Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000232932
Ethics application status
Approved
Date submitted
13/02/2020
Date registered
25/02/2020
Date last updated
8/11/2021
Date data sharing statement initially provided
25/02/2020
Date results information initially provided
8/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
How do different message framing manipulations influence the effects of active placebos?
Scientific title
How does positive and negative message framing affect the placebo effect in a model of active placebos for sleep difficulty? A randomised controlled study in sleep-impaired adults
Secondary ID [1] 300545 0
None
Universal Trial Number (UTN)
Nil known
Trial acronym
Nil known
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sleep difficulty 316272 0
Insomnia 316356 0
Condition category
Condition code
Mental Health 314551 314551 0 0
Other mental health 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 four groups: three active placebo groups that receive either a positive, negative, or no message framing, or to a no-treatment control group. Message framing is a process whereby communicators act to construct a point of view that encourages the facts of a given situation to be interpreted by others in a particular manner. The positive message framing will inform participants that the experience of the target side effect, i.e. red-ish urine means that their body has absorbed and metabolised the medication well and the medication is likely to improve their sleep. The negative message framing will inform participants that the experience of the target side effect, i.e. red-ish urine means that their body has not absorbed and metabolised the medication well and the medication is not likely to improve their sleep. After the randomisation participants in the placebo groups will be handed an information sheet about the new formulation under investigation that will contain the message framing. After participants have read the message framing in the presence of the psychologist conducting the experiment, he will ask if they have any questions, clarify potential questions and repeat the most important parts of the information, verbally repeating the message framing. Participants only receive the message framing on one occasion during the second study visit in written and verbal form, they will not be reexposed to the message framing. Participants randomised to the active placebo groups will be blind towards their framing condition, and told they are receiving an 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 active placebo groups will receive four capsules per day for 7 nights containing each 625 mg of the food colour E 162, i.e. beetroot extract and 125 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 to the capsules 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] 316849 0
Treatment: Other
Comparator / control treatment
Active placebo group with no message framing and no-treatment group. Placebo treatment will consist of four gelatine capsules per day for 7 nights containing each 625 mg of the food colour E 162, i.e. beetroot extract and 125 mg oxalic acid
Control group
Placebo

Outcomes
Primary outcome [1] 322871 0
Insomnia severity assessed using the Insomnia Severity Index (ISI)
Timepoint [1] 322871 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] 322872 0
Reports of daily bothersome of red urine colouration assessed as part of 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 – the target side effect. We assessed how bothersome the complaints are on a visual analogue scale (VAS) ranging from 0 (= “not bothersome at all”) to 100 (= “absolutely bothersome”), with 33 (= “mildly bothersome”) and 66 (= “moderately bothersome”)
Timepoint [2] 322872 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] 380086 0
Sleep quality (self-report) using the Consensus Sleep Diary Version C (CSD-C)
Timepoint [1] 380086 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] 380087 0
Total sleep time (self-report) using the Consensus Sleep Diary Version C (CSD-C)
Timepoint [2] 380087 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] 380088 0
Sleep onset latency (self-report) using the Consensus Sleep Diary Version C (CSD-C)
Timepoint [3] 380088 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] 380089 0
Total sleep time (objective) using Actigraphy (Activinsights, GENEActive Original)
Timepoint [4] 380089 0
Baseline (assessed daily during the 7 nights prior to randomisation)
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [5] 380091 0
Sleep onset latency (objective) using Actigraphy (Activinsights, GENEActive Original)
Timepoint [5] 380091 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] 380092 0
Adherence to medications (self-report), using a single numerical question about the daily capsule intake
Timepoint [6] 380092 0
Treatment (assessed daily during the 7 nights receiving treatment after randomisation)
Secondary outcome [7] 380093 0
Quality of life using the World Health Organisation’s quality of life assessment (WHOQOL-BREF)
Timepoint [7] 380093 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 [8] 380095 0
Recall and recognition of the message framing (RMF), using an open recall and a forced-choice recognition question with the options (0=no framing, 1=positive framing, 2=negative framing)
Timepoint [8] 380095 0
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
Sex
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 block randomisation using the randomisation module included in REDCap
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
SAMPLE SIZE CALCULATIONS
For the sample size estimation regarding message framing effects, we referred to an earlier study about the influence of different message framing conditions and their effects on treatment efficacy (Wilhelm et al., 2018). Based on the results of Wilhelm et al. 2018 the required sample size would be 37 per framing condition (f = 0.3, alpha = .05, and 1-beta = .80).
The power analysis was conducted with the software environment R version 3.6.1 (R Core Team, 2019) and the WebPower package (Zhang & Yuan, 2018). Based on this power analyses we decided to allocate participants to the four groups using a 1:1:1:1 randomisation ratio for active placebo receiving a positive framing: active placebo receiving a negative framing: active placebo receiving no framing: no-treatment control, until we reach the desired total sample size of 148 participants.

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 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 4 out of 7 nights, with nonadherence leading to exclusion from efficacy analyses. We will also exclude participants from the analysis that report experiencing 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. Relevant 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
Outcome measures (ISI, GASE, CSD-C, Actigraphy, WHOQOL-BREF) between the baseline and intervention week will be analysed with analysis of co-variance (ANCOVAs), using orthogonal planned contrasts to analyse differences between 1) the three placebo groups vs. the no-treatment group, 2) the negative and no framing group vs. the positive framing group, 3) the negative framing group vs. the no framing group. Baseline scores for each respective outcome measure will be included as covariates.
The outcome measure adherence between the three placebo groups during the intervention week will be analysed with an analysis of variance (ANOVA), using orthogonal planned contrasts to analyse differences between 1) the negative and no framing group vs. the positive framing group, 2) the negative framing group vs. the no framing group.
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). Differences in the outcome measure (RMF) at the end of treatment will be analysed using logistic regression to analyse differences between 1) the three placebo groups vs. the no-treatment group, 2) the negative and no framing group vs. the positive framing group, 3) the negative framing group vs. the no framing group.
All analyses will be carried out using the software environment R version 3.6.2 (R Core Team, 2019), 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”), (2) likelihood side effects (VAS ranging from 0 (= “not likely at all”) to 100 (= “highly likely”), and (3) concerns about side effects (VAS ranging from 0 (= “not concerned at all”) to 100 (= “very concerned”). VASs are assessed at a single timepoint post-randomisation, but prior to receiving treatment. We will also conduct mediation analysis on (4) 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 three 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 3.6.2 (R Core Team, 2019). Further, we will perform subgroup analyses between participants reporting the target (framed) side effect and participants who did not experience the target side effect on primary and secondary outcomes. An additional exploratory analysis will be calculated to analyse the recall and recognition of the side effect (RSE) information, using an open recall and a forced-choice recognition question with the options (0=no, 1=yes). RSE will be assessed post-treatment at a single timepoint at the end of the seven-night period receiving treatment.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Other reasons/comments
Other reasons
Delays due to the SARS-CoV-2 pandemic.
Date of first participant enrolment
Anticipated
2/03/2020
Actual
9/03/2020
Date of last participant enrolment
Anticipated
16/03/2021
Actual
13/05/2021
Date of last data collection
Anticipated
1/07/2021
Actual
2/06/2021
Sample size
Target
148
Accrual to date
Final
104
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 304958 0
University
Name [1] 304958 0
The University of Sydney
Country [1] 304958 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] 305316 0
None
Name [1] 305316 0
Address [1] 305316 0
Country [1] 305316 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305368 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 305368 0
Human Ethics Office
Margaret Telfer Building (K07)
University of Sydney
Camperdown NSW 2006
Ethics committee country [1] 305368 0
Australia
Date submitted for ethics approval [1] 305368 0
Approval date [1] 305368 0
20/02/2018
Ethics approval number [1] 305368 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 and evaluated an active placebo that elicits side effects but has no other effects on sleep. Prior research has shown that perceived treatment allocation and beliefs about side effects can influence an intervention’s effectiveness. We therefore want to further understand the role of participants beliefs about side effects. The main aim of this study is therefore to test whether framing participants beliefs about side effects influences the efficacy and tolerability of an active placebo. We hypothesise that participants receiving positive framing will demonstrate a larger placebo effect for sleep than a no-framing condition, and that a negative framing condition will show the smallest placebo effect.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100138 0
Mr Christoph Patrick Werner
Address 100138 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 100138 0
Australia
Phone 100138 0
+61 466214021
Fax 100138 0
Email 100138 0
[email protected]
Contact person for public queries
Name 100139 0
Mr Christoph Patrick Werner
Address 100139 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 100139 0
Australia
Phone 100139 0
+61 466214021
Fax 100139 0
Email 100139 0
[email protected]
Contact person for scientific queries
Name 100140 0
Mr Christoph Patrick Werner
Address 100140 0
Room 243 Top South Badham Building (A16)
School of Psychology
The University of Sydney
Camperdown NSW 2006
Country 100140 0
Australia
Phone 100140 0
+4915153595979
Fax 100140 0
Email 100140 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
6906Study protocol https://osf.io/xufc6/[email protected]
6907Statistical analysis plan https://osf.io/xufc6/[email protected]
6908Informed consent form https://osf.io/xufc6/[email protected]
6909Ethical approval https://osf.io/xufc6/[email protected]
6910Analytic code https://osf.io/xufc6/[email protected]



Results publications and other study-related documents

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