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NIDA
NATIONAL INSTITUTE
ON DRUG ABUSE
National Drug Abuse Treatment
Clinical Trials Network
New Findings from a Randomized Controlled Trial OsmoticRelease Methylphenidate (OROS-MPH) for ADHD
in Adolescents with Substance Use Disorders
AACAP Annual Meeting
New York City, October 26-31, 2010
Overview of
Main Study Findings
Background
Aims
• ADHD 3-5x more common in • AIM 1: To evaluate the
efficacy of OROS-MPH vs.
adolescents with SUD
placebo in adolescents with
(30-50%)
ADHD and SUD
concurrent CBT
• Associated with poorer
• AIM 2: Impact of OROStreatment outcomes
MPH + CBT vs placebo +
CBT on substance
• Little known about safety /
treatment outcomes
efficacy in adolescents
• AIM 3: Safety, tolerability,
with ADHD and SUD
abuse
3
Study Design
• 16-week RCT
• OROS-MPH+ CBT* vs
placebo + CBT
• N=303 adolescents w/
ADHD, SUD
•
Interventions
–
–
Sample Size, Power,
Analytic Approach
• Intent-to-treat (ITT)
• Power
• N=300; > .80 power
OROS-MPH vs placebo
on ADHD
OROS-MPH 72mg daily dose
CBT: weekly, individual,
manual-standardized
outpatient substance tx across
participating sites
• .80 power to detect
mediated effect size = >
0.4 OROS-MPH vs
placebo on substance
outcomes
4
Figure 15.2
Study
Flow Diagram
Study
Flow
Diagram
Telephone Prescreened
N=1334
Informed Consent
Baseline Screening
N=446
143 Excluded (32%)
 139 Not eligible (97.2%)
 4 Other (2.8%)
Randomized
N=303
OROS-MPH + CBT
N=151
Non-completes N=33 (21.9%)
 11 withdrew consent
 3 moved form area
 2 practical problems
 4 incarceration
 1 pressure/advice from outsiders
 9 failed to return to clinic and lost
 3 other
79% research visit attendance
72% CBT sessions attended (mean=11.1)
16 week completes N=118 (78.1%)
Completed 1-month follow-up
N=109 (72.2%)
Placebo + CBT
N=152
Non-completes N=43 (28.3%)
 11 withdrew consent
 1 moved form area
 3 practical problems
 5 incarceration
 1 pressure/advice from outsiders
 1 feels treatment not working
 17 failed to return to clinic and lost
 4 other
76% research visit attendance
68% CBT sessions attended (mean = 10.4)
16 week completers N=109 (71.7%)
Completed 1 month follow-up
N=105 (69.1%)
Medication compliance = 80% Tolerability: 96% achieved 72 mg daily dose; 86% sustained
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Demographics
Race
• 60% Caucasian
• 22% African
American
• 18% other
Ethnicity
• 15% Hispanic
Baseline Clinical Characteristics
OROS-MPH + CBT
N=151
PLACEBO + CBT
N=152
38.2 (9.0)
39.3 (8.7)
Abuse diagnoses
0.9 (1.1)
0.8 (1.0)
Dependence diagnoses
1.2 (0.9)
1.1 (0.9)
Abuse + Dependence dx
2.1 (1.2)
1.9 (1.3)
Days of past 28 day
drug use
14.0 (9.6)
15.1 (9.4)
ADHD
DSM IV ADHD symptom
checklist score (adolescent)
Substance Diagnoses
& Past 28 day use
Current/past methamphetamine ab/dep and current opiate dependence excluded
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Significant Differences in 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
Abdominal
Discomfort
• OROS-MPH
(5.3%) related
>
2/152AEs/subject
(1.3%)
0.016
+ CBT8/151
> study
Nervousness
12/151 (7.9%) >
3/152 (2.0%)
compared to placebo +
CBT (2.4 v 1.6;
p=0.022) 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
5/122 (4.1%)
0/117 (0.9%)
0.024
• SAEs(males only)
Palpitations
• OROS-MPH
Statistical
Trend
>
= 1 study related SAE/4 total
Migraine
Headaches = 3 study4/151
(2.6% )SAEs/7
> 0/152
(0.0%)
• Placebo
related
total
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
Clinician-Administered, Adolescent ADHD RS
by Treatment Group
• Clinically and statistically significant reduction in
Clinically
statistically
reduction
ADHDand
symptoms
insignificant
both groups
in ADHD symptoms in both treatment groups
(OROS + CBT 46%; placebo + CBT 45%; p<0.0001)
(50%)
• No difference between groups
..but no difference between groups on
the primary ADHD outcome measure
Estimated decrease from baseline to study end for the OROS-MPH + CBT group was -19.2
(95% CI, -17.1, -21.2; p < 0.001) and for the placebo + CBT group was -21.2 (95% CI -19.1,9
23.2, p < 0.001
Past 28 Day Substance Use
Clinically and statistically significant reduction in past 28 day drug use in
The trajectories of past 28 day drug use based on adolescent self-reports did not
both groups, but no difference between groups
differ between treatment groups (Chi-square = 3.04, 3 df, p = 0.3855 ; Proc Glimmix).
18
Similar to reduction in days of drug use other evidence based
substance treatments
16
Placebo= - 4.9 days; 33% p<0.0001
14
OROS MPH= -6.1 days; 43%; p<0.0001
Days of Use
12
10
NS
8
6
Placebo
4
OROS
2
0
Secondary Outcomes Favored OROS-MPH : 1. More negative UDS in OROS-MPH
(3.8) vs placebo (2.8) p< 0.05; 2. Trend for more participants treated with OROS-MPH
of 8Study
0to have > 75% reduction
4
12
16
in drugWeek
use(
p=0.08)
STUDY LIMITATIONS
RESULTS MUST BE INTERPRETED WITH CAUTION
Limitations
• Hawthorne Effect?
• Heavy reliance on
adolescent selfreports
Steps taken to address
limitations
• Careful attention to
adolescent psychoeducation
• ADHD symptoms
• Clinical severity ratings
• Inclusion criteria ADHD
RS = > 22 adolescent
(without parent)
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Summary of Main Study Findings
1. OROS – MPH safe, well-tolerated
2. Treatment compliance, completion = > than reported
for youths with less severe psychopatholgy and
SUD
3. Substance outcomes as good or better than in youth
with less severe psychopathology
4. Reduction in ADHD symptoms => than reported for
psychostimulant treatment of ADHD in youth
without SUD
5. Similar reduction of ADHD symptoms in placebo +
CBT suggests contribution of CBT to both SUD
and ADHD outcomes
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Emerging Research Supports the Efficacy of CBT for
ADHD
Adults
• Safren et al, 2005, 2010: 56% treatment
responders medication + CBT vs 13%
treatment responders medication alone
• Solanto et al, 2010: Meta-cognitive therapy
effective for adults with ADHD Amer J
Psychiatry, March, 2010
Interpretation of Results in the 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)
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Interpretation of Results in the Context of
Previous Research
Psychostimulant treatment
•? Medication
Results
are
inconsistent
• 20-50% continue to have
compliance
functional impairment; no long
•? validity of
• With
most
controlled
trials
of
psychostimulant
term benefit
adolescent self
vs placebo (alone) for ADHD
(Molina et al 2009; Safren et al., 2005; Advokat,
2009)
Results are consistent
report
•? contribution
of CBT
• With 3 controlled psychostimulant trials in adults
Whereas, 2 controlled trials in adolescents
concurrently
receiving
weekly
individual
CBT for SUD
(pemoline)
and adults
(atomoxetine):
Active
(Levin et al 2006; 2007; Schubiner et al 2004)
medication > efficacy than placebo in the
absence of concurrent behavioral treatment
for SUD (Riggs et al 2004; Wilens et al 2008)
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NEW FINDINGS
Secondary Outcomes
Post-Hoc Analyses
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Secondary ADHD Outcome Measures
P<0.02
P<0.0023
P<0.023
ARCQ
ARCQ
ARCQ
P<0.0015
Clinician-Rated ADHD Treatment Responders (CGI-I)
ITT Sample
Responders v Non responders
ADHD RESPONDERS (N=55) (CGI-I; regardless of
medication group assignment)
• 2X > NEGATIVE UDS
• Responders (N=55) = 6.2
• Non-responders (n=172) = 3.1 p<0.0001
• MORE DAYS OF ABSTINENCE
• Responders, median = 94 days
• Non-responders, median = 77 days
p<0.001
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Depression as Predictor of Outcomes?
MDD is frequently comorbid with substance use disorders (SUD) and with ADHD and
SUD. IMPACT OF MDD on substance treatment outcomes unknown
MDD (N=38) vs Non- MDD (N=265)
MDD > Non-MDD
• Baseline
– days/28 day substance use
baseline
– > cannabis days of use/28
days baseline
• End of Treatment
DEPRESSED subjects continue to
use > days/28 throughout tx
No Difference
– nicotine severity
– trajectories of
change or magnitude
of reduction in days
of substance use
– tx
adherence/completio
20
n
Trajectories of Change in Marijuana and
Cigarette Smoking
BACKGROUND
• Cigarette smoking is common in adolescents with
ADHD and SUD
• However, little is known about the relationship
between nicotine and cannabis use trajectories
in the context of treatment for both ADHD and
SUD
Kevin M. Gray, M.D.1, Paula D. Riggs, M.D.2, Sung-Joon Min, Ph.D.2, Susan K. Mikulich, Ph.D.2,
Dipankar Bandyopadhyay, Ph.D.1, Theresa Winhusen, Ph.D.3
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Advances in Research Support
Treatment for Smoking Cessation/Nicotine
Dependence During SUD Treatment
Adolescents with SUD have
• Higher rates of smoking; more negative health
consequences and greater risk for progression to more
serious nicotine dependence compared to adolescent
smokers without other SUD (Meyers and Prochaska, 2008)
• As many as 80% of report current tobacco use; many
daily smokers; 50-60% nicotine dependent.
• Smoking cessation interventions during SUD treatment
was associated with higher rates of abstinence from
alcohol and other drugs 12-months following SUD
treatment (meta-analysis Prochaska et al., 2004).
Priming
Treatment for MJ
use of the second
substance
smoking/drinking)
Adolescents
may have
more (e.g.
without
smoking
•difficulty
Primingachieving
may be an even more important factor in
adolescents
abstinence
from marijuana if cessation may
- MJ/cigarettes
- common routeinadvertently
administration
they
continue to smoke
– Marijuana
is priming
the most commonly used illicit drug used
cigarettes
due to
contribute
to
more
in
adolescents
and
5.9
times
more
likely
to
be
current,
effects (cue-reactivity)
heavier smokers/>nicotine dependent
compared
to
severe
nicotine
marijuana non-users (Agrawal and Lynskey 2009; Okoli et al
2008).
dependence
• The use of one substance may act as a cue to prime the
– Despite the strong relationship between marijuana and
cigarette smoking, little is known about the
relationship between changes in cigarette smoking in
adolescents attempting to reduce their marijuana use
and vice versa.
Trajectories of Change in Marijuana and Cigarette
Smoking
METHODS
• Participants completed nicotine and cannabis
use self-report at baseline and throughout
treatment.
• Analyses were performed to explore the
relationships between nicotine use, cannabis use,
and other factors, such as medication treatment
assignment
• Regular cannabis and cigarette smokers defined as using
> 14 days baseline
• Substance tx responders => 50% decline in days of nontobacco substance use
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Trajectories of Change in Marijuana
and Cigarette Smoking
Baseline
• Baseline cigarette
smoking was
positively correlated
with cannabis use
p < 0.05
Results
• SUD treatment responders
reduced cigarette use
• from 6.7 to 4.7 days/week
p = 0.0008
• from 10.8 to 6.2 cigarettes
per day
p = 0.0007
Conclusions
Significant reduction in cannabis use during substance treatment
associated with modest reduction, not increased, cigarette smoking