1. Amphetamine Addiction in Iceland and efficacy of pharmacotherapy Valgerður Rúnarsdóttir, M.D., Vogur Hospital Iceland SAA National Center of Addiction Medicine Ingunn Hansdóttir, PhD, Assistant Professor University of Iceland Research Counsil Member SAA National Center of Addiction Medicine Symposium on Emerging Data on Efficacy and Clinical Applications of Extended Release Naltrexone Formulations, presented at 75th Annual Meeting - College on Problems of Drug Dependence - June 15-20, 2013, San Diego, CA 1

2. Disclosure of relevant financial relationships Extended Release Naltrexone for Treating Amphetamine Dependence in Iceland NIDA research grant (2P50-DA012756-11) Alkermes provided study drug Naltrexone/placebo extended release formulation 2

3. Investigators University of Pennsylvania: George Woody, M.D Helen Pettinati, PhD Charlotte Royer-Malvestuto Biostatistician: Kevin Lynch, PhD NIDA project Manager Jamie Biswas, MD Vogur Hospital: Thor Tyrfingsson, M.D. Val Runarsdottir, M.D. Ingunn Hansdottir, PhD Data Manager: Magnus Einarsson Lead investigators Project co-ordinators Data analysis Other collaborators 3 Brown University Milunka Kojic, MD Alkermes Avani Desai, PharmD

4. Background Amphetamine addiction is a growing problem – Number of patients seeking treatment for amphetamine addiction has almost tripled over the past two decades – Proportion of patients has risen, gone from <10% in 1984 to a current rate around 36% Amphetamines used intravenously, increased risk of HIV and Hepatitis Increased use among youth No medications approved for treating amphetamine addiction Several suggestions that Naltrexone might be effective. 4

5. Swedish studies Jayaram-Lindstrom et al Am.J. Psychiatry, 2008 Significant effect using oral naltrexone in ramdomized, placebo-controlled 12 week trial of 80 amphetmine dependent outpatients. 5

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7. Rationale Can these results be replicated with extended release formula? Study proposed in Iceland – why Iceland? 7

8. Icelandic setting Centralized addiction treatment Good access to treatment, free or minimal fee Vogur hospital lynchpin in addiction trmt Population endorses disease concept Well trained staff Evidence based practice 8

9. Icelandic setting - Treatment as usual: Detox Hospitalization 7-10 days Residential: 4 weeks Intensive outpatient 5x week for 1 mo (60 hrs) 1x week for 3 mo (12 hrs) Outpatient follow-up 2x week for 3 mo (24 hrs) 1x week for 9 mo (36 hrs) 9

10. Study Design -I 100 amphetamine dependent treatment seeking patients at Vogur Hospital Randomized, double blind trial and 6 month trmt with VIVITROL® or VIVITROL®placebo and Treatment as usual Stratified by gender and IV status. All participants detoxed at Vogur Hospital and consented. Randomized before going to outpatient status. 10

11. Study Design-II First study injection 11

12. Screening and randomization 12

13. Study design - III Repeat injections weeks 4, 8, 12, 16, 20 Baseline assessments: Medical & social history, liver panel (wk3, 11, 23), HepC & HIV (wk24), ASI (wk 12, 24), Fagerström (wk 12, 24) RAB (wk 24), AUDIT (wk 24), Blood for genetics Brief weekly assessments urine, alcohol breath, AE‘s, TLFB, TSR, Craving Monthly assessments relapse, pregnancy, BDI, EuroQol, Month 12, mail-in assessment 13 Wk 24

14. Study Design- outcomes Primary outcome Proportion of amphetamine negative urines during weeks 1-24 of outpatient treatment Secondary outcomes Time to relapseDrug use HIV risk behaviorCriminal activity Treatment retention Depression Amphetamine cravingQuality of Life 14

15. Inclusion criteria Aged 18 or above. Primary diagnosis of current amphetamine dependence as defined by DSM-IV-TR with =>10 days of amphetamine use in past month. Successfully complete 7-10 day assessment and study baseline measures at Vogur. Abstinent from substances for at least 7 days Provision of contacts of 3 people Written consent 15

16. Exclusion criteria AST or ALT >5 times the top limit of normal. Physiologically dependent on opioids or other substances (nicotine excepted) or known concomitant or planned use of opioid analgesics, positive opioid urine drug test or positive naloxone challenge, No severe psychiatric, cognitive, or medical problems and no known hypersensitivity to naltrexone 16

17. Sample characteristics No significant differences between treatment grps on sample characteristics. Males 75% Caucasian 100% Average age 31 years – (19-30 years 49%; 30-40 36%; 40-58 15%) IV injecting20 HIV +0 HEP C9 17

18. Baseline demographics No significant differences between treatment grps on baseline demographics. Stable housing 88% Never married 37% Living with partner (>1year)14% Education completed 10th grade 59% Not completed 13% Employment (>11 days past mo)12% 18

19. Baseline diagnosis DSM-IV checklist physician diagnosis N (%) Amphetamine dependence100 Alcohol dependence75 Cannabis dependence69 Cocaine dependence26 Methylphenidate dependence15 Sedative dependence30 Opiate dependence0 19

20. Baseline Placebo Treatment (N = 49) (N = 51) Prior admissions, mean # 3 3 BDI score13 14 RAB drug risk0.8 1.5 RAB sex risk5.2 5.7 Amphetamine craving47 41 (VAS 0-100) 20

21. Self-reported amphetamine use 4 weeks prior to study TLFBmean Amphetamine use past month18 days Methylphenidate use past motnh0,6 Craving – VAS44 (0-100) 21 No difference at baseline between trmt grps

22. Missing data and retention 53% of treatment grp provided UDS at wk 24 47% of placebo grp provided UDS at wk 24 No differences in distributions of time to drop out between the trmt grps (log-rank test) 22

23. Retention Number of subjects receiving study treatment 23 Four or more injections: 22 treatment (29<4) 28 placebo (21<4)

24. Negative urines;% 1247 urines collected (1194-/53+) 2400 urines target

25. % Drug Positive Urines (N=1257) Amphetamine: 4.25 Benzodiazepines: 8.26 Marijuana: 6.98 Cocaine: 1.44 Opioids: 0.96 25

26. Ampetamine Craving Scale by trmt grp

27. Relapse 29 subjects self-reported amphetamine relapse (3 days or more) over 6 months – Treatment group: 14 – Placebo group: 15 32 subjects self-reported alcohol relapse (3 days or more) over 6 months – Treatment group: 19 – Placebo group: 13 27

28. SAE 15 participants had a SAE with 20 events 17 hospitalization due to relapse 1 pneumothorax 1 abdominal pain, elevated liver enzymes 1 potential suicide attempt with relapse 28

29. AE severity mild, moderate, severe

30. Adverse Events (total) 64 subjects reported an adverse event 38 subjects reported pain/swelling injection site 30

31. Placebo BSL Placebo W24 Treatm BSL Treatm W24 n=49n=28n=51n=24 BDI score14.88156 RAB drug risk0.80.151.51.0 RAB sex risk5.24.55.74.0 Amphetamine craving 47164112 31 Secondary outcomes

32. Conclusions Robust response to treatment as usual for those who stayed in trmt with no additional benefit from Naltrexone. Results did not replicate previous findings Similarties to other studies: in regards to severity of dependence BSL and retention Difference in amount of treatment received, start off in detox and 61% residential trmt before getting study drug. Trend towards worse outcome for those going directly to outpatient (37% /56% +UDS res/out) 32

33. Thank you! 33 Thanks for your attention