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Trial registered on ANZCTR


Registration number
ACTRN12618002048268
Ethics application status
Approved
Date submitted
19/12/2018
Date registered
21/12/2018
Date last updated
21/12/2018
Date data sharing statement initially provided
21/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Do placebos that elicit side effects influence perceived treatment allocation and enhance the placebo effect for sleep compared with conventional placebos?
Scientific title
Do active placebos influence perceived treatment allocation and enhance the placebo effect for sleep compared with benign placebos? A double-blind randomised controlled trial in sleep-impaired adults
Secondary ID [1] 296916 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 310868 0
Condition category
Condition code
Mental Health 309538 309538 0 0
Studies of normal psychology, cognitive function and behaviour

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 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 blind towards their treatment condition, and told they are receiving either the antihistaminic drug or placebos. 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 seven consecutive days containing only lactose fibres as filler material. The active placebo group will receive four capsules per day for seven consecutive days containing each 500 mg of the food colour E 162, i.e. beetroot extract and 250 mg oxalic acid to stabilize 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 have not taken at the end of the study.
Intervention code [1] 313188 0
Treatment: Other
Comparator / control treatment
Benign placebo group and no-treatment group
Control group
Placebo

Outcomes
Primary outcome [1] 308488 0
Perceived treatment allocation (PTA), using a forced-choice question with the options (0=no-treatment group, 1=placebo group, 2=doxylamine group)
Timepoint [1] 308488 0
Baseline (assessed at a single timepoint post-randomisation, but prior to receiving treatment)
Mid-treatment (assessed at a single timepoint on the day after 3 nights of treatment
Post-treatment (assessed at a single timepoint at the end of the seven-night period receiving treatment)
Primary outcome [2] 308489 0
Insomnia severity assessed using the Insomnia Severity Index (ISI)
Timepoint [2] 308489 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 [1] 355140 0
Total sleep time (self-report) using the Consensus Sleep Diary Version C (CSD-C)
Timepoint [1] 355140 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [2] 355141 0
Sleep onset latency (self-report) using the Consensus Sleep Diary Version C (CSD-C)
Timepoint [2] 355141 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] 355142 0
Reports of daily symptoms using an amended 10-item version of the General Assessment of Side Effects (GASE). We shortened the GASE to only include the most relevant items and added a question regarding urine colouration. Additionally, we changed the items from a 4-point multiple choice about the severity of the symptoms to a visual analogue scale (VAS) ranging from 0 (= “not present”) to 100 (= “severe”), with 33 (= “mild”) and 66 (= “moderate”)
Timepoint [3] 355142 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] 355143 0
Quality of life using the World Health Organisation’s quality of life assessment (WHOQOL-BREF)
Timepoint [4] 355143 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] 355144 0
Total sleep time (objective) using Actigraphy (Activinsights, GENEActive Original)
Timepoint [5] 355144 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [6] 355145 0
Sleep onset latency (objective) using Actigraphy (Activinsights, GENEActive Original)
Timepoint [6] 355145 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [7] 355146 0
Participants’ certainty of their choice regarding perceived treatment allocation (cPTA), operationalised as VAS ranging from 0 (= “not certain at all”) to 100 (= “absolutely certain”)
Timepoint [7] 355146 0
Baseline (assessed at a single timepoint post-randomisation, but prior to receiving treatment)
Mid-treatment (assessed at a single timepoint on the day after 3 nights of treatment
Post-treatment (assessed at a single timepoint at the end of the seven-night period receiving treatment)

Eligibility
Key inclusion criteria
(1) at least 18 years of age; (2) threshold score of >=10 on the ISI
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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; (6) gastric problems or sensitive stomach (e.g. acid reflux)

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using the randomisation module included in REDCap stratified by sex and baseline ISI (categorised as <10, 10-15, >15)
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
None
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
SAMPLE SIZE CALCULATIONS
For the sample size estimation regarding perceived treatment allocation, we referred to an earlier study about the influence of feedback on placebo effects in double-blind RCTs (Colagiuri & Boakes, 2010). Based on their results and adjusting for the fact that our active placebo elicits the desired side effect in 50% of participants compared to the 100% of feedback participants got in Colagiuri and Boakes (2010), the required sample size would be 13 per group (f =0 .895, alpha = .05, and 1-beta = .90).
For the sample size estimation regarding the placebo effect on the sleep outcome, we referred to a study about influences of active placebos compared to benign placebos on pain (Rief & Glombiewski, 2012). The power analysis resulted in a required completer sample of at least 46 participants in each of the placebo groups (f = 0.34, alpha = .05, and 1-beta = .90).
The power analyses were conducted with the software environment R version 3.5.1 (R Core Team, 2018) and the pwr package (Champely et al., 2018) for general linear models using two groups. Based on these power analyses we decided to allocate participants to the three groups using a 2:2:1 randomisation ratio for active placebo: benign placebo: control, until we reach 46 participants in the two respective placebo groups and 23 participants in the no-treatment group. This is because we are primarily interested in the difference perceived treatment and sleep outcomes between the two placebo groups, with the no treatment group serving only as a measure of the overall placebo effect. Due to expected attrition, recruitment will go on until we reach the necessary numbers in each group.

DATA-BASED EXCLUSIONS
Participant data will be excluded if they do 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 impossible, e.g. sleeping for 25 hours per day). Adherence is defined as taking at least 2 capsules on at least 5 out of 7 nights, with nonadherence leading to exclusion from analysis. We will also exclude participants from the analysis that reportedly experienced the flu, common cold, or gastroenteritis for more than one day, as this may confound the sleep and side effect data.

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. The Depression Anxiety Stress Scale (DASS-21) at baseline (assessed at a single timepoint on the day starting treatment, for the 7 nights period prior to receiving treatment) will be included as an additional baseline characteristic.


PRIMARY AND SECONDARY ANALYSES
Changes in outcome measures (PTA, ISI, CSD-C, GASE, Actigraphy, WHOQOL-BREF, cPTA) between the baseline and intervention week will be analysed with analysis of co-variance (ANCOVAs), using 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 the mentioned statistical models 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), with alpha = .05.

EXPLORATORY ANALYSIS
We will conduct mediation analyses to examine the influence of expectations regarding the (1) treatment efficacy (VAS ranging from 0 (= “not effective at all”) to 100 (= “highly effective”), and (2) side effects (VAS ranging from 0 (= “not likely at all”) to 100 (= “highly likely”). Both VASs are assessed at a single timepoint post-randomisation, but prior to receiving treatment. Additionally, (3) perceived sensitivity to medications (using the Perceived Sensitivity to Medicines (PSM) scale; assessed at a single timepoint pre-randomisation) 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
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 25235 0
2006 - The University Of Sydney

Funding & Sponsors
Funding source category [1] 301487 0
University
Name [1] 301487 0
The University of Sydney
Address [1] 301487 0
The University of Sydney
Camperdown NSW 2006
Country [1] 301487 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] 301181 0
None
Name [1] 301181 0
Address [1] 301181 0
Country [1] 301181 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302231 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 302231 0
Human Ethics Office
Margaret Telfer Building (K07)
University of Sydney
Camperdown NSW 2006
Ethics committee country [1] 302231 0
Australia
Date submitted for ethics approval [1] 302231 0
Approval date [1] 302231 0
20/02/2018
Ethics approval number [1] 302231 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 (or other inert substances) do not elicit side effects and therefore do not fully resemble all features of the drug. We therefore developed an active placebo that will elicit side effects, but otherwise has no effect on sleep. The main aim of this study is to test whether participants who are given a placebo under ‘double-blind’ conditions are more likely to believe that they are been given a real medication if they receive an active placebo eliciting side effects, compared with a benign placebo that only contains lactose fibres. Additionally, we will evaluate if side effects increase the effectiveness of an otherwise inactive placebo treatment. We hypothesise that active placebos demonstrate a larger placebo effect for sleep compared with conventional placebos.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89522 0
Mr Christoph Patrick Werner
Address 89522 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 89522 0
Australia
Phone 89522 0
+61 466214021
Fax 89522 0
Email 89522 0
christoph.werner@sydney.edu.au
Contact person for public queries
Name 89523 0
Mr Christoph Patrick Werner
Address 89523 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 89523 0
Australia
Phone 89523 0
+61 466214021
Fax 89523 0
Email 89523 0
christoph.werner@sydney.edu.au
Contact person for scientific queries
Name 89524 0
Mr Christoph Patrick Werner
Address 89524 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 89524 0
Australia
Phone 89524 0
+61 466214021
Fax 89524 0
Email 89524 0
christoph.werner@sydney.edu.au

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?
Study protocol
Statistical analysis plan
Informed consent form
Analytic code
Summary results
No Results