Background
Germany is host to a large number of refugees from various war-torn countries. In the home countries as well as on their dangerous journey to Germany, refugees have experienced numerous traumatic experiences. Since the likelihood to develop mental health disorders increases with accumulating traumatic events in a dose-dependent manner [
1,
2], a high prevalence of mental ill-health can be expected in this population, in particular high rates of post-traumatic stress disorder (PTSD) and comorbid disorders. So far, evidence regarding the prevalence rate of mental health disorders of refugees in Germany is limited. However, an initial study indicates that approximately one half of refugees living in a German refugee accommodation were screened positive for mental health problems [
3]. In a representative sample of Syrian refugee children from a German reception camp, PTSD was diagnosed in 33% of children aged 7–14 years [
4].
Although the majority of trauma survivors recover without treatment over time, war-related PTSD seems to be highly persistent [
5]. PTSD is characterized by symptoms like concentration difficulties, loss of interest in social activities, insomnia and irritability that involve a high impairment in everyday functioning [
6]. Furthermore, higher PTSD symptom severity is associated with an increased risk of poor physical health [
7]. In addition, PTSD symptoms in children and adolescents are correlated with neuropsychological dysfunctions in a range of cognitive tasks [
8,
9] as well as with reduced school performance [
10]. PTSD symptoms but not trauma exposure are related to reduced intellectual capabilities [
9] in particular in verbal skills [
11]. A study with war-affected children in Sri Lanka found that children with PTSD presented with lower school grades in language-related subjects [
12]. In a treatment-seeking sample of refugees in Switzerland, the severity of PTSD symptoms was associated with social integration difficulties [
13]. Taken together, it is likely that next to the individual suffering, PTSD symptoms interfere with integration into the host country, as well as academic achievement. Consistent with this assumption, a study in Sweden has shown that Iraqi refugees with PTSD had a significantly delayed performance in language schools [
14]. In the face of the expectedly high prevalence rate of PTSD in the current refugee population and the probable interference of PTSD with integration, the development of effective, evidence-based and pragmatic treatments for PTSD, especially for these populations, should be a public health priority.
Cumulating evidence from clinical studies indicates that the different variants of the so-called trauma-focused psychotherapies are the treatments of first choice for PTSD in children [
15]. Trauma-focused treatments have in common that they target traumatic memories through exposure or cognitive interventions. A recent independent evaluation indicated that, on the basis of the rationale as well as the available efficacy, Narrative Exposure Therapy (NET) is probably advantageous for the treatment of traumatized refugees in comparison to other trauma-focused approaches [
16]. However, current evidence is limited with regard to the treatment of war-affected
children with PTSD. The available knowledge relies on case-series and cohort studies with only a few exceptional randomized trials. A systematic literature research in MEDLINE identified 12 published randomized controlled trials (RCTs) with war-affected children (see Table
1). Out of these, five studies reported the effectiveness of school-based cognitive behavior therapy (CBT)-like interventions that did not screen for or exclude children with high values of PTSD symptoms (four of these did not find a significant effect on PTSD symptoms), one screened youths for distress and did also not find an effect on PTSD, two applied trauma-focused-CBT in groups and one applied individual trauma-focused-CBT and found a significant effect on PTSD. Three trials studied the effectiveness of Narrative Exposure Therapy for Children (KIDNET), also with a significant effect on PTSD symptoms. Only a single RCT studied PTSD treatment (KIDNET) in refugee children [
26].
Table 1
Results of a systematic literature search in MEDLINE on 16 February 2018
| Indonesian children, 7–14 years, screened for PTSD | Individual tf-CBT | Problem-solving | Significant reduction of PTSD in both groups |
| War-affected child migrants in Australia, 10–17 years, screened for PTSD, only individuals with mild to moderate PTSD symptoms included | TRT (CBT based, in group) | Waiting list | No effect on PTSD symptoms |
Betancourt et al. 2014 [ 19] | Sierra Leone youth, 14–24 years, screened for distress, not for PTSD | CBT based, no trauma focus | Waiting list | No effect on PTSD symptoms |
| Burundi children, 8–17 years, no specific screening | School-based intervention, no trauma focus | Waiting list | No effect on PTSD symptoms |
McMullen et al. 2013 [ 21] | Boys in Congo, 13–17 years, screened for war exposure | tf-CBT in group | Waiting list | Significant effect on PTSD symptoms |
O’Callaghan et al., 2013 [ 22] | Girls in Congo, 12–17 years, screened for sexual violence | tf-CBT in group | Waiting list | Significant effect on PTSD symptoms |
| Children in Sri Lanka, 9–12 years, no specific screening | School-based intervention, no trauma focus | Waiting list | No effect on PTSD symptoms |
| Children in Palestine, 10–13 years, no specific screening | School-based intervention, no trauma focus | Waiting list | Only overall effect on PTSD symptoms |
| Former child soldiers in Uganda, 12–25 years, with PTSD | NET | Waiting list, academic counseling | Significant reduction of PTSD symptoms, superiority of NET |
| Refugee children in Germany, 7–16 years, with PTSD | NET | Waiting list | Significant reduction of PTSD symptoms, superiority of NET |
| Sri Lankan children after war and tsunami, 8–14 years, with PTSD | NET | Meditation | Significant reduction of PTSD in both groups |
| Bosnian children and youth, 13–19 years, with major PTSD symptoms | Trauma-focused school-based intervention | Psychoeducation and skills | Reduction of PTSD in both groups, Superiority of trauma-focus |
A recent independent review [
29] confirmed that, consistent with the literature from war-affected adults [
30], KIDNET is one of the most promising and best-studied treatment approaches for war-affected children with PTSD and has generally caused a clinically significant improvement in treated children.
In the three available KIDNET trials that included children and adolescents, KIDNET has been compared to meditation for school children in Sri Lanka [
27], academic counseling and a waiting-list control condition in former child-soldiers in Uganda [
25], as well as a waiting-list control group in asylum seekers in Germany [
26]. Taken together, these studies show that individual short-term behavioral interventions can be effective for the treatment of PTSD across cultural contexts and age ranges. The three currently available trials of KIDNET for children and adolescents show that KIDNET is a safe, efficient and robust treatment that can be implemented in schools [
27], communities [
25] and outpatient clinics [
26]. However, it is questionable whether the results from these trials can be easily transferred to the current situation of young refugees in Germany. The trial by Catani et al. [
27] studied survivors of the war and the tsunami within 4 weeks after the 2009 tsunami catastrophe in Sri Lanka and may be considered as an intervention for acute PTSD rather than chronic war trauma. The study by Ertl et al. [
25] included older adolescents as well as young adults and was restricted to child soldiers. The trial of Ruf et al. [
26] is probably the most relevant study for the current refugee situation, since it investigated refugee children who had fled to Germany. Even though this study is generally methodologically sound, it is characterized by a small sample size (
N = 13 per group) and a limited range of outcome measures.
Although current evidence suggests that trauma-focused psychotherapy is probably effective for the treatment of PTSD in war-affected refugee children and adolescents, the provision of effective psychotherapy for traumatized refugee children is currently not a priority within the German health care system and there have been only very limited improvements after the sudden increased influx of refugees in 2015 [
31]. Against this background, this trial is urgently needed as it may advance the evidence of the possibilities and limitations of psychotherapy for PTSD and comorbid disorders in refugee children and adolescents. In particular, this trial is characterized by advanced and state-of-the art methods to reduce bias (multi-center trial, blinding of assessors, manualized and standardized treatment, fidelity rating, etc.), an extended range of outcome measures, including depression, physical health, integration parameters, as well as limited exclusion parameters to enhance the external validity of the results.
Aim of the trial
The YOURTREAT trial is part of the study consortium “Stress, Health and Integration of Young Refugees: Discovering the Interrelations and Improving Access to Healthcare (YOURHEALTH)” funded by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF). This funding agency had no influence on the trial design and will not influence data collection, data management, data analyses, interpretation of study results, publication nor report writing. Within this consortium, the clinical trial YOURTREAT aims to test whether the treatment of young refugees (10–18 years) with KIDNET causes an effective reduction of PTSD and comorbid symptoms. In more detail, KIDNET will be implemented within an innovative complementary health care system that is attached to outpatient clinics of universities and university hospitals. The treatment in the outpatient clinics will be supported by Intercultural Therapy Assistants (ITAs) who will interpret the diagnostic interviews and therapy sessions if required, but can also further support the therapeutic process by accompanying young refugees on their way to and from the therapy, or support the recruitment and eligibility screening into the study. The treatment with 11 sessions of KIDNET supported by ITAs will be compared to treatment as usual (TAU) for young refugees within the general health care system in Germany.
The primary hypothesis of this trial is that, 6 and 12 months after randomization, children who received KIDNET compared to children referred to the regular health care system in the TAU condition will show a greater PTSD symptom reduction. The secondary hypothesis refers to a superiority of KIDNET for the reduction of comorbid depressive, internalizing and externalizing symptoms, as well as suicidal ideation and a reduction of strain caused by discrimination, as well as an improvement of physical health. Furthermore, a lower rate of individuals who still meet the diagnostic criteria of PTSD and a greater response rate is expected in the KIDNET group as opposed to the TAU group.
Statistics
Power analysis and sample size calculation
The Ruf et al. pilot study [
26] achieved a treatment effect size of 1.9 for NET and 0.3 for the waiting-list control group. However, we expect that the contrast will be smaller for this study, as we will have an active control condition and will provide detailed information to children and adolescents from the TAU condition on how to seek treatment in the regular health care system. Therefore, we base the effect size calculation at a conservative estimation of a between-group effect size of
d = 0.6. To test the hypothesis that a treatment with KIDNET is more effective than TAU, with a one-sided alpha level set at 0.05 and a power level of 0.8, we need to enroll
N = 72 subjects (
N = 36 per group) into the present study. Once randomized, loss to follow-up was small (generally lower than 5%) in the Ruf et al. study [
26] as well as in other NET studies [
50]. Most importantly, as the main analysis of the primary outcome measure will be calculated using a mixed-effects model, all randomized cases can be included in the statistical analyses. Therefore, the intended sample size of
N = 80 will be sound to answer the research questions of the trial.
Data analyses
The confirmatory analysis of this study will be calculated as a mixed-effects model with the CAPS-CA-5 score as the outcome variable. Mixed models are especially suited for longitudinal studies as they can account for serial correlation within participants, are relatively robust to randomly missing data, and can incorporate certain nonrandom missing data without biasing model estimates. In detail, participants will be modeled as a random factor (including random intercepts or random intercepts and slopes), while time and intervention (KIDNET vs. TAU), as well their interaction, will be modeled as fixed factors. The hypothesis that KIDNET is superior to TAU in the treatment of PTSD will be evaluated by the significance test of the interaction effect time × intervention.
In case of a significant interaction effect, two planned general linear hypotheses will be calculated as post-hoc tests for linear mixed-effect models in order to test between-group differences at t2 and t3. One-sided p values will be adjusted for multiple comparisons following the Holm procedure.
We will perform an intention-to-treat analysis; that is, all trial participants will be analyzed as randomized, even if they discontinue treatment or are unavailable for one or both of the follow-up interviews. The between-group effect size (Cohen’s d) will be calculated at each follow-up assessment (t2 and t3). The intention-to-treat analysis will be supplemented by a modified intention-to-treat analysis which will include only those participants who participated in at least one post-randomization diagnostic interview. Furthermore, participants who were randomized to KIDNET will be included only if they participated in at least one KIDNET therapy session.
Continuous secondary outcome measures are analyzed in the same way. In the absence of a valid cut-off score for clinically significant change or treatment response of the CAPS-CA-5, the rate of subjects with clinically significant improvement as well as worsening based on the RCI will be compared between groups using Fisher’s exact tests at the follow-up assessments t
2 and t
3, separately. For this purpose, the RCI will be calculated based on the pre-treatment scores of the study sample following the suggestion of Jacobson and Truax [
39]. Missing values due to premature withdraw will be considered as treatment failure (classified as no response).
In addition, in case of significant treatment effects, center effects regarding the primary efficacy endpoint are investigated. For this purpose, the change in CAPS-CA-5 at t3 (compared to baseline t1) are analyzed exploratively using a mixed-effects model that includes participants as a random factor and center, intervention and center × intervention as fixed factors. The significance level will be set at 0.05 for all analyses.
Safety and ethical aspects of the trial
The trial procedures follow the Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice (ICH-GCP) [
51]. The Ethics Committee of the German Psychological Association (Deutsche Gesellschaft für Psychologie, DGPs) approved the study procedures (approval date: 6 May 2019). Modifications of the protocol, which are not merely of administrative nature, such as minor corrections or clarifications, and which might impact patient safety, ethical aspects of the trial or the conduct, and scientific evaluation of the trial, will be submitted as protocol amendments to the Ethics Committee and require approval. Furthermore, the record at the trial registry DRKS will be updated and the BMBF will be informed in case of protocol amendments. Such amendments will be agreed upon by the PI after consultation with the External Advisory Board.
Safety aspects
So far, no trial has ever reported serious adverse events (SAEs) caused by psychotherapy of trauma-related disorders in children and adolescents [cf.
52,
53]. Since the planned treatment study can be, therefore, considered as safe, we refrain from installing an external Safety Monitoring Committee for pragmatic reasons. Instead, we have appointed a SAE Management Committee constituted of the lead investigators at the sites (Areej Zindler, Rita Rosner, Anselm Crombach, Michael Odenwald), the PI (Frank Neuner), the independent biostatistician and the External Advisory Board of the trial who will supervise the safety of the study.
The following dangerous occurrences will be defined as SAEs in accordance to the ICH-GCP and will be closely monitored during treatment, and at the follow-up assessments:
All such dangerous events and other safety aspects will be forwarded to the SAE Management Committee. In addition, the independent biostatistician will conduct interim analyses after 30% and 50% of the completed 6-month follow-ups in order to monitor the symptom development as well as the occurrence of potential SAEs. If an SAE is identified, the SAE Management Committee will investigate whether there is a causal link between the trial and the SAE. If the SAE Management Committee decides that further trial participation would be a safety concern for the patient, the patient will be withdrawn from the study. In the case of serious safety concerns, the trial will be stopped.
Trained psychologists or physicians (minimum bachelor’s degree) will introduce the study procedures to the participants. Our study population of young refugees is particularly vulnerable, as their age as well as their limited knowledge of the German health system might impair their ability to understand the aims and procedures of the study. In order to assure the comprehension of the information of the informed consent, and to standardize the informed consent between the centers, we have decided to supplement the written informed consent for the trial by a video which reads out the exact wording of the informed consent. Furthermore, the informed consent is written in easy language. The written informed consent will be available in the languages of the participants. They will detail the study procedures including diagnostic interviews, randomization, treatment options, potential temporary distress after interviews or therapeutic sessions, the possibility of terminating study participation without any disadvantage, and data management. Trained psychologists or physicians (minimum bachelor’s degree) will answer questions arising, and will subsequently obtain written informed consent from subjects who decide to participate in the trial. In addition, participants will be asked whether they want to give informed consent to be contacted for the participation in ancillary studies. They will be informed that this decision does not affect their participation in the YOURTREAT trial.
Coping with distress
Similar to the re-experiencing symptoms that PTSD patients experience in everyday life, patients might also experience high and distressing levels of anxiety or other unpleasant emotional reactions during assessments or sessions of exposure-based psychotherapy. However, in contrast to their everyday experience, where they usually have to deal with these symptoms on their own, the assessor/therapist can help them to cope with these reactions, e.g., by reinforcing reality or by providing psychoeducation.
Post-trial care
Individuals assigned to the TAU condition who still suffer from PTSD will be offered a treatment with KIDNET or an equally effective therapy within the participating outpatient clinics. Furthermore, participants who do not benefit from KIDNET (i.e., still suffer from PTSD at the last follow-up) will be offered additional treatments at the participating centers or will be referred to appropriate inpatient or outpatient treatments.
Discussion
In spite of the known detrimental consequences of trauma originating from war and flight on the mental and physical health of refugees and their integration into the host culture, the evidence regarding effective treatment options for this vulnerable population is very limited [
54]. As presented in the literature review in the introduction, research regarding effective interventions for
young refugees is even sparser. Furthermore, different barriers including language difficulties, fear of stigma, and limited knowledge about treatment options for mental health disorders make it difficult for refugees to seek for help. This is aggravated by bureaucratic obstacles for psychotherapists to receive payments for psychotherapy delivered to refugees with unsecure asylum status, and the required interpreters. Finally, many practitioners are hesitant to deliver evidence-based PTSD treatments due to fears of symptom aggravation or treatment discontinuation [
55,
56]. In order to counteract these barriers, and to improve the mental health care for young refugees in the German health care system, systematic studies are urgently required to inform the scientific and clinical community as well as public health decisions.
The lack of systematic studies on effective interventions for war-affected refugee children and adolescents suffering from PTSD might have several reasons. First of all, the group of adolescents might be of greater risk of dropping out of treatment trials due to the developmental tasks in this age period, and unstable mood and motivation [
57]. Even more, young refugees face unstable living and housing situations and might be relocated at short notice, making it even more difficult to prevent attrition from the trial. Furthermore, a trial with young refugees requires a close collaboration with, and intense training of, interpreters from different cultures, demanding additional resources from the research team.
Against this background, the current trial aims at providing the required knowledge regarding effective treatment options for young refugees. Strengths and innovative aspects of the trial include (1) the unique study sample of young refugees hosted in Germany, (2) the systematic assessment of PTSD with the CAPS-CA-5, the gold standard in the diagnosis of PTSD, (3) the wide range of outcome measurements, (4) the limited exclusion criteria, which enhance the external validity of the trial, (5) the short and pragmatic nature of the delivered treatment, (6) an evaluation of the usual treatment (TAU) within the German health care system and (7) the implementation and evaluation of a support structure by ITAs, who can interpret and support the therapeutic process.
A potential limitation of the trial could be the danger of drop-outs due to the instability of the investigated population. However, a previous study with young refugees treated with NET also managed to achieve a low attrition rate [
26]. Furthermore, we intend to increase the retention of subjects by closely collaborating with ITAs from the community of the study participants as well as with the caregivers of the young refugees.
In addition, we have to note that the trial is led by Frank Neuner, one of the developers of (KID)NET. Therefore, a high treatment loyalty could be stated as a limitation of the trial. However, it is important to note that two of the three other centers taking part in the study have no prior experience with (KID)NET and previously predominantly used other treatment approaches for trauma-related disorders. This increases the external validity and generalizability of the trial.
In sum, this trial has the potential for a scientific impact on major public-health-related decisions in Germany; for example, regarding the usefulness of complementary treatment structures for refugees and the necessity to pay costs for interpreters for treatment. In addition, we expect that this trial can inform the regular health care system (clinics, psychotherapists in outpatient clinics, psychotherapist in private practices) as well as the treatment centers for refugees about the effect of short-term therapy for refugee children and adolescents and, ultimately, improve the quality of care. As there is a lack of methodological sound RCTs for refugee children, we expect that this trial can have a major impact on the guidelines for the treatment of PTSD.
Dissemination
The trial results will be disseminated to the scientific community by publications in international peer-reviewed journals. The results regarding the primary outcome of the trial will be published regardless of the direction and statistical significance of the effect. Next to the publication of the results in scientific journals, we will communicate the results to national and international psychological and psychiatric associations as well as to the policy-makers in Germany, and the public media.
Trial status
Protocol version 1.5, 19 October 2019.
Recruitment into the trial started in June 2019.
Recruitment will be completed in approximately May 2021.
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