Previous treatment studies of AN have focused on a number of problems, the most daunting of which is the difficulty in recruiting sufficient participants although this difficulty appears less problematic in adolescents than adults.(7
) In a multisite trial enrolling a majority of adults it appeared that the pool of potential participants began to shrink after 2 years and was largely drained within 4 years.(8
) In retrospect this is not surprising because the adult pool is refilled slowly as those who have failed treatment in adolescence come into the pool. Many of these individuals are unwilling to seek treatment. The adolescent pool on the other hand is continually refilled with new cases and adolescents are essentially unable to refuse treatment.
In the RIAN study the numbers entered varied between sites as did the entry rates and one site was discontinued because of a low entry rate. This raises a difficult problem for future research. Because AN has a relatively low incidence many studies will have to rely on a multisite design. For this reason it will be necessary to identify sites in the U.S. capable of recruiting sufficient participants to engage in such trials. Our study makes it clear that forecasting recruitment rates is difficult unless there is prior experience in each of the sites with a similar trial. In the RIAN trial none of the original sites (all but Stanford) had experience in recruiting adolescents with AN to treatment studies although some sites had experience recruiting adults with AN. The original recruitment rate was set at approximately 2 participants/month per site based on the experience of two sites in a previous multisite study.(30
) However, the recruitment rate for the RIAN trial averaged 0.9/month per site with considerable variability between sites. With medication the rate was slower averaging 0.6/month per site. The rate for adult AN trials will likely be considerably less. This raises the question whether future multisite studies should include more sites than appear to be needed in order to ensure successful recruitment. In the RIAN trial it was fortuitous that another site (Stanford) with therapists trained in each modality and with prior experience in recruitment of adolescents with AN was available to replace the site with recruitment difficulties.
A further problem noted in many AN studies is a large dropout rate (8
), sometimes close to half the participants in adult trials.(56
) This raises the question at which level of dropout has the initial randomization been lost making the study impossible to analyze.(10
) Moreover, it is possible that there will be an interaction between participant characteristics and treatment type for dropouts. Again, this problem appears less severe in adolescents. However it is clearly important to put into place measures to ameliorate treatment and study dropout rates.
Although studies of medications are potentially important, adults with AN often refuse them for fear of weight gain and other undesirable side effects,(8
). Parents of younger patients appear to be reluctant to experiment with the use of medications at least without more specific preliminary support for their effectiveness.(60
) Treatment studies employing medications are likely to be hampered by these limitations, as was the case in the RIAN trial, resulting in a major redesign of the study. A previous controlled study of olanzapine was abandoned because only 7 of 27 (ratio=0.26) eligible patients were enrolled due to fears concerning the medication and reluctance to consider medication as a treatment option.(62
) This rate is about one half of that achieved in the RIAN trial (ratio=0.54). These figures suggest that it would have taken 6-years for the RIAN sites to recruit 240 participants for a medication study. Hence, 12 sites would have been needed to complete recruitment in a reasonable time. Our experience highlights the need for researchers planning a study of this type to consider clinical epidemiology and process to avoid repeating mistakes from previous studies.
Although the participant safety issues were resolved for this trial, they form an important precedent for other trials. Safety procedures for adolescent AN treatment studies should include the following. First, monitoring of physiologic variables should be done within the treatment sites allowing results to be rapidly reviewed and decisions regarding hospitalization to be made by study personnel. Second, in this study we elected to continue brief psychiatric interviews on a regular basis to monitor vital signs, depression, and suicidality, even though medication had been discontinued. Regular pediatric care continued outside the trial. Whether or not to bring such pediatric care within the site is a difficult decision to make. Obviously such a decision would increase trial costs. Most sites in the RIAN trial elected to use a small group of pediatricians. These were pediatricians that were often affiliated with the treatment site allowing for close communication between the pediatrician and the trial personnel. This may be the ideal arrangement, but it would restrict studies to a relatively few comprehensive treatment centers. Similar arrangements concerning physiologic monitoring and medical surveillance might be considered for treatment trials of adults with AN. The requirement regarding adequate resources should hospitalization be needed also appears important because it allows for continuity of care as well as enhanced participant safety.
Although medical monitoring of adolescents with AN is crucial to providing safety in an outpatient clinical trial, the lack of clear medical guidance on the necessary procedures may lead to undue burden and discomfort for patients. For example, although guided by clinical knowledge, there was no research basis supporting the frequency of tests decided on for this study, and the frequencies chosen probably diverge from the practice of many pediatricians providing medical monitoring for cases of adolescent AN. Should the frequency of testing be the same for all participants or should the frequency vary depending on the clinical status of the participant? Some form of algorithm governing the frequency of testing in light of the patient’s progress toward recovery might be considered in future studies. Moreover, it is unclear which tests provide the most information regarding the physiological stability of adolescents with AN.(49
) Further research on this, and other aspects of medical safety is needed.
The need to make changes in study design in response to these challenges had significant impacts on study progress. As a result of delays and study changes, recruitment began 6 months later than expected. This hiatus made it more difficult for therapists to maintain mastery of treatments, disrupted assessment procedures, and delayed data entry and protocol finalization. We utilized this time to provide therapists with extra training and supervision both at individual sites and across sites. Nonetheless, each of the factors independently had the potential to cause major problems, but taken together, they significantly challenged the ability of the PIs to complete the study. Removal of the medication arms of the trial led to faster recruitment, however by the time the decision was made, agreed on by the DSMB, and the new design approved by each site based IRB, more recruitment time was lost. Recruitment difficulties also led to the replacement of one site that was not able to recruit at a sufficient rate. Again it took several months to detect this problem and to start-up a new site. These experiences highlight the need when designing such studies to address the possibilities of such delays and anticipate that procedural changes require careful review and take time.
Although it is promising that NIH is providing much needed stimulus for the study of treatments for AN the reality is that it is a difficult illness to study. Especially careful consideration of experience in recruitment, retention, and experience with treating participants with AN is warranted. In addition, dilemmas about competing philosophies of treatment and competing treatment modalities should be addressed in assessing the feasibility of a particular setting. For both adults and children with AN medication trials are particularly challenging. To date, studies mostly document the failure of acceptability of this treatment modality, rather than efficacy data.