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NIDA
NATIONAL INSTITUTE
ON DRUG ABUSE
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
Financial Disclosures
• Active medication and placebo
provided by McNeil Pharmaceuticals
• Dr. 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 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 ADHD
Study Aims
Aim 1: To evaluate the efficacy of OROS-MPH
vs. placebo in treating ADHD is substanceabusing 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 substanceabusing adolescents with ADHD
Study Design
16-week multisite, randomized controlled trial
OROS-MPH + CBT vs. placebo + CBT


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Eleven participating sites
N=303
Intent-to-Treat (ITT) analysis
Target dose = 72 mg/day
(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 13-18
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
Age
Gender
Percent Court Mandated
OROS-MPH
Placebo
16.4
16.6
Male
81%
Female 19%
Male
77%
Female 23%
23%
26%
Caucasian
64%
59%
African American
21%
25%
15%
16%
15%
15%
Race
Other
Ethnicity
Hispanic
* No statistically significant differences
Baseline Clinical
Characteristics
DSM IV ADHD symptom
checklist score (adolescent)
Number of Abuse and
Dependence Diagnoses
Number of Days Used Drugs
(out of past 28)
OROS-MPH
Placebo
38.1 (9.0)
39.3 (8.7)
2.1 (1.2)
1.9 (1.3)
14.0 (9.6)
15.1 (9.4)
* No statistically significant differences
Baseline DSM-IV
Substance Use Disorders
(CIDI-SAM)
100
90
80
70
60
50
40
30
20
10
0
Abuse
Dependence
Abuse/Dep
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Study Findings
1334 Individuals Screened by Telephone
450 Assessed for Eligibility and Consented
147 Excluded (32.7%)
139 Not eligible (94.6%)
8 Other (5.4%)
303 Participants
Randomized
151 Assigned to Receive
OROS-MPH + CBT
152 Assigned to Receive
Placebo + CBT
118 Completed Trial (78.1%)
33 Non-Completers (21.9%)
109 Completed Trial (71.7%)
43 Non-Completers (28.3%)
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
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
151 Included in Analysis
152 Included in Analysis
Medication Tolerability
• 96% achieved 72 mg daily dose
• 86% sustained 72 mg dose across study
• Permanent dose reductions
OROS-MPH
Placebo
16/149 (10.7%)
10/148 (6.8%)
• Last dose prescribed
OROS-MPH
Placebo Group
Mean dose = 67.05 mg
Mean dose = 67.99 mg
• 80% compliance with prescribed
medication
ADHD Outcomes
Adolescent DSM-IV ADHD Checklist
by Treatment Group
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
Estimates are derived from the cubic longitudinal model with random subject and
linear time effects and serially-correlated residual errors.
Secondary ADHD
Outcome Measures
40
OROS-MPH + CBT
Placebo + CBT
p = 0.02
p < 0.001
30
20
10
p = 0.002
p = 0.023
0
Problem Solving
(ARCQ)
Focused Coping
Skills
Parent DSM-IV
ADHD Checklist
Parent DSM-IV
ADHD Checklist
(ARCQ)
8 weeks
16 weeks
Substance Use Outcomes
Past 28 Day Non-nicotine
Substance Use
Clinically and statistically significant
OROS MPH= - 5.7 days; 41%; p<0.001
reduction in past 28 day drug use in
Placebo=
both
groups- 5.2 days; 34% p<0.001
No difference between groups
18
16
14
Days of Use
12
10
8
6
Placebo
4
OROS
2
0
0
4
Week of8Study
12
16
Secondary Substance
Use Outcomes
Negative Urine Drug Screen
• OROS-MPH = 3.8
• Placebo = 2.8
p < 0.05
> 75% Reduction Days Drugs Used
• OROS-MPH = 41.2%
• Placebo = 29.9%
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 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
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%)
Statistical Trend
> 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
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
Questionnaire
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 Scale
Item
OROS
Placebo
Significance*
(Scoring Range 1 = not at all; 10 = very much)
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
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 cooccurring 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