Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001331123
Ethics application status
Approved
Date submitted
6/09/2019
Date registered
30/09/2019
Date last updated
22/10/2021
Date data sharing statement initially provided
30/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Improving outcomes from exposure therapy for post-traumatic stress disorder (PTSD) with acute exercise: Augmenting Brain Derived Neurotrophic Factor (BDNF) as a mechanism of change?
Scientific title
A randomised controlled trial to investigate the effect of an acute moderate intensity exercise intervention and Brain Derived Neurotrophic Factor (BDNF) on treatment response to exposure therapy in PTSD
Secondary ID [1] 299058 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-traumatic Stress Disorder (PTSD) 314086 0
Depression 314087 0
Condition category
Condition code
Mental Health 312463 312463 0 0
Other mental health disorders
Mental Health 312464 312464 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This Randomised Controlled Trial (RCT) investigates whether combining acute moderate intensity (aerobic) exercise with gold-standard Prolonged Exposure (PE) (Foa et al., 2007) would increase treatment efficacy of PE in PTSD and examines whether this effect is related to increased levels of Brain Derived Neurotrophic Factor (BDNF), which are elevated by acute moderate intensity exercise and have been shown to facilitate fear extinction.

PE is a cognitive behavioural intervention that involves helping the person address their trauma memories and avoided situations in a supportive, controlled and safe environment, and confront them in a graduated way in order to promote gradual extinction of the fear response and to modify interpretations of the traumatic event that are impeding recovery. In this trial all participants will receive 10-weekly sessions of 90-minute face-to-face manualised PE treatment. The treatment elements and delivery will be identical to the gold-standard manualized PE intervention which is the best researched therapy with the strongest evidence-base of efficacy for PTSD. The first session of the PE treatment consists of psycho-education and overall introduction of rationale for the therapy. In the second session, common reactions to trauma will be discussed, the rationale for in vivo PE will be presented and a hierarchical list of avoided situations will be developed. From session three to ten imaginal PE will be conducted. In these sessions, participants will be encouraged to imagine/describe the trauma in detail while focusing progressively more in the most distressing aspects of the trauma and discussing thoughts and feelings evoked during exposure. Additionally, in the last session (session 10) changes in the experience of PE, trauma memory over the course of therapy and overall progress will be reviewed and relapse prevention strategies will be discussed. During all sessions participants distress will be monitored using Subjective Units of Discomfort/Distress Scale (SUD).

Acute moderate intensity exercise in this RCT is proposed as an augmentation intervention to improve the treatment response to PE. Previous research suggested that BDNF (a neuropeptide) facilitates fear extinction learning which is the core mechanism underlying PE. Therefore, increasing BDNF levels during the PE treatment may enhance underlying fear extinction processes to improve response to PE. Research shows that a well-validated way to increase BDNF is via a bout of moderate intensity exercise. In this trial acute moderate intensity exercise will be combined with the PE treatment to increase BDNF levels during PE to enhance underlying fear extinction learning and facilitate response to PE in PTSD patients.
The exercise intervention will be delivered prior to each PE session one to one via cycling on a stationary bicycle. These sessions will last for 20 minutes which will be an additional 20 minutes to the each 90 minutes PE session (110 minutes together). The intensity of the exercise will be based on participants’ individual cardio-respiratory fitness levels (Maximal Oxygen Uptake; VO2max) determined at a prior physical assessment session by the trial exercise physiologists. The intensity of the exercise will set to 55-70% of VO2max level of the participants. Having the flexibility in the range of exercise intensity aims to ensure participant capacity and comfort. The exercise intervention will be administered by the trial exercise physiologists until the 3rd PE session. From PE session 3 to 10, exercise intervention will be administered by a trained research assistant or the participant's trained therapist as per the exercise protocol by trial exercise physiologists. Both PE sessions and exercise sessions will be delivered at the Phoenix Traumatic Stress Research Clinic (Royal Park).

The output from all exercise sessions (data regarding participants’ heart rate, workload used in the exercise, rate of perceived exertion, signs and symptoms etc.) will be recorded in hard-copy and in a computer and the fidelity of the exercise sessions will be assessed by trial exercise physiologists via regular fortnightly review of these outputs. All PE sessions will be audio recorded (with patient consent) and reviewed in fortnightly supervision sessions with the principle investigator Professor Felmingham. Fidelity checks of a random 10% of client cases will be conducted by a clinical psychologist with expertise in PE to ensure that specific sessions pertain to the specific therapy components required by the manual.

UPDATE to the protocol: Due to pandemic related restrictions and cessation of face-to-face treatment, existing participants' remaining sessions were converted into online telehealth sessions using the zoom platform if they agreed and were able to self-direct the aerobic exercise component while being monitored by the trial research assistant trained on the exercise protocol. Furthermore, the same change in the treatment and intervention modality has also been applied to the new participants enrolled in the trial during the cessation of research activities in the Phoenix Traumatic Stress Research Clinic (n=5). During this time all psychological assessments were completed online or over the phone.

Participants' respective clinicians checked and ensured that participants had a safe and private space, and reliable internet connection and devices for sessions. In the initial session, clinicians developed a Telehealth management plan (TMP) with the participant which documented agreed steps for managing any risk-related situations or disruptions in connection that may arise during the course of telehealth sessions. TMP included contact details (name, email, phone, and address) of participants' (at least) two nominated support persons who were close to them both personally and physically (i.e. approximately 5-10 minutes from the session location), and able to assist in emergencies. Furthermore, TMP included the location and address where participants joined the telehealth sessions from, and a backup phone number as an alternative contact. TMPs were updated at the beginning of each session. Also, clinicians reviewed the appropriateness of telehealth for participants in each session. A telehealth risk management protocol was put in place to assess risk and respond accordingly. Risk management was disclosed to the participants in the first telehealth session.

Exercise sessions were conducted via telehealth right before each therapy session with the participants. Before exercise sessions, each participant's access to exercise equipment at home (e.g., exercise bike, heart rate monitor, blood pressure monitor etc.) was assessed. For participants who did not have an exercise bike, aerobic exercise was completed using an aerobic stepper. Stepping was deemed both feasible and appropriate since it has been shown to be an effective way of conducting aerobic exercise and creating an exercise-induced BDNF response (Kneapen et al., 2010). Prior to exercise sessions, participants were sent home aerobic exercise guides to get prepared for these sessions along with rate of perceived breathing (RPB) and rate of perceived exertion (RPE) scales to bring to the session. All exercise sessions have been monitored online by the trained research assistant on the exercise protocol while each participant was completing the exercise. At the beginning of each session, the participant’s location, address and personal contact details were collected as detailed above.

In the very first session, participants’ were trained on how the exercise sessions will be conducted by the research assistant. Also, they were informed of signs and symptoms where they should stop exercising (e.g., chest pain, dizziness, nausea etc.). During exercise, all participants were asked to report their RPE and RPB each minute. If participants had access to heart rate monitors, they were asked to measure and report their heart rate and blood pressure at the beginning and at the end of the session. Also, they were asked to report their heart rate on the heart rate monitor each minute during the exercise. Heart rate was used to ensure that participants were exercising at exercise intensity corresponding to participants' pre-determined VO2max levels for the existing participants. For existing participants this VO2max level and corresponding heart rate were estimated at the clinic at the very beginning of the trial by the exercise physiologists. To ensure the administration of exercise at the adequate intensity for the new participants, their heart rate were aimed to be kept around 70-80% of their age-predicted maximum heart rate (HRmax) during the sessions which was expected to approximately correspond to their heart rate at 50-70% VO2max. These participants age-predicted HRmax were calculated using the formula 208 – (0.7 x participant’s age). For participants (both existing and new) who did not own a heart rate monitor, RPE levels were used to ensure that they are exercising in the aerobic exercise zone (RPE of 12 to 14). Participants owning a exercise bike at home were asked to report their speed (revolutions per minute; kept at 60) and were asked to increase/decrease intensity (watts) on the bike depending on their heart rate and/or RPE and RPB (kept below 5 - strong or hard breathing) values to ensure correct exercise intensity and to prevent any possible adverse events. Participants using an aerobic stepper were instructed to step on the stepper following a metronome set by the research assistant. The number of steps decreased or increased depending on the RPE and RPB levels and/or heart rate of the participants. The average number of steps required to get participants exercise in the aerobic zone ranged from 20-28 depending on the participants exercise tolerance and fitness. All exercise data collected during sessions was recorded on soft-copy exercise datasheets and saved in the trial database. Each exercise session lasted for 20 mins as per trial protocol.

Participants in the aerobic exercise group who had remaining sessions when the pandemic related restrictions were in place and agreed to complete their treatment via telehealth (n=3) completed their remaining therapy and exercise sessions without any complications. Furthermore, no complications have been recorded for new participants enrolled in the trial who were allocated to the aerobic exercise condition. Upon resumption of research activities in the Phoenix clinic, the original trial protocol will be resumed.
Intervention code [1] 315330 0
Treatment: Other
Comparator / control treatment
The control group participants will receive gentle stretching sessions prior to each PE session for 20 minutes (110 minutes together). All treatment and assessment components of the study will be identical between intervention and control groups apart from the exercise/stretching sessions prior to the PE sessions. The gentle stretching will be administered following a gentle stretching protocol approved by the trial exercise physiologists. The gentle stretching protocol will include stretches such as side bend stretch, hamstring, calf, quadriceps stretches of the legs, biceps and triceps stretches of arms and side tilt and rotation of the neck, and shoulder squeeze. All control group participants will receive the identical gentle stretching protocol. The intensity of stretching will be monitored using Borg’s rate of perceived exertion (RPE) and rate of perceived breathing (RPB) scales. To ensure that the intensity of the stretching is light, RPE values will be kept between 6 to 8 (none to very, very light) and RPB value will be kept between 0 to 1 (normal to very mild shortness of breath).

The PE treatment will be delivered by trained trial clinicians to the control group. Also, identical to the exercise intervention group, the stretching intervention will be administered by the trial exercise physiologists until the 3rd PE session. From PE session 3 to 10 stretching intervention will be administered by a trained research assistant or the participant's trained therapist as per the stretching protocol by the trial exercise physiologists. Both PE sessions and gentle stretching sessions will be delivered at the Phoenix Traumatic Stress Research Clinic (Royal Park). Using a stretching control group will give participants equal opportunities for social interaction with the staff and researcher/s administering exercise/stretching sessions or increased physical mobility, which can affect mood and hypothalamic pituitary adrenal (HPA) axis activity (Baker et al., 2010) with implications on the treatment outcome.

UPDATE to the protocol: Due to pandemic related restrictions and cessation of face-to-face treatment, existing participants' remaining sessions were converted into online telehealth sessions using the zoom platform if they agreed and were able to self-direct the gentle stretching at home while being monitored by the trial research assistant trained on the stretching protocol. The deliverance of treatment, development of the treatment protocol and telehealth risk management will be conducted in the same way described above for the aerobic exercise intervention group. Furthermore, the same change in the treatment and gentle stretching modality also has been applied to the new participants enrolled in the trial during the cessation of research activities in the Phoenix Traumatic Stress Research Clinic (n=6). During this time all psychological assessments were also completed online or over the phone.

Participants' respective clinicians checked and ensured that participants had a safe and private space, and reliable internet connection and devices for sessions. In the initial session, clinicians developed a Telehealth management plan (TMP) with the participant which documented agreed steps for managing any risk-related situations or disruptions in connection that may arise during the course of telehealth sessions. TMPs included contact details (name, email, phone, and address) of participants' (at least) two nominated support persons who were close to them both personally and physically (i.e. approx 5-10 minutes from the session location), and able to assist in emergencies. Furthermore, TMPs included the location and address where participants joined the telehealth sessions from, and a backup phone number as an alternative contact. TMPs were updated at the beginning of each session. Also, clinicians reviewed the appropriateness of telehealth for participants in each session. A telehealth risk management protocol was in place to assess risk and respond accordingly. Risk management was disclosed to participants in the first telehealth session.

Stretching sessions were conducted via telehealth right before each therapy session with the participants. Prior to stretching sessions, participants were sent home gentle-stretching guides with instructions and pictures of each stretching movement and along with RPE and RPB scales. For stretching sessions a yoga mat or a substitute for a yoga mat (e.g., clean towel) was used depending on participants access to these. At the beginning each session, participants location, address and personal contact details were collected as detailed above. In the very first session, participants were trained on how the stretching sessions will be conducted by the research assistant. All stretching sessions were monitored and accompanied online by the research assistant on the gentle stretching protocol. During stretching sessions, the trial research assistant completed each stretching movement with the participants. Also, during these sessions, all participants were asked to report their RPE and RPB levels as per trial protocol. Each stretching session lasted for 20 mins as per trial protocol.

Participants in the stretching group who had remaining sessions when the pandemic related restrictions were placed and agreed to complete their treatment via telehealth (n=3) completed their remaining therapy and stretching sessions without any complications. Furthermore, no complications has been recorded for new participants (n=6) enrolled in the trial who were allocated to the gentle stretching condition. Upon resumption of research activities in the Phoenix clinic, the original trial protocol will be resumed.
Control group
Active

Outcomes
Primary outcome [1] 321106 0
PTSD symptom severity as measured by the Clinician Administered PTSD Scale for DSM-5 (CAPS-5)
Timepoint [1] 321106 0
Pre-treatment (2 weeks prior to commencing treatment), Post-treatment (2 weeks after the completion of the last treatment session)
Secondary outcome [1] 374009 0
PTSD symptom severity as measured by the CAPS-5
Timepoint [1] 374009 0
6-month follow-up (6 months after the post-treatment assessment completion)
Secondary outcome [2] 374010 0
PTSD caseness (i.e., diagnosis) as measured by the CAPS-5
Timepoint [2] 374010 0
Pre-treatment (2 weeks prior to commencing treatment), post-treatment (2 weeks after the completion of the last treatment session), 6-month follow-up (6 months after the post-treatment assessment completion)
Secondary outcome [3] 374011 0
Severity of PTSD symptoms as measured by the PTSD Checklist for DSM-5 (PCL-5)
Timepoint [3] 374011 0
Pre-treatment ( 2 weeks prior to commencing treatment), post-treatment (2 weeks after the completion of the last treatment session), 6-month follow-up (6 months after the post-treatment assessment completion)
Secondary outcome [4] 374318 0
Severity of depression as measured by the Patient Health Questionnaire (PHQ-9)
Timepoint [4] 374318 0
Pre-treatment (2 weeks prior to commencing treatment), post-treatment (2 weeks after the completion of the last treatment session), 6-month follow-up (6 months after the post-treatment assessment completion)
Secondary outcome [5] 374320 0
Quality of life as measured by the Assessment of Quality of Life Questionnaire - 6D (AQoL-6D)
Timepoint [5] 374320 0
Pre-treatment ( 2 weeks prior to commencing treatment), post-treatment (2 weeks after the completion of the last treatment session), 6-month follow-up (6 months after the post-treatment assessment completion)
Secondary outcome [6] 374602 0
Cardio-respiratory fitness level (indexed by the Maximal Oxygen Uptake) measured using a Sub-maximal fitness test
Timepoint [6] 374602 0
Pre-treatment (2 weeks prior commencing the treatment), post-treatment (right after the completion of the last treatment session-session 10)

Eligibility
Key inclusion criteria
(a) aged between 18 and 70 years old
(b) Meeting diagnostic threshold for PTSD on the MINI 7 (PTSD module) after experiencing a traumatic event (at any time-point in their life)
(c) Provision of consent to partake in therapy
(d) English comprehension at a level to make informed consent
(e) If on psychotropic medication, on a stable dose for the last 4 weeks, and not intending to change for the duration of the treatment phase
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Having a medical condition which may put the individual at risk of adverse consequences (e.g., cardiac, respiratory or neuromuscular disorders)
(b) Active mania or psychosis or suicidal ideation or other active risk
(c) Cognitive impairment
(d) Severe alcohol or substance use disorder
(d) Currently receiving psychological treatment (involving exposure therapy or Cognitive Behavioural Therapy for PTSD)
(e) History of moderate to severe traumatic brain injury, neurological disorder or epilepsy
(f) Significant other medical illness
(g) Hormonal or menstrual disorders, pregnancy or breast-feeding
(h) Beta-blocker use
(i) Weighing over 125kg


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 will occur following the determination of eligibility by the study assessor, coordinated via the REDCap randomisation software by the project manager. Randomisation will be conducted according to a computer generated randomisation list provided by the blinded study statistician.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation will be conducted using a randomisation table created by computer software (i.e. computerized sequence generation). Allocation will be stratified to improve the chance of balance among treatment groups, with respect to the following stratification variables:
PTSD severity ( measured by CAPS-5) and Antidepressant use (yes/no)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


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:

Power calculations have been conducted to determine sample sizes large enough to provide statistically significant results. Using Cohen’s formula, the power to detect the proposed difference in treatment outcome between study groups was estimated to be 80%, effect-size as moderate and alpha at p = .05. The moderate effect size was based on two previous data sets; a pilot trial data comparing exercise with exposure therapy, compared to exposure alone (Powers et al., 2015; reporting large pre-post effect size; Cohen’s d= 1.08) and a prior study examining the impact of intensive exercise on fear extinction learning (reporting moderate effect size). Given this former pilot trial utilized pre to post effect sizes, we will benchmark to a moderate effect size (Cohen’s f = 0.25). According to the sample size calculations in G*Power for two groups repeated measures testing for between group differences, total sample size required is 86 (approximately 42 per group). To detect the mediating effect of peripheral BDNF levels on the relationship between of treatment condition and treatment outcome of PE, simulations were run in the statistical program R. Assuming a medium effect size of BDNF level association with exposure therapy/fear extinction (Felmingham et al., 2013) and medium effect size of peripheral BDNF levels and PTSD symptoms (Angellucci et al., 2014; Dell-Osso et al., 2009), a sample size of 94 was found to yield 80% power to detect the specific indirect effect (X>M>Y). From previous exposure therapy trials, it is expected that 80% of patients will be retained for follow-up assessments. Therefore, factoring in potential attrition rates of 20% requires 112 participants (56 per group).Thus, across the three years of data collection in the project, 112 PTSD participants will be recruited. It is anticipated we will recruit an equal number of females and males for the trial.

Statistical analyses:

Analyses addressing the effect of study group on treatment outcome will follow the intention to treat principle. Latent growth curve model (LGM) analyses will be conducted to compare rates of change across time for each condition. Evaluation of model fit in the LGM models will occur using common fit statistics and associated cut-off criteria: standardised root mean square residual (SRMR; close to .08 or below), root mean square error of approximation (RMSEA, close to .06 or below); Tucker-Lewis index (TLI) and comparative fit index (CFI) (both CFI and TLI: close to .95 or above). Multi-group analyses will be completed for the defined LGM which will compare the slopes of change in CAPS-5 scores over time within and across the study groups. Missing data will be handled by applying robust maximum likelihood (MLR) estimator which is robust against non-normality of data.

In terms of the minimum number of sessions required for treatment completion, there are two instances in which a participant in the trial will be classified as a ‘treatment completer’. Firstly, a participant will be classified as a ‘treatment completer’ if they attend at or above 70% of treatment sessions (this equates to 7.0 sessions out of a total of 10 sessions). Secondly, in situations where the client has attended less than 70% of sessions, but both the therapist and client agree that the goals of therapy have been met and the client feels they no longer require treatment. These participants will also be regarded as ‘treatment completers’.

Analysis regarding the mediating effect of exercise induced changes in BDNF levels will be
conducted using LGM as well. Standard linear and mixed effects models will be used to investigate the effects of time and group on the secondary outcome measures, and the change in pre to post-exercise serum BDNF levels, while standardised within-group and between-group effect sizes will also be produced.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/10/2019
Actual
3/10/2019
Date of last participant enrolment
Anticipated
21/03/2022
Actual
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
112
Accrual to date
21
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 303593 0
Government body
Name [1] 303593 0
National Health and Medical Research Council (NHMRC)
Country [1] 303593 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
The University of Melbourne
Parkville, Victoria, 3010
Country
Australia
Secondary sponsor category [1] 303678 0
None
Name [1] 303678 0
Address [1] 303678 0
Country [1] 303678 0
Other collaborator category [1] 280926 0
Other
Name [1] 280926 0
Phoenix Australia, Centre for Posttraumatic Mental Health, Department of Psychiatry, University of Melbourne
Address [1] 280926 0
161 Barry Street, Carlton, VIC, Australia, 3053
Country [1] 280926 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304121 0
The University of Melbourne, Psychology, Health and Applied Sciences Human Ethics Sub-Committee (HESC)
Ethics committee address [1] 304121 0
Ethics committee country [1] 304121 0
Australia
Date submitted for ethics approval [1] 304121 0
15/04/2019
Approval date [1] 304121 0
19/06/2019
Ethics approval number [1] 304121 0
1954422.1

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

Contacts
Principal investigator
Name 95886 0
Prof Kim L Felmingham
Address 95886 0
Melbourne School of Psychological Sciences
Level 12, Redmond Barry Building, Tin Alley
The University of Melbourne
Parkville, VIC, 3010
Country 95886 0
Australia
Phone 95886 0
+61 3 8344 1523
Fax 95886 0
Email 95886 0
k.felmingham@unimelb.edu.au
Contact person for public queries
Name 95887 0
Katherine Chisholm
Address 95887 0
Phoenix Australia - Centre for Posttraumatic Mental Health
Level 3 Alan Gilbert Building
161 Barry Street
Carlton, VIC, 3053
Country 95887 0
Australia
Phone 95887 0
+61 3 9035 5599
Fax 95887 0
Email 95887 0
katherine.chisholm@unimelb.edu.au
Contact person for scientific queries
Name 95888 0
Kim L Felmingham
Address 95888 0
Melbourne School of Psychological Sciences
Level 12, Redmond Barry Building, Tin Alley
The University of Melbourne
Parkville, VIC, 3010
Country 95888 0
Australia
Phone 95888 0
+61 3 8344 1523
Fax 95888 0
Email 95888 0
k.felmingham@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.