Fifty-four weeks after publishing the “PACE” study, The Lancet published another study of behavioral intervention for CFS that has drawn lots of attention and raised plenty of hackles. The March 1, 2012 early online edition of The Lancet includes an article by Sanne L. Nijhof et al., titled, “Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): A randomized controlled trial.” The paper is accompanied by a commentary, “CFS: Treatment without a cause,” by Peter D. White and Trudie Chalder.
The pair of articles attracted media coverage by BBC, NPR, WebMD, MedPageToday and a slew of other international, regional and local outlets. The headlines provided a sense of déjà vu all over again, thinking back to the mid-February 2011 media blitz following the PACE study. The good news? This time the word “cure” appeared in few headlines. It’s also good news that young people with CFS are a focus of study and that the kids in the FITNET arm of the trial got the benefit of a program that involved orchestrated care from their parent(s), a specially trained therapist and a school mentor. That doesn’t happen often enough. But just as some accused when the results of the rituximab trial were announced last fall, the 66 percent recovery rate reported for FITNET might be more optimistic than warranted.
The FITNET Study Design
The study was conducted by Dr. Nijhof and colleagues at the University Medical Centre in Utrecht, The Netherlands (UMCU). The Expert Centre for Chronic Fatigue in Nijmegen provided consultation. The trial was funded by the Netherlands Organization for Health Research and Development. Screening began in January 2008. FITNET stands for Fatigue in Teenagers on the interNET. The FITNET trial protocol was reported in the open access journal BMC Neurology in February 2011.
All pediatricians in The Netherlands were informed about the study through the National Surveillance Centre for Children. This network provided referrals of teens aged 12-18 years old whom physicians thought might have CFS based on the 1994 Fukuda definition. Teens and their parent(s) were referred to the UMCU clinic where a single pediatrician familiar with CFS conducted a medical history, a physical examination and laboratory tests. The authors note that the 94 Fukuda definition was used because it was the one physicians in The Netherlands are most familiar with. They also noted that 39 percent (95 of 243) of the individuals referred to the study did not meet CFS criteria upon closer evaluation, suggesting that the referring pediatricians didn’t carefully apply the criteria before making referrals. Individuals were excluded if they had primary depression, anxiety or were at risk for suicide. 135 individuals were enrolled and assigned to either FITNET or “usual care” arms of the study.
There is little description of the “usual care” delivered to 67 individuals in the study. It appears that usual care refers to a continuation of whatever behavioral care the child was receiving before being enrolled in the study, if any. There is no mention of traditional allopathic medical treatment. More than half (38 of 67) of the subjects received more than one form of therapy, usually face-to-face cognitive behavioral therapy (CBT) plus graded exercise therapy (GET). Here are the reported treatments that comprised usual care over the six months of the trial:
|“Usual Care” Therapy||Number of subjects receiving therapy|
|Cognitive Behavioral Therapy (face-to-face)||44|
|Graded Exercise Therapy||33|
|Alternative Therapy (not described)||16|
|Individual or group rehab (no described)||15|
The FITNET arm was designed to test the effectiveness of CBT delivered by five specially trained therapists over the internet to teens and their parents. Sixty-eight teens were assigned to this arm; results are reported on 67 of them. Key features of the program:
- There were 21 interactive modules for the patients and their parents to complete (see below for titles);
- They were able to access the program and send e-consults at any time of the day or night;
- Each participant was assigned to one of the five therapists;
- Therapists responded to messages from patients or parents within a week and were available on an immediate basis for emergencies;
- Parents received the same program as their son or daughter, but were not able to see their son’s or daughter’s communications with the therapist;
- Parents of younger children (under age 15) were advised to “coach” their child through the program; parents of older children (15-18) were to “encourage” their child to take responsibility for her/his participation in the program;
- Subjects agreed that they would not undertake any other medical evaluation or treatment during the six-month trial;
- A school mentor was enlisted to coach, advise and tutor each child as needed;
- The goal was a return to full-time education; and,
- School attendance was reported by the child, the parent(s), the therapist and the school mentor.
The FITNET program was aimed at changing fatigue-related cognitions and a gradual increase of activities, based on other CBT programs designed to alleviate CFS symptoms and help patients better cope with their illness. As described in the FITNET protocol in BMC Neurology, physical activity patterns were a primary assessment tool for subtyping participants into “relative active” and “relative passive” groups. Use of an actimeter to measure activity patterns is described in the protocol; however, no data is reported in The Lancet study. Five diaries are listed in the protocol; again, no data collected from such diaries is reported with the results. The titles of the 21 internet modules are provided below:
|21 FITNET Program Modules|
|1. To introduce myself||8. Changing my attention to fatigue||15. My social activities|
|2. How does this treatment work?||9. Step up my physical activities (passive patients)||16. To reach goals|
|3. Assessing my present possibilities||10. Balance between activity and rest (relative active patients)||17. My schedule for work|
|4. My parents||11. Step up my physical activities (relative active patients)||18. To have a night out|
|5. My goals||12. Recognizable problems with the treatment||19. Do I still see myself as a patient with CFS|
|6. My sleep routine||13. Step up my mental activities||20. My evaluation|
|7. My thoughts||14. My schedule for school||21. Follow-up|
Subjects in the two arms of the study were similar with an average age of 15.8 years and about 82 percent girls. There were more subjects with acute or postviral onset in the FITNET arm (44%) compared to the usual care arm (36%). The subjects in the usual care arm had been ill longer (19 months on average) compared to the FITNET arm (16 months). School attendance over the past two weeks was roughly similar:
|Frequency of attendance||FITNET||Usual Care|
|≥85%||4 (6%)||9 (13%)|
|<85%||64 (94%)||58 (87%)|
Fatigue was measured by a 20-item instrument called the Checklist Individual Strength (CIS20) and physical functioning was measured by an 87-item instrument called the Child Health Questionnaire (CHQ-CF87). Both are standardized self-report measures. The CIS-20 has been used to measure disability in populations of workers, to measure fatigue in M.S. studies and in other CFS studies. The validity of the CHQ to measure physical functioning has been questioned in at least one study that showed poor test-retest concordance on these measures when testing chronically ill children. (Raat et al., Quality of Life Research, 2002)
Subjects also rated their improvement subjectively. They answered “yes” to one of the following statements: “I have completely recovered,” “I feel much better but still experience some symptoms,” “I still have the same complaints,” or ”I have become much worse” compared to the last evaluation. Either of the first two responses was counted toward recovery totals, even though they may express very different levels of response to the therapy. Self-rating is included in most clinical trials. It carries surprising weight in the U.S. regulatory process when drugs are evaluated by the Food and Drug Administration for possible marketing approval.
Recovery was defined by the authors after the study was complete. They note (accurately) in the paper, “There is no universal definition of recovery in patients with CFS during therapy.” This fact has been a barrier to defining a standard of care, as the results of therapeutic trials have used inconsistent definitions for improvement and/or recovery. The use of dozens of different instruments to measure symptoms and function has also made comparisons difficult. Couple this with different definition or different subtyping criteria, and it is even more challenging for patients and physicians to assess the potential benefit of a particular therapy. It is worth noting that the recovery rate in children with CFS has been reported to be higher than for individuals whose illness begins in adulthood. No non-treatment control group was included for comparison against spontaneous recovery, although 7 teens in the usual care arm received no treatment at all. (Their results are not reported separately within the usual care group.)
For the FITNET study, recovery was defined as less than 10 percent school absence in the prior two weeks (at the end of six months), a fatigue score of less than 40 and physical function score of greater than 85 PLUS a self-rating of feeling improved. The post-hoc and loose nature of the way recovery is defined in this study may be one of its pitfalls. White and Chalder stated in the accompanying commentary,
“The investigators defined recovery post hoc. However, the criteria used to define recovery were not stringent and some individuals who entered the study were already attending school fairly frequently. The investigators used liberal criteria, such as the population mean plus two rather than one standard deviation, as their thresholds for recovery by continuous measures such as fatigue. Therefore, the 63% of patients reported as recovered might have included those who had a significant improvement rather than being fully recovered. This proportion of patients does not detract from the still impressive difference from the 8% of participants who were judged to be recovered after usual care.” — Peter White and Trudie Chalder in accompanying commentary
After six months of therapy, the authors stated that 63 percent (42 of 67) teens in the FITNET arm met the primary and secondary outcome measures that defined recovery, compared to 8 percent (5 of 64) teens in the usual care arm. The results reported in The Lancet are as follow:
There were no serious adverse events reported in either arm of the study. Four subjects were lost to follow-up; one in the FITNET arm and three in the usual care arm. Two subjects (one in each arm) recovered and two (both receiving usual care) did not wish to return for the post-intervention interview.
The subjects in the FITNET arm and their parents made heavy use of the internet program. Over 26 weeks, the following activity was recorded:
- Average of 266 log-ons per user (including parents)
- Patients sent an average of 66.6 e-consults (each) to therapists
- Parents sent an average of 22.8 e-consults (each) to therapists
- Therapists sent an average of 28.7 e-consults to each patient
- Therapists sent an average of 19.5 e-consults to each parent or set of parents
There were not significant differences between the five therapists in the results achieved during the study.
Subjects in the FITNET arm were permitted to continue the program for an additional six months and subjects in the usual care arm were invited to start the FITNET program after the six-month point for a period of six months. The follow-up results reported in The Lancet follow:
In the discussion, the authors describe the strengths of the FITNET program:
“First the FITNET rogram involved parents in their children’s treatment. The results of earlier studies have shown the importance of family-focused cognitive behavioural therapy in the successful treatment of adolescents. Furthermore, hardly any loss of follow-up occurred, thus reducing the risk of bias. … The high participation rate is a sign of the low threshold and high acceptance of internet-based health care. A particular strength is that the main outcome (school attendance) was checked and double checked by the investigators, parents, teachers and therapists.
Internet-based treatment has general advantages: it is available at any time, avoids face-to-face treatment barriers (i.e., treatment delay due to poor accessibility, inconvenience of scheduling appointments, missing school or work, travelling to and from a clinician’s office), and reduces treatment time and costs. This unique cognitive behavioral therapy seems to appeal to modern youth, who grow up using the internet as their main source of information.” — Nijhof et al., in The Lancet
While the authors conclude that, “With FITNET effective treatment is within reach for any adolescent with CFS,” White and Chalder note that there are problems with the generalizability of the program. They write, “…only 30 percent of the world’s population have internet access (percentages higher in Europe [58%] and North America [78%]). Patients and parents need to be reasonably literate with no language barriers. The results of the trial cannot be generalised to adults.”
If, as White and Chalder suggest, the authors had used one standard deviation to measure “recovery,” the results would have been less favorable, but would have still supported the benefits of internet-based CBT over usual care (as provided in The Netherlands) — 36 percent of FITNET participants would have met primary and secondary outcomes for recovery, compared to 5 percent in the usual care arm. From the online appendix to the Lancet paper:
Based on experiences relayed by parents and young people who have endured the first few years of CFS with little support from medical, mental health or education professionals, the benefits arising from a team approach by the young person, her or his parent(s), a dedicated therapist and a school mentor are not surprisingly superior to a hit-or-miss combination of CBT plus graded exercise. Hopefully the students in this study will be followed for a longer period of time, especially after the FITNET program is no longer available to them, to evaluate how well the improvement holds and whether it translates to longer term academic success (versus simply evaluating school attendance) and post-secondary success.
This study makes no suggestion that CFS is a mental health problem or that the positive outcomes achieved have cured or resolved the underlying medical disorder. The authors note that internet-based CBT has been used succesfully to help individuals with depression, anxiety, headache and smoking cessation. News articles also mentioned successful applications in Parkinson’s and cancer.
Even though CBT is (by far) the best-studied intervention for CFS, it’s unlikely this will be the last study of CBT we will see reported. In the U.S., the National Institutes of Health has invested heavily in this form of therapy, nearly to the exclusion of medical approaches. A $1 million study of telephone-based CBT in adult CFS patients led by Michael Antoni of University of Miami has resulted in one publication in April 2011 in the Journal of Psychosomatic Research. Fred Friedberg, PhD, of SUNY-Stonybrook recently secured a second NIH award to continue his studies of self-help programs, with funding totaling $1.15 million. Friedberg’s second award will evaluate whether he can “establish a commercially viable program of illness self- management in people with unexplained chronic fatigue (UCF) and chronic fatigue syndrome (CFS).” So, academic publications are likely to flow from these (and other) awards and business opportunitites may follow as well.
Nijhof SL, Bleijenberg G, Uiterwaal CSPM, Kimpen JLLL, van de Putte EM. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial.Lancet. March 1, 2012 (epub ahead of print). DOI: doi:10.1016/S0140-6736(12)60025-7
Link to study abstract:
Link to full text:
White PD, Chalder T. Chronic fatigue syndrome: treatment without a cause. Lancet. March 1, 2012 (e-pub ahead of print). DOI: doi:10.1016/S0140-6736(12)60197-4
Link to summary:
Nijhof SL, Bleijenberg G, Uiterwaal CSPM, Kimpen JLLL, van de Putte EM. Fatigue In Teenagers on the interNET – The FITNET Trial. A randomized clinical trial of web-based cognitive behavioural therapy for adolescents with chronic fatigue syndrome: study protocol. BMC Neurology. Feb. 11, 2011. DOI: doi:10.1186/1471-2377-11-23
Link to full text: http://www.biomedcentral.com/1471-2377/11/23
Raat H, Landraft JM, Bonsel GJ, Gemke RJ, Essink-Bot ML. Reliability and validity of the child health questionnaire-child form (CHQ-CF87) in a Dutch adolescent population. Quality of Life Research. 2002 Sep;11(6):575-81.
Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/12206578
K. Kimberly McCleary served as the Association’s chief staff executive from 1991-2013.March 4, 2012