DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY OF EFFECTIVENESS OF IMPLANTABLE NALTREXONE (PRODETOXONE) FOR TREATMENT OF HEROIN ADDICTION (Interim analysis) Е. Krupitsky, E. Zvartau, V. Egorova, D. Masalov, А. Burakov, М. Tsoy, N. Bushara, Т. Romanova, Е. Verbitskaya, Ch. О’Brian, G. Woody St.-Petersburg Pavlov State Medical University, University of Pennsylvania Supported by NIDA Grant R01-DA-017317

Implantable Naltrexone: Route and Dosage PRODETOXONE, tablets for implantation 1000 mg of naltrexone 2

Pharmacokinetics of Prodetoxone (data from the manufacturer) Concentration, ng/ml 10 20 30 40 50 60 70 Time after implantation, days Naltrexone metabolite Naltrexone Blood samples were collected in one week, one and two months after implantation

METHODS 306 male and female heroin addicts after detoxification, giving informed consent and passing a Naloxone challenge had been randomly assigned to one of three treatment groups (102 PATIENTS EACH). Three cell study design: 1. Naltrexone Implant (1000 mg) (3 times, every 2 months) + Oral Placebo (OP+NI). 2. Oral Naltrexone (50mg/day) + Implant Placebo (3 times, every 2 months) (ON+PI). 3. Implant Placebo (3 times, every 2 months) + Oral Placebo (OP+PI). All patients received biweekly clinical management / compliance enhancement counseling. Treatment lasted 6 months. Control of abstinence, compliance, psychiatric symptoms, and side effects – every other week. All patients had at least one family member who was able to supervise medication compliance. Study design: Double blind double dummy placebo controlled randomized clinical trial.

Recruitment details 358 approached 309 met inclusion criteria 306 got randomized 5

Demographics and Clinical Characteristics Group OP+PI ON+PI OP+NI N 102 Gender (female) 27,5% Age (M±SEM) 28,0±0,40 27,9±0,40 28,7±0,45 Duration of heroin dependence (M±SEM) 7,8±0,38 7,9±0,41 8,3±0,39 Number of previous treatments (M±SEM) 3,8±0,31 4,3±0,37 4,9±0,41

Retention in treatment (Remission) (% of patients) * * * * * P<0.01 to placebo * * * * * * * * * * * * * * * * * * * * * * Надо исправить подпись к красной линнии: PO+I => PO+IN Надо подписать ось абсцисс: Weeks Weeks

Kaplan-Meier Survival Functions: Drop out Log Rank (Mantel-Cox) Sig. P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069 8

Kaplan-Meier Survival Functions: Relapse Log Rank (Mantel-Cox) Sig. P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,024 9

Retention: End of treatmernt (6 months) OP+NI > OP+PI (P<0,001) OP+NI > ON+PI (P<0,001) (P<0,001) (P<0,001) 10

Relapses in Naltrexone implant group Вопрос: Почему по оси ординат указаны проценты? Проценты от чего? От суммы всех «досрочных» релапсов в группе Продетоксона WEEKS

Treatment Effectiveness Score (TES): [Heroin positive + Missed visits] (%) Average TES per group P<0,001 P=0,046 * * * * * * * * * * * * * - P<0,01 Fisher's Exact Test Надо исправить подпись к крайнему левому столбику: PO+I => PO+IN Надо добавить надпись WEEKS под осью абсцисс на левом верхнем графике; На нем по оси ординат - % от 102 анализов/визитов в каждой точке Надо добавить подзаголовок над правым нижним графиком (что это за график?) Что отложено на правом нижнем графике по оси ординат – т.е. в чем здесь измeрена TES? - Среднее количество положительных+пропушеных анализов у человека WEEKS

Opiate negative visits * P<0,001 * * * * * * * * * * * P=0,046 * - P<0,01 Fisher's Exact Test

Genetic Analysis Thomas Kosten, MD David Nielsen, PhD Baylor College of Medicine I). Gens of µ-opiate receptors: OPRM11, 2) OPRM12, 3) OPRM13 II). Gene of ζ-opiate receptor: OPRK1 III). Gene of the enzyme COMT: COMT

Effect of genotype on the completion of the treatment: Uncertainty Coefficients (I) [OPRM13,COMT,OPRK1] 0,0 0,1 0,2 0,3 0,4 0,5 0,6 PO/NI (p=0.9) ON/PI (p=0.056) PO/PI (p=0.031) [AAAGTT] or [AGAGTT] the others

Effect of genotype on the completion of the treatment: Uncertainty Coefficients (II) [OPRM11,COMT,OPRK1] 0,1 0,2 0,3 0,4 0,5 0,6 PO/NI (p=0.89) ON/PI (p=0.075) PO/PI (p=0.056) [CCAGTT] or [CTAGTT] the others

Effect of genotype on the completion of the treatment: Kaplan-Meier Survival Functions

Effect of genotype on the completion of the treatment: Treatment Effectiveness Score

Use of other drugs Benzos Amphetamines THC Вопрос: Почему по оси ординат указаны проценты? Проценты от чего – от числа больных в данной точке? да, в процентах от больных, Вы же это как раз и просили поменять Fisher's Exact Test P=0,003 19

Craving for opiats

Anxiety and Depression State Anxiety (Spielberger scale) Depression (Beck scale) Надо вставить график депрессии Бека!!! Он пропал при пересылке!!!

Anhedonia (Chapman at al.) Physical Anhedonia Social Anhedonia Достоверных различий по Физической ангедонии нет? - Нет! При учете всех ковариат, вы это уже раз десять спрашивали

Anhedonia (J. Ferguson et al.) LACK OF INTEREST LACK OF PLEASURE

AE (non-surgical) (% patients) AT (surgical) (% patients) No SAE in either group

AE (non-surgical) (% visits) AE (surgical) (% implants) POP+IP=0.02 No SAE in either group PON+IP=0.002

ALT & AST Достоверных различий по АЛТ и АСТ нет? Нет вы уже спрашивали….

Summary Implantable naltrexone demonstrated greater effectiveness in the treatment of heroin dependence in comparison to oral naltrexone and placebo. Implantable naltrexone is basically comparable to oral naltrexone and placebo in terms of safety and tolerability except surgical adverse events.

LIMITATIONS for PRODETOXONE Surgical procedure Wound infections (particularly in HIV+ individuals) Cosmetic defects Relatively easy to take out within the first few weeks after implantation Dos not provide 2 months long blockade in some patients (small proportion)