Prevention of post-traumatic stress disorder: Lessons learned from a terminated RCT of prolonged exposure.

The main purpose of the current trial was to test if a brief trauma-focused cognitive-behaviour therapy protocol (prolonged exposure; PE) provided within 72 h after a traumatic event could be effective in decreasing the incidence of post-traumatic stress disorder (PTSD), thus replicating and extending the findings from an earlier trial. After a pilot study (N = 10), which indicated feasible and deliverable study procedures and interventions, we launched an RCT with a target sample size of 352 participants randomised to either three sessions of PE or non-directive support. Due to an unforeseen major reorganisation at the hospital, the RCT was discontinued after 32 included participants. In this paper, we highlight obstacles and lessons learned from our feasibility work that are relevant for preventive psychological interventions for PTSD in emergency settings. One important finding was the high degree of attrition, and only 75% and 34%, respectively, came back for the 2-month and 6-month assessments. There were also difficulties in reaching eligible patients immediately after the event. Based on our experiences, we envisage that alternative models of implementation might overcome these obstacles, for example, with remote delivery of both assessments and interventions via the internet or smartphones combined with multiple recruitment procedures. Lessons learned from this terminated RCT are discussed in depth.

RCT Entities:   Population Interventions Outcomes

Introduction

Psychologically traumatic events affect about 70% of the global population [1]. A clinically substantial proportion, an estimated 5.6% in Sweden, develop post-traumatic stress disorder (PTSD) [1], which includes symptoms of re-experiencing the event, avoidance, cognitive and mood changes, and hyperarousal [2]. PTSD is a detrimental condition and is associated with increased risk of suicide, drug and alcohol dependence, and sick leave [3] as well as with a higher prevalence of somatic problems including neurological, vascular, respiratory, gastrointestinal, and autoimmune diseases [4, 5].

Despite the high societal and individual burdens associated with PTSD, only a fraction of cases are detected by the healthcare system [6], and evidence-based trauma-focused treatments for PTSD are seldom available in real-world settings [7, 8]. One way to decrease the prevalence of PTSD is to intervene before the disorder develops [9]. A pilot trial (N = 137) from the US by Rothbaum et al. [10] indicated that a modified version of prolonged exposure (PE; the first-line treatment for PTSD [11]) may be effective in preventing the onset of PTSD symptoms in emergency trauma care patients. The results from studies on early interventions are mixed. Studies on critical incident stress debriefing provided within the first days after the traumatic event indicates that the intervention is ineffective in preventing PTSD and may even worsen long-term symptoms of post-traumatic stress [12]. It has been suggested that these effects are due to trauma survivors being encouraged to talk about their experiences without having sufficient opportunity to emotionally process the traumatic event [12]. Other studies investigating 5–6 weeks of trauma-focused cognitive behaviour therapy starting within a couple of weeks after exposure to trauma as a treatment for acute stress disorder are more encouraging. Three trials have shown that trauma-focused cognitive behaviour therapy is more efficacious in reducing symptoms of post-traumatic stress compared to supportive counselling [13-15]. In the Rothbaum et al. [10] study, the PE intervention was initiated within 72 hours after trauma, followed by two weekly sessions. The authors motivated setting the time frame to 72 hours because it has been argued that failure of recovery after exposure to trauma (e.g. development of PTSD) may in part be explained as a failure of fear extinction [16], and animal research suggests that early extinction training has the potential to modify consolidation of the original fear memory [17]. In their trial, PE was superior to the assessment-only control group in reducing PTSD symptoms 12 weeks after the event [10], and the intervention seemed to reduce the risk for PTSD development [18]. The three-session protocol has more recently been evaluated against one session of intervention and an assessment-only comparator. No differences between the groups were found in the level of symptoms of post-traumatic stress, although the study was underpowered to detect between-group differences [19].

In 2016, our research group set out to replicate and extend the findings by Rothbaum et al. [10], originally with the aim to assess the effectiveness of the modified PE protocol in a larger sample and using an active control group of non-directive support [20, 21], blinded assessors, and longer follow up. After a pilot trial of 10 consecutive trauma patients, we subsequently launched a large-scale RCT. Given the estimated effect sizes in the previous trial by Rothbaum et al., we calculated that 352 participants (176 in both groups) were needed in order to detect a standardised effect size (Cohen´s d) of 0.3 (10% data attrition allowed, two tailed tests, p = .05, 80% power). However, a major reorganisation at the recruiting site posed such a large barrier to the recruitment that the RCT had to be terminated prematurely. In this paper, we describe the methods we used and the combined results from a total of 32 participants. We highlight different implementation issues of delivering PE for psychological trauma in patients within a hospital context and provide suggestions on how to resolve these issues.

Method

Pilot and main RCT design

The pilot study of 10 participants and the subsequent large-scale trial used an identical randomised controlled design and procedures. Study participants were patients seeking medical care at an emergency department (ED) after experiencing a potentially traumatic event within the past 72 hours. Participants were randomly allocated to either modified PE or a control condition. The sample reported throughout this paper is the pooled sample of 10 participants from the pilot study and the first 22 participants from the RCT.

Participants

Eligible participants were Swedish-speaking patients over 16 years of age attending the ED at Karolinska University Hospital in Solna, Sweden, within 72 hours after experiencing a psychologically traumatic event according to the DSM-5 criterion A for PTSD (i.e., exposed to death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence). Exclusion criteria were a) ongoing intoxication (e.g. due to alcohol or other drugs), b) low cognitive capacity, and c) other serious psychiatric comorbidity (ongoing psychotic symptoms or ongoing manic episode, suicidal ideation). Common traumatic events that lead to attendance at the ED were motor vehicle accidents and assaults.

Procedure

The recruitment included several steps. A pre-selection screening was done each weekday morning at an out-patient clinic nearby the ED by a clinical psychologist who scanned the digital medical records of newly arrived patients in order to assess criterion A and potential exclusion criteria. Potentially eligible patients were then assessed on the inclusion and exclusion criteria using a structured assessment interview developed for the purpose. As an aid in conducting the assessment, the self-rating questionnaires Immediate Stress Response Checklist [ISRC; 22] and Montgomery Åsberg Depression Rating Scale–Self-rated version [MADRS-S; 23] were included. The assessment was conducted by one of four clinical psychologists involved in the study team either in the emergency room or at bedside in the hospital ward. In the measures section, a more detailed description of the trauma assessment procedures can be found. Patients who had been discharged before screening were interviewed via telephone and, if eligible, invited to the hospital to receive the intervention in the office of the clinical psychologist. Eligible patients received both written and verbal information about the study. After the eligible patients had signed the informed consent form, the psychologist conducted the baseline assessments and subsequently opened the sealed envelope containing the randomisation assignment. The intervention was delivered starting immediately after randomisation. Participants in both groups were assessed at weeks 1–3 (during the intervention) and at 2 months and 6 months after the intervention. The primary endpoint was 6 months. The participants were not reimbursed for their participation in the study. The study started recruitment on 18 April 2017 and was terminated on 11 November 2017. All included individuals continued the intervention and assessment procedures, even after the recruitment was terminated, as stated in the informed consent.

Measures

The primary outcome was PTSD symptom severity assessed using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) [24, 25]. Before the interview, the participants filled out the self-report measure Life Events Checklist for DSM-5 (LEC-5), which screens for potentially traumatic events in a respondent’s lifetime. The incident leading to the ED visit was defined as the index traumatic event during the CAPS-5 interview. One participant who reported distress due to exposure to another previous traumatic event was scheduled for a separate visit to assess symptoms due to this particular event. The assessors (n = 4) were clinical psychologists who were experienced in conducting structured diagnostic interviews. Each assessor had received extensive training, up to 2 ½ days, in the administration and scoring of the CAPS-5. Inter-rater agreement was excellent (Intra-Class Correlation between 0.91 and 0.98 on the different assessment test sessions). Supervision was provided for difficult cases. Secondary outcomes were the PTSD Symptom Checklist for DSM-5 (PCL-5) [26], an intrusion diary [27, 28], MADRS-S [23], the World Health Organization Disability Assessment Schedule-12 (WHODAS) [29], EQ-5D (Euroqol-5D) [30], and the Insomnia Severity Index (ISI) [31].

Symptoms of post-traumatic stress were assessed by the PCL-5 [26], a self-report measure assessing the 20 DSM-5 symptoms of PTSD. Participants were instructed to use the incident leading to the ED visit as the index event when completing the PCL-5. The participants also completed an intrusion diary, which assessed the daily number of intrusive memories of the traumatic event from day one of the intervention to the last session. This intrusion diary has been used in previous early intervention studies [27, 28] and was translated into Swedish by the first author.

Depressive symptoms were assessed using the MADRS-S [23], general functioning was assessed using the WHODAS-12 [29], quality of life was assessed using the EQ-5D [30], and sleep quality was assessed using the ISI [31]. Participants who were unable to attend the follow-up assessments at the clinic were interviewed via telephone.

The frequency of adverse events was assessed at session two and three of the intervention and at 2 and 6 months’ follow up using a structured interview. To control for possible bias due to expectation and non-specific factors between the PE and control group, we used the Treatment Credibility Scale [32] at session 1.

Interventions

Participants in both conditions received a three-session intervention in which the first session was provided immediately after the screening, which took place less than 72 hours after the traumatic event. The therapists were five clinical psychologists with extensive experience and training in PE. All therapists received an additional 1-day training in the adapted PE protocol used in this study as well as how to deliver the control intervention. Supervision was provided when needed.

Prolonged exposure (PE)

The brief PE intervention protocol from the Rothbaum et al. [10] study was provided to us by the study authors. The protocol was translated into Swedish by the first author, who has been trained and certified in PE by the original treatment developer (Professor Edna Foa) and who, prior to the study, worked clinically with PE for 17 years. PE is based on the emotional processing theory developed by Foa and Kozak [33]. This theoretical framework posits that PTSD symptoms reflect pathological fear structures that do not accurately represent reality and are seen as signs that the traumatic memory has not been sufficiently emotionally processed. This theory stipulates that in order to achieve emotional processing of the trauma memories, the patient needs to repeatedly activate the fear structure and access corrective information about the trauma memory. A failure in emotional processing is conceptualised to occur due to avoidance of the memory itself and its associated feelings, thoughts, and situations related to the trauma, which limits the activation of the fear structure and access to corrective information. These avoidance behaviours are thought to maintain the individual’s erroneous negative perceptions about themselves and the world. PE aims to inhibit avoidance patterns by gradually approaching the trauma-related stimuli, which is hypothesised to activate the fear structure and subsequently provide corrective information about the feared consequences of trauma. The adapted PE intervention used in this study has the same basic aim as traditional PE for PTSD with the difference that this early intervention has the potential to more swiftly modify the consolidation of the fear memory from the traumatic event [34].

In the first session, the participant is first given a brief rationale for the modified PE protocol and the function of avoidance behaviours for trauma memories. The rationale is followed by imaginal exposure in which the participant is instructed to re-activate the trauma memory (i.e., to visualise the event in their mind’s eye) for 20–30 minutes by recounting the traumatic event, talking in the present tense, and repeating the memory if necessary to reach the time limit. Subjective units of distress (SUD) are assessed regularly during each imaginal exposure. After the imaginal exposure, reflective questions are used to address erroneous trauma-related cognitions. The imaginal exposure is recorded on a voice recorder, and the participant is instructed to listen to the session on a daily basis in order to achieve emotional processing of the trauma memory.

In addition to imaginal exposure, the participant is also given psychoeducation about common reactions after trauma and the importance of breaking avoidance patterns of situations that trigger trauma memories. Exposure in vivo is carried out through a homework assignment. The participant also is given basic skills in a breathing retraining technique. Sessions two and three follow the same format with continued imaginal and in-vivo exposure. The intervention ended at session three with a summary of what the participant had learned from the sessions. All sessions were 60 minutes long and were conducted on a weekly basis.

Control group

The main purpose of the control group was to provide a credible intervention that is in line with international recommendations on early interventions after trauma [20, 21], including psychoeducation about common reactions after trauma and general non-directive support aimed at promoting safety, calmness, connectedness, self-efficacy, and hope. The sessions followed the same structure and were matched to the intervention in frequency and duration. In the sessions, the therapist usually discussed, in a supportive way, how the week had progressed for the participant, but participants were free to address any issues at each session. If the participants talked about experiencing symptoms of post-traumatic stress, the therapist would normalise the reactions, provide emotional and practical support, calm the participant if necessary, and try to instil hope. The participants were free to discuss their traumatic event with their therapist; however, the therapist did not provide any rationale and/or suggestions for exposure exercises.

Randomisation and masking

Block randomisation was conducted by an independent party (Karolinska Trial Alliance) in a 1:1 ratio. The participants were randomised after the baseline assessment using sealed envelopes. The sealed envelopes were otherwise kept safe and accessible only to persons authorised to unblind, and the randomisation key was kept at the clinic. Participants were blinded to the conditions in order to control for expectation confounders. Therefore, participants were simply told that they would receive one of two interventions aiming to prevent the onset of PTSD.

Ethics approval and consent to participate

The study was registered at Clinicaltrials.gov (ID: NCT03116165) and approved by the Regional Ethical Review Board in Stockholm, Sweden (ID: 2015/1820-31). The study is reported in accordance with the CONSORT statement for nonpharmacological treatments.

Eligible patients received both written and verbal information about the study and were not included in the study until after signing the written informed consent.

Results

Study progression

Unforeseen major organisational changes at the hospital negatively affected the recruitment. At the start of the RCT, 30% of the trauma patients at the ED had been recruited into the current study. This proportion decreased rapidly to only 2.8% after the organisational changes in the subsequent months (illustrated in Fig 1). All trauma care was moved to an entirely new hospital, Karolinska University Hospital, which was designed for highly qualified specialised trauma care. The hospital was now mandated to take on only very severely injured patients, leading to a markedly lower number of patients overall and a lower proportion of eligible patients for the study. The recruitment continued for 6 months because there was uncertainty as to whether the decline in eligible patients would become permanent, but the low inclusion rate due to the organisational changes ultimately forced the discontinuation of the study. Treatment adherence and credibility were rated as high, whereas many participants dropped out at the follow-up assessments.

Fig 1

Recruitment rate of patients attending the ED during the study period.

The flow of participants is shown in Fig 2. There were 292 trauma patients who were screened using the digital screening record, and 32 participants were included in the study. The most common reasons for exclusion were not fulfilling criterion A (n = 71), not being able to contact the patient (n = 41), and that more than 72 hours had already passed since the traumatic event (n = 38). Twenty-five participants had experienced an accident and seven were victims of assault. On average, a mean of 35 hours had passed from the traumatic event to the intervention. All but one of the participants had slept before the intervention.

Fig 2

Participant flow chart.

There were gender differences between the included participants (12 men and 20 women) and patients who were eligible but declined participation (31 men and 8 women). Younger people were also more likely to decline participation in the study, and the included patients had a mean age of 42 years while those patients who declined participation were on average 32 years old. Baseline characteristics for the included participants are presented in Table 1.

Table 1

Baseline characteristics for included participants by intervention condition.

	Prolonged exposure	Control condition
	(n = 15)	(n = 17)
Gender
Women, n (%)	9 (60%)	11 (64%)
Age (years)
Age, mean (SD)	41 (13)	44 (10)
Occupational status
Working	14 (93%)	14 (82%)
Student	0	1 (6%)
On sick leave	0	1 (6%)
Parental leave	0	1 (6%)
Unemployment	0	1 (6%)
Traumatic event
Accident, n (%)	11 (73%)	14 (82%)
Assault, n (%)	4 (27%)	3 (18%)
Time since traumatic event, mean hours (range)	37 (4.5–57)	33.5 (12.5–71)
Admitted as in-patient, n (%)	3 (20%)	3 (18%)
History of trauma and mental illness
Prior exposure to trauma as an adult, n (%)	6 (40%)	6 (35%)
Prior exposure to trauma as a child, n (%)	6 (40%)	4 (23.5%)
Previous or current mental illness, n (%)	8 (53%)	8 (47%)
Baseline measures
ISRC score, mean (SD)	28.5 (12.9)	26.9 (12.5)
MADRS-S score, mean (SD)	15.6 (9.6)	16.5 (11.6)

Abbreviations: ISRC, Immediate Stress Response Checklist; MADRS-S, Montgomery Åsberg Depression Rating Scale, Self-rated

Preliminary outcome data

SUD ratings for all three intervention sessions are shown in Fig 3. The CAPS-5, PCL-5, and MADRS-S scores are shown in Table 2. The participants reported no adverse events that could be attributed to either of the interventions.

Fig 3

Individual subjective units of distress ratings across the intervention sessions.

A decrease in the participants’ mean subjective level of distress during the intervention is seen (session 1 –pre-SUD 35, peak-SUD 61, post-SUD 40; session 2 –pre-SUD 42, peak-SUD 56, post-SUD 33; session 3 –pre-SUD 24, peak-SUD 33, post-SUD 28).

Table 2

Treatment outcomes for included participants by intervention condition.

	Prolonged exposure		Control condition
Outcomes	N	mean (SD)	N	mean (SD)
Primary outcome CAPS-5
2-months	n = 10	17.9 (15.7)	n = 14	13.1 (15.3)
6-months	n = 5	4.0 (4.4)	n = 6	9.5 (11.8)
Secondary outcomes
PCL-5
post-intervention	n = 9	20.4 (13.9)	n = 13	24.8 (20.2)
2-months	n = 8	17.8 (15.2)	n = 10	13.4 (16.8)
6-months	n = 5	7.3 (5.6)	n = 6	8.6 (5.3)
MADRS-S
2-months	n = 9	11.9 (10.3)	n = 9	9.7 (13.7)
6-months	n = 5	7.6 (15.3)	n = 6	13.7 (16.6)
Baseline measures
ISRC sum score	n = 14	28.5 (12.9)	n = 17	26.9 (12.5)
MADRS-S sum score	n = 15	15.6 (9.6)	n = 16	16.5 (11.6)

Abbreviations: CAPS-5, Clinician-Administered PTSD scale for DSM-5; PCL-5, Posttraumatic stress disorder checklist for DSM-5; MADRS-S, Montgomery Åsberg Depression Rating Scale, Self-rated; ISRC, Immediate Stress Response Checklist

The scores on the Treatment Credibility Scale were overall high in both conditions (M = 41.2, M = 37.5). Four participants, two from each condition, dropped out of the intervention. One participant perceived that being randomised to the control condition was negative and declined further participation. The other participant in the control condition did not give a reason for leaving the study. One participant in the PE group left the study and stated that it was due to them perceiving the intervention as too emotionally demanding. The other participant in the PE group stated not needing the intervention as the reason for dropping out.

A total of 24 of the 32 enrolled participants (75%) completed the CAPS-5 assessment at the 2-month follow-up, and 11 (34%) completed it at the 6-month follow-up. Seven of the 24 assessments (29%) at the 2-month follow-up were conducted by telephone. We saw a small gender difference in who attended the 6-month follow-up assessment–with 30% (6/20) of the recruited women returning and 41% (5/12) of the recruited men returning.

Nine (60%) participants in the PE group completed the intrusion diary between sessions 1 and 2, and 7 (47%) completed it between sessions 2 and 3. The corresponding figures for the control condition were 12 (70%) between sessions 1 and 2 and 9 (53%) between sessions 2 and 3. SUD ratings collected during the imaginal part of the PE sessions were available from 13 (86%) participants.

The mean numbers of intrusive memories are shown in Fig 4. The mean number of daily intrusions between sessions 1 and 2 was 4.68 in the PE group and 4.68 in the control condition. Between sessions 2 and 3, the mean number of daily intrusions was 0.19 in the PE group and 2.54 in the control condition.

Fig 4

Frequency scatter graphs of the number of intrusive memories per day recorded in the intrusion diary during the intervention period for patients who returned the diary in each condition (the left graph depicts the PE group and the right the control condition).

The circle size illustrates the number of participants who reported the indicated number of intrusive memories for each day.

Discussion

The current study was designed as a preventive intervention for PTSD to replicate and extend the Rothbaum et al. [10] trial. After a successful pilot trial, we aimed to recruit 352 patients at the ED in an RCT to test the effects of modified PE compared with an active control condition. The RCT started out with a fair recruitment rate of 30% of attending patients but had to be discontinued after the hospital underwent unforeseen major organisational changes and started to treat only severely injured patients, which led to a drastic decline in the number of eligible patients that could be recruited into this study.

In this study, we took advantage of already established procedures and infrastructure at the hospital. For example, we used regular hospital psychologists and the hospital´s medical record system at the ED department to find and approach eligible trauma patients. We consider this regular clinic approach to be a major strength in the study because it would have enhanced implementation after study completion. The reliance on personnel and infrastructure at one specific hospital unfortunately became a major obstacle in this study because recruitment rates fell significantly during the re-organisation. In hindsight, we might have circumvented the problem with recruiting patients if we had developed study procedures that were able to function independently of regular hospital routines and organisational changes within the hospital. The current study also had rather high levels of attrition.

Another option for future research to overcome the problems mentioned above would be to recruit, assess, and provide trauma patients with early interventions remotely, for example, by using smartphone or internet-delivered approaches. Studies on internet-based CBT have shown promising results for the treatment of PTSD [35, 36]. This approach could ensure swift and easy recruitment, assessment, and provision of interventions as well as facilitate stability in study procedures independent of the current hospital organisation. Internet-delivered psychological treatments can also increase accessibility when implemented in regular care [37]. An interesting future innovation would therefore be to investigate if it is possible to reach trauma patients remotely in the early aftermath of traumatic events. As previously mentioned, an important aspect in this current trial was the high degree of attrition. Many individuals recruited in this trial were not PTSD cases and may therefore not have been motivated to undergo any more follow-up assessments because it might have been inconvenient (e.g., traveling to the hospital, navigating to a new clinician, or missing work). Remotely delivered and easily accessible technological tools could potentially circumvent some of the attrition found in this study. However, one large-scale trial from 2013 found relatively low compliance rates for an automated internet-based psychological preventive intervention for PTSD [38]. Future trials could add therapist support to internet-delivered interventions because this has been shown to lead to a higher degree of compliance and improved efficacy [39].

A significant proportion of ED patients (24%) in the current study were excluded due to the time criterion. Many patients had already returned home after their visit to the ED when we detected them in the medical record system, and they could thus only be scheduled for treatment the day after the traumatic event. Memory consolidation theory proposes that the optimal time to intervene before completed memory consolidation is within 6 hours after the traumatic event has taken place [34]. From that perspective, it is important to develop simple interventions that can be delivered to the patient at an early stage in the hospital, for example, as recently shown by Iyadurai et al. [27]. Furthermore, sleep has been hypothesised to play a role in memory consolidation [40], and thus the optimal timeframe for early interventions might be before the patient first sleeps after the event. In the current study, all but one patient had slept before the start of the intervention. Future research could investigate in more detail whether sleep has a moderating effect on early interventions for trauma.

Although memory consolidation theory proposes a narrow time window of 6 hours, this might not be clinically feasible for many patients experiencing trauma. Some patients are too physically ill to receive psychological interventions within this time frame, and other patients might be more motivated to undergo psychological interventions a few weeks post-trauma. The recruitment rates in three previous trials investigating early interventions after trauma varied between 2% and 26% [10, 19, 27]. One opportunity to increase inclusion rates could therefore be to extend the time criterion of 72 hours to up to a week or more. A recent systematic review showed that, of 61 studies investigating the efficacy of early interventions for trauma, the majority of these studies investigated interventions that were provided within weeks or even months after exposure to trauma. The conclusions drawn from this review point to evidence for the provision of early interventions provided only to individuals with impairing symptoms rather than to everyone who recently experienced trauma [41]. One suggestion would thus be to provide early PE to individuals who experience significant intrusive memories or other symptoms that can be readily addressed with existing interventions. This indicated approach seems to have potential to be more effective because individuals with more symptoms also tend to be more motivated to complete both treatment and assessment procedures.

To summarise, this prematurely terminated trial generated important scientific and clinical experiences. Based on these experiences, we suggest that future research into the prevention of PTSD might benefit from considering implementation models with remotely delivered, easily accessible intervention and assessment procedures that are independent of regular health organisation routines, as well as simple and easily delivered interventions provided by non-specialists at the ED to patients with a certain level of symptoms of post-traumatic stress. In addition, future studies of early interventions may need to evaluate the potential benefits of a very short time-frame for inclusion against the difficulties in recruitment and attrition that arise from such a narrow time-frame.

Limitations

A major limitation with the study is the small sample size and limited follow-up data. The data from the pilot study and the RCT were combined, which might have introduced excess variability in the data. However, in this trial the pilot phase did not lead to any significant changes in the study procedure and thus the variability introduced would be negligible. Nonetheless, due to the small sample size the preliminary outcome data were not subjected to statistical analysis and should be regarded as tentative. Furthermore, the termination of this trial was due to organisational changes specific to the study context, and the significance for other trials should be interpreted with caution. Similarly, the participants were not assessed in depth for current PTSD due to other events or psychiatric comorbidity. Nonetheless, the difficulties with low recruitment rates and high attrition rates at follow-up assessments have been noted by other trials of early intervention as well [10, 19, 27]. We suggest therefore that this terminated trial contributes to a growing body of literature that indicates important lessons on the feasibility aspects of conducting early intervention trials of psychological interventions for trauma victims.

Consort guideline checklist for the study.

(DOC)

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Baseline data.

(DOCX)

Click here for additional data file.

Follow up data at 2 months.

(XLSX)

Click here for additional data file.

Follow up data at 6 months.

(XLSX)

Click here for additional data file.

17 Jun 2020

PONE-D-20-01989

Prolonged Exposure as early intervention in an emergency department context: lessons learned from a terminated RCT.

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: N/A

Reviewer #2: Yes

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Reviewer #2: No

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently.

Since this paper highlight obstacles and lessons learned from a terminated RCT / feasibility work relevant for preventive psychological interventions for PTSD in emergency settings, the title should indicate it (inclusion of word PTSD is must), in my opinion. Present title gives the impression that the paper is about methodology ‘regarding how to learn lessons from any terminated RCT’ in general. Look at the ‘objectives’ given in line 25-28.

This RTC is terminated even before recruiting 10% of targeted (minimum required) sample size of 352 participants [32/352=9.09% or 22/352=6.25%], so that the lessons learned from this terminated RCT data are not much meaningful. As said in lines 35-37 “One important finding was the high degree of attrition: only 78% and 34% respectively came back for the two months and six-months assessments” does that mean that although recruitment stopped, data collection continued?

Is it correct to combine data from the pilot study and whatever available from terminated RCT? as said in lines 81-83 [The sample reported throughout this paper is the pooled sample of 10 participants from the pilot study and the first 22 from the RCT]. Please check typing error in sentence in lines 117-8 that “Inter-rater agreement was excellent (Inter Class Correlation between 0.91-0.98).” which should be “Inter-rater agreement was excellent (Intra-Class Correlation Coefficient between 0.91-0.98).” because we assess Inter-rater agreement by Intra-Class Correlation Coefficient (and not by Inter Class Correlation). Further, note that there is only one value of Intra-Class Correlation Coefficient and a range as given. If you intend to mean differently, please clarify.

I believe that ‘Procedures’ (given in lines 96-111) & subsequent account {like Measures, etc.} are part of ‘protocol’ [because the trial is terminated], in that case ‘The study started recruitment 18th of April 2017 and was terminated 11th November 2017’ (lines 110-11) means it took more than six months to recruit 22 subjects {or was that also planned?}. Check the ‘tense’ of the entire text.

In my considered opinion [despite the fact which is highly appreciable that tools used (or proposed to be used) are very appropriate] whatever authors want to communicate [definitely important to communicate], could be communicated in just a letter-to-editor or brief communication (and not a full-length paper/article).

Reviewer #2: This is an important study that describes an early intervention for PTSD. Although the study was not completed, the results are important in this field given the paucity of studies. My comments are as follows:

The results and methodology are not completely in sync in terms of previous psychological trauma and psychiatric disorder. How were these assessed? Were participants with current PTSD (ie relating to a previous event) excluded from the study? If not, why not?

Please provide more information regarding the follow up assessments - were those who attended follow up different from those who did not?

The authors mention sleep but this is not elaborated upon in the discussion given the literature regarding memory consolidation and sleep this is important.

The authors do not cover the general field of early intervention of PTSD. The results of the few studies that have been carried out in the first 72 hours, taken together, are not particularly encouraging. Most of the studies of early intervention have concluded that it is most effective with symptomatic survivors, not whole populations, and the few studies examining very early (ER based) interventions are not consistent. This is not reflected in the manuscript, neither in the introduction "One way to decrease the prevalence of PTSD is to intervene before the disorder develops" nor in the discussion, where the recommendation for the use of Internet based interventions or memory consolidation is made without examining the studies that do not support these results. The complexity of this issue should be discussed properly. Additionally the inclusion of participants more than 72 hours after the event raises questions about the use of memory consolidation that should be clarified.

The authors state that a number of reasons led to the premature end to the study, but only mention one.

**********

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Reviewer #1: No

Reviewer #2: No

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Submitted filename: renamed_0eebc.docx

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7 Aug 2020

PONE-D-20-01989

Journal Requirements:

1. We have updated the manuscript to meets PLOS ONE's style requirements.

2. We have thoroughly discussed and elaborated potential limitations of the study.

3. Our ethics statement now appear in the Methods section of the manuscript.

4. We have added captions for our Supporting Information files. Thank you for changing the file type for CONSORT checklist Lessons learned .doc file.

5. a. We have confirmed that our declarations of interest does not alter our adherence to all PLOS ONE policies on sharing data and materials, and included including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

b. We have included the updated Competing Interests statement in our cover letter.

6. We have uploaded the minimal data set underlying the results as Supportive information files. Thank you for taking care of the update on our Data Availability statement.

Dear Reviewer #1 and Reviewer #2,

First, we want to thank you for valuable comments. We have revised the manuscript accordingly and we think that it is greatly improved. Below follows a detailed description of the changes made point by point:

Reviewer #1

1. Since this paper highlight obstacles and lessons learned from a terminated RCT / feasibility work relevant for preventive psychological interventions for PTSD in emergency settings, the title should indicate it (inclusion of word PTSD is must), in my opinion. Present title gives the impression that the paper is about methodology ‘regarding how to learn lessons from any terminated RCT’ in general. Look at the ‘objectives’ given in line 25-28.

Response: We thank Reviewer #1 for this thoughtful comment and we have incorporated the word PTSD in the title of the manuscript (page 1, Prevention of Post-Traumatic Stress Disorder: Lessons Learned from a Terminated RCT of Prolonged Exposure).

2. This RTC is terminated even before recruiting 10% of targeted (minimum required) sample size of 352 participants [32/352=9.09% or 22/352=6.25%], so that the lessons learned from this terminated RCT data are not much meaningful.

Response: We agree that the outcome data come with great uncertainty and we have elaborated on this further in the limitation section (page 18, first paragraph). As highlighted by Reviewer #1 in point 6 below, it took us nearly six months to recruit 22 participants. The study started out with a fair recruitment rate, 30% of the daily intake of trauma patients at the ED were included, but this figure declined swiftly to only 2.8% of trauma patients. This significant decline was due to major organizational changes at the recruiting site and was not expected. Although the number of included participants compared to the target sample was relatively low, we argue that the long recruitment period and sudden shift in recruitment rate provides the reader with important data on the role of organizational factors in early provided psychological interventions after trauma. Also, we do not judge 22-32 subjects as a meaningless sample size but sufficient to say something about the feasibility of using prolonged exposure as an early intervention in a hospital context. We agree with Reviewer #1 that statistical analysis of the sample may not be meaningful, and hence we have not conducted any such analyses. However, in line with Reviewer #2 below, we think the study still holds important lessons for both clinicians and researchers working with individuals early after exposure to trauma.

3. As said in lines 35-37 “One important finding was the high degree of attrition: only 78% and 34% respectively came back for the two months and six-months assessments” does that mean that although recruitment stopped, data collection continued?

Response: Yes, this is correct, as recruitment stopped, we continued the follow up as stated in the verbal and signed informed consent with the included participants. We deemed this to be best ethical practice as participants expected to receive a clinician visit (with the possibility to be offered further treatment, if there would be any need, for mental health issues). We agree with Reviewer #1 that this needs further clarification and we have added information about this on page 5, last paragraph, continuing on page 6.

4. Is it correct to combine data from the pilot study and whatever available from terminated RCT? as said in lines 81-83 [The sample reported throughout this paper is the pooled sample of 10 participants from the pilot study and the first 22 from the RCT].

Response: Because the trial was terminated early, we decided to include also the feasibility data from the pilot study. The participants in the pilot study underwent clinical procedures and routines that were identical to the participants in the RCT. Including participants also from this part of the larger study gave us greater precision to investigate feasibility aspects of using prolonged exposure as an early intervention in a hospital context. We think this improves the quality of the manuscript significantly but we are open to revise this if the Editor thinks differently. We have added a discussion of this under Limitations (page 18, first paragraph).

5. Please check typing error in sentence in lines 117-8 that “Inter-rater agreement was excellent (Inter Class Correlation between 0.91-0.98).” which should be “Inter-rater agreement was excellent (Intra-Class Correlation Coefficient between 0.91-0.98).” because we assess Inter-rater agreement by Intra-Class Correlation Coefficient (and not by Inter Class Correlation). Further, note that there is only one value of Intra-Class Correlation Coefficient and a range as given. If you intend to mean differently, please clarify.

Response: We thank reviewer #1 for pointing us this typing error in the manuscript. The inter-rater agreement is assessed by the Intra-Class Correlation Coefficient. We have changed this in the manuscript (page 6, last sentence). We have also clarified that the range given is from multiple assessment sessions.

6. I believe that ‘Procedures’ (given in lines 96-111) & subsequent account {like Measures, etc.} are part of ‘protocol’ [because the trial is terminated], in that case ‘The study started recruitment 18th of April 2017 and was terminated 11th November 2017’ (lines 110-11) means it took more than six months to recruit 22 subjects {or was that also planned?}.

Response: We have structured the manuscript closely to standard reporting of RCT:s in order to facilitate the reading of the manuscript. We therefore include standard headings in the Methods section, although we do see that it might make sense to revise the structure. Nevertheless, we would suggest to keep the current structure. As to the question from the Reviewer on the prolonged recruitment, we have clarified in the study progression paragraph in the Results section that, “The recruitment continued for six months as there was uncertainty as to whether the decline in eligible patients would become permanent, however, the low inclusion rate due to the organizational changes ultimately led to the discontinuation of the study “(page 11, first paragraph). Also note, as we point to in the manuscript, that the trial highlights the difficulty in recruiting participants in this early stage after exposure to trauma. Problems in recruiting have occurred also in other similar trials testing early intervention for patients who experienced trauma, with a low proportion of eligible participants among patients [1-3]. For example, the more recent trial by the Rothbaum et al research group investigating early provided prolonged exposure was terminated before reaching the target number of participants, leaving the study underpowered [2]. We suggest that an important lesson is that this is a factor to consider overall when planning early intervention studies and clinical routines.

7. Check the ‘tense’ of the entire text.

Response: We have re-read the manuscript with this in mind and adjusted the tense accordingly, and made additional language edits – we hope that the language now is up to standard.

8. In my considered opinion [despite the fact which is highly appreciable that tools used (or proposed to be used) are very appropriate] whatever authors want to communicate [definitely important to communicate], could be communicated in just a letter-to-editor or brief communication (and not a full-length paper/article).

Response: We have had extensive discussions in our research group about how to communicate the findings from this study. We agree that the lessons learned could be summarized rather briefly. However, our conclusion is that a full-length manuscript is the best option. A brief communication has its advantages but it would also mean that we would have to exclude many important aspects of the trial (e.g. the rigorous study procedures, both feasibility efficacy and process data, in-depth discussion about organizational aspects and ideas for future research and clinical policy for early interventions for trauma).

Reviewer #2:

1. This is an important study that describes an early intervention for PTSD. Although the study was not completed, the results are important in this field given the paucity of studies.

Response: We thank Reviewer #2 for pointing out the importance of these types of studies.

2. The results and methodology are not completely in sync in terms of previous psychological trauma and psychiatric disorder. How were these assessed? Were participants with current PTSD (ie relating to a previous event) excluded from the study? If not, why not?

Response: We agree with Reviewer #2 that this needs more clarification. As previously shown, exposure to psychological trauma is highly frequent and as much as one-third of the general population will during their life-time experience at least four potentially traumatic events [4]. As reported in the manuscript (table 1, page 12) we assessed history of traumatic events and has clarified that we used a structured assessment interview for this purpose (page 5 under Procedures, first paragraph). Previous traumatic events were not an exclusion criterion. However, a limitation of our study was that we did not assess for current psychiatric disorders and we do not know how many participants that might have fulfilled criteria for PTSD at baseline – this has been added to the limitations (page 18, first paragraph). The clinicians in the current study were very careful to assess the current index trauma (i.e. symptoms that occurred after the incident that lead to the emergency department visit) when scoring the CAPS-5. Participants who reported distress due to exposure to another previous traumatic event received an additional visit to assess symptoms related to this particular event (this extra visit occurred only in one case). Participants were also explicitly instructed to have the current index event in mind when completing the self-rated PCL-5 questionnaire. We have clarified that in the manuscript (page 6, under Measures, first paragraph).

3. Please provide more information regarding the follow up assessments - were those who attended follow up different from those who did not?

Response: Reviewer #2 raises an important question. Given the low number of recruited participants we did not conduct any statistical analysis. At the 2 months-follow up there was no gender difference in attendance, but at 6-months follow up we saw a small difference, 30 % (6/20) of the recruited women came back and 41% (5/12) of the recruited men. We have added this information on page 14, last paragraph.

The authors mention sleep but this is not elaborated upon in the discussion given the literature regarding memory consolidation and sleep this is important.

Response: We thank the reviewer for this suggestion, and we elaborate briefly on the role of sleep in early interventions for trauma in the discussion (page 16, last paragraph).

4. The authors do not cover the general field of early intervention of PTSD. The results of the few studies that have been carried out in the first 72 hours, taken together, are not particularly encouraging. Most of the studies of early intervention have concluded that it is most effective with symptomatic survivors, not whole populations, and the few studies examining very early (ER based) interventions are not consistent. This is not reflected in the manuscript, neither in the introduction "One way to decrease the prevalence of PTSD is to intervene before the disorder develops" nor in the discussion, where the recommendation for the use of Internet based interventions or memory consolidation is made without examining the studies that do not support these results. The complexity of this issue should be discussed properly. Additionally the inclusion of participants more than 72 hours after the event raises questions about the use of memory consolidation that should be clarified.

Response: We agree with Reviewer #2 that this issue needs to be clearer in the manuscript and we have elaborated on the current literature in the Discussion (page 17, first paragraph). We have also added to the introduction the findings from a recent study on early intervention (page 3, second paragraph).

5. The authors state that a number of reasons led to the premature end to the study, but only mention one.

Response: We thank Reviewer #2 for making us aware of that. The reason for the termination of the trial was one, namely organizational changes in the recruiting site that affected the number of eligible participants in a negative way. We have clarified that in the manuscript (page 4, first paragraph and in the results section).

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

1. Iyadurai L, Blackwell SE, Meiser-Stedman R, Watson PC, Bonsall MB, Geddes JR, et al. Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial. Molecular psychiatry. 2018;23(3):674-82. Epub 2017/03/30. doi: 10.1038/mp.2017.23. PubMed PMID: 28348380; PubMed Central PMCID: PMCPMC5822451.

2. Maples-Keller JL, Post LM, Price M, Goodnight JM, Burton MS, Yasinski CW, et al. Investigation of optimal dose of early intervention to prevent posttraumatic stress disorder: A multiarm randomized trial of one and three sessions of modified prolonged exposure. Depression and anxiety. 2020. Epub 2020/04/06. doi: 10.1002/da.23015. PubMed PMID: 32248637.

3. Rothbaum BO, Kearns MC, Price M, Malcoun E, Davis M, Ressler KJ, et al. Early intervention may prevent the development of posttraumatic stress disorder: a randomized pilot civilian study with modified prolonged exposure. Biol Psychiatry. 2012;72(11):957-63. Epub 2012/07/07. doi: 10.1016/j.biopsych.2012.06.002. PubMed PMID: 22766415; PubMed Central PMCID: PMCPMC3467345.

4. Benjet C, Bromet E, Karam EG, Kessler RC, McLaughlin KA, Ruscio AM, et al. The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium. Psychol Med. 2016;46(2):327-43. Epub 2015/10/30. doi: 10.1017/s0033291715001981. PubMed PMID: 26511595; PubMed Central PMCID: PMCPMC4869975.

Submitted filename: Response to reviewers .docx

Click here for additional data file.

30 Dec 2020

PONE-D-20-01989R1

Prevention of Post-Traumatic Stress Disorder: Lessons Learned from a Terminated RCT of Prolonged Exposure

PLOS ONE

Dear Dr. Bragesjo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Negar Fani, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thank you for the opportunity to evaluate this manuscript. We apologize for the delays in the review process. Reviewers have found many merits to this manuscript but have also outlined some necessary changes (see comments, below) that will need to be addressed before this is suitable for publication in PLOS ONE.

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Reviewers' comments:

Reviewer's Responses to Questions

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

**********

6. Review Comments to the Author

Reviewer #4: The current manuscript reports data from a terminated RCT of a brief trauma focused intervention aimed at preventing the onset of posttraumatic stress disorder. The RTC was terminated due to structural changes within the hospital that led to low recruitment rates. The authors provide recommendations for improving recruitment and delivery of early interventions for PTSD in the context of issues that were encountered in the present study. The original design of the study included many strengths such as the inclusion of an active control therapy, adaptation of an existing evidenced based treatment for PTSD, and longer follow up of participants than previous studies. The authors have largely addressed the concerns of the previous reviewers, however, a few issues remain:

1. The current study reports two main methodological issues: low recruitment rates (largely due to hospital infrastructure) and high attrition (not due to hospital reorganizational changes). The authors primarily provide recommendations for addressing the first issue, but not the second. It would be helpful is recommendations for each of these issues were more specifically specified.

2. With regards to recruitment and retention rates, it is unclear how these rates compare to previous studies that have used similar methods. Are the issues specific to studies recruiting individuals with trauma? Are the issues specific to the hospital at which the study took place?

3. More detail could be provided about the control psychotherapy condition, such as the content that was delivered at each treatment session.

4. Regarding comment #4 or original reviewer #2, I agree that more background on early intervention for PTSD as well as internet delivery could be provided. Some of these details are already included in the Supplement research plan, but could be added to the main text. For example, the authors could note issues with previous brief interventions (e.g. Debriefing). A fuller discussion of the timing chosen for the present study and recommendations could similarly be helpful. It is not clear how treatment within 72 hours addresses the proposed theory of memory consolidation when it is stated that this occurs within 6 hours of an event, and the Rothbaum study used a different time frame (12-24 hours). The authors could discuss strategies and limitations for treating patients that may be hospitalized for acute injuries within such a short time frame. Finally, the authors could add additional research about the use of internet based treatment.

5. Provide the baseline CAPS and PCL-5 scores for both groups.

6. Minor – there is an extra indent on lines 192, 312 and 373

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

14 Jan 2021

PONE-D-20-01989

Dear Editor,

First, we want to thank you and Reviewer #4 for encouraging feedback. We have revised the manuscript accordingly. Below follows a detailed description of the changes made point by point:

Reviewer #4

1. The current manuscript reports data from a terminated RCT of a brief trauma focused intervention aimed at preventing the onset of posttraumatic stress disorder. The RTC was terminated due to structural changes within the hospital that led to low recruitment rates. The authors provide recommendations for improving recruitment and delivery of early interventions for PTSD in the context of issues that were encountered in the present study. The original design of the study included many strengths such as the inclusion of an active control therapy, adaptation of an existing evidenced based treatment for PTSD, and longer follow up of participants than previous studies. The authors have largely addressed the concerns of the previous reviewers.

Response: We thank Reviewer #4 for highlighting the strengths of the original study design.

2. The current study reports two main methodological issues: low recruitment rates (largely due to hospital infrastructure) and high attrition (not due to hospital reorganizational changes). The authors primarily provide recommendations for addressing the first issue, but not the second. It would be helpful is recommendations for each of these issues were more specifically specified.

Response: As Reviewer #4 points out, our main issues in the study were the low recruitment rate and the high data attrition levels. We have clarified our recommendations to solves these issues in further studies in the Discussion section (eg. page 17, second paragraph). All changes have been highlighted in red.

3. More detail could be provided about the control psychotherapy condition, such as the content that was delivered at each treatment session.

Response: We have clarified the content of the control psychotherapy condition in the Control group section (page 11, first paragraph).

4. With regards to recruitment and retention rates, it is unclear how these rates compare to previous studies that have used similar methods. Are the issues specific to studies recruiting individuals with trauma? Are the issues specific to the hospital at which the study took place?

Response: Important point raised by Reviewer #4. This is indeed a common problem also seen in other trials on early interventions after trauma exposure [1-3] and we have clarified this in the Discussion (page 18, first paragraph).

5. Regarding comment #4 or original reviewer #2, I agree that more background on early intervention for PTSD as well as internet delivery could be provided. Some of these details are already included in the Supplement research plan, but could be added to the main text. For example, the authors could note issues with previous brief interventions (e.g. Debriefing). A fuller discussion of the timing chosen for the present study and recommendations could similarly be helpful. It is not clear how treatment within 72 hours addresses the proposed theory of memory consolidation when it is stated that this occurs within 6 hours of an event, and the Rothbaum study used a different time frame (12-24 hours). The authors could discuss strategies and limitations for treating patients that may be hospitalized for acute injuries within such a short time frame. Finally, the authors could add additional research about the use of internet based treatment.

Response: We agree with Reviewer #4 and we have added a section in the Introduction on debriefing and a short update on the current status on early interventions after trauma (page 3, second paragraph). We have also clarified the reason for the time-criterium of 72 hours used in the Rothbaum et al (2012) trial [1] (page 4, first paragraph). Our aim with our study was to replicate and extend these findings and we therefore used the same time-criterium for inclusion (page 4, second paragraph). In the Discussion, we also discuss strategies and limitations for providing hospitalized trauma victims within such a short time frame (page 18, second paragraph) and the use of internet-based treatment (page 17, second paragraph).

6. Provide the baseline CAPS and PCL-5 scores for both groups.

Response: Baseline symptom levels for PTSD was not assessed in this current trial due to the long recall time of CAPS-5 and PCL-5 (CAPS-5 is to be used at the earliest one month after exposure to trauma). The only trauma-related baseline measure used in this study was the Immediate Stress Reaction Checklist (see table 1, page 14).

6. Minor – there is an extra indent on lines 192, 312 and 373.

Response: Adjusted accordingly.

1. Rothbaum BO, Kearns MC, Price M, Malcoun E, Davis M, Ressler KJ, et al. Early intervention may prevent the development of posttraumatic stress disorder: a randomized pilot civilian study with modified prolonged exposure. Biol Psychiatry. 2012;72(11):957-63. Epub 2012/07/07. doi: 10.1016/j.biopsych.2012.06.002. PubMed PMID: 22766415; PubMed Central PMCID: PMCPMC3467345.

2. Maples-Keller JL, Post LM, Price M, Goodnight JM, Burton MS, Yasinski CW, et al. Investigation of optimal dose of early intervention to prevent posttraumatic stress disorder: A multiarm randomized trial of one and three sessions of modified prolonged exposure. Depression and anxiety. 2020. Epub 2020/04/06. doi: 10.1002/da.23015. PubMed PMID: 32248637.

3. Iyadurai L, Blackwell SE, Meiser-Stedman R, Watson PC, Bonsall MB, Geddes JR, et al. Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial. Molecular psychiatry. 2018;23(3):674-82. Epub 2017/03/30. doi: 10.1038/mp.2017.23. PubMed PMID: 28348380; PubMed Central PMCID: PMCPMC5822451.

Submitted filename: Response to reviewer 4.docx

Click here for additional data file.

19 Feb 2021

PONE-D-20-01989R2

Prevention of Post-Traumatic Stress Disorder: Lessons Learned from a Terminated RCT of Prolonged Exposure

PLOS ONE

Dear Dr. Bragesjö,

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Kind regards,

Negar Fani, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

We appreciate the time taken to revise this manuscript. Although there are noted improvements, it would be informative to include between-group statistics for treatment outcomes and related interpretation of any observed differences. Please see my comments on this and other issues to address, noted below:

Abstract: either include all section headings (background, method, results, conclusions) or no headings/paragraph form.

Objective: the word “of” is omitted in “three sessions … PE”

Results: should be “two-month and six-month assessments”

Figures: In general, resolution is poor, such that the labels are unreadable in Figure 3, please change to high resolution images

Figure 2 What is described as the control condition is described as placebo here, please be consistent with naming

Introduction:

“the intervention seemed to mitigate genetic predisposition to PTSD” is misleading, as psychotherapy cannot “mitigate” genetics—please rephrase to “reduce risk for PTSD development”.

Method:

Control group: line 229, should be “instill hope”

Table 1 should be referenced in the manuscript and a column added for relevant statistics and indication of any significant differences between intervention groups (Chi square, Fisher’s z, t statistic)

Table 2: given that 4 participants dropped out, 2 from each intervention, and the starting number is 32, shouldn’t the correct n be 13 and 15, respectively? Please also indicate the correct sample size for each group at 2 and 6 month follow up in the table, which is significantly smaller than the 32 that is listed in the top row.

Results: Even though PTSD was not assessed at baseline and sample size is small, please provide statistics both in Table 2 (in a column at the right) and in the text for all outcome measures. Although the numbers for each group are small, it is possible to examine differences in treatment outcomes, particularly with assessments that were also given at baseline (e.g., MADRS-S – repeated measures ANOVA

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #4: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: N/A

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Reviewer #4: Yes

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Reviewer #4: Yes

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Reviewer #4: The present manuscript is a revised submission that provides recommendations for providing brief interventions for trauma patients to prevent the onset of PTSD. The authors have addressed the reviewers' comments.

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Reviewer #4: No

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29 Mar 2021

PONE-D-20-01989R2

Dear Editor,

We are grateful for the valuable feedback from you and Reviewer #4 and we now submit our revised manuscript for review. Below you will find a detailed description of the changes made point by point:

Reviewer #4

1. The present manuscript is a revised submission that provides recommendations for providing brief interventions for trauma patients to prevent the onset of PTSD. The authors have addressed the reviewers' comments.

Response: We thank Reviewer #4 for their helpful comments and positive judgement of our revised manuscript.

Editor Comments

1. We appreciate the time taken to revise this manuscript. Although there are noted improvements, it would be informative to include between-group statistics for treatment outcomes and related interpretation of any observed differences. Please see my comments on this and other issues to address, noted below:

Response: We thank the Editor encouraging feedback. While we appreciate the editor´s feedback, we respectfully disagree on adding statistical tests. The study is not powered to detect any statistically significant changes between groups with the small sample size we ended up with. We fear that adding these analyses post hoc would be potentially misleading. Adding p-values might deflect attention from the actual size of an effect. We note that the reviewers are content with the way we have described the collected data which we feel supports our concern.

2. Abstract: either include all section headings (background, method, results, conclusions) or no headings/paragraph form.

Response: We have excluded the section headings in the abstract (page 2).

3. Objective: the word “of” is omitted in “three sessions … PE” Results: should be “two-month and six-month assessments”

Response: We have proof read the manuscript and added the word “of” on page 2 in the Abstract section and have used the word two-month and six-month assessment consequently. All changes are highlighted in red through the manuscript.

4. Figures: In general, resolution is poor, such that the labels are unreadable in Figure 3, please change to high resolution images. Figure 2 What is described as the control condition is described as placebo here, please be consistent with naming.

Response: We have updated the figures to a higher resolution. We have also changed the wording in figure 2 to “control group”.

5. Introduction: “the intervention seemed to mitigate genetic predisposition to PTSD” is misleading, as psychotherapy cannot “mitigate” genetics—please rephrase to “reduce risk for PTSD development”.

Response: We have rephrased the sentence to “reduce risk for PTSD development” (page 4, first paragraph).

6. Method: Control group: line 229, should be “instill hope”

Response: We have corrected to phrase to be “instill hope” (page 11, first paragraph).

7. Table 1 should be referenced in the manuscript and a column added for relevant statistics and indication of any significant differences between intervention groups (Chi square, Fisher’s z, t statistic)

Response: Table 1 is now referenced on page 13, second paragraph. As for the statistical tests, we refer to our response to comment no. 1.

8. Table 2: given that 4 participants dropped out, 2 from each intervention, and the starting number is 32, shouldn’t the correct n be 13 and 15, respectively? Please also indicate the correct sample size for each group at 2 and 6 month follow up in the table, which is significantly smaller than the 32 that is listed in the top row.

Response: We thank the editor for pointing out that the number of respondents is unclear in table 2. We have redesigned table 2 in order to clarify the number of respondents at each timepoint.

9. Results: Even though PTSD was not assessed at baseline and sample size is small, please provide statistics both in Table 2 (in a column at the right) and in the text for all outcome measures. Although the numbers for each group are small, it is possible to examine differences in treatment outcomes, particularly with assessments that were also given at baseline (e.g., MADRS-S – repeated measures ANOVA

Response: Please see answer to point 1. We agree that such analysis could be interesting, but fear that they would be misleading. We believe that it is possible to examine the differences by looking at the data points provided for the outcome measures and exercising judgment on the absolute differences across time points.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

6 May 2021

Prevention of Post-Traumatic Stress Disorder: Lessons Learned from a Terminated RCT of Prolonged Exposure

PONE-D-20-01989R3

Dear Dr. Bragesjo,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Negar Fani, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please upload higher resolution Figure 3

Reviewers' comments:

15 May 2021

PONE-D-20-01989R3

Prevention of Post-Traumatic Stress Disorder: Lessons Learned from a Terminated RCT of Prolonged Exposure

Dear Dr. Bragesjö:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Negar Fani

Academic Editor

PLOS ONE