The specific aims of CAMS were:
Aim 1. To compare the relative efficacy of each active treatment (COMB, SRT, CBT) against PBO in reducing anxiety symptoms and associated disability over 12 weeks of acute treatment.
Aim 2. To compare the relative efficacy of each monotherapy (SRT, CBT) against COMB in reducing anxiety symptoms and associated disability over 12 weeks of acute treatment.
Aim 3. To identify predictors, moderators, and potential mediators of acute response to treatment.
Aim 4. To identify differences in rate of response, dropout, premature termination, safety and adverse events, and consumer satisfaction.
Aim 5. To explore the impact of COMB, SRT, and CBT over a 6-month open follow-up period on functioning, relapse and recurrence rates, and utilization of other treatments.
Each of the above aims was addressed through a two-phase clinical trial. Phase I involved a 12-week randomized controlled trial comparing CBT, SRT, COMB, against pill PBO. Phase II was a 6-month treatment maintenance period, in which Phase I treatment responders were seen by their Phase I clinician(s) monthly. Participants assigned to CBT received monthly booster sessions, while those assigned to SRT received monthly medication monitoring visits. Phase I non-responders to active treatments were referred to community providers. However, Phase I PBO non-responders were provided their choice of an active CAMS treatment at the end of Phase I or at any time during Phase I if their symptoms worsened. In as much as possible (e.g., with the exception of study dropouts), all subjects were evaluated at scheduled assessment points (Weeks 0, 4, 8, 12, 24, and 36) regardless of initial treatment response or participation in Phase II CAMS booster sessions or non-CAMS treatments. In addition to parent, child, and clinician questionnaires that evaluated changes across a wide variety of domains, primary outcomes were assessed by blind independent evaluators (IEs).
A schematic representation of the study is presented in Figure . The six performance sites involved in the trial were: New York State Psychiatric Institute; Duke University Medical Center; Johns Hopkins Medical Institutions; Temple University; University of California at Los Angeles; and Western Psychiatric Institute and Clinic. A multi-layered administrative structure with representation from all sites facilitated cross-site coordination and quality assurance. The CAMS Executive Committee (EC) was comprised of a chair (Dr. John Walkup), co-chair (Dr. Anne Marie Albano), executive secretary (Dr. Scott Compton), lead study coordinator (Dr. Courtney Keeton), and representation from NIMH (Dr. Joel Sherrill). The EC met weekly via teleconference calls and was responsible for overseeing the successful and consistent implementation of the study protocol across all performance sites.
Child/Adolescent Anxiety Multimodal Study (CAMS) Experimental Design.
Another essential governing committee, the CAMS Steering Committee (SC), was comprised of principle investigators, co-investigators, and study coordinators from each site. The SC met weekly via teleconference calls to review recruitment progress at each site, discuss and clarify questions sites might have regarding the implementation of the protocol, address clinical concerns with study participants, and report and discuss adverse events and protocol deviations (if any). Subcommittees for each treatment modality were also created. The CBT and PT (pharmacotherapy) committees were comprised of CAMS treatment clinicians, and met separately via teleconference calls to provide cross-site supervision and present and discuss clinical cases on a rotating basis. The CBT committee held weekly conference calls, while the PT committee held bi-weekly conference calls. The difference in the frequency of the calls between the committees was due to differences in the frequency of treatment visits. Participants assigned to CBT met weekly with their therapist, while participants assigned to PT met bi-weekly, with the exception of the first four treatment visits, which were weekly. The IEs also met bi-weekly via teleconference calls for cross-site supervision. The goal of these meetings was to ensure that the assessments were administered similarly across the 6 performance sites. Each performance site also had cross-site responsibilities. Trial wide study coordination was the responsibility of study staff at Johns Hopkins Medical Institutions. CBT, PT, and IE quality assurance was the responsibility of study staff at Temple University, University of California at Los Angeles, and New York State Psychiatric Institute, respectively. Western Psychiatric Institute and Clinic (first three years) and Duke University Medical Center (last three years) served as the data centers (Note: the data center was moved to Duke University Medical Center because of unplanned personnel changes at the original site). A schematic representation of the organizational structure of CAMS and list of performance sites is presented in Figure .
Child/Adolescent Multimodal Study (CAMS) Organizational Structure and Performance Sites.
Randomization and Enrollment
To maintain reasonably good balance among the four treatment groups, participants were randomized using a stratified block randomization procedure. Factors utilized in this procedure were treatment site, age, and gender.
Subjects were enrolled using a multiple gating procedure in which parents/guardians of prospective participants first completed an initial telephone screen (Gate A). Following the phone screen, those families who met basic eligibility criteria were then invited to the site's clinic. At the clinic, informed consent and assent were obtained and then the IEs conducted a structured diagnostic interview (Gate B; note: the same IE conducted all future assessments). If the child or adolescent met all inclusion criteria, and no exclusion criteria, a baseline assessment and randomization visit was scheduled a week later (Gate C1 and C2). Immediately following the baseline assessment (Gate C1), the family met with the Principle Investigator (or his/her designate) to answer any remaining questions the family might have about the study. A secondary, yet important, purpose of this meeting was to make certain the family understood how participation in a clinical trial differed from standard clinical care (e.g., treatment followed a standardized research protocol with appropriate clinical safeguards) and to ensure the family was willing to accept randomization to a treatment condition (even if the family had a preference for a particular treatment). Upon completion of this informal re-consenting procedure, participant's randomization was revealed. The first treatment visit typically followed immediately after Gate C2. The expected average time from Gate A to Gate C2 (randomization) was 2-3 weeks, with a range of 2 (minimum) to 6 (maximum) weeks.
Participants completed their 12-week assessment (end of acute treatment) by day 84 (± 5 days). At the end of Phase I, participants in the medication-only treatment conditions (either SRT or PBO) were unblinded; however, the IE remained blinded to treatment status throughout the entire trial. Based upon the IE evaluation of clinical response at the week 12 assessment, responders (defined as CGI-I ≤ 2) entered Phase II. Non-responders (CGI-I > 2) to any of the active treatments were referred to the community for treatment or follow-up care. PBO non-responders (CGI-I > 2) met with their clinician and were offered their choice of a CAMS treatment (e.g., CBT, SRT, or COMB) for an additional 12 weeks. This treatment was provided during Phase II by CAMS study clinicians. PBO responders entered Phase II and continued to meet monthly with their clinician. If at any time during Phase II, PBO responders relapsed, they received the same option of their choice of a CAMS treatment for an additional 12 weeks.
During Phase II, those participants receiving medication (e.g., participants in COMB or SRT) remained at their Week 12 dose of mediation. Downward medication adjustments were allowed in response to emergent side effects. Participants who required a medication dose increase during Phase II were prematurely terminated from the study and continued with the assigned assessments. Participants categorized as CBT responders met with their clinician for monthly 50-minute maintenance CBT sessions. During these sessions no new material was introduced, but the CBT therapist was permitted to revisit the stimulus hierarchy, and reinforce the necessity of exposure activities to promote maintenance and generalization. Responders in the COMB group received both continued stable medication as well as monthly CBT maintenance visits. At the end of Phase II all subjects met with his/her clinician(s) and were given end-of-treatment recommendations and, if necessary, referrals for continued clinical care.
As a group, the CAMS investigators had substantial experience with multicenter comparative treatment trials and carefully considered several different treatment designs before deciding upon the final design for CAMS. At the time CAMS was developed, there were realistically three design choices that would allow for a comparison of the two monotherapies and their combination. First, a 1 × 4 parallel groups design (CBT vs. SRT vs. SRT+CBT vs. PBO). This design had been used successfully in several previously funded NIMH trials (e.g., MTA,[39
] and POTS[27
]) and had established a precedent for large multicenter comparative treatment trials. Second, a 1 × 5 parallel groups design (CBT vs. SRT vs. SRT+CBT vs. PBO+CBT vs. PBO) that added a balanced pill PBO+CBT condition, for which there was little precedent in the research literature. This design was carefully considered due to concerns about the lack of a PBO+CBT control condition in the first design option. And third, a fully 2 × 2 factorial design (Factor One: CBT vs. Sham CBT; Factor Two: Active Medication vs. Pill PBO). After thorough consideration of the scientific merits and feasibility of implementation of each of these designs, CAMS investigators chose the unbalanced 1 × 4 parallel groups design with pill PBO as the control condition as the best option. The pill PBO condition was deemed necessary to protect against a failed trial and to control for the effect of positive engagement on the part of clinicians and treatment expectancies on the part of participants and parents.
The 1 × 5 parallel groups design was a serious contender but ultimately rejected due to cost and the inherent difficulty of creating a credible and inert sham psychosocial treatment condition [31
]. The addition of a PBO+CBT treatment arm would have increased the total cost of the trial by approximately 4 million US dollars. For example, to be able to detect a between group difference of at least 10% between the active treatments would require an increase in sample size from approximately 140 to approximately 290 participants per active treatment group. Thus, the total sample size required to complete the trial would have increased from 480 to 1015 participants, again cost prohibitive. A fully factorial design, although scientifically attractive, was rejected as it was deemed better suited for a true efficacy study given that one of the treatment arms would have been the pill PBO and shame psychosocial treatment. Ultimately, despite its known limitations, [42
] CAMS followed in the footsteps of other large pediatric comparative treatment trials and chose an unbalanced 1 × 4 parallel groups design because it represented the best compromise between ecological validity, feasibility of implementation, scientific rigor, and cost.
Other alternative designs choices were also considered for the follow-up maintenance period (Phase II) of the CAMS trial, but ultimately rejected due to feasibility, cost (e.g., re-randomizing Phase I non-responders to new treatments), and ethical considerations (e.g., continuing PBO throughout phase II).
Decision to Focus on Three Anxiety Disorders
The decision to target children and adolescents with DSM-IV-TR SAD, GAD, or SoP was made for both pragmatic and theoretical reasons. From a pragmatic perspective, there was a strong historical precedent to study these three disorders in the same trial [10
]. SAD, GAD, and SoP share a similar response to CBT and SSRI treatments, exhibit strong associations with each other (comorbidity), and as a group, have historically been considered distinct from other childhood-onset DSM-IV anxiety disorders (e.g., OCD or PTSD).
Primary Outcome Measures
CAMS had two primary outcome measures, one categorical and one continuous: (1) responder status (i.e., "responder" or "non-responder") based on the 7-point Clinical Global Impression-Improvement Scale [16
]. (CGI-I) score of 1 ("very much improved") or 2 ("much improved"); and (2) the total score on the Pediatric Anxiety Rating Scale (PARS) [17
]. Scores on both outcome measures were based on an interview with the child and parent(s) by the IE. The child and parent(s) were interviewed together as is standard practice for the PARS (Note: whenever possible, ADIS assessments were conducted separately). IEs were trained to handle questions of adolescent confidentiality and parent-child conflict that arose at times during joint interviewing.
The inability to fully mask the CBT and COMB conditions in other pediatric comparative clinical trials has been criticized because of the potential for differential expectancy effects and differences in time and attention provided by clinicians [42
]. From a pure efficacy perspective these criticisms are valid. However, in CAMS the goal was ecological validity with an emphasis on effectiveness in as much was feasible. Moreover, masking of the primary outcome variables was maintained by the use of independent evaluators who were blind to treatment status. Thus, the use of blind IEs removed rater expectancy as a source of potential bias in outcomes.
Efforts to ensure that IEs maintained blindness were multifaceted. First, on-site supervision for IEs was held separate from any meetings with treatment clinicians. For example, during each site's weekly research meeting, IEs were excused from the meeting when the focus of the meeting shifted to discussing clinical information about study participants. Second, IE offices were required to be in a location separate from the offices of clinicians and other study staff (e.g., in a different area or floor of the building). Third, all study staff were trained to assist in maintaining the blind and participants were repeatedly reminded to refrain from discussing or mentioning their study treatment. Fourth, given the significant experience CAMS investigators had with prior clinical trials, rigor in maintaining the blind was as good or better than previous multisite trials, although as with any clinical trial there was the occasional error. To assess the impact that unblinding may have had on outcomes, IEs were asked to complete a questionnaire following the week 12 assessment which asked them to guess which treatment the participant received and indicate their degree of confidence in this rating. Given the rigorous efforts to maintain the blind, the frequency of incidents that led to breaking the blind (e.g., seeing the participant with a therapist) was minimal.
Participants were encouraged to complete all scheduled assessments and were compensated for time and travel consistent with local IRB guidelines. Participants who withdrew from treatment at any point during Phase I or Phase II were asked if they would be willing to complete all future assessments, and if so, they were classified as "treatment drops." Participants whose clinical picture worsened or developed a clinical crisis that lead the site clinical team to recommend an out of protocol treatment(s) were classified as "prematurely terminated." Prematurely terminated participants continued treatment within their assigned treatment arm (in so far as clinically possible), as well as all regularly scheduled assessments. Participants who terminated prematurely were distinguished from "study drops" who were participants who refused study treatment and assessments. Stated differently, study drops were defined as those participants who withdrew consent for continued participation in the study.
Sample Size and Power Estimates
The primary measure used for sample size estimation was the IE's rating of Phase I treatment response. Using chi-square, power estimates for detecting differences in treatment response among the four treatment conditions were computed using the following assumptions: (1) Ha: P(SRT) = 0.60, P(CBT) = 0.60, P(COMB) = 0.80, and P(PBO) = 0.30; (2) sample sizes of 136 for each active treatment condition and 70 for the PBO condition; (3) no adjustment for multiple comparisons; (4) power set at 80%; and (5) alpha = 0.05, two-tailed test. Given these assumptions, power analysis revealed that CAMS was sufficiently powered to detect a 0.19 difference in Phase I response rates between PBO and each active treatment condition and a 0.17 difference in Phase I response rates between COMB and each active monotherapy condition.
Sampling Frame and Participant Recruitment
CAMS recruited a volunteer sample of children and adolescents between the ages of 7 and 17 years. Inclusion and exclusion criteria are presented in Tables and . A complete description of the clinical characteristics of the sample can be found in Kendall and colleagues [43
With the exceptions noted below and in Table , CAMS investigators sought to enroll a sample of anxious youth representative of the full range of ethnic/minority backgrounds and as similar as possible to those seen in general clinical/hospital practice and community clinical settings. Youth with a co-primary diagnosis (defined as an ADIS CSR equal to that of at least one of the target disorders) for which a different disorder-specific treatment was indicated were not included (i.e., substance abuse disorder, eating disorder). However, to enhance the generalizability of the results, youth with an Axis I disorder(s) with an ADIS CSR less than that of one of the target disorders, with the exception of those disorders listed in Table , were included to ensure a broadly representative sample of anxious youth. Given that children with major depressive disorder (MDD) respond to SSRIs and that standard CBT for anxiety disorders does not specifically target symptoms of depression, participants who met DSM-IV criteria for MDD (at any ADIS CSR level) were excluded. This decision was made to ensure a sample whose outcomes could be most clearly interpreted as related to the anxiety disorders of interest.
Using similar procedures, sites recruited participants from mental health pediatric and primary care clinics, community mental health centers, schools, churches, community organizations, and paid and unpaid advertisements in all forms of local media. Special outreach efforts dedicated to enhance minority enrollment were made. These outreach efforts were planned and implemented at each site in consultation with local academic experts and minority community leaders, including educators and clergy. Specific outreach activities included educational talks to schools, churches, and other community groups in minority neighborhoods, articles and paid advertisements in minority-targeted press and media, and direct mail.
English-fluency was a requirement for child enrollment in CAMS, and parents were required to speak sufficient English to provide informed consent for study participation and completion of study treatment and assessment requirements. However, CAMS sites in areas with high percentage of Spanish-speaking families employed bilingual screeners and clinical staff in order to increase the comfort level of bilingual parents and enhance recruitment and retention of these families. In addition, efforts were made at all sites to employ clinical and research staff representative of the ethnic/minority makeup of the local population.
Although, the racial/ethnic diversity of the CAMS sample (21%) is comparable with other published child anxiety treatment studies,[18
] the recruitment of ethnic minority populations into clinical trials remains one of the most significant challenges common to all studies. Establishing effective relationships with the leadership of minority organizations that serve ethnic minority communities can facilitate minority recruitment efforts [45
]. Anecdotally, with respect to ethnic minority recruitment efforts in CAMS, challenges faced by investigators were primarily logistical barriers. Most minority participants, for example, had to travel a great distance to participate in the trial. Study reimbursement (paying) for transportation did not seem to enhance enrollment and retention for these participants, suggesting that time was the primary barrier. For future studies, one potential solution to minimize this problem would be to set-up satellite treatment and assessment clinics within local minority communities. Although this solution would likely lead to higher rates of minority participation, it would likely be costly. Further attention to these and other strategies that would enhance minority and ethnic enrollment and engagement is warranted, not only to ensure that research samples are diverse and generalizable, but also because these same barriers that impact study participation likely impact the access and utilization of clinical care in these communities.
CAMS treatments reflected current state-of-the-art interventions. Although study protocols established the timing and content of each intervention, treating clinicians were able to work collaboratively with participants and their families to maximize adherence and benefit, and minimize adverse events.
The CAMS medication management strategy was designed to maximize treatment adherence and study participation, enhance and maintain the doctor-patient relationship, instill hope for improvement, and acquire data necessary for medical decision-making without implementing CBT. Medication visits lasted approximately 30 minutes (with the exception of the first which lasted approximately 60 minutes) and were devoted to a review of the participant's symptomatology, overall functioning, response to treatment, and presence of adverse events, all in a context of supportive clinical care.
Pharmacotherapy (PT) visits were scheduled at weeks 1-4, 6, 8, 10, 12 during Phase I. Interim phone visits were scheduled at weeks 5, 7, 9, and 11. Monthly maintenance visits for treatment responders occurred during the six-month follow-up period of Phase II. Consistent with good medical practice, every effort was made to use the most effective and tolerated dose of SRT. Medication was administered daily using a "fixed-flexible" dosing strategy that was linked to the PT therapist-assigned, 7-point CGI-Severity score and the ascertainment of clinically significant side effects. In general, participant's medication dose was adjusted upward in 50 mg/day increments if the clinician-rated anxiety severity on the CGI-S was 3 (mild) or greater. The dose was held, or adjusted downward, if the participant had few anxiety symptoms (CGI-S of 1 or 2) or if there were impairing side effects.
Cognitive Behavioral Therapy
CAMS adapted the evidence-based "Coping Cat" CBT protocol [25
]. Guidelines assisted the therapist in adapting the manual flexibly and in a standardized manner for a client's age and developmental level. "The C.A.T. Project,[47
] a version of the Coping Cat modified for use with adolescent participants, allowed therapists to provide developmentally appropriate CBT across the full age range of the study. Across both child and adolescent CBT protocols, the number of session was reduced from 16-20 60-minute treatment sessions (in the original protocols) to 14. Twelve of these sessions were individual child/adolescent sessions and 2 were parent sessions, which were scheduled immediately after the child session at weeks 3 and 5. CBT responders received monthly CBT maintenance sessions during the six-month follow-up period of Phase II.
The first six CBT sessions taught new skills to the child/adolescent (e.g., the FEAR plan), whereas the second six sessions provide opportunities to practice newly learned skills (exposure tasks) within and outside of the sessions. The overall goal of CBT was to teach youth to recognize the signs of unwanted anxiety, let these signs serve as cues for the use of more effective anxiety management strategies, and face rather than avoid anxiety provoking situations.
Participants in the combination treatment condition (COMB) received all the components from the medication-only and CBT-only treatment conditions, with the exception that the participant, parent(s), and clinician were aware that the child/adolescent was receiving active SRT and active CBT. Pharmacotherapy and CBT visits typically took place on the same day, with the participant seeing the PT therapist first. Clinicians were encouraged to discuss the clinical status of each COMB patient to allow for treatment integration. For example, the PT therapist could increase the dose of SRT (or not), depending on whether the participant was making sufficient progress in CBT. With the exception of one site, COMB treatment visits were held at the same location.
Patient Safety and Adjunctive Services to Prevent Study Attrition
Participant safety was a foremost consideration, and from a public health point of view, the ascertainment of adverse events in each treatment condition was a critical aspect of the trial. Primary concerns included possible untoward reactions to study treatments and the risk that the participant may not improve or may deteriorate during treatment. CAMS protocols for monitoring safety and providing additional treatment visits to manage clinical crises and concerns that inevitably arise during the course of a trial facilitated standardized, yet flexible, clinically appropriate "best practice" standards and maximized participant retention.
Side effects and adverse events were assessed immediately before each treatment visit by the study coordinator by asking both the child and parent if they had experienced or noticed any health or other problems since the last treatment visit. Responses were recorded and then provided to the treating clinician who reviewed the list with the child and parent to determine its severity, association with study treatments, and actions to be taken by the study team. This 2-stage strategy was used to ensure standardized ascertainment of adverse events across the four treatment conditions.
In response to FDA black box warning regarding the risk for suicidality events associated with SSRIs,[38
] and in consultation with NIMH and the CAMS Data Safety and Monitoring Board, a harm to self and others questionnaire was developed and implemented. The participant's treating clinician administered this form at each treatment session to document the onset or change in harm-related ideation or behavior.
To ensure cross-site uniformity in the management of clinically emergent situations, CAMS followed procedures implemented in other pediatric comparative trials [39
]. Up to 2 additional treatment sessions ("ASAP sessions") were permitted per participant in both Phase I and II to manage any newly emergent clinical needs and facilitate participant retention. Participants whose clinical needs required more than two ASAP sessions per study Phase were "prematurely terminated" by the site team and referred for additional treatment outside the study.
The CAMS assessment battery evaluated the impact of treatment on the presence and degree of anxiety symptomatology, associated comorbid symptoms, and psychosocial functioning across multiple functional domains. Additional assessments included a wide range of demographic variables, comorbid symptomatology, parental psychopathology, family functioning and environment, treatment adherence, cognitive self-talk, and treatment-related expectancies and beliefs. Finally, measures were included for quality assurance purposes and to assess the adequacy of the blind. A summary of primary and secondary assessment measures, and the domains measured, are provided in Table .
Primary and Main Secondary Assessment Measures
CAMS participants completed three "full" IE assessment sessions: baseline, week 12, and week 36; and three "partial" IE assessment sessions: weeks 4, 8, and 24. Participants were reimbursed for time and expense involved in completing the assessments in accordance with local IRB regulations.
All study personnel passed their local institutions' required certifications for the ethical conduct of research and HIPAA training. Candidates wishing to be study clinicians (i.e., CBT therapists, PT therapists) and independent evaluators (i.e., IEs) underwent a rigorous certification process which included: (1) a review of credentials (MA or PhD for CBT therapists; MD or NP for PT therapists; and MA, RN, PhD, or MD for IEs) and clinical experience treating anxious youth; (2) reading study related materials; (3) passing a test on the treatment and study protocols (passing was defined as a score of 80% or greater); (4) completing a training workshop; and (5) passing a videotape or audiotape review of a training case(s) for evaluation of fidelity and competence by the QA reviewers (i.e., as noted earlier, Temple University conducted QA for CBT sessions, UCLA for PT sessions, and NYSPI for IE assessments). After certification, CBT, PT, and IE staff received onsite supervision by a study supervisor and ongoing cross-site supervision during separate and independent one-hour conference calls. CBT therapists had weekly onsite and cross-site supervision, IEs had weekly onsite supervision and every other week cross-site supervision, and PT therapists had monthly onsite supervision and every other week cross-site supervision. In addition to the supervision provided onsite and cross-site via conference call, there was an initial in person start-up training workshop (3 days for CBT and IEs) followed by annual in-person recalibration and training sessions for all study staff throughout the 6-years of the trial. These procedures allowed the investigative team to correct any drift and address the management of clinical issues and situations in a similar fashion that could potentially impact the integrity of the trial while facilitating a collaborative study culture across sites.
Design Weaknesses and Challenges
The primary weakness of the CAMS design, and other clinical trials similar to CAMS (e.g., MTA, TADS, and POTS), is that the CBT and COMB participants were not blinded. The only double-blinded treatment conditions were SRT and PBO. CBT participants knew they were receiving CBT and COMB participants knew they were receiving both CBT and SRT. This leaves results from the CAMS trial open to the criticism that participant and family expectancy effects may potentially bias outcomes. However, as argued in other similar comparative treatment trials,[48
] the decision not to blind certain treatment conditions are design choices rather than necessarily design flaws. In the case of CAMS, the design chosen represented the best balance between scientific rigor, potential for public health impact, ecological validity, feasibility of implementation, and cost. Moreover, CAMS investigators recognized this limitation in the design chosen and took deliberate steps to minimize threats to the internal validity of the trial by using IEs who were blind to participant's treatment assignment to measure outcomes.
The CAMS study experienced challenges, as well as successes, when it came to monitoring adverse events. The CAMS Data Safety Monitoring Board (DSMB) initially approved an adverse event monitoring policy based on procedures that were used in the TADS study [40
]. This policy consisted of only recording adverse events that caused moderate to severe distress or resulted in functional impairment. The implication of the policy was that mild adverse events that did not result in functional impairment were not recorded. However, several months into the trial the DSMB reversed its decision and mandated the collection and reporting of all adverse events, including mild events. Further complicating adverse event collection procedures, several years into the study the DSMB required CAMS clinicians to systematically query and collect information about the presence of any harm related adverse events from all study participants and parents at each study visit (i.e., non-suicidal self-harm, suicidal ideation, homicidal ideation, suicidal behavior, and homicidal behavior). Although moderate and severe adverse event data were systematically collected throughout the entire trial, the shifting methods used to elicit and record adverse events complicates the conclusions that can be made about the presence or absence of adverse events throughout the entire trial for all subjects.
Despite this limitation, CAMS utilized an adverse event procedure that was very effective. In response to the finding in the TADS study that CBT therapists did not monitor adverse events as closely as did the PT therapists, a different procedure was implemented in CAMS for eliciting adverse events than is typically used in clinical trials. In most clinical trials, clinicians (whether a psychologist or psychiatrist) asks the participant or parent(s) if they noticed any changes since their last treatment visit. However, to avoid the problem found in TADS, the elicitation of adverse events was assessed immediately before each treatment visit by the site project coordinator across all treatment conditions. This ensured that the elicitation of adverse events did not vary by treatment condition. This novel adverse event monitoring procedure was effective in standardizing the elicitation of adverse events across different treatment conditions and will allow for comparisons of relative safety across the four treatment conditions.