign placebo group. Baseline scores for each respective outcome measure will be included as covariates. In case assumptions for ANCOVAs are not fulfilled, we will refer to generalised linear mixed models (GLMMs) as recommended by Jakobsen et al., (2015).
All analyses will be carried out using the software environment R version 3.5.1 (R Core Team, 2018).

MIDPOINT MANIPULATION CHECK
After at least 12 participants in each group have completed the study an interim midpoint manipulation check analysis will be conducted to evaluate if the active placebo is eliciting changes in urine colour (the target ‘side effect’). This will involve comparing reports of changes in urine colouration across groups. The study will only be continued if 50 percent or more of participants in the active placebo group do report at least one occurrence of red urine colouration during the intervention week, and if the rate of reporting red urine in the active placebo group is at least double that of the benign placebo and control groups during the intervention week. No other study outcomes will be assessed at this point, unless the decision is made to terminate the study. If the study does continue, then the researchers will be re-blinded.

EXPLORATORY ANALYSIS
We will conduct mediation analyses to examine the influence of expectations regarding the (1) treatment efficacy, and (2) anxiety about side effects (both operationalised as visual analogue scales ranging from 0 (= “not at all”) to 100 (= “completely”; assessed at a single timepoint post-randomisation, but prior to receiving treatment), (3) treatment satisfaction (using the Treatment Satisfaction Questionnaire for Medication version II amended to ask about expected satisfaction (TSQM-II-future); assessed at a single timepoint post-randomisation, but prior to receiving treatment), and (4) perceived sensitivity to medications (using the Perceived Sensitivity to Medicines (PSM) scale; assessed at a single timepoint post-randomisation, but prior to receiving treatment) on all primary and secondary outcomes, if there is a statistically significant difference between the two placebo groups in the primary and secondary analyses. The mediation analyses will be calculated using the mediation package (Tingley et al., 2013) within the software environment R version 3.5.1 (R Core Team, 2018).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
21/05/2018
Date of last participant enrolment
Anticipated
19/10/2018
Actual
17/10/2018
Date of last data collection
Anticipated
4/11/2018
Actual
31/10/2018
Sample size
Target
72
Accrual to date
Final
71
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 23834 0
2006 - The University Of Sydney

Funding & Sponsors
Funding source category [1] 300545 0
University
Name [1] 300545 0
University of Sydney
Country [1] 300545 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 300031 0
None
Name [1] 300031 0
Address [1] 300031 0
Country [1] 300031 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301341 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 301341 0
Human Ethics Office
Margaret Telfer Building (K07)
University of Sydney
Camperdown NSW 2006
Ethics committee country [1] 301341 0
Australia
Date submitted for ethics approval [1] 301341 0
29/01/2018
Approval date [1] 301341 0
20/02/2018
Ethics approval number [1] 301341 0
2018/107

Summary
Brief summary
The underlying principle of trials evaluating the effectiveness of pharmacological treatments is to compare a drug against a placebo. The difference in effectiveness is then attributed to the active ingredient of the drug. Typically, placebos are designed to resemble the drug as much as possible, but conventional placebos that only contain lactose fibres do not elicit side effects and therefore do not fully resemble all features of the drug. The primary aim of this study is to evaluate if side effects increase the effectiveness of an otherwise inactive placebo treatment. We therefore developed an active placebo that will elicit side effects, but otherwise has no effect on sleep. We hypothesise that active placebos eliciting side effects demonstrate a larger placebo effect for sleep compared with conventional placebos that only contain lactose fibres.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86674 0
Mr Christoph Werner
Address 86674 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 86674 0
Australia
Phone 86674 0
+61 466 214 021
Fax 86674 0
Email 86674 0
[email protected]
Contact person for public queries
Name 86675 0
Christoph Werner
Address 86675 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 86675 0
Australia
Phone 86675 0
+61 466 214 021
Fax 86675 0
Email 86675 0
[email protected]
Contact person for scientific queries
Name 86676 0
Christoph Werner
Address 86676 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 86676 0
Australia
Phone 86676 0
+61 466 214 021
Fax 86676 0
Email 86676 0
[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?
All of the individual participant data collected during the trial, after de-identification will be available on the Open Science Framework.
When will data be available (start and end dates)?
Immediately following publication (scientific journal article or thesis), no end date.
Available to whom?
Anyone who wishes to access it.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Unrestricted access via the Open Science Framework: https://osf.io/xufc6/


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
483Study protocol   



Results publications and other study-related documents

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