Design overview

The project entitled Chronic Fatigue Following Acute Epstein-Barr Virus Infection in Adolescents (CEBA) encompasses a prospective postinfectious cohort study followed by a clinical trial of a mental training programme in those participants that developed CF (figure 1). The overall design of CEBA has been described elsewhere.18 In short, from March 2015 until November 2016, EBV infected individuals fulfilling the following criteria were assessed for eligibility in the postinfectious cohort study: (1) a serological pattern indicating acute EBV infection; (2) age between 12 and 20 years; and (3) living in one of the Norwegian counties Oslo, Akershus or Buskerud. Exclusion criteria were (1) more than 6 weeks since debut of symptoms suggesting acute EBV infection; (2) any chronic disease that needed regular use of medication; (3) pregnancy.

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Figure 1

Flow chart of study participants. CFQ, Chalder Fatigue Questionnaire; EBV, Epstein-Barr virus; RCT, randomised controlled trial.

A total of 200 adolescents with acute EBV infection were included and followed for 6 months in the postinfectious cohort study. A total of 195 participants attended the 6 months follow-up visit and were classified as non-CF or CF (dichotomised response <or ≥ 4, respectively, on the Chalder Fatigue Questionnaire (CFQ)19).

The CF cases (n=91) were assessed for eligibility in a separate clinical trial (ClinicalTrials ID: NCT02499302). This trial compared a mental training programme combining music therapy and CBT against care as usual within a randomised controlled design, as described in the present paper. The inclusion period of the trial lasted from September 2015 until May 2017; total follow-up time after randomisation was 15 months.

Participation in the trial was based on informed consent, and thorough information both orally as well as in writing was provided to the participants and (if younger than 16 years) to their parents/guardians.

Investigational program

At all encounters in CEBA, participants were subjected to a standardised investigational programme encompassing clinical assessment as well as biomarker sampling. A comprehensive overview is provided elsewhere18; here, only investigations relevant for the present study are detailed:

Physical activity was monitored by the activPAL accelerometer device (PAL Technologies, Glasgow, Scotland) during seven consecutive days. The accelerometer was attached in the anterior midline on the participants’ thigh with custom made, waterproof adhesive tape. The participants were instructed to wear the device at all times, and only take it off when the recording period was finished. The activPAL provides reliable data on both steps and position20; in the present study, the mean number of steps per day was selected as the primary endpoint.

Symptoms were charted by a composite questionnaire encompassing six different instruments; in the entire postinfectious cohort, Cronbach’s alpha for these instruments ranged from 0.75 to 0.94, which was considered acceptable. The CFQ19 charts subjective experience of physical and mental fatigue, it has shown acceptable validity among adolescents,21 and it has been translated and validated for a Norwegian population.22 It consists of 11 items scored on four-point Likert scales; in the present study, dichotomous scoring (each item scored 0-0-1-1) was used for definition of fatigue caseness,5 whereas ordinal scoring (0-1-2-3) was applied in the analyses of efficacy. The symptom of postexertional malaise, often considered a hallmark of CFS,3 was charted with one single item (“How often do you experience more fatigue the day after an exertion?”) and scored 1–5 on a Likert scale; higher scores imply more severe symptom burden. The Brief Pain Inventory (BPI) uses four items to assess pain severity23; each item is scored on 10-point Likert scales, and the total sum score (range from 0 to 40) is reported in the present paper. BPI is validated for adolescents.24 The Karolinska Sleep Questionnaire is a validated questionnaire charting insomnia and other sleep disturbances,25 and has previously been applied in research on adolescent fatigue.26 It consists of 14 items scored one to six on Likert scales; the total sum score (range from 14 to 84) is reported in the present paper, and lower scores imply more symptoms of sleep problems. The Hospital Anxiety and Depression Scale charts symptoms of depression and anxiety and is validated for adolescents27 28; it consists of 14 items scored 0–3 on Likert scales, and total sum score (range from 0 to 42) is reported in the present paper. The Pediatric Quality of Life Inventory is translated and validated for the Norwegian population.29 A total of 23 items are scored on five-point Likert scales, each point valued zero, 25, 50, 75 or 100; here, the mean score (range 0–100) is reported, higher scores indicate better quality of life. Functional Disability Inventory measures disability related to everyday activities, and has been thoroughly validated in different adolescent populations.30 31 It consists of 15 items scored on five-point Likert scales; total sum score (range from 0 to 60) is applied, where higher scores suggest stronger disability.

Possible side effects related to the mental training programme was charted by a separate set of items using five-point Likert scales; the answers were dichotomised (present vs not present) prior to analyses. In addition, the questionnaire contained items related to the different diagnostic criteria of CFS as well as simple questions on demographics.

Randomisation and blinding

Participants were randomised to either mental training or care as usual in a 1:1 probability by a computer-based routine for block randomisation; block size varied randomly between 4 and 6. It was not possible to blind for treatment. End-point evaluation was concealed from patients and therapists, and allocation concealment was ensured using sequentially numbered, opaque, sealed envelopes.

The mental training program and care as usual

The intervention consisted of a 10-week mental training programme offered to the relevant individuals as soon as possible after inclusion and randomisation. The programme encompassed one introductory session followed by nine individual therapy sessions (one per week) of 1.5 hours duration and related home-work, combining elements from CBT and music therapy (figure 2). The introductory session was carried out by a researcher, a music therapist and a cognitive therapist, with both the patient and his/her parents/guardians present. In this first session, personal experiences were also shared by a young adult voluntary patient who had himself recovered from CFS. Of the following nine treatment sessions, four were given by a music therapist (session no. 2, 3, 5 and 9) and five were given by a cognitive therapist (session no. 4, 6, 7, 8 and 10). At three of the sessions with cognitive therapists (session 4, 7 and 10), parents/guardians had the option to participate if the therapist considered it advantageous and the adolescent consented.

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Figure 2

Graphical depiction of the 10 therapy sessions in the mental training programme. CBT, cognitive–behavioural therapy.

Normally, neither general practitioners nor paediatricians in Norway schedule appointment with postinfectious CF patients unless they have strongly reduced physical function. Thus, ‘care as usual’ implies that the relevant individuals would not receive any healthcare for their CF condition in the follow-up period apart from the follow-up visits in the present study.

Therapists, techniques and principles in the mental training program

The mental training of all participants allocated to the intervention group was carried out by two therapists only: a child and adolescent psychiatrist holding a specialty in CBT and a Music Therapist affiliated with the Centre for Research in Music and Health at the Norwegian College of Music. Both of them had previous experiences with adolescents suffering from CF and other somatic health complaints. They participated in developing the techniques and principles of the present study; no further training was provided, but other experienced cognitive therapists and music therapists were available for supervision and discussion throughout the study period.

The first individual sessions in the mental training programme were used to chart activity and sleep patterns, altered functional abilities, withdrawal from social life and changed family dynamics. Thereafter, a variety of therapeutic principles were applied, such as psychoeducation, instructions in techniques for relaxation and visualisation by using music, challenging of automatic thoughts (primarily related to stimulus and outcome expectancies), and behavioural ‘experiments’.32 Together with the patient, the therapist sought to identify negative thoughts and feelings, and to motivate for mental effort/activity to control such negative thoughts and feelings. Cognitive therapy sessions typically blend content and process issues to help make effective changes in attitudes, beliefs and expectations. Collaborative empiricism, guided discovery and the Socratic method provide a comprehensive framework for the processes involved in therapy, while remaining aligned with the core concepts of cognitive therapy.33 A central principle throughout the training programme was to achieve therapeutic alliance, which may have a strong impact on treatment effect.

The treatment programme assumes active participation from the patient between the sessions, and the therapists tried to communicate the necessity of individual effort. Parents/guardians are the most essential caregivers for the patient, and can in a positive way motivate the patient and provide guidance through the principles and specific techniques which were introduced in the treatment programme. At the same time, parents/guardians may also strengthen a negative illness behaviour and disease attribution, which in turn may have a negative impact on the prognosis. Therefore, it was of great importance to involve the parents/guardians in the treatment programme. Therapist fidelity was ensured by a protocol (see online supplemental file 1) detailing the content of every therapy session,32 as well as close supervision from senior research collaborators.

As compared with existing CBT protocols for CFS,5 6 the present mental training programme deviated mainly on the following points:

• Music therapy was integrated with traditional cognitive techniques.

• Emotions were focused to a greater extent, and specific techniques (such as mindful presence and visualisation) were introduced to increase access to positive feelings.

• Unconscious/automatic experiences were given more attention. Consequently, a fixed plan for graded activity was not an integrated part in the programme, whereas spontaneous experiences not involving conscious planning were encouraged.

• There was an individual adaption regarding specific psychological issues, and parents/guardians were included in some of the treatment sessions.

Effect monitoring

Assessment of beneficial and possible harmful effects was carried out 3 months after inclusion (ie, immediately after completion of the mental training programme), and 15 months after inclusion. Endpoints included steps/day count during seven consecutive days, symptoms (such as fatigue, postexertional malaise, pain) and quality of life/functional capacity. Recovery was defined as being classified as non-CF (ie, dichotomised response<4 on the CFQ)

Patient and public involvement

Representatives from the patient organisation ‘Recovery Norway’ as well as representatives from the ‘Youth Council’ at Dept. of Paediatrics and Adolescent Medicine, Akershus University Hospital, Norway, were involved in the design of the present study. Also, we received input from a group of adolescent CFS/ME sufferers and their next-of-kin through a pilot test of modified CBT. We carefully assessed the burden of the trial interventions on patients. We intend to disseminate main results to the trial participants, as well as to relevant patient organisations and other stakeholders.

Power considerations and statistical analyses

In a previous research project from our institution, CFS adolescents had a mean (SD) steps/day count of approximately 4500 (2400), and a mean (SD) CFQ total score of 19.1 (6.3).34 This given, more than 120 participants would be needed in order to detect a moderate effect size (Cohen’s d≈0.5), such as an increase in steps/day of 1200 or a reduction in CFQ total score of 3 (α=0.05, β=0.2). In the present study, the total number of eligible individuals were 91 (defined as CF cases 6 months after acute EBV infection), and only 43 consented to inclusion. Hence, the study was strongly underpowered regarding efficacy.

All statistical analyses were carried out using SPSS statistical software (IBM SPSS Statistic 26). The ‘full analysis set’ (all randomised participants) was used for intention-to-treat analyses of efficacy (see online supplemental file 2). A total of 55% of the included cases had missing data points. A convenient ‘rule of thumb’ suggests that the number of imputations should be similar to the percentage of cases that are incomplete.35 Thus, multiple imputation with 55 iterations was performed using the procedure implemented in SPSS. For normally distributed variables with definite minimum and maximum, constraints were defined. In addition, a non-imputed dataset was used for per-protocol analyses. Continuous variables were reported as means or medians, as appropriate. Categorical variables were reported as numbers and percentages. General linear models (ANCOVA, analysis of covariance) were used for analyses of treatment effect; the baseline values of each efficacy endpoint were included as covariates. Safety data were summarised descriptively through appropriate data tabulations and descriptive statistics.