National Drug Abuse Treatment Clinical Trials Network National Drug Abuse Treatment Clinical Trials Network A Randomized Controlled Trial of OROS-MPH + CBT in Adolescents with ADHD and Substance Use Disorders Robert Davies, M.D. Associate Professor, Psychiatry University of Colorado Denver School of Medicine A Randomized Controlled Trial of OROS-MPH + CBT in Adolescents with ADHD and Substance Use Disorders Robert Davies, M.D. Associate Professor, Psychiatry University of Colorado Denver School of Medicine NATIONAL INSTITUTE ON DRUG ABUSE NID A A

Financial Disclosures Active medication and placebo provided by McNeil PharmaceuticalsActive medication and placebo provided by McNeil Pharmaceuticals Dr. Davies previously participated on Speaker’s Bureaus for Eli Lilly, PfizerDr. Davies previously participated on Speaker’s Bureaus for Eli Lilly, Pfizer

Background & Significance ADHD 3-5x more common in adolescents with SUD (30-50%) compared to those without SUD (7-10%) and is associated with poorer treatment outcomesADHD 3-5x more common in adolescents with SUD (30-50%) compared to those without SUD (7-10%) and is associated with poorer treatment outcomes The safety and efficacy of psychostimulant medication for ADHD in youths without SUD is well-established, but research is lacking in substance abusing adolescents with ADHDThe safety and efficacy of psychostimulant medication for ADHD in youths without SUD is well-established, but research is lacking in substance abusing adolescents with ADHD

Study Aims Aim 1: To evaluate the efficacy of OROS-MPH vs. placebo in treating ADHD is substance- abusing adolescents Aim 2: To evaluate the impact of OROS-MPH + CBT vs. placebo + CBT on substance treatment outcomes Aim 3: To evaluate the tolerability, safety, and abuse potential of OROS-MPH in substance- abusing adolescents with ADHD

Study Design 16-week multisite, randomized controlled trial OROS-MPH + CBT vs. placebo + CBT  Eleven participating sites  N=303  Intent-to-Treat (ITT) analysis  Target dose = 72 mg/day (titrated over first study month) (titrated over first study month) Cognitive Behavioral Therapy  Weekly, Individual – focused on Substance Abuse  Manualized - Attempt to standardized outpatient substance treatment across participating sites

Inclusion/Exclusion Criteria Inclusion  Adolescents years  DSM-IV ADHD (per K-SADS)  Non-nicotine SUD, use within past month  DSM-IV ADHD Checklist score ≥ 22  Medically healthy Exclusion  Serious medical or cardiac illness, tic disorder, or pregnancy  Bipolar, psychosis, suicide risk  Opiate dependence  Methamphetamine abuse or dependence  Psychotropic medication; other MH/SUD treatment

Baseline Characteristics

Demographics OROS-MPHPlacebo Age Gender Male 81% Female 19% Male 77% Female 23% Percent Court Mandated 23%26% Race Caucasian64%59% African American21%25% Other15%16% Ethnicity Hispanic15% * No statistically significant differences

Baseline Clinical Characteristics OROS-MPHPlacebo DSM IV ADHD symptom checklist score (adolescent) 38.1 (9.0)39.3 (8.7) Number of Abuse and Dependence Diagnoses 2.1 (1.2)1.9 (1.3) Number of Days Used Drugs (out of past 28) 14.0 (9.6)15.1 (9.4) * No statistically significant differences

Baseline Clinical Characteristics - ADHD Subtype 28.1% 68.6% 2.6% 0.7%

Baseline DSM-IV Substance Use Disorders (CIDI-SAM)

Study Findings

151 Assigned to Receive OROS-MPH + CBT 147 Excluded (32.7%) 139 Not eligible (94.6%) 8 Other (5.4%) 1334 Individuals Screened by Telephone 151 Included in Analysis 118 Completed Trial (78.1%) 33 Non-Completers (21.9%) 11 Withdrew Consent 3 Moved from Area 2 Practical Problems 4 Incarceration 1 Pressure/Advice from Outsiders 9 Failed to Return to Clinic and Lost 3 Other 109 Completed Trial (71.7%) 43 Non-Completers (28.3%) 11 Withdrew Consent 1 Moved from Area 3 Practical Problems 5 Incarceration 1 Pressure/Advice from Outsiders 17 Failed to Return to Clinic and Lost 1 Feels Treatment not Working 4 Other 303 Participants Randomized 152 Included in Analysis 152 Assigned to Receive Placebo + CBT 450 Assessed for Eligibility and Consented

Medication Tolerability 96% achieved 72 mg daily dose 86% sustained 72 mg dose across study Permanent dose reductions OROS-MPH 16/149 (10.7%) Placebo 10/148 (6.8%) Last dose prescribed OROS-MPH Mean dose = mg Placebo Group Mean dose = mg 80% compliance with prescribed medication

ADHD Outcomes

Adolescent DSM-IV ADHD Checklist by Treatment Group Estimates are derived from the cubic longitudinal model with random subject and linear time effects and serially-correlated residual errors. Clinically and statistically significant decrease in ADHD symptoms in both groups - OROS-MPH (50%; -19.2, p<0.001) - Placebo (54%; -21.2, p<0.001) No difference between groups

Secondary ADHD Outcome Measures Problem Solving (ARCQ) Focused Coping Skills (ARCQ) Parent DSM-IV ADHD Checklist 8 weeks Parent DSM-IV ADHD Checklist 16 weeks p = 0.002p = p = 0.02 p < 0.001

Substance Use Outcomes

Past 28 Day Non-nicotine Substance Use Placebo= days; 34% p<0.001 OROS MPH= days; 41%; p<0.001 Clinically and statistically significant reduction in past 28 day drug use in both groups No difference between groups

Secondary Substance Use Outcomes Negative Urine Drug Screen OROS-MPH = 3.8 Placebo = 2.8 > 75% Reduction Days Drugs Used OROS-MPH = 41.2% Placebo = 29.9% p < 0.05 p = 0.08

ADHD Responders vs. Non-responders (CGI-I) Negative Urine Drug Screens Responders = 5 (median) Non-responders = 1 (median) Mean difference = 2 (p < 0.001) Days of Abstinence Responders = 94 (median) Non-responders = 77 (median) Mean difference = 15 (p < 0.001)

Safety, Tolerability and Abuse Potential

Adverse Events by Treatment Group Adverse EffectOROS-MPH Placebop - value Statistical Significance Excoriation14/151 (9.3%) > 4/152 (2.6%)0.016 Nervousness12/151 (7.9%) > 3/152 (2.0%)0.018 Heart Rate Increased8/151 (5.3%) > 1/152 (0.7%)0.019 Heart rate = > 10019/149 (12.8%) > 8/148 (5.4%)0.028 Decreased Appetite25/151 (16.6%) > 9/152 (5.9%)0.003 Statistical Trend Abdominal Discomfort8/151 (5.3%) > 2/152 (1.3%)0.061 Migraine Headaches4/151 (2.6% ) > 0/152 (0.0%)0.06 Anorexia6/151 (4.0%) > 1/152 (0.7%)0.067 Mood Altered4/151 (2.6%) > 0/152 (0.0%)0.06 Road Traffic Accidents4/151 (2.6%) > 0/152 (0.0%)0.06 Limb Injury1/151 (0.7%) < 7/152 (4.6%)0.067 Systolic BP = > 14027/149 (18.1%) > 16/148 (14.5%)0.073

Serious Adverse Events by Treatment Group OROS-MPH 1 study-related SAE (psychosis) Placebo 3 study-related SAEs

MGH Abuse/Diversion Questionnaire ItemOROS (% Yes) Placebo (% Yes) Significance Do you remember to take medication p = 0.143; NS Do you think it helps p <.0001 Ever sold you medication to others2.11.4p = 1.000; NS Ever let others take your medication3.51.4p = 0.447; NS Ever taken more than supposed to4.22.8p = 0.749; NS Ever got high on medication4.97.1p = 0.444; NS Ever taken med other than how prescribed2.10.7p = 0.622; NS Ever not taken so that you could use drugs/alcohol p = 0.418; NS Ever used drugs/alcohol on days took med p = 0.385; NS Ever had a reaction to drugs/alcohol while taking medication p = 1.000; NS

MGH Abuse/Diversion Questionnaire ItemOROS (% Yes) Placebo (% Yes) Significance Do you remember to take medication p = 0.143; NS Do you think it helps p <.0001 Ever sold you medication to others2.11.4p = 1.000; NS Ever let others take your medication3.51.4p = 0.447; NS Ever taken more than supposed to4.22.8p = 0.749; NS Ever got high on medication4.97.1p = 0.444; NS Ever taken med other than how prescribed2.10.7p = 0.622; NS Ever not taken so that you could use drugs/alcohol p = 0.418; NS Ever used drugs/alcohol on days took med p = 0.385; NS Ever had a reaction to drugs/alcohol while taking medication p = 1.000; NS

MGH Liking Scale Item (Scoring Range 1 = not at all; 10 = very much) OROSPlaceboSignificance* Medication effective6.04.5p<.001 Like how it makes you feel4.94.4p = 0.058; NS How high/euphoric do you get2.72.1p = 0.101; NS How depressed/down do you get2.42.0p = Do you ever crave medication1.31.4p = 0.673; NS Crave other drugs when on med2.42.5p = 0.835; NS How physically active do you feel5.34.9p = *non-parametric tests

Summary of Main Study Findings 1.ADHD outcomes as good or better than in adolescents without SUD 2.OROS-MPH safe, well-tolerated 3.Results suggest contribution of CBT to both SUD and ADHD outcomes 4.Substance outcomes as good or better than in youth with less severe psychopathology 5.Treatment compliance, completion superior to that reported in studies of youths with less severe SUD and psychopathology

Interpretation of Results in Context of Previous Research Results are inconsistent With most controlled trials of psychostimulant vs placebo (alone) for ADHD Results are consistent With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) With growing literature that cognitive behavioral and behavioral interventions effective for ADHD in adults and youth without SUD (Safren et al, 2005; Fabiano et al, 2009; Solanto et al, 2010)

If replicated, results have important clinical implications Results suggest that clinically significant reductions in co- occurring ADHD symptoms may be important in helping adolescents achieve greater abstinence during substance treatment. In the context of individual CBT (for SUD), significant reductions in ADHD symptoms may occur with or without pharmacotherapy. If ADHD does not improve early in treatment, OROS-MPH may be considered as safe and likely effective pharmacotherapy for ADHD even if not yet abstinent (with regular monitoring and in the context of ongoing substance treatment) OROS-MPH demonstrated low abuse/diversion liability. Secondary outcomes indicated some added benefit with OROS-MPH compared to placebo