REGULAR ARTICLE       Challenges in Conducting a Multi-Site Randomized       Clinical Trial Comparing Treatments for Adole...
TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSAthe US6 In response to this workshop and the lack             sions related to s...
LOCK ET AL.TABLE 1.      Intervention sites and data center1. Stanford University School of Medicine, PI: W. Stewart Agras...
TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSAsystem and how they ‘‘organize’’ themselves as a              were taped and rev...
LOCK ET AL.emaciation, including bradycardia, hypotension,           practice of previous controlled trials in adult and a...
TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSATABLE 2.      Within site medical and psychiatric assessments for medical safety...
LOCK ET AL.FIGURE 1. Graph showing the rates of study contacts, assessment, and study entries for all sites combined. The ...
TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSATABLE 4.    Numbers of individuals contacted, screened, eligible, interviewed, a...
LOCK ET AL.TABLE 5.      Reasons for exclusion from the study                                                       Cornel...
TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSAwould increase trial costs. Most sites in the RIAN            also led to the re...
LOCK ET AL.      controlled comparison of two family interventions. J Child Psy-      32. Couturier J, Lock J. Review of m...
TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSA52. Le Grange D, Crosby R, Rathouz P, Leventhal B. A randomized               ni...
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Challenges in Conducting a Clinical Trials in Comparing Treatments for Adolescent Anorexia Nervosa


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Article to describe obstacles in the implementation of a controlled treatment trial of adolescent anorexia nervosa for practitioners.

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Challenges in Conducting a Clinical Trials in Comparing Treatments for Adolescent Anorexia Nervosa

  1. 1. REGULAR ARTICLE Challenges in Conducting a Multi-Site Randomized Clinical Trial Comparing Treatments for Adolescent Anorexia NervosaJames Lock, MD, PhD1* ABSTRACT Objective: To describe obstacles in the resulting in a comparison of two types of family therapy with a projected sampleHarry Brandt, MD2 implementation of a controlled treat- size of 160. One site was unable to recruitBlake Woodside, MD3 ment trial of adolescent anorexia nervosa and was replaced.Stewart Agras, MD1 (AN). Discussion: Problems with the delinea-W. Katherine Halmi, MD4 Method: The original aim was to enter tion of safety procedures, recruitment, re-Craig Johnson, PhD5 240 participants with AN to one of four design of the study, and replacement of aWalter Kaye, MD6 cells: Behavioral family therapy (BFT) site, were the main elements resulting in a plus fluoxetine; BFT plus placebo; sys- 1-year delay. Suggestions are made forDenise Wilfley, PhD7 tems family therapy (SFT) plus fluoxetine; overcoming such problems in future AN SFT plus placebo. trials. V 2011 by Wiley Periodicals, Inc. C Results: Recruitment was delayed Keywords: anorexia nervosa; adoles- pending a satisfactory resolution con- cents; behavioral family therapy; systems cerning participant safety. After 6 months family therapy; RIAN trial of recruitment it became clear that the medication was associated with poor recruitment leading to a study redesign (Int J Eat Disord 2012; 45:202–213) and a lack of standardized outcome measures. As aIntroduction result of these difficulties the published trials areThere are few randomized controlled trials (RCTs) mostly small in scale, with average cell sizes belowof psychosocial treatments for Anorexia Nervosa 20 per group. Hence, they provide limited guidance(AN), a serious psychiatric disorder typically with to clinicians. The failure of existing studies toonset during adolescence and a clinical course address these problems can be viewed as a signifi-leading to significant medical morbidity and mor- cant factor in the overall lack of evidence-basedtality.1–3 Of the 15 published RCT’s 9 involved treatments for AN.adults and 6 adolescents.4 Studies are limited by a In 2002 the National Institute of Mental Healthrange of problems including difficulty with recruit- (NIMH) convened a workshop to review the statement limiting sample size, high attrition rates of research in AN.5 This revealed that less than a(especially in adult studies threatening the validity dozen psychotherapy trials had been published atof randomization), use of inadequate assessments, that time and that only one had been carried out in 1 Accepted 13 January 2011 Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Stanford, California Supported by 1 U01 MH 076290, MH 076287, K24 MH-074467 2 Department of Psychiatry, Sheppard-Pratt Health System,from Stanford; 1U01 MH 076254 from Sheppard-Pratt; 1 U01 MH Physician’s Pavilion North, Baltimore, Maryland076253 from Toronto; 1 U01 MH 076251 from Cornell; 1U01 MH 3 Department of Psychiatry, Toronto University, Toronto, On-076253 from UCSD; 1 U01 MH 076250 from Laureate; 1 U01 MH tario, Canada M5G 2C4076255, 5K24 MH70446 from Washington University-St Louis; Astra 4 Department of Psychiatry, Weill Medical College, Cornell Uni-Zeneca Pharmaceuticals. versity, White Plains, New York The authors have the following financial disclosures: Drs. Lock 5 Department of Psychiatry, University of California, San Diego,and Agras receive royalties from Guilford Press for books related to Eating Disorder Treatment and Research, La Jolla, CaliforniaFamily-Based Treatment. Dr. Lock provides training and consulta- 6 Eating Recovery Center, University of Oklahoma College oftion for the Training Institute for Child and Adolescent Eating Dis- Medicine, Denver, Coloradoorders. Dr. Kaye is a consultant for the Denver Eating Disorder Cen- 7 Department of Psychiatry, Washington-St Louis University, St.ter and receives grant funding from Astra Zeneca Pharmaceuticals. Louis, MissouriDrs. Halmi, Brandt, Wilfley, Woodside, and Johnson report no fi- Published online 14 April 2011 in Wiley Online Librarynancial disclosures. ( DOI: 10.1002/eat.20923 *Correspondence to: James Lock, MD, PhD, Department of V 2011 Wiley Periodicals, Inc. CPsychiatry & Behavioral Sciences, Stanford University, School ofMedicine, 401 Quarry Road, Stanford, CA 94305. E-mail: jimlock@stanford.edu202 International Journal of Eating Disorders 45:2 202–213 2012
  2. 2. TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSAthe US6 In response to this workshop and the lack sions related to symmetry, exactness, and order.of evidence-based treatments for AN, the NIMH This is underscored by a finding that OC-ED symp-issued an RFA [MH-05-009 ‘‘Request for Applica- toms may moderate the outcome of FBT in thattions for Research on Interventions for Anorexia those with higher scores on the trait did less wellNervosa (RIAN)’’] to encourage new treatment with short-term treatment.29 Fluoxetine has beenresearch. This report summarizes the challenges shown to be helpful in treating anxiety disordersfaced by the group of investigators who were and obsessive-compulsive behaviors in adoles-funded through this RFA to conduct a treatment cents,.30,31 While these medications are often pre-study for adolescent AN. In the process of imple- scribed for adolescents with AN, their role in treat-menting the study, a number of significant ment in this age group remains uninvestigated.32obstacles arose necessitating changes in the Therefore, an additional question to be addressedresearch design and timing of the research project. was whether the addition of fluoxetine in the con-In this article we describe how we addressed these text of family therapy would enhance outcome byobstacles in hopes of aiding future studies.7 addressing obsessive and anxious traits that might interfere with treatment response.29Study Background Original Study Design The choice of an adolescent study was guidedfirst by the findings that adult trials were plaguedby high rates of non-compliance to assigned treat- Overview. On the basis of these background data,ments and high study dropout.8 Moreover, there our initial study was designed to address two majorwas no evidence that any treatment in adults was specific aims:effective.4 Further, studies suggested that not onlywas the onset of AN largely in adolescence, but that 1. To compare the relative effectiveness of FBTadolescents were more likely to remain in and to SFT for adolescent AN in an adequatelyrespond to treatment,9 especially if it involved fam- powered randomized controlled trial (RCT) toilies.10 Four small-scale clinical trials suggested determine whether the effects of FBT arethat a specific form of family-based therapy (FBT) due to specific or nonspecific elements ofwas likely to be effective with adolescent patients treatment.with AN.6,11–14 In two of these trials, FBT appeared 2. To compare the relative efficacy of fluoxetineto outperform individual therapy, though studies versus placebo in augmenting recovery andwere modest in scale and conclusions appropri- preventing relapse after treatment with eitherately circumspect.6,13,14 Although these initial stud- FBT or SFT in adolescents with AN.ies were encouraging, it had been hypothesized butnot definitively demonstrated that the procedures To accomplish these aims, the initial proposalunique to FBT, namely charging parents with re- called for 240 adolescents with a diagnosis of ANfeeding their child, were responsible for its effec- to be randomly assigned to one of the two familytiveness.15 A study that targeted adolescents and therapy treatments at six sites (40 per site) with thecompared FBT to another family approach that did addition of either fluoxetine or placebo. Medicationnot charge parents to re-feed their child, Systems was to be continued for 6 months following theFamily Therapy (SFT),16 would provided new end of family therapy. Participants would then beinsight into the effectiveness and mechanism of followed for an additional 6 months. This designaction of FBT. would allow evaluation of the added effects of Other data suggested that some characteristics of fluoxetine to family therapy during both treatmentadolescents might contribute to their response to and maintenance of weight restoration as sug-treatment. Patients with AN are frequently perfec- gested by two small-scale studies in adults at thetionistic and have obsessive-compulsive personal- time.33,34 Comprehensive assessments of weight,ity traits in childhood. These traits are often evident eating psychopathology, psychological, and familybefore the onset of their eating disorder.17,18 In factors would occur at baseline, end of treatment,addition, a substantial body of literature suggests and 6-month and 1-year follow-up. The primarythat early onset anxiety disorders are a risk factor outcome was to be change in weight as measuredfor the development of AN in girls.19–23 Studies24–28 by age adjusted body mass index (BMI).35,36 Inhave also found that patients who have recovered addition, both parents were to be assessed. Thefrom AN continue to manifest residual anxiety, per- assessments involved standardized research inter-fectionism, inflexible thinking, restraint in emo- views, patient reports, and questionnaires. An inde-tional expression, social introversion, and obses- pendent assessor not involved in treatment deliveryInternational Journal of Eating Disorders 45:2 202–213 2012 203
  3. 3. LOCK ET AL.TABLE 1. Intervention sites and data center1. Stanford University School of Medicine, PI: W. Stewart Agras, MD, Co-PI: James Lock, MD, PhD (data and coordinating center) (Later added as an Intervention site under James Lock, MD, PhD)2. Cornell University, PI: Katherine Halmi, MD (intervention site)3. Laureate Psychiatric Clinic and Hospital, PI: Craig Johnson, PhD (intervention site, but removed as an intervention site for failure to recruit)4. Sheppard-Pratt Medical Center, PI: Harry Brandt, MD (intervention site)5. University of California at San Diego, PI: Walter Kaye, MD (intervention site)6. University of Toronto, PI: Blake Woodside, MD, Co-PIs: Debra K. Katzman, MD, Leora Pinhas, MD (intervention site)7. Washington University, PI: Denise Wilfley, PhD, Co-PI: Kimberli McCallum, MD, Monica Bishop, MD (intervention site)and therefore blind to randomization would con- obtaining IRB approval. See Table 1 for Interven-duct all assessment interviews. Assessments were tion sites and DCC involved.selected to evaluate outcome, as well as modera- Family Treatments. Both FBT41 and SFT42 consist oftors, and mediators of treatment. 14 treatment sessions conducted over a 9-monthDefining AN. As the literature attests there are sev- period, each lasting 1 h. Sessions are spaced weeklyeral problems with the DSM-IV criteria for the diag- for the first 8 weeks, bi-weekly for the next 4 weeks,nosis of AN.37 In line with these criticisms we made and monthly for the remaining two sessionstwo modifications to the criteria. We dropped the although some flexibility is allowed.amenorrhea criteria.38 Second, we modified the Family Based Treatment (FBT) is a three-phaseweight criterion for entry to this study to an Ideal manualized treatment that has been used in previ-Body Weight (IBW) of 87% or below based on ous treatment studies of adolescent AN.29,41 In theexclusions in previous studies.29,39 By making these first phase (Sessions 1–8), therapy is focused on thechanges, we believe we identified a research popu- eating disorder, and includes a family meal atlation that is typical of most adolescents presenting Session 2. The latter provides the therapist with anwith AN in clinical settings. In addition, based on opportunity for direct observation of the familialinconsistencies between different observers when interaction patterns around eating. The therapistthe CDC charts were used by hand to calculate makes careful and persistent requests for unitedIBW, a computerized system was developed to cal- parental action directed toward weight restoration,culate IBW using an Excel program. When using which is the primary concern at this early point ofthis program the assessment date is first entered, the treatment. In addition, the therapist directs thethen the patient’s gender, date of birth, height in discussion in such a way as to create and reinforceinches and weight in pounds. The program then a strong parental alliance around their efforts atcalculates and displays the % IBW based on the weight restoration of their offspring on the oneCDC tables for height and weight adjusted for age. hand, and aligning the patient with the sibling sub-Collaborating Sites. Highly specialized clinical and system on the other. Phase 2 (Sessions 9–12) beginsresearch sites were identified in North America to after patient demonstrates steady weight gaincarry out this research (see Table 1). The treatment under parental supervision and the parents feelsites chosen were directed by established clinicians their child is able to begin age-appropriate eatingand researchers in the field of eating disorders. As more independently again. Symptoms remain cen-such, these sites were considered likely to be suc- tral in the discussions and weight gain with mini-cessful in the recruitment, evaluation and treat- mum tension is encouraged. Only when the adoles-ment of participants. In addition an independent cent is able to eat independently and demonstrateData and Coordinating center (DCC) with experi- freedom from the preoccupations of AN, do otherence in the management and coordination of mul- issues about adolescent development and termina-tisite clinical trials with eating disorders was tion come to the fore (Phase 3, Sessions 13–14).included.8,29,40 Based on recruitment rates of 20 ad- Systemic family therapy (SFT) is a slightly modi-olescent participants/year from previous stud- fied family psychotherapy that was developed andies29,39 it was thought that six treatment sites would manualized by researchers at Leeds University as aallow for recruitment of 240 participants over a 2- model of treatment that is used in practice. It isyear period. In addition, this number of sites per- based on family-systems therapy.42,43 SFT ismitted geographical and sociodemographic diver- focused on patterns of behavior and beliefs thatsity that could lead to better generalization of the have developed in the family over the course offindings. The study was funded using an NIH U- time. Understanding these patterns provides theMechanism grant structure. NIMH appointed a therapist with the opportunity to give new informa-Data and Safety Monitoring Board (DSMB) to pro- tion through which different solutions can be gen-vide oversight of the study in addition to each site erated. This treatment deals with the family as a204 International Journal of Eating Disorders 45:2 202–213 2012
  4. 4. TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSAsystem and how they ‘‘organize’’ themselves as a were taped and reviewed by the site supervisor, andfamily in terms of their different roles and relation- supplemented by weekly face-to-face supervision.ships. The goals of Stage 1 (Sessions 1 and 2) are to Once a therapist had successfully completed a(1) outline therapy boundaries and structure; (2) phase of the treatment, tapes were forwarded toengage and involve all family members; (3) gather the relevant training supervisor (JL for FBT, LD forand clarify information; and (4) establish goals and SFT) at the DCC. Supervisors would provide feed-objectives of the therapy. In undertaking these tasks back and eventually certify the therapist as compe-the therapist provides a supportive environment, tent in the treatment. After competence wasremains neutral, and enlists everyone’s involve- achieved, the therapist could accept randomizedment. During Stage 2 (Sessions 3–8) the goals are to participants.(1) explore beliefs and assumptions, challenging Once cases began to be randomized, therapistsexisting patterns and assumptions; reframe con- continued to be involved in weekly face-to-facestraining ideas; and open new possibilities for supervision at their local site. All sessions wereexamination. During Stage 3 (Sessions 9–14) the recorded and viewed by the site supervisor totherapist focuses on information gathering and assess adherence to the manuals and to assist withreviewing and refining the material brought by the the clinical supervision of the cases. Two additionalfamily to sessions as in Stage 2, though the focus of group training sessions were held for each treat-the information is likely to be considerably differ- ment type under the direction of the trainingent. It is more common in the end sessions for the supervisors at 1-year intervals to allow for thera-focus to be on amplifying change, enhancing pists from all sites to meet and to review problemsmastery, re-framing, and developing new explana- that had arisen related to adherence to the models,tions. Termination occurs with the therapist invit- and clinical difficulties that had been encountereding the family to review the process of therapy with in the treatment of the families. In addition to sitethe aim of preventing future difficulties and plan- supervision, a schema of paired-site teleconfer-ning for any future needs for therapeutic services. ences was developed, where two sites would be To ensure that the two family treatments were rotated in pairs for several months to minimize sitedelivered in a comparable fashion across sites, spe- drift. There was a monthly site supervisors’ supervi-cial attention was given to the identification, train- sion conducted by the training therapists in theing, supervision, and monitoring of therapists over DCC to support the site supervisors with particu-the study period. The criteria for selection of poten- larly challenging cases and to increase supervisorytial therapists included requirements that they hold consistency across sites.a Master’s or PhD level qualification in psychology, Medication Treatment. A secondary aim of the origi-social work, or family therapy, and that they have nal design called for fluoxetine or placebo treat-had at least 1 years’ experience in treating individu- ment to begin at the point of randomization. Theals with eating disorders. With six sites, an average plan was for medication treatment to be supervisedof two therapists per site per condition allowed for by psychiatrists at each site. Changes in symptomsthe decision to be made that therapists would be and side effects would be monitored at each ses-trained in only one of the two treatments. It was sion with particular attention to suicidal ideation.felt that with this number of therapists, therapist Treatment would begin with a dose of 20 mg fluox-non-specific factors would be spread across a etine, and could be increased to 60 mg basedrelatively large group, thereby mitigating potential on clinical status. Medication could be increased atconfounding effects of these factors on outcome. 2-week or longer intervals if indicated. TreatmentTraining events were therefore held separately for was scheduled to continue for 6-months after theeach treatment type. Therapists from all sites using end of family therapy. At the end of this period theeach type of therapy were trained together, begin- blind would be broken and the family and partici-ning with a 2-day intensive workshop. Both train- pant informed of whether the patient had been oning sessions employed manuals that formed the active medication. For those wishing to continuebasis of treatment in both conditions. Training on active medication their physician would be con-was conducted by highly experienced and trained tacted and, with the family’s permission, giventherapists in each condition (JL in FBT and LD in details regarding dosage, side effects, etc. ThoseSFT). In addition to training therapists, each site wishing to stop medication would be withdrawnhad a supervisor in both conditions. from medication under supervision of the site psy- After the initial workshops, therapists were chiatrist.assigned two pilot cases to complete under the Participant Safety. There can be serious medicaldirect supervision of local site supervisors. Sessions problems associated with severe malnutrition andInternational Journal of Eating Disorders 45:2 202–213 2012 205
  5. 5. LOCK ET AL.emaciation, including bradycardia, hypotension, practice of previous controlled trials in adult and ad-hypothermia, orthostatic hypotension, as well as olescent populations.29,39 It was expected that theelectrolyte and fluid abnormalities.44 Emergency required laboratory tests and medical examinationscoverage of participants was to be provided at each would be paid for by the participant’s by the therapists, study PI and the participant’s However in this study because there were insuffi-pediatrician. Initial and ongoing medical oversight cient funds to cover hospitalization costs, in theof participants was a requirement for all partici- consenting process participants and their parentspants to ensure medically stability for outpatient were notified that they would be responsible for thetreatment. The criteria for medical stability of ado- costs of hospitalization either through insurance orlescents with eating disorders used in the study personal finances should it become necessary. Thiswere those identified by the Academy of Pediatrics was particularly important as the study design man-and the Society of Adolescent Medicine.44,45 The dated hospitalization for safety reasons at 75% ofdecision to hospitalize patients was to be made on Ideal Body Weight (IBW) or other signs of significantthese standardized criteria by a pediatrician blind medical instability.44,45 Interestingly only two poten-to the treatment group to which the patient was tial participants were excluded for this reason.assigned. These specific criteria included: vital sign Medication Use with Anorexia Nervosa. During theinstability (heart rate less than 50, orthostatic blood first year of the study there was considerable dis-pressure changes greater than 35 points, or clini- cussion between the investigators and the DSMBcally significant symptoms or findings, e.g., concerning participant safety particularly becauseevidence of gastrointestinal bleeding, dizziness, of the use of fluoxetine.46 The basic issue was thatsyncope), IBW 75%, hypothermia (body tempera- the DSMB considered that responsibility forture less than 368C), electrolyte abnormalities, or enhanced safety monitoring must reside within theprolonged QTC interval on electrocardiogram. After trial rather than with an outside pediatrician. Ulti-hospitalization, participants would return to their mately, the DSMB required recruitment to ceaseallocated therapeutic arm unless they were hospi- until these issues were resolved. Following detailedtalized for more than 28 consecutive days, in which discussions with the DSMB a schedule for surveil-case they would be withdrawn from treatment. lance of weight, vital signs, suicidality, liver func-Records of all hospitalizations (date, reason for tion, EKG, and other tests was developed (seehospitalization, length of stay and types of treat- Tables 2 and 3). These safety assessments were toment received) were to be obtained for all patients be paid for by the trial intervention sites and deci-hospitalized and entered into the database to sions regarding participant safety were to be madeexamine any potential differences in hospital use by the trial psychiatrist and the PI at each site inbetween treatment groups. consultation with the outside pediatrician when necessary. Outside pediatricians continued to mon-Challenges with Implementation of the itor each participant’s medical stability and theOriginal Design within-trial test results were sent to these pediatri- The limited database on treatment studies for cians. Establishment of the new safety guidelinesAN is related to a variety of difficulties that can with clearance from the DSMB and updating con-interfere with the completion of such studies.7,8 sent forms led to a 6-month delay in recruitment.Gowers et al. in one of the first papers describing Hence recruitment began on January 1, 2008.the methodological problems encountered in a In addition to safety concerns with fluoxetine,treatment study of anorexia nervosa commented recruitment of adolescent participants was nega-‘‘From the onset methodological problems were tively affected because of participant/family resist-evident. As the study progressed more have relent- ance to fluoxetine. Prior to initiation of recruitment,lessly emerged.’’ We also encountered a number of there was widespread public concern and significantproblems during the early implementation of the media attention suggesting that that the use of anti-study. We describe these difficulties and our depressants may increase the likelihood of suicidalresponse to them to illustrate problems that others behavior in youths.46 Following a thorough andmight face. We also explain how the study design comprehensive review of all the available publishedchanged in response to these problems. and unpublished controlled clinical trials of antide-Potential Need for Hospitalization During the Study. In pressants in children and adolescents, the US Foodthe original design, pediatric monitoring, including and Drug Administration (FDA) issued a publicphysical examinations and laboratory tests, was to warning ( accomplished by physicians outside the study in InformationbyDrugClass/UCM096273) in Octoberorder to minimize study costs. This followed the 2004 about an increased risk of suicidal thoughts or206 International Journal of Eating Disorders 45:2 202–213 2012
  6. 6. TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSATABLE 2. Within site medical and psychiatric assessments for medical safetyAssessment Baseline Week 1 Weeks 2–4 Weeks 5–20 Months 6–9Vital signs 31 32 Weekly Bi-weekly MonthlyWeight and height 31 32 Weekly Weekly MonthlySymptom functioning, suicidality 31 32 Weekly Bi-weekly MonthlyTABLE 3. Medical monitoring and laboratory testing Consequently, the PI Steering Committee decided Baseline Week-8 6-months 9-months to remove the medication arms of the study toEKG X X X X enhance recruitment. To address these changes,Electrolytes X Monthly participants on medication were unblinded andLiver Function Tests X X XBUN X X X X given the opportunity to stop or continue fluoxe-Creatinine X X X X tine. The majority elected to stop the medicationCPK X X X X and fluoxetine was withdrawn under supervision ofUrinalysis X X X XPregnancy test X Months 3, 6, 12, 15 the study psychiatrist at each site. Withdrawal was managed on a graduated schedule dependent on dosage and clinical response with weekly visitsbehavior in children and adolescents treated with until withdrawal was completed and the partici-SSRI’s.46 In 2006, an advisory committee to the FDA pant was stable. Because suicidal ideation mayrecommended that the agency extend the warning increase during this particular phase particularto include young adults up to Age 25. More recently, attention was paid to both depression and suicidalresults of a comprehensive review of pediatric trials thinking during the withdrawal period. Only threeconducted between 1988 and 2006 suggested that participants remained on fluoxetine. These partici-the benefits of antidepressant medications likely pants will be included in the group of participantsoutweigh their risks to children and adolescents who were on medication at entry to the study orwith major depression and anxiety disorders. The who were placed on medication during the, partially funded by NIMH, was published in Hence medication status will be analyzed as athe April 18, 2007, issue of the Journal of the Ameri- moderator of treatment outcome.can Medical Association47 and was widely reported Family Treatment Alone vs. Multimodal, Multidiscipli-in the press shortly before recruitment to the trial nary Treatment. Another significant barrier towas scheduled to begin (July 1, 2007). Because of recruitment centered on participant concernsthese warnings the following additional risks of tak- about entering a trial where family therapy was theing these medications were added to the consent only treatment modality. This was particularly trueand assent documents: the risk of developing a at sites that had previously promoted or empha-serotonin syndrome in participants taking triptans sized the availability, and importance of multi-(migraine medications) with an SSRI and risk of modal, multi-disciplinary treatment for eating dis-neonatal persistent pulmonary hypertension in orders. The study was designed to evaluate the spe-infants born to mothers taking SSRIs after the 20th cific role of family therapy in adolescent AN, andweek of pregnancy. The DSMB also encouraged specifically excluded the use of nutritional counsel-investigators to include a description of risks ing, individual psychotherapy, and other forms ofobserved in animal studies of fluoxetine (including intervention. Despite ongoing, intensive efforts todevelopmental effects and emotional behaviors). recruit participants, some of the RIAN sites found The negative media attention about antidepres- that their traditional multimodal treatments weresant risk together with the risks detailed in the con- being selected instead of the research protocol bysent forms had a profound impact on early recruit- potential research participants. Ultimately, suchment. After 6 months of recruitment (July 1, 2008), problems led to the need to withdraw one site fromonly 20 individuals had been entered to the study participating because of failure to recruit sufficient(see Fig. 1). Forty-seven percent of individuals eligi- participants. The site recruited only three partici-ble for the study had refused fluoxetine and a fur- pants in 9 months and recruitment was notther 10% were on medications that called for exclu- enhanced after the removal of the study medica-sion. It therefore became clear to the study steering tion. The site was replaced with an additional inter-committee and to the DSMB that fluoxetine was a vention site to assure the study could completemajor barrier to recruitment. Moreover, even at this recruitment in a timely fashion. The change wasearly stage of the trial, 25% of participants had feasible because the new site had clinicians alreadywithdrawn from the medication arm of the study. trained in both therapies, as well as a team trainedInternational Journal of Eating Disorders 45:2 202–213 2012 207
  7. 7. LOCK ET AL.FIGURE 1. Graph showing the rates of study contacts, assessment, and study entries for all sites combined. The medica-tion arm of the study was removed (including DSMB and sites IRB approval) on January 1, 2009 and the Stanford sitebegan recruiting at the same the assessment procedures. Further, the site had that emerged in recruitment of participants wasa history of successful recruitment of adolescent that many potential participants were not at a suffi-AN participants into treatment trials. The substi- ciently low weight for inclusion. They met DSM-IVtute site began recruiting in January 2009. Recruit- criteria for EDNOS as opposed to AN, even thoughment from the combined sites then attained a fairly the cut-point for entry to the study was an IBW ofsteady pace of 7 participants/month over the next 87%. Although evidence suggests these patients are12 months compared with 3.75 participants/month often as medically vulnerable as those who meetfor the previous year. full diagnostic thresholds,48 and early interventionRandomization Difficulties Related to Publicity About is likely the best approach (Hoek and Hoekan);‘‘Maudsley’’ Family Therapy. An unanticipated recruit- these cases had to be excluded.ment obstacle at some sites resulted from the bur- Conversely, some participants presented to treat-geoning interest in, and publicity about, the ment sites meeting study weight criteria but with‘‘Maudsley Model,’’ or FBT. Because so little is serious medical/physiological morbidity and ill-known about effective treatments for AN, and pre- ness severity warranting treatment in higher levelsliminary studies have supported FBT, many fami- of care (i.e., in-patient or day treatment). This haslies were interested in receiving this treatment. posed another recruitment obstacle, not onlyWhile on the surface this would appear to be of because the participant was initially ineligible tosubstantial benefit in recruiting participants, para- enter the trial because it was unsafe to treat thedoxically, some parents and participants were hesi- patient as an outpatient, but also because in sometant to enter a randomized trial with a 50% chance cases, weight gained in the higher level of care wasof not receiving FBT. This recruitment issue was of a magnitude (i.e., [ 87% IBW) that ultimatelyfurther complicated by community discussion by excluded the participant from the trial. This prob-potential research participants and their families at lem is, in part, created by an incomplete under-support groups and on web-based eating disorder standing of the role of medical and psychiatric hos-chat groups (e.g., Maudsley Parents (www.maud- pitalization for adolescent AN. While guidelines and F.E.A.S.T ( medical safety of these patients have been pub-Controversies Related to Weight Criteria and Use of Hos- lished, the basis of the specific thresholds arepitalization for Medical Stabilization. Another issue derived from professional consensus rather than208 International Journal of Eating Disorders 45:2 202–213 2012
  8. 8. TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSATABLE 4. Numbers of individuals contacted, screened, eligible, interviewed, and randomized by site Cornell Laureate Sheppard Pratt Stanford Toronto UCSD Washington University TotalContacted 77 30 106 81 79 118 73 564Screened 74 30 106 80 77 118 73 558Eligible 41 9 59 55 45 56 40 305Interview 31 4 31 40 36 36 38 216Entered 30 3 22 28 28 25 28 164scientific study.44,49 This is particularly the case for inpatient unit was closed for renovations for 1 year.weight thresholds, where medical discharge varies Recruitment rates also varied considerably withfrom 75 to 100% of IBW depending on program Stanford recruiting at the rate of 1.6 participants/treatment philosophy.50 month compared with an average of 0.9 partici- pants/month at the other sites (excluding theFinal Study Design Laureate site). These data illustrate that multisite The changes outlined above resulted in a 6 site 3 studies may recruit from different settings and2 treatments (FBT and SFT) design. This reduced emphasize the importance of careful delineation ofthe participant recruitment burden from 240 par- ‘‘caseness’’ in the context of an RCT in order toticipants to 160 participants with an 88% power to assure that similar participants are included acrossdetect a moderate difference between groups. A the sites.moderate effect in this case is a Cohen’s d (standar-dized mean difference between two groups) of 0.5.With this effect size, the probability that a ran-domly selected participant in one group, say FBThas an outcome clinically preferable to one from Discussionthe other group, say SFT, is 63.8%. Previous treatment studies of AN have focused on a number of problems, the most daunting of which isFinal Recruitment Results the difficulty in recruiting sufficient participants As shown in Table 4 and Figure 1, 564 potential although this difficulty appears less problematic inparticipants were contacted of which 216 were adolescents than adults.7,8,29,51,52 In a multisite trialinterviewed and 164 entered into the study in 29 enrolling a majority of adults it appeared that themonths (January 1, 2008 to May 31, 2010). Reasons pool of potential participants began to shrink afterfor exclusion are shown in Table 5. The most com- 2 years and was largely drained within 4 years.8 Inmon reason was not meeting the weight criteria for retrospect this is not surprising because the adultthe study (N 5 154) i.e. having a weight below 75% pool is refilled slowly as only those who have failedIBW or above 87% IBW. The next most common treatment in adolescence come into the pool.reason (N 5 101) was refusal to stop current treat- Many of these individuals are unwilling to seekment or refusal of family therapy. treatment. The adolescent pool on the other hand Forty-nine participants were entered during the is continually refilled with new cases and adoles-first year of recruitment and 115 after January 1, cents are essentially unable to refuse treatment.2009. As can be seen in Figure 1, the ratio of initial In the RIAN study the numbers entered variedcontacts to entries increased over the course of the between sites as did the entry rates and one sitestudy. However, the ratio of those assessed to those was discontinued because of a low entry rate. Thisentered changed much less, suggesting that over raises a difficult problem for future research.the course of the study a larger number of unsuit- Because AN has a relatively low incidence manyable potential participants were referred. This studies will have to rely on a multisite design. Forincreases the workload as recruitment progresses. this reason it will be necessary to identify sites inAs shown in Table 1, the ratios of entered partici- the US capable of recruiting sufficient participantspants to contacts ranged from 10% at Laureate the to engage in such trials. Our study makes it clearleast efficient, to 39% at Cornell the most efficient. that forecasting recruitment rates is difficult unlessOnly one site did not have an inpatient unit from there is prior experience in each of the sites with awhich the bulk of cases were recruited namely, similar trial. In the RIAN trial none of the originalUCSD. Hence, it took the most contacts (118) to sites (all but Stanford) had experience in recruitingenter 25 participants because this site relied on adolescents with AN to treatment studies althoughrecruitment from the community. However, Cornell some sites had experience recruiting adults withmaintained its efficient ratio despite the fact its AN. The original recruitment rate was set at 2 par-International Journal of Eating Disorders 45:2 202–213 2012 209
  9. 9. LOCK ET AL.TABLE 5. Reasons for exclusion from the study Cornell Stanford Washington University Laureate Sheppard-Pratt University Toronto UCSD University TotalIneligible by study protocol Does not meet weight criteria 16 10 29 16 19 39 25 154 Does not want to discontinue present treatment 14 3 0 2 2 4 8 33 Out of age range 5 2 0 2 5 7 2 23 On prohibited medications 2 2 9 1 3 2 1 20 Barriers (no insurance, transportation, language) 0 1 1 0 1 6 5 14 Medical or psychiatric exclusion 1 1 2 1 3 3 0 11 Previous family therapy 0 0 4 1 1 1 0 7 Not able to fulfill time requirements 0 0 2 2 0 2 0 6 Parents excluded 0 1 1 3 0 0 0 5 Other 0 2 0 0 1 2 0 5 Substance dependence 0 0 0 0 0 0 0 0Ineligible by subject/family decision Prefer other treatment /Refuse family therapy 11 2 15 19 6 12 3 68 Lost contact 0 1 10 2 3 5 1 22 Refuses medication 2 3 7 0 2 2 1 17 Out of area 0 0 1 2 3 10 1 17 Other 4 0 4 1 3 0 0 12 Did not show for interview 0 0 2 3 0 3 0 8 Refuses to participate in randomization process 0 0 1 1 1 2 0 5 Did not sign consent 0 0 0 1 0 1 0 2ticipants/month per site based on the experience support for their effectiveness.58–60 Treatment stud-of two sites in a previous multisite study.29,39 How- ies employing medications are likely to be ham-ever, the recruitment rate for the RIAN trial aver- pered by these limitations, as was the case in theaged 0.9/month per site with considerable variabil- RIAN trial, resulting in a major redesign of theity between sites. With medication the rate was study. A previous controlled study of olanzapineslower averaging 0.6/month per site. The rate for was abandoned because only 7 of 27 (ratio 5 0.26)adult AN trials will likely be considerably less. This eligible patients were enrolled due to fears con-raises the question whether future multisite studies cerning the medication and reluctance to considershould include more sites than appear to be medication as a treatment option.60 This rate isneeded in order to ensure successful recruitment. about one half of that achieved in the RIAN trialIn the RIAN trial it was fortuitous that another site (ratio 5 0.54). These figures suggest that it would(Stanford) with therapists trained in each modality have taken 6 years for the RIAN sites to recruit 240and with prior experience in recruitment of adoles- participants for a medication study. Hence, 12 sitescents with AN was available to replace the site with would have been needed to complete recruitmentrecruitment difficulties. in a reasonable time. Our experience highlights the A further problem noted in many AN studies is a need for researchers planning a study of this typelarge dropout rate,8,53 sometimes close to half the to consider clinical epidemiology and process toparticipants in adult trials.54 This raises the ques- avoid repeating mistakes from previous studies.tion at which level of dropout has the initial Although the participant safety issues were re-randomization been lost making the study impossi- solved for this trial, they form an important prece-ble to analyze.10,55–57 Moreover, it is possible that dent for other trials. Safety procedures for adoles-there will be an interaction between participant cent AN treatment studies should include the fol-characteristics and treatment type for dropouts. lowing. First, monitoring of physiologic variablesAgain, this problem appears less severe in adoles- should be done within the treatment sites allowingcents. However it is clearly important to put into results to be rapidly reviewed and decisions regard-place measures to ameliorate treatment and study ing hospitalization to be made by study personnel.dropout rates. Second, in this study we elected to continue brief Although studies of medications are potentially psychiatric interviews on a regular basis to monitorimportant, adults with AN often refuse them for vital signs, depression, and suicidality, even thoughfear of weight gain and other undesirable side medication had been discontinued. Regular pediat-effects.8,54 Parents of younger patients appear to be ric care continued outside the trial. Whether or notreluctant to experiment with the use of medica- to bring such pediatric care within the site is a diffi-tions at least without more specific preliminary cult decision to make. Obviously such a decision210 International Journal of Eating Disorders 45:2 202–213 2012
  10. 10. TREATMENTS FOR ADOLESCENT ANOREXIA NERVOSAwould increase trial costs. Most sites in the RIAN also led to the replacement of one site that was nottrial elected to use a small group of pediatricians. able to recruit at a sufficient rate. Again it took sev-These were pediatricians that were often affiliated eral months to detect this problem and to start-upwith the treatment site allowing for close commu- a new site. These experiences highlight the neednication between the pediatrician and the trial per- when designing such studies to address the possi-sonnel. This may be the ideal arrangement, but it bilities of such delays and anticipate that proce-would restrict studies to a relatively few compre- dural changes require careful review and takehensive treatment centers. Similar arrangements time.concerning physiologic monitoring and medical Although it is promising that NIH is providingsurveillance might be considered for treatment tri- much needed stimulus for the study of treatmentsals of adults with AN. The requirement regarding for AN the reality is that it is a difficult illness toadequate resources should hospitalization be study. Especially careful consideration of experi-needed also appears important because it allows ence in recruitment, retention, and experience withfor continuity of care as well as enhanced partici- treating participants with AN is warranted. In addi-pant safety. tion, dilemmas about competing philosophies of Although medical monitoring of adolescents treatment and competing treatment modalitieswith AN is crucial to providing safety in an outpa- should be addressed in assessing the feasibility of atient clinical trial, the lack of clear medical guid- particular setting. For both adults and childrenance on the necessary procedures may lead to with AN medication trials are particularly challeng-undue burden and discomfort for patients. For ing. To date, studies mostly document the failure ofexample, although guided by clinical knowledge, acceptability of this treatment modality, ratherthere was no research basis supporting the fre- than efficacy data.quency of tests decided on for this study, and thefrequencies chosen probably diverge from thepractice of many pediatricians providing medicalmonitoring for cases of adolescent AN. Should thefrequency of testing be the same for all participants Referencesor should the frequency vary depending on the 1. Hoek H, Hoeken DV. Review of prevalence and incidence ofclinical status of the participant? Some form of eating disorders. Int J Eat Disord 2003;34:383–396.algorithm governing the frequency of testing in 2. Sullivan PF. Mortality in anorexia nervosa. Am J Psychiatrylight of the patient’s progress toward recovery 1995;152:1073–1074.might be considered in future studies. Moreover, it 3. Crow S, Peterson C, Swanson S, Raymond N, Specker S, Eckert ED, et al. Increased mortality in bulimia nervosa dn other eat-is unclear which tests provide the most information ing disorders. Am J Psychiatry 2009;166:1342–1346.regarding the physiological stability of adolescents 4. Bulik CM, Berkman ND, Brownley KA, Sedway JA, Lohr KN. Ano-with AN.48 Further research on this, and other rexia nervosa: A systematic review of randomized clinical trials.aspects of medical safety is needed. Int J Eat Disord 2007;40:310–320. 5. Agras WS, Brandt H, Bulik CM, Dolan-Sewell R, Fairburn CG, The need to make changes in study design in Halmi CA, et al. Report of the National Institutes of Healthresponse to these challenges had significant im- Workshop on overcoming barriers to treatment research inpacts on study progress. As a result of delays and anorexia nervosa. Int J Eat Disord 2004;35:509– changes, recruitment began 6 months later 6. Robin A, Siegal P, Moye A, Gilroy M, Dennis A, Sikand A. Athan expected. This hiatus made it more difficult controlled comparison of family versus individual therapy for adolescents with anorexia nervosa. J Am Acad Child Adolescfor therapists to maintain mastery of treatments, Psychiatry 1999;38:1482–1489.disrupted assessment procedures, and delayed 7. Halmi CA. The perplexities of conducting randomized, double-data entry and protocol finalization. We utilized blind, placebo-controlled treatment trials in anorexia nervosathis time to provide therapists with extra training patients. Am J Psychiatry 2008;165:1227–1228.and supervision both at individual sites and across 8. Halmi CA, Agras WS, Crow SJ, Mitchell J, Wilson GT, Bryson S, et al. Predictors of treatment acceptance and completion insites. Nonetheless, each of the factors independ- anorexia nervosa: Implications for future study designs. Archently had the potential to cause major problems, Gen Psychiatry 2005;62:776–781.but taken together, they significantly challenged 9. Steinhausen H. Outcome of eating disorders. Child Adolescthe ability of the PIs to complete the study. Re- Psychiatr Clin North Am 2009;18:225–242.moval of the medication arms of the trial led to 10. Lock J, Couturier J, Bryson S, Agras WS. Predictors of dropout and remission in family therapy for adolescent anorexia nerv-faster recruitment, however by the time the deci- osa in a randomized clinical trial. Int J Eat Disord 2006;39:639–sion was made, agreed on by the DSMB, and the design approved by each site-based IRB, more 11. Eisler I, Dare C, Hodes M, Russell G, Dodge E, Le Grange D. Fam-recruitment time was lost. Recruitment difficulties ily therapy for adolescent anorexia nervosa: The results of aInternational Journal of Eating Disorders 45:2 202–213 2012 211
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