Internet-Based Cognitive Behavioral Therapy in Stepped Care for Chronic Fatigue Syndrome: Randomized Noninferiority Trial

Background Internet-based cognitive behavioral therapy (I-CBT) leads to a reduction of fatigue severity and disability in adults with chronic fatigue syndrome (CFS). However, not all patients profit and it remains unclear how I-CBT is best embedded in the care of CFS patients. Objective This study aimed to compare the efficacy of stepped care, using therapist-assisted I-CBT, followed by face-to-face (f2f) cognitive behavioral therapy (CBT) when needed, with f2f CBT (treatment as usual [TAU]) on fatigue severity. The secondary aim was to investigate treatment efficiency. Methods A total of 363 CFS patients were randomized to 1 of the 3 treatment arms (n=121). There were 2 stepped care conditions that differed in the therapists’ feedback during I-CBT: prescheduled or on-demand. When still severely fatigued or disabled after I-CBT, the patients were offered f2f CBT. Noninferiority of both stepped care conditions to TAU was tested using analysis of covariance. The primary outcome was fatigue severity (Checklist Individual Strength). Disabilities (Sickness Impact Profile -8), physical functioning (Medical Outcomes Survey Short Form-36), psychological distress (Symptom Checklist-90), and proportion of patients with clinically significant improvement in fatigue were the secondary outcomes. The amount of invested therapist time was compared between stepped care and TAU. Exploratory comparisons were made between the stepped care conditions of invested therapist time and proportion of patients who continued with f2f CBT. Results Noninferiority was indicated, as the upper boundary of the one-sided 98.75% CI of the difference in the change in fatigue severity between both forms of stepped care and TAU were below the noninferiority margin of 5.2 (4.25 and 3.81, respectively). The between-group differences on the secondary outcomes were also not significant (P=.11 to P=.79). Both stepped care formats required less therapist time than TAU (median 8 hours, 9 minutes and 7 hours, 25 minutes in stepped care vs 12 hours in TAU; P<.001). The difference in therapist time between both stepped care formats was not significant. Approximately half of the patients meeting step-up criteria for f2f CBT after I-CBT did not continue. Conclusions Stepped care, including I-CBT followed by f2f CBT when indicated, is noninferior to TAU of f2f CBT and requires less therapist time. I-CBT for CFS can be used as a first step in stepped care. Trial Registration Nederlands Trial Register NTR4809; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4809 (Archived by WebCite at http://www.webcitation.org/74SWkw1V5)

INTRODUCTION 2a) In INTRODUCTION: Scientific background and explanation of rationale 1b-iv) RESULTS section in abstract must contain use data Does your paper address subitem 1b-iv?
1b-v) CONCLUSIONS/DISCUSSION in abstract for negative trials Does your paper address subitem 1b-v? 2a-i) Problem and the type of system/solution Does your paper address subitem 2a-i? * It is stated that the problem is that I-CBT has been developed for chronic fatigue syndrome (CFS), with the intention of being more cost-effective than f2f CBT. Although I-CBT took less therapist time to deliver, it appeared less effective than f2f CBT. The solution this study focused on was stepped care, with I-CBT as a first step and f2f CBT as a second step, for CFS: "If stepped care is as effective as TAU (i.e. f2f CBT), this would imply that I-CBT can be used in routine clinical care for CFS. Treatment intensity would then be decreased for the substantial group of patients for which I-CBT suffices. Furthermore, stepped care may be more time efficient than TAU, in that less therapist time would be needed to deliver stepped care [18]. This could increase cost-effectiveness." 2b) In INTRODUCTION: Specific objectives or hypotheses METHODS 3a) Description of trial design (such as parallel, factorial) including allocation ratio 3b) Important changes to methods after trial commencement (such as eligibility criteria), with reasons 2a-ii) Scientific background, rationale: What is known about the (type of) system Does your paper address subitem 2a-ii? * It was stated that not much is known of the effects of stepped care containing I-CBT. I-CBT is often not investigated in the context of stepped care, and I-CBT as well as stepped care are often not compared to a high intensity treatment: "Unfortunately, there is lack of data to conclude that combinations of internet-based and f2f CBT are as effective as established f2f treatments. Additionally, it is not known what an optimal format of blending of both treatment formats would be, e.g. non-sequential versus sequential; in what order) [17]." Does your paper address CONSORT subitem 2b? * The objectives were reported: "The primary objective of this study was to determine whether stepped care for CFS, with I-CBT as a first and f2f CBT as second step, would be as effective as TAU." ... "The efficacy in reduction of fatigue and efficiency in reduction of therapist time needed of stepped care was compared to TAU." There were two I-CBT arms, differing in the format of therapist feedback. Objective (exploratory): "We explored in the present study how therapist guidance during I-CBT influenced outcome of stepped care. More specifically, 1) whether the difference in therapist time needed between the I-CBT arms persisted in stepped care; and 2) whether the proportion of patients stepping up to f2f CBT after I-CBT differed in both formats, as the format of therapist feedback may influence the willingness to step up to f2f CBT." Does your paper address CONSORT subitem 3a? * It was stated that the study "was designed as a three arm parallel randomized non-inferiority trial". The allocation ratio was mentioned in the 'sample size' section of the methods. 4a) Eligibility criteria for participants Does your paper address CONSORT subitem 3b? * This was not applicable and therefore not mentioned.

3b-i) Bug fixes, Downtimes, Content Changes
Does your paper address subitem 3b-i? Does your paper address CONSORT subitem 4a? * Eligibility criteria were stated in the 'participants' section. It was explained how the diagnosis of CFS was confirmed and what the in-and exclusion criteria were: "being 18 years or older; ability to speak, read and write Dutch; meeting the CDC criteria, revised in 2003, for CFS [1, 2]; severely fatigued (Checklist Individual Strength subscale fatigue severity score of ≥ 35 [25]); severely disabled (Sickness Impact Profile 8 total score of ≥700 [26]); able to use a computer and have access to the internet; given written informed consent. Exclusion criteria were being involved in a legal procedure concerning disability/benefit claims and/or participating in other CFS research [27]." 4a-i) Computer / Internet literacy Does your paper address subitem 4a-i?
As an inclusion criterion it was explicitly mentioned that the patient should be: "able to use a computer and have access to the internet" 4b) Settings and locations where the data were collected 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: Does your paper address subitem 4a-ii? * In the 'participant section', it is explained that the intervention was only offered to patients of the treatment centre, not specially attracted for this study: "Participants were all recruited from adult CFS patients consecutively referred to a tertiary CFS treatment centre at a university hospital.". Furthermore, we added that "It was a closed study; only patients referred to the expert centre could participate.". It is mentioned which parts of the procedures were f2f and which were online. 4a-iii) Information giving during recruitment Does your paper address subitem 4a-iii? Does your paper address CONSORT subitem 4b? * In the 'participants' section, it is stated that the study was performed at a "tertiary CFS treatment centre at a university hospital". It was mentioned which diagnostic data was collected f2f: "All patients were first seen by a consultant of the outpatient clinic of the department of Internal Medicine of the hospital. The consultant checked the medical status to confirm that patients were sufficiently examined and, if not, examined the patients according to the national CFS guidelines [23]. Patients meeting CDC criteria for CFS [1, 2] underwent a clinical assessment at the treatment centre, including a structured interview (MINI [24]), to rule out psychiatric disorders that could explain the presence of fatigue." In the 'trial design' section it was stated that "Assessments were online questionnaires." 5) The interventions for each group with sufficient details to allow replication, including how and when they were actually administered 4b-i) Report if outcomes were (self-)assessed through online questionnaires Does your paper address subitem 4b-i? * In the 'trial design' section it is stated that "Assessments were online questionnaires." 4b-ii) Report how institutional affiliations are displayed Does your paper address subitem 4b-ii? 5-i) Mention names, credential, affiliations of the developers, sponsors, and owners Does your paper address subitem 5-i? 5-ii) Describe the history/development process Does your paper address subitem 5-ii?

5-iii) Revisions and updating
Does your paper address subitem 5-iii?

5-iv) Quality assurance methods
Does your paper address subitem 5-iv? 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used Does your paper address subitem 5-v? 5-vi) Digital preservation webcitation.org Does your paper address subitem 5-vi?

5-vii) Access
Does your paper address subitem 5-vii? * In the Interventions / stepped care section, it was mentioned that "The I-CBT was accessible via a website, with a username and password that the patient received by e-mail. Patients did not have to pay to use the intervention, although internet-access was not provided." 5-viii) Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework Does your paper address subitem 5-viii? * In 'interventions', Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework of both the intervention and the comparator were described.
For the comparator, in section 'Interventions/ Treatment as usual (Direct f2f CBT) [28]', it is stated that "the F2f CBT was delivered according to a treatment protocol [28], that was also used in previous RCTs [16,18]." An in-depth description of the content is given, the aim of the therapy and the interventions are described. It is mentioned how the activity program is tailored to the individual needs of the patient: "The graded activity program is tailored to the activity pattern of the patient: relatively active patients learn to spread activity evenly first, while low active patients start directly with graded activity. An actometer, a motion-sensing device, was used to determine the activity pattern [27,29]." Stepped care: It is made clear that the content of I-CBT (the first step of stepped care) is based on the same treatment protocol as the comparator. The mode of delivery was described: The I-CBT was delivered through a platform and contained 7 modules, the name and content (briefly) of each module is given. It was also described that not all modules were accessible at once, but partly sequential: "When goals are submitted, the next five modules are accessible"; "When this module is completed the last module becomes accessible: '7. Evaluation and the future'.". Specific features and functionalities are not described, as it has been described extensively in other papers. A reference is given for further details on the I-CBT. Furthermore, it is described how and when therapist feedback was obtained. This differed in both conditions. It was also stated that " feedback was aimed at motivating the patient to put the instructions of the intervention into practice". Furthermore, it is described how, when stepping up to f2f CBT was needed, it was decided what the additional f2f CBT would aim at.

5-ix) Describe use parameters
Does your paper address subitem 5-ix?
5-x) Clarify the level of human involvement 6a) Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed Does your paper address subitem 5-x? 5-xi) Report any prompts/reminders used Does your paper address subitem 5-xi? * It was stated that reminders were sent, depending on the I-CBT condition: in In the protocol-driven feedback condition "the therapist asked the patient to report on the progress made, on fixed time-points" ... "the therapist gave feedback via e-mail and sent a reminder if no update was received.". In the 'feedback on demand' format, "patients received feedback only when they indicated a need for advice. No reminders were send." 5-xii) Describe any co-interventions (incl. training/support) Does your paper address subitem 5-xii? * In the intervention / stepped care section, it was stated that "Patients were not trained to use the platform and could ask for support by e-mail." Does your paper address CONSORT subitem 6a? * For outcome measures that were questionnaires, in the 'trial design' section it is stated how and when they were assessed. In the sections 'measures/primary outcome measure' and measures/secondary outcome measures', they were specified explicitly. It is also stated how invested therapist time is recorded/calculated. 6b) Any changes to trial outcomes after the trial commenced, with reasons 7a) How sample size was determined NPT: When applicable, details of whether and how the clustering by care provides or centers was addressed 6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed Does your paper address subitem 6a-i? 6a-ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored Does your paper address subitem 6a-ii? 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained Does your paper address subitem 6a-iii?
Does your paper address CONSORT subitem 6b? * This was not applicable and therefore not mentioned. 7b) When applicable, explanation of any interim analyses and stopping guidelines 8a) Method used to generate the random allocation sequence NPT: When applicable, how care providers were allocated to each trial group 8b) Type of randomisation; details of any restriction (such as blocking and block size) 9) Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned 7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size Does your paper address subitem 7a-i? Does your paper address CONSORT subitem 7b? * This was not applicable and therefore not mentioned.
Does your paper address CONSORT subitem 8a? * In the 'randomisation and blinding' section, it was stated that "Randomization was computer-generated, in blocks of twelve patients." Does your paper address CONSORT subitem 8b? * In the 'randomisation and blinding' section, it was stated that "Randomization was computer-generated, in blocks of twelve patients." 10) Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions 11a) If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how NPT: Whether or not administering co-interventions were blinded to group assignment Does your paper address CONSORT subitem 9? * In the 'randomisation and blinding' section, it was explained that the sequence was automatically administered, by computer. "The randomization program was programmed by a statistician, not involved in this study.". An administrative assistant could press the randomization button, "in the presence of the patient and the therapist". "After randomization, therapists and patients could read the result from the computer screen: '1) internet therapy'; '2) internet therapy' or 'wait list'." Does your paper address CONSORT subitem 10? * In the 'randomisation and blinding' section, it was stated that "the randomization program was programmed by a statistician, not involved in this study." and that an administrative assistant allocated participants, by using the program.
11a-i) Specify who was blinded, and who wasn't Does your paper address subitem 11a-i? * This was stated in the 'randomization and blinding section: "Participants were partly blinded: they were unaware of the existence of two I-CBT formats and were told that they could either receive I-CBT followed by CBT if needed, or f2f CBT."; therapists were not blinded: "therapists and patients could read the result from the computer screen: '1) internet therapy'; '2) internet therapy' or 'wait list'. The therapist knew that condition '1' of I-CBT was protocol driven feedback and '2' was feedback on demand.". The researchers were blinded as much as possible:' "Statistical analysis was performed on a data file, which blinded the researcher performing the analysis to patient and allocation to condition. Postanalysis, allocation to condition was unmasked to enable the authors to interpret results." 11b) If relevant, description of the similarity of interventions (this item is usually not relevant for ehealth trials as it refers to similarity of a placebo or sham intervention to a active medication/intervention) 12a) Statistical methods used to compare groups for primary and secondary outcomes NPT: When applicable, details of whether and how the clustering by care providers or centers was addressed 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" Does your paper address subitem 11a-ii?
Does your paper address CONSORT subitem 11b? * This was not applicable and therefore not mentioned.
Does your paper address CONSORT subitem 12a? * In the section 'statistical analyses / Outcomes of both versions of stepped care compared to direct f2f CBT', it was explained what statistical methods were used to compare the intervention groups with the comparator. 12a-i) Imputation techniques to deal with attrition / missing values Does your paper address subitem 12a-i? * In the 'statistical analyses' section, it is described how imputation was done. In the section 'statistical analyses / Outcomes of both versions of stepped care compared to direct f2f CBT' the sensitivity analyses that were performed were explained. 16-i) Report multiple "denominators" and provide definitions 17a) For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) 17b) For binary outcomes, presentation of both absolute and relative effect sizes is recommended Does your paper address subitem 16-i? * For all results, n's were given and in case of subgroups it was mentioned who were included. Example from section 'results / therapist time invested': "The analysis including only patients who started treatment shows different results." In the accompanying table the n's are provided.
16-ii) Primary analysis should be intent-to-treat Does your paper address subitem 16-ii?
Does your paper address CONSORT subitem 17a? * All these results were depicted in 'results', in Table 2: Treatment effect. 17a-i) Presentation of process outcomes such as metrics of use and intensity of use Does your paper address subitem 17a-i? Does your paper address CONSORT subitem 17b? * There were no binary outcomes. 18) Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing prespecified from exploratory 19) All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Does your paper address CONSORT subitem 18? * These results are provided as described in the methods. For therapist time, it is stated that "As the data on therapist time was not normally distributed, medians were compared with Mann-Whitney U tests." DISCUSSION 22) Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence NPT: In addition, take into account the choice of the comparator, lack of or partial blinding, and unequal expertise of care providers or centers in each group 20) Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 19-ii) Include qualitative feedback from participants or observations from staff/researchers Does your paper address subitem 19-ii? 22-i) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use) Does your paper address subitem 22-i? * In the first two indentations of the Discussions the sttudy questions were answered, without restating them. Primary outcomes and process outcomes were adressed. About the CONSORT EHEALTH checklist Does your paper address CONSORT subitem 23? * In the abstract, the methods and in the acknowledgements the number and name of trial registry was given.

22-ii)
Does your paper address CONSORT subitem 24? * In the 'methods / trial design' section, it is explained that "This study was registered in the Dutch trial register (NTR4809)" and that it was a "follow-up study of an RCT testing the efficacy of I-CBT for CFS (NTR4013)". The latter had a full trial protocol, that is referred to and can be accessed. Small changes to this protocol for this follow-up study can be found in the trial registration of the present study.
Does your paper address CONSORT subitem 25? * In the abstract it is stated that there was no specific funding for this study. X27-i) State the relation of the study team towards the system being evaluated Does your paper address subitem X27-i? As a result of using this checklist, did you make changes in your manuscript? *