National Drug Abuse TreatmentClinical Trials Network

National Drug Abuse TreatmentClinical Trials Network

A Randomized Controlled Trial of OROS-MPH + CBT in Adolescents

with ADHD and Substance Use Disorders

Robert Davies, M.D.Robert Davies, M.D.Associate Professor, PsychiatryAssociate Professor, Psychiatry

University of Colorado Denver School of MedicineUniversity 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.Robert Davies, M.D.Associate Professor, PsychiatryAssociate Professor, Psychiatry

University of Colorado Denver School of MedicineUniversity of Colorado Denver School of Medicine

NATIONAL

INSTITUTE ON DRUG

ABUSE

NATIONAL

INSTITUTE ON DRUG

ABUSENIDNIDAA

Financial Disclosures

• Active medication and placebo Active medication and placebo provided by McNeil Pharmaceuticalsprovided by McNeil Pharmaceuticals

• Dr. Davies previously participated on Dr. Davies previously participated on Speaker’s Bureaus for Eli Lilly, PfizerSpeaker’s Bureaus for Eli Lilly, Pfizer

Background & Significance• ADHD 3-5x more common in adolescents ADHD 3-5x more common in adolescents

with SUD (30-50%) compared to those with SUD (30-50%) compared to those without SUD (7-10%) and is associated with without SUD (7-10%) and is associated with poorer treatment outcomespoorer treatment outcomes

• The safety and efficacy of psychostimulant The safety and efficacy of psychostimulant medication for ADHD in youths without medication for ADHD in youths without SUD is well-established, but SUD is well-established, but research is research is lacking in substance abusing adolescents lacking in substance abusing adolescents with ADHDwith ADHD

Study AimsStudy Aims

Aim 1Aim 1: To evaluate the efficacy of OROS-MPH : To evaluate the efficacy of OROS-MPH vs. placebo in treating ADHD is substance-vs. placebo in treating ADHD is substance-abusing adolescentsabusing adolescents

Aim 2Aim 2: To evaluate the impact of OROS-MPH : To evaluate the impact of OROS-MPH + CBT vs. placebo + CBT on substance + CBT vs. placebo + CBT on substance treatment outcomestreatment outcomes

Aim 3Aim 3: To evaluate the tolerability, safety, and : To evaluate the tolerability, safety, and abuse potential of OROS-MPH in substance-abuse potential of OROS-MPH in substance-abusing adolescents with ADHDabusing adolescents with ADHD

Study DesignStudy Design

16-week multisite, randomized controlled trial 16-week multisite, randomized controlled trial OROS-MPH + CBT vs. placebo + CBTOROS-MPH + CBT vs. placebo + CBT

Eleven participating sitesEleven participating sites N=303 N=303 Intent-to-Treat (ITT) analysis Intent-to-Treat (ITT) analysis Target dose = 72 mg/day Target dose = 72 mg/day (titrated over first study month)(titrated over first study month)

Cognitive Behavioral Therapy Cognitive Behavioral Therapy Weekly, Individual – focused on Substance AbuseWeekly, Individual – focused on Substance Abuse ManualizedManualized

- Attempt to standardized outpatient substance treatment - Attempt to standardized outpatient substance treatment across participating sitesacross participating sites

Inclusion/Exclusion Inclusion/Exclusion CriteriaCriteria

InclusionInclusion Adolescents 13-18 Adolescents 13-18

yearsyears

DSM-IV ADHD DSM-IV ADHD (per K-SADS)(per K-SADS)

Non-nicotine SUD, use Non-nicotine SUD, use within past month within past month

DSM-IV ADHD Checklist DSM-IV ADHD Checklist score ≥ 22score ≥ 22

Medically healthyMedically healthy

Exclusion Serious medical or cardiac Serious medical or cardiac

illness, tic disorder, or illness, tic disorder, or pregnancypregnancy

Bipolar, psychosis, suicide Bipolar, psychosis, suicide riskrisk

Opiate dependenceOpiate dependence

Methamphetamine abuse or Methamphetamine abuse or dependencedependence

Psychotropic medication; Psychotropic medication; other MH/SUD treatmentother MH/SUD treatment

Baseline CharacteristicsBaseline Characteristics

DemographicsDemographicsOROS-MPH Placebo

Age 16.4 16.6

Gender Male 81%Female 19%

Male 77%Female 23%

Percent Court Mandated 23% 26%

Race

Caucasian 64% 59%

African American 21% 25%

Other 15% 16%

Ethnicity

Hispanic 15% 15%

* No statistically significant differences

Baseline Clinical Baseline Clinical CharacteristicsCharacteristics

OROS-MPH PlaceboDSM 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 DSM-IV Substance Baseline DSM-IV Substance Use Disorders (CIDI-SAM)Use Disorders (CIDI-SAM)

0102030405060708090

100

Cannabis

Alcohol

Halluc inogens

Opioids

Cocaine

Amph/M

eth

Sedatives

Abuse

Dependence

Abuse/Dep

Study FindingsStudy 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 Outsiders17 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 TolerabilityMedication 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 = 67.05 mg

Placebo Group Mean dose = 67.99 mg

• 80% compliance with prescribed medication

ADHD OutcomesADHD Outcomes

Adolescent DSM-IV ADHD Checklist Adolescent DSM-IV ADHD Checklist by Treatment Groupby 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 Secondary ADHD Outcome MeasuresOutcome Measures

0

10

20

30

40 OROS-MPH + CBT

Plac ebo + CBT

Problem Solving

(ARCQ)

Focused Coping Skills

(ARCQ)

Parent DSM-IV ADHD Checklist

8 weeks

Parent DSM-IV ADHD Checklist

16 weeks

p = 0.002 p = 0.023

p = 0.02 p < 0.001

Substance Use OutcomesSubstance Use Outcomes

Past 28 Day Non-nicotine Substance Past 28 Day Non-nicotine Substance UseUse

Placebo= - 5.2 days; 34% p<0.001

OROS MPH= - 5.7 days; 41%; p<0.001Clinically and statistically significant reduction in past 28 day drug use in both groups

No difference between groups

Secondary Substance Secondary Substance Use OutcomesUse 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. ADHD Responders vs. Non-responders (CGI-I)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 Safety, Tolerability and Abuse PotentialAbuse Potential

Adverse Events by Treatment GroupAdverse Events by Treatment Group

Adverse Effect OROS-MPH Placebo p - value

Statistical Significance

Excoriation 14/151 (9.3%) > 4/152 (2.6%) 0.016

Nervousness 12/151 (7.9%) > 3/152 (2.0%) 0.018

Heart Rate Increased 8/151 (5.3%) > 1/152 (0.7%) 0.019

Heart rate = > 100 19/149 (12.8%) > 8/148 (5.4%) 0.028

Decreased Appetite 25/151 (16.6%) > 9/152 (5.9%) 0.003

Statistical Trend

Abdominal Discomfort 8/151 (5.3%) > 2/152 (1.3%) 0.061

Migraine Headaches 4/151 (2.6% ) > 0/152 (0.0%) 0.06

Anorexia 6/151 (4.0%) > 1/152 (0.7%) 0.067

Mood Altered 4/151 (2.6%) > 0/152 (0.0%) 0.06

Road Traffic Accidents 4/151 (2.6%) > 0/152 (0.0%) 0.06

Limb Injury 1/151 (0.7%) < 7/152 (4.6%) 0.067

Systolic BP = > 140 27/149 (18.1%) > 16/148 (14.5%) 0.073

Serious Adverse Events Serious Adverse Events by Treatment Groupby Treatment Group

• OROS-MPH1 study-related SAE (psychosis)

• Placebo3 study-related SAEs

MGH Abuse/DiversionMGH Abuse/DiversionQuestionnaireQuestionnaire

Item OROS (% Yes)

Placebo (% Yes)

Significance

Do you remember to take medication 86.6 80.1 p = 0.143; NS

Do you think it helps 53.5 29.8 p < .0001

Ever sold you medication to others 2.1 1.4 p = 1.000; NS

Ever let others take your medication 3.5 1.4 p = 0.447; NS

Ever taken more than supposed to 4.2 2.8 p = 0.749; NS

Ever got high on medication 4.9 7.1 p = 0.444; NS

Ever taken med other than how prescribed 2.1 0.7 p = 0.622; NS

Ever not taken so that you could use drugs/alcohol

4.2 6.4 p = 0.418; NS

Ever used drugs/alcohol on days took med 67.6 72.3 p = 0.385; NS

Ever had a reaction to drugs/alcohol while taking medication

2.8 2.1 p = 1.000; NS

MGH Abuse/Diversion MGH Abuse/Diversion QuestionnaireQuestionnaire

Item OROS (% Yes)

Placebo (% Yes)

Significance

Do you remember to take medication 86.6 80.1 p = 0.143; NS

Do you think it helps 53.5 29.8 p < .0001

Ever sold you medication to others 2.1 1.4 p = 1.000; NS

Ever let others take your medication 3.5 1.4 p = 0.447; NS

Ever taken more than supposed to 4.2 2.8 p = 0.749; NS

Ever got high on medication 4.9 7.1 p = 0.444; NS

Ever taken med other than how prescribed 2.1 0.7 p = 0.622; NS

Ever not taken so that you could use drugs/alcohol

4.2 6.4 p = 0.418; NS

Ever used drugs/alcohol on days took med 67.6 72.3 p = 0.385; NS

Ever had a reaction to drugs/alcohol while taking medication

2.8 2.1 p = 1.000; NS

MGH Liking ScaleMGH Liking Scale

Item(Scoring Range 1 = not at all; 10 = very much)

OROS Placebo Significance*

Medication effective 6.0 4.5 p< .001

Like how it makes you feel 4.9 4.4 p = 0.058; NS

How high/euphoric do you get 2.7 2.1 p = 0.101; NS

How depressed/down do you get 2.4 2.0 p = 0.044

Do you ever crave medication 1.3 1.4 p = 0.673; NS

Crave other drugs when on med 2.4 2.5 p = 0.835; NS

How physically active do you feel 5.3 4.9 p = 0.034

*non-parametric tests

Summary of Summary of Main Study FindingsMain 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 Interpretation of Results in Context of Previous Researchof Previous Research

Results are inconsistentResults are inconsistent

• With most controlled trials of psychostimulant vs placebo (alone) for ADHD

Results are consistentResults 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 If replicated, results have important clinical implicationsclinical 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