Transcript Slide 1

2013 CTN Web Seminar Series
DEVELOPING MEDICATION
ASSISTED TREATMENT (MAT)
PROTOCOLS
Presented by:
Andrew J. Saxon, MD
July 17, 2013
Produced by: NIDA CTN CCC Training Office
"This training has been funded in whole or in part with Federal funds from the National Institute on Drug Abuse,
National Institutes of Health, Department of Health and Human Services, under Contract No.HHSN271201000024C."
Objectives:
• Consider some of the prior medication assisted
treatment protocols conducted in the CTN for
lessons learned.
• Identify design decisions that need to be made
concerning medication assisted treatment
protocols, including considerations about
blinding and adherence strategies.
• Describe regulatory aspects of medication
assisted treatment protocols.
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DESIGNING MEDICATION
ASSISTED PROTOCOLS
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Specific Topics to Consider
• Investigational New Drug Application (NDA) from
FDA?
• Open label or blinded MAT trial?
• Placebo or active comparator?
• Dosing strategy—Fixed or flexible?
• Adherence strategy?
• More exclusive or more inclusive enrollment
criteria?
• What, if any, behavioral platform?
• Safety monitoring plan
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REGULATORY
CONSIDERATIONS
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IND
• An Investigator IND is submitted by a physician
who both initiates and conducts an investigation,
and under whose immediate direction the
investigational drug is administered or
dispensed. A physician might submit a research
IND to propose studying an unapproved drug, or
an approved product for a new indication or in a
new patient population.
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IND
• CDER's Pre-Investigational New Drug
Application (IND) Consultation Program5 fosters
early communications between sponsors and
new drug review divisions to provide guidance
on the data necessary to warrant IND
submission. The review divisions are organized
generally along therapeutic class and can each
be contacted using the designated Pre-IND
Consultation List (PDF - 19KB)6.
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IND Examples
• Injectable risperidone for methamphetamine
dependence
– Drug company sponsor – wanted IND
– Use in new population – FDA requested IND
• Prazosin for Alcohol Dependence
– University/NIH sponsor – no position on IND
– Given widespread use of prazosin, has probably been
used by patients with AUD
– No plans to seek a change in labeling or advertising
– Exempt from IND
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Controlled Substances
• Obtain appropriate DEA licensure
• Obtain licensure specific to each state
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BLINDING AND PLACEBO
STRATEGIES
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Open Label vs. Blinded Study
Enck et al., 2013
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Open Label Advantages
• Good for pilot studies to test:
– tolerability
– safety
– possibly dose effects
• More real world
• For some medications expectancies are
component of efficacy
– Disulfiram (Antabuse)
• Less complex/costly
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Blinding Advantage
• Accounts for expectancy effects
– Patients
– Research staff
• Double blind vs. single blind
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Benedetti et al., 2005
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Placebo Response
Benedetti et al., 2005
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Placebo vs. Active Comparator
• If active medication has profound, observable
effects, inert placebo may break blind
• Active “placebo” possible
• If an already approved medication for indication
exists, head to head comparison informative
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Lessons Learned in the CTN
PRIOR MEDICATION ASSISTED
TREATMENT PROTOCOLS
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START Study Schema
1920
Number screened for participation
1269
740 Buprenorphine/Naloxone
340 Evaluable
400 Failed to remain on assigned
medication for 24 wks
0
Failed to provide ≥ 4 LT samples
261 Completed 32-week follow-up
Randomized
529 Methadone
391 Evaluable
136 Failed to remain on assigned
medication for 24 wks
2 Failed to provide ≥ 4 LT samples
330 Completed 32-week follow-up
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CTN 0028
OROS-Methylphenidate ADHD/SUD
Titrated to 72 mg
per day
Riggs et al., 2011
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CTN 0048 CURB Study Schema
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Fixed vs. Flexible Dosing
• Fixed dosing
– requires less physician time
– Fixed dosing may miss optimum dose
• Flexible dosing
–
–
–
–
Titrate to effects/side effects
Need algorithm to guide study physician
More real world
More complex analytic approach may be needed
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CTN 0003 Buprenorphine Taper
Total
Stabilization
Dose
Total
8 mg
48 (9.3%)
16 mg
141 (27.3%)
24 mg
327 (63.4%)
516 (100%)
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ADHERENCE STRATEGIES
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Potential Adherence Measures
• Observed dosing
• Pill counts
• Biologic marker
• Electronic monitoring
• Self report
• Plasma or urine drug concentrations
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Lessons Learned in the CTN
PRIOR MEDICATION ASSISTED
TREATMENT PROTOCOLS
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0053 Achieving Cannabis Cessation - Evaluating
N-Acetylcysteine Treatment (ACCENT)
Consent &
Eligibility
Assessment
Twice weekly urine testing and contingency management
Post-treatment
Weeks 1-12 (NAC 1200 mg or placebo twice daily)
Wk 16
Randomization
NAC n=150
Placebo n=150
Start medication
Weekly compliance enhancement
End of treatment
• The primary objective is to evaluate impact of
N-acetylcysteine (NAC) 1200 mg versus matched
placebo (PBO) twice daily, added to compliance
enhancement (CE) and contingency management (CM),
on cannabis use among treatment-seeking cannabisdependent adults.
• Medication adherence will be assessed using selfreport, blister pack pill counts, and urine riboflavin
testing.
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0052 Randomized Controlled Evaluation of
Buspirone for Relapse-Prevention in Adults with
Cocaine Dependence (BRAC)
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0052 Randomized Controlled Evaluation of
Buspirone for Relapse-Prevention in Adults with
Cocaine Dependence (BRAC)
• The primary objective is to evaluate the efficacy of
buspirone, relative to placebo, in preventing relapse in
cocaine-dependent adults in inpatient/residential
treatment who are planning to enter outpatient treatment
upon inpatient/residential discharge.
• MEMS, pill count, and participant self-report of
medication adherence will be collected.
• Urine samples will be shipped to a central lab, and
samples from the buspirone group will be assayed
for buspirone and/or its metabolite.
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MEMS
• The Medication Event Monitoring System, (MEMS) is a
medication bottle cap with a microprocessor that records
the occurrence and time of each bottle opening.
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INCLUSION/EXCLUSION
STRATEGIES
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Enrollment Criteria
• More restrictive
– Increase safety
– Possibly increase likelihood of effect
• Less restrictive
– Increase generalizability
– Interventions found efficacious in clinical trials often
fail in real world
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Lessons Learned in the CTN
PRIOR MEDICATION ASSISTED
TREATMENT PROTOCOLS
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Exclusions 0027 START
• ALT or AST values > 5 times the upper limit of
normal
• Known diagnosis of acute psychosis, severe
depression or imminent suicide risk
• Poor venous access such that venipuncture
could not be accomplished from a vein in an
extremity during eligibility
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Exclusions 0052 BRAC
• Medical or psychiatric condition that, in the judgment
of the study physician, would make study
participation unsafe or which would make treatment
compliance difficult. Medical conditions that may
compromise participant safety or study conduct
include, but are not limited to:
– AIDS
– liver function tests greater than 3X upper limit of normal
– serum creatinine greater than 2 mg/dL
• Psychiatric disorder requiring continued treatment
with a psychotropic medication
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Potential Behavioral Platforms
• Medications alone not expected to be fully
efficacious for SUD
• More intensive behavioral intervention
– Could overwhelm medication effects
– Could provide sufficient support and/or synergy to
allow medication to work
• Less intensive behavioral intervention
– Less likely to overwhelm medication effects
– May not hold patients in treatment sufficiently to
allow medication to work
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Lessons Learned in the CTN
PRIOR MEDICATION ASSISTED
TREATMENT PROTOCOLS
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Behavioral Interventions from CTN
MAT Trials
• Bup Taper and START
– Counseling as usual
• OROS-methylphenidate ADHD/SUD
– CBT (highly efficacious)
• ACCENT
– compliance enhancement (CE) and contingency
management (CM)
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CTN 0028
OROS-Methylphenidate ADHD/SUD
Riggs et al., 2011
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SAFETY MONITORING
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Safety Monitoring
• Data Safety Monitoring Board
– Established for CTN MAT Trials
• Plan to assess adverse events and serious
adverse events
• Laboratory monitoring
– e.g., liver tests, glucose, CBC
• Cardiac monitoring
– ECG
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Recap / Highlights
• Designing MAT trials involves numerous
decision points and trade-offs
• MAT trials conducted in CTN can provide
considerable guidance in making these
decisions for design of future MAT trials
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Q&A – Questions / Comments
Alternatively, questions can be directed to the presenter by sending an email to
[email protected].
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References
• Saxon et al., Buprenorphine/Naloxone and methadone
effects on laboratory indices of liver health: A
randomized trial. Drug and Alcohol Dependence 128:7176, 2013.
• Riggs et al., Randomized controlled trial of osmoticrelease methylphenidate with cognitive-behavioral
therapy in adolescents with attention deficit/hyperactivity
disorder and substance use disorders. Journal of the
American Academy of Child & Adolescent Psychiatry
50:903-914, 2011.
• Ling et al., Buprenorphine tapering schedule and illicit
opioid use. Addiction 104:256-265, 2009.
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Survey Reminder
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directly following this webinar session. Watch for the email notification!
Also, please visit the Training Suggestion Box to post general comments:
https://www.surveymonkey.com/s/CTNTrainingSuggestionBox
Upcoming Webinar
Social Media – Using Social Media as
a Clinical Trials Research Tool
Wednesday, August 21, 2013
1:00 pm to 2:00 pm ET
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A copy of this presentation will be available
electronically after this session.
http://ctndisseminationlibrary.org
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Thank you for participating.
NIDA CTN Web Seminar Series
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