Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000635460
Ethics application status
Approved
Date submitted
12/05/2016
Date registered
17/05/2016
Date last updated
5/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Stress-Mediated Widespread Hypersensitivity in People with Irritable Bowel Syndrome
Scientific title
Stress-Mediated Widespread Hypersensitivity in People with Irritable Bowel Syndrome
Secondary ID [1] 289184 0
Nil known
Universal Trial Number (UTN)
U1111-1179-7762
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Irritable bowel syndrome 298740 0
Stress 298741 0
Condition category
Condition code
Oral and Gastrointestinal 298785 298785 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Mental Health 298786 298786 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
MATERIALS:
Both groups will be screened for the minimum eligibility criteria over the phone in the recruitment phase using the “Medical Checklist”. The Medical checklist was composed for this study to rule out any physical or psychiatric variables that may put the participant at risk during the experiment or may confound the results.

The remaining questionnaires will be completed before the participant begins the experiment session.
Demographic
Demographic variables will be assessed in “Generic Demographic Questionnaire”. Questions include: age, gender, ethnicity, height, weight (used to calculate BMI), smoking status.

Depression, anxiety and stress
DASS21
The DASS21 (Lovibond & Lovibond, 1995) is a shortened version of the original 42 item self-report measure of depression, anxiety and stress that has demonstrated adequate reliability and validity in normative (Crawford & Henry, 2003; Henry & Crawford, 2005) and clinical samples (Antony, Bieling, Cox, Enns, & Swinson, 1998; Brown, Chorpita, Korotitsch, & Barlow, 1997). It is opted for in place of the Beck Depression Inventory used in (Piche et al., 2010; Piche et al., 2011) to get baseline measures of trait stress and anxiety which is relevant to the proposed study. Those participants who meet caseness on the DASS21 for depression or anxiety will be included in the study and their scores controlled for in the data analysis. They will also be notified of their scores for the purposes of enabling them to seek medical attention if they wish.

The Pain Catastrophizing Scale (PCS)
The PCS (Sullivan, Bishop, & Pivik, 1995) is a 13 item scale that asks respondents to reflect on a painful experience and the frequency they were thinking or feeling each item in relation to that experience. It has three subscales: rumination, magnification and helplessness. The PCS has been found to significantly independently predict conditioned pain modulation in IBS participants (Piche et al., 2011)

Pain unpleasantness and intensity
Pain unpleasantness and intensity will be measured on two separate numeric rating scales. Each 11-point (0-10) scale will be anchored at three points: no pain/unpleasantness (0), moderate pain/unpleasantness (5), extreme pain/unpleasantness (10). Unpleasantness will include both unpleasantness related to pain and non-painful discomfort produced by the stimulus (Piche et al., 2010).

Stress
Stress will be measured on a 11 point (0-10) numeric rating scale anchored at three points: no stress (0), moderate stress (5) and extreme stress (10).

Triers Social Stress Test (TSST)
The TSST (Kirschbaum, Pirke, & Hellhammer, 1993) is commonly used test to experimentally induce a stress response from which physiological measures can be taken as a proxy for how stressed the individual is. The aim of the TSST in this study is elevate levels of stress for which perceived and actual stress levels can be measured. The public speaking component of the TSST will be utilised (see procedure) and participants will be given a sheet with a list of five topic pointers: What is your dream job? Why do you want this job? Why do you think you deserve this job? What personal attributes do you bring to the position? What are some of your personal strengths and weaknesses?

Physiological measures
Heart rate (HR) and heart rate variability (HRV) will be monitored using a RS800 Polar HRV wristwatch and chest band which is non-invasive (Darragh, Vanderboor, Booth, Sollers, & Consedine, 2015). HR and HRV will be used as objective measures of stress and worn by the participants for the duration of the experiment where HR is used as an index of physiological arousal and HRV measures the variance between adjacent beats (Sztajzel, 2004).

Cold packs
A pack of five reusable Green Cross hot/cold packs will be ordered from Industrial First Aid Supplies Limited. Uni-Grip elastic tubular support bandages will be placed around the cold pack over the arm to hold the cold pack in place. Kleenex antibacterial wipes will be used to clean the ice pack and the bandages will be washed between participants.
Participant information sheet and consent forms:
Both IBS patients and controls will receive PIS-CF so read and sign before attending the lab session. The document is 6 pages long and includes information about the study, what their participation would involve, safety measures, ethical statements that require consent and contact information.

PROCEDURE:
The procedure for this study is in two general stages. The first stage is the recruitment and screening stage and the second stage is the experiment session. IBS patients and healthy controls will undergo the same procedure with minor differences in the recruitment and screening stage. IBS patients will be identified from patient records through the Department of Gastroenterology and Hepatology and contacted by telephone to invite them to participate in the study. If they are interested they will be screened for the minimum inclusion and exclusion criteria. If they meet the inclusion criteria, they will be sent a participant information sheet and consent form. They will be followed up a few days later when their consent form has been received to ensure that they are still interested in the study and if they have any questions. Next they will be booked into an experiment session at the University of Auckland Clinical Research Centre. Healthy controls will be recruited by flyers placed in various public spaces and posts on relevant Facebook pages. They will be given a number that they can contact me on where the procedure from this point will then be the same as for the IBS participants.

The second stage is the experiment session which will be the same for both groups with the only difference being that IBS patients will have additional questionnaires to complete. The experiment will take place in a closed body room where the power is not connected the the mains. When the participants arrive for the experiment session, they will be asked to complete a series of questionnaires. IBS participants will complete an IBS information checklist, a demographic questionnaire, and the short version of the Depression, Anxiety and Stress Scale (DASS21), the Pain Catastrophizing Scale as well as completing a hard copy of the inclusion and exclusion criteria that they were screened for on the phone (Medical Checklist –IBS). Healthy controls will complete all of these questionnaires except the IBS information checklist.

The experiment will involve taking objective and subjective measures of pain and stress. The general procedure is in three stages: 1. establish baseline pain and stress measures during a counter-irritation paradigm, 2. complete a stress task, 3. repeat the counter-irritation paradigm. The pain stimulus will be electrocutaneous delivered by an electrode to the forearm and the counter-irritation paradigm will be based on methods of Piche et al. (2010). The equipment is expected to be a PowerLab and Digitizer/Stimulator made by ADInstruments.

The counter-irritation paradigm will be modified version based on the methods used by Piche et al. (2011) and (Piche et al., 2010). Electrical stimulation will begin with a stabilization period which aims to control habituation that can occur during this kind of stimulation. Shocks will be delivered approximately every 12 seconds. Then a baseline period will begin where 10 stimuli are delivered every 12 seconds followed by the induction of the counter-irritation stimulus where a cold pack at -12C will be wrapped around the contralateral forearm for two minutes while another 10 electrical stimuli are delivered every 12 seconds. The cold pack will be held in place using a bandage sleeve. After two minutes the cold pack will be removed and another 10 stimuli ever 12 seconds will be delivered which constitutes the recovery period. Ratings of pain intensity, pain unpleasantness and stress will be made on numeric rating scales before stabilisation, before the application of the cold pack and after the removal of the cold pack. Pain unpleasantness, pain intensity and stress ratings in response to counterirritation stimulus (cold pack) will be made at the end of the recovery period. Numeric rating scales will be printed off as slips for the participants to complete. This is to avoid experimenter effects and impression management bias which can result from from participants scoring out loud. The PCS will also be completed at the end of the recovery period

The level of electrical stimulation delivered will be based on a modified version of the staircase method established in earlier studies such as Gracely, Lota, Walter, and Dubner (1988) and (Willer, 1977). This method has been modified in two recent studies; (Piche et al., 2010; Piche et al., 2011) in which the method of this study will aim to partially replicate. Participants will be subject to an increasing level of stimulation until pain tolerance is reached, 80% of that stimulation will be used to deliver the electrical stimulation at for each participant. This will be established using a pain intensity numeric rating scale where 80% of tolerance will be inferred at when a score of 8 is given.

After the counter-irritation paradigm, participants will then engage in a 10 minute resting period (Kirschbaum et al., 1993) before beginning the TSST. The stress task will be a modified TSST which will involve the participant preparing a five-minute speech to present to A ‘selection committee’ about why they should receive their dream job. They will have 10 minutes to prepare this speech using topic pointers but they cannot use this during the delivery of their speech. They will also be informed that their speech will be recorded to perform a voice analysis on later. This will involve one of the committee members holding up their phone and pointing it at the participant claiming to be filming them. In reality, the participant is not being filmed and this deception is used to help elevate stress levels. When they have completed the stress task, they will have a five-minute rest period. Finally, they will engage in the counterirritation-paradigm described above to test for the effects of stress on the pain responding. For the entire duration of the experiment, participants will be wearing a polar watch which will be recording their heart rate and heart rate variability which will be used and an objective measures of stress. At the end of the experiment participants will be debriefed about not being filmed while delivering their speech and will be invited to ask any questions or raise any concerns.

WHO: I, Katrina Simpson, will be conducting the experiment. I am second yer Master in Health Psychology student. I have worked for the non-emergency triage service for the NHS while living in the UK.

MODE: The experiment involve initially screening participants over the phone then will be run face-to-face and will involve myself and one participant at a time.

DURATION: The experiment will be a one-off, one hour laboratory session. Please see "procedure" above for information about the delivery of the conditioned pain modulation paradigm.

LOCATION: The experiment will be held in the Department of Physiology labs, in the University of Auckland Medical school.

PERSONALISATION: Each participant will have their pain tolerance established to which shocks will be delivered at 80% (see PROCEDURE above).
Intervention code [1] 294718 0
Other interventions
Comparator / control treatment
There is a control group to compare the results of IBS participants to. These will be healthy controls with no current or history of gastrointestinal diseases or disorders. They will undergo the same experimental procedure.
Control group
Active

Outcomes
Primary outcome [1] 298273 0
Effect of stress on pain sensitivity as assessed by ratings of pain intensity scores during the counter-irritation paradigm on a NRS
Timepoint [1] 298273 0
After TSST
Primary outcome [2] 298290 0
Effect of stress on pain sensitivity as assessed by ratings of pain unpleasantness scores during the counter-irritation paradigm on a NRS.
Timepoint [2] 298290 0
After TSST.
Primary outcome [3] 298291 0
Effect of stress on pain sensitivity as assessed by ratings of stress scores during the counter-irritation paradigm on a NRS.
Timepoint [3] 298291 0
After TSST
Secondary outcome [1] 323730 0
Difference between groups on heart rate variability during counter-irritation paradigm, assessed using a polar heart rate monitor watch.
Timepoint [1] 323730 0
Baseline (before TSST) and after TSST.
Secondary outcome [2] 323787 0
Difference between groups on heart rate during counter-irritation paradigm, assessed using a polar heart rate monitor watch.
Timepoint [2] 323787 0
Baseline (before TSST) and after TSST
Secondary outcome [3] 323788 0
Mean DASS21 scores for stress for each group
Timepoint [3] 323788 0
Baseline
Secondary outcome [4] 323789 0
Mean DASS21 scores for anxiety for each group
Timepoint [4] 323789 0
Baseline
Secondary outcome [5] 323790 0
Mean DASS21 scores for depression for each group
Timepoint [5] 323790 0
Baseline
Secondary outcome [6] 323791 0
Mean pain Catastrophizing scores for each group
Timepoint [6] 323791 0
Baseline

Eligibility
Key inclusion criteria
All participants must speak fluent English and be between the ages of 18-64. IBS participants must have received a diagnosis of IBS from a gastroenterologist.
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Both groups will be screened for the minimum eligibility criteria over the phone in the recruitment phase using the “Medical Checklist”. The Medical checklist was composed for this study to rule out any physical or psychiatric variables that may put the participant at risk during the experiment or may confound the results. Due to the nature of the study, the exclusion criteria for each group is extensive:


IBS:

* Any other chronic pain diagnosis
* Any injury or medical condition that may affect ability to sense pain
* A diagnosis of a cardiovascular condition such as hypertension
* Recent acute illness two weeks prior to the study – specifically illnesses affecting the abdomen
* Any other GI diagnosis
* Ingestion of medication two weeks prior participating excluding the oral contraceptive pill
* Pregnancy
* Diagnosis of depression or anxiety or any neuropsychiatric disorder

Healthy Controls:

* Any GI diagnosis
* Family history of GI disorders
* Any chronic pain diagnosis
* Any injury or medical condition that may affect ability to sense pain
* A diagnosis of any cardiovascular diseases such as hypertension.
* Recent acute illness two weeks prior to the study – specifically illnesses affecting the abdomen
* Ingestion of medication two weeks prior participating excluding the oral contraceptive pill
* Pregnancy
* Currently taking psychoactive drugs
* Diagnosis of depression or anxiety or any neuropsychiatric disorder

Study design
Purpose of the study
Educational / counselling / training
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
No sequence generation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This study will be a between group repeated measures experiment using healthy matched cases. The two groups will be IBS participants and healthy controls who will form a community sample recruited by consecutive sampling methods. The procedure involves three general steps which both groups will be exposed to. The first will be the baseline pain routine which will involve the participant receiving a series of non-harmful electric shocks to their forearm. This will be followed by attaching cold packs to the contralateral forearm as a counterirritation stimulus to test their CPM ability. The second stage is the stress task which will involve delivering a five-minute speech about why they should receive their dream job to a ‘panel of judges’ stimulus to test participants. The final stage involves repeating the pain routine to establish the effects of stress on pain sensitivity. Both groups in both conditions will be wearing a polar watch to record heart rate and heart rate variability as an index of stress as well as completing stress, pain and unpleasantness measures. These measures will be used to answer the question of the effect of stress on pain sensitivity by way of CPM. Due to the nature of the study, the order of the conditions will not be reversed.
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
The primary hypothesis is that the stressful task will increase pain intensity more in patients with IBS than in healthy controls. It is also hypothesised that pain will be higher in the IBS group than the healthy control group across both tasks, and that pain will be higher after the stress task in both groups. Using G power and a repeated measures between factors analysis and 80% power at the alpha level of .05 two tailed, To detect a medium effect size of F = 0.25 (Cohen, 1988), A sample of 98 participants is required. We chose a medium effect because Piche et al. (2010) reported a medium size effect for pain being higher in IBS patients that controls. Statistical analysis will be conducted in statistic software package IBM SPSS. Given the size of the sample, it is predicted that the assumptions for parametric testing will be met. In the event that they do not, non-parametric equivalent tests will be utilised instead. Each analysis will be carried out as two-tailed, with an alpha level of <.05 to detect statistically significant results. Pearson’s correlations will be used to examine the association between predictor variables of heart rate and heart rate variability and perceived stress with pain thresholds.

To examine the first and second hypotheses that IBS patients will differ from controls in pain related outcomes, a mixed MANOVA will be used (assuming there are at least moderate correlations between pain outcomes) OR ANOVA followed by post-hoc analyses of planned contrasts. The interaction effect between stress and pain will also be tested. This may be eventually run as a MANCOVA/ANCOVA and include demographic and clinical variables, as well as DASS and pain catastrophizing scores which may modulate or predict pain intensity and unpleasantness and stress. Large differences at baseline will determine this.

To examine the third hypothesis of stress in explaining variance in pain related outcomes, A series of multiple forced entry regressions will be conducted on pain related outcomes with all of demographic, Clinical and psychological variables included. This is because the characteristics of the sample will be different to Piche et al. (2010) with a slight change in measures used. For the relationship between perceived and actual stress levels, Pearson’s correlations will be used.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/05/2016
Actual
13/07/2016
Date of last participant enrolment
Anticipated
30/11/2016
Actual
13/09/2016
Date of last data collection
Anticipated
Actual
20/09/2016
Sample size
Target
98
Accrual to date
Final
36
Recruitment outside Australia
Country [1] 7873 0
New Zealand
State/province [1] 7873 0
Auckland

Funding & Sponsors
Funding source category [1] 293574 0
University
Name [1] 293574 0
University of Auckland
Country [1] 293574 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
The University of Auckland
Private Bag 92019
Victoria Street West
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 292395 0
None
Name [1] 292395 0
Address [1] 292395 0
Country [1] 292395 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295021 0
Health and Disability Ethics Committees
Ethics committee address [1] 295021 0
Ethics committee country [1] 295021 0
New Zealand
Date submitted for ethics approval [1] 295021 0
31/03/2016
Approval date [1] 295021 0
11/05/2016
Ethics approval number [1] 295021 0
16/STH/35

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65774 0
Miss Katrina Simpson
Address 65774 0
Department of Psychological Medicine
Level 12, Room 12.101
Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland 1023, New Zealand
Country 65774 0
New Zealand
Phone 65774 0
+6427 4065 023
Fax 65774 0
NA
Email 65774 0
ksim948@aucklanduni.ac.nz
Contact person for public queries
Name 65775 0
Katrina Simpson
Address 65775 0
Department of Psychological Medicine
Level 12, Room 12.101
Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland 1023, New Zealand
Country 65775 0
New Zealand
Phone 65775 0
+6427 4065 023
Fax 65775 0
NA
Email 65775 0
ksim948@aucklanduni.ac.nz
Contact person for scientific queries
Name 65776 0
Katrina Simpson
Address 65776 0
Department of Psychological Medicine
Level 12, Room 12.101
Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland 1023, New Zealand
Country 65776 0
New Zealand
Phone 65776 0
+6427 4065 023
Fax 65776 0
NA
Email 65776 0
ksim948@aucklanduni.ac.nz

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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