1. Overview of Substance Use Outcomes in Other SUD trials
Brian D. Kiluk, Ph.D.
Yale School of Medicine
ACTTION Meeting March 23, 2018

2. OUTLINE
Published reviews of outcomes in trials for tobacco, alcohol, stimulants
Assessments for measurement of outcomes
Definitions of treatment success
Consideration of grace period
Recommended/approved outcomes

3. ALCOHOL: Assessment Days of drinking/abstinence
Quantity of drinks per day
Self-report (Timeline FollowBack – TLFB, Form 90, etc.)
Breath Alcohol Concentration (very recent alcohol use <12 hours)
EtG – urine metabolite (sensitive to heavy drinking in past hours)
Liver enzymes – GGTP, ASAT, ALAT
Transdermal alcohol monitor (SCRAM bracelet)
Biochemical / objective measures of drinking

4. ALCOHOL: Assessment
* Self-reports are generally accurate and can be used with confidence when:
Alcohol free when interviewed
Given written assurances of confidentiality
Interviewed in setting that encourages honest reporting
Clearly worded objective questions
Provided memory aids

5. ALCOHOL: Common Outcomes
Percent days abstinent (PDA) or Percent days drinking (PDD)
Days of alcohol abstinence (or use) / Total days
Percentage of Heavy Drinking Days (PHDD)
Heavy drinking day = any day consuming 4+/5+ drinks for women/men
Drinks per Day (DPD)
Number of total drinks / number of days during specified period
Drinks per Drinking Day (DDD)
Number of total drinks / number of drinking days during specified period
* Biomarkers commonly used to validate self-report, not as outcome
* Transdermal alcohol monitors – days of no drinking

6. ALCOHOL: Preferred Outcomes
Executive summary of conference sponsored by NIAAA
Goal of selecting a “sentinel” outcome measure to include in clinical trials
Percentage of Heavy Drinking Days – PHDD (continuous)
Allen (2003)
Percent of subjects abstinent (i.e., completely abstinent for specified period)
Percent of subjects with no heavy drinking days – PSNHDD (dichotomous)
No heavy drinking days associated with lower risk of AUD and negative consequences
FDA approved endpoints

7. ALCOHOL: Grace Period Falk et al 2010 PSNHDD
Effect sizes based on various grace periods
COMBINE and Topiramate

8. ALCOHOL: Reduction Measures
World Health Organization (WHO) risk levels
Increased mortality risk at each level of consumption
European Medicines Agency
Reduction by 2 categories
Nalmefene approval
Witkiewitz et al 2017 (COMBINE)
1-level reduction
Reduced DrInC; better mental health
Hasin et al 2017 (NESARC) – Table 1
Lowered odds of alcohol dependence

9. TOBACCO: Assessment Self-report (TLFB, Nicotine Use Inventory, etc.)
Biochemical verification
Exhaled carbon monoxide (> 6-8ppm indicative of recent smoking; although 3-5ppm suggested recently)
Cotinine (plasma, saliva, urine – detection times of several days to a week)
Abstinence measures
Number of cigarettes per day
Use measures

10. TOBACCO: Outcomes Hughes et al., (2003)
Workgroup formed by Society of Nicotine and Tobacco Research
Gathered information via literature searches to evaluate pros and cons of abstinence measures
Included logic, clinical wisdom, and consensus among experts
Abstinence measures based on percentage of individuals abstinent
Any smoking treated as failure
Those lost to follow-up treated as SMOKERS

11. TOBACCO: Common Outcomes
Continuous abstinence
Proportion of people not smoking at all since quit date
Prolonged abstinence
Proportion abstinent for some specified interval of extended duration
Point prevalence abstinence
Proportion not smoking at a point in time (immediately preceding follow-up)
Repeated point prevalence
Point prevalence abstinence at 2 or more follow-ups between which smoking is allowed

12. Hughes, Carpenter, & Naud (2010)
28 RCTs of validated pharmacotherapies
Reported both PA & PP
PP & PA highly correlated
r = .88
Produce similar estimates of effect size
PP slightly higher when absolute difference used

13. TOBACCO: Recommendations from workgroup
2-week grace period recommended
Definition of failure requires smoking on several occasions (not just a puff)
Smoking on 7 consecutive days, or at least once each week for 2 consecutive weeks
Prolonged abstinence is preferred measure
Many trials have reported only point prevalence
7-day window can be verified by blood or saliva cotinine
Definition of failure for 7-day point prevalence is any smoking (even a puff)
7-day point prevalence should also be reported

14. STIMULANTS: Assessment
Day-by-day calculation of abstinence / drug use
Longest duration of abstinence
Self-report (TLFB)
Urine toxicology – 3-4 days detection
Saliva / sweat / hair
Percentage of negative/positive results
Biochemical verification
No accepted meaningful outcomes based on use (i.e., no heavy use equivalent)
No standard quantity
Use Measures

15. STIMULANTS: Common Outcomes
Percentage of days abstinent (PDA)
Self-reported days of abstinence / total days in specified period
Longest duration of abstinence
Maximum number of self-reported days
Percentage of positive (or negative) urine toxicology results
Urine result only; highly variable based on denominator
Percentage of subjects achieving abstinence of ‘x’ duration
Based on dichotomous indicator of achieving abstinence or not
Donovan et al, Addiction (2012)
No single clinical metric appropriate for all trials
Ideally would combine self-report and biological indicators
Most appropriate outcome will vary by study methods and goals

16. STIMULANTS: Comparison of Outcomes
Carroll et al (2014)
Pooled data across 5 RCTs evaluating treatment for cocaine (N=434)
Compared common continuous and dichotomous outcomes
Reduction indicators based on days of cocaine use
Evaluated correlations with cocaine use during follow-up
Determined sensitivity to effects of pharmacologic and behavioral treatments
* Rates of discordance b/w self-report and urine results ranged 8-16%

17. Percent cocaine negative urine specimens -.31 -.28 -.30 -.16 .33 .00
Days of cocaine Use Month 1
Days of cocaine Use Month 3
Days of cocaine Use Month 6
Days of cocaine Use Month 12
Abstinent throughout FU
Percent cocaine negative urine specimens r
-.31
-.28
-.30
-.16
.33 p
.00
.01
Maximum consecutive days of abstinence
-.24
-.26
-.12
.30
.02
Percent days of abstinence
-.39
-.37
-.35
.19
Days of consecutive abstinence during participants last two weeks of treatment
-.46
-.21
.32
Percent completely abstinent last two weeks of treatment
-.25
-.19
-.07
.28
.25
Percent attaining 3+ weeks of abstinence
-.33
Percent attaining 2+ weeks of abstinence
-.14
.24
Percent attaining 1+ week of abstinence
-.27
-.22
-.10
.11
.05
Percent abstinent during treatment
-.08
-.11
-.09
.23
.12
.03
.09
Percent reduction in frequency of cocaine
-.32
.18
.07
Percent attaining 50% reduction
-.02
-.01
.04
.65
.76
.67
.49
Percent attaining 75% reduction
-.04
.08
.14
.42
.92

18. STIMULANTS: Preferred Outcomes
MOST Meeting - Kiluk et al (2016)
No single preferred outcome
Reduction-based measures defined by quantity should be abandoned
Any reduction should be based on days of use
Urine drug screens are essential component
Used to corroborate self-report rather than primary outcome
Pursue low-risk cocaine use by evaluating patterns (‘intermittent use’)
E.g., 1-4 days per month

19. SUMMARY OF OUTCOMES Alcohol Tobacco Stimulants
Only substance with approved ‘low-risk’ outcome (PSNHDD)
WHO risk-levels promising as reduction indicator
Alcohol
Abstinence-based only (PA or PP)
7-day point prevalence (self-report w/ verification)
Missing as failure
Tobacco
Prolonged abstinence
Frequency-based only (not quantity)
Urine results commonly used as outcome
Stimulants