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

Pharmacokinetics of Prodetoxone(data from the manufacturer)

Blood samples were collected in one week, one and two months after implantation

010 20 30 40 50 60 70

Time after implantation, days

Co

nce

ntr

atio

n, n

g/m

l

Naltrexone metabolite Naltrexone

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

Demographics and Clinical Characteristics

Group

OP+PI ON+PI OP+NI

N 102 102 102

Gender (female) 27,5% 27,5% 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

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 19 20 22 230

0.2

0.4

0.6

0.8

1

1.2

PO+PION+PIPO+NI

*

*

*

* P<0.01 to placebo

* *

* * ** * *

***

Weeks

** *

***

**

***

*

Retention in treatment (Remission) (% of patients)

Log Rank (Mantel-Cox) Sig.

P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069

Kaplan-Meier Survival Functions: Drop out

Kaplan-Meier Survival Functions: Relapse

Log Rank (Mantel-Cox) Sig.

P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,024

PO+PI ON+PI PO+NI0%

10%

20%

30%

40%

50%

60%

11%

16%

53%

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)

Relapses in Naltrexone implant group

WEEKS

Treatment Effectiveness Score (TES): [Heroin positive + Missed visits] (%)

P<0,001

P<0,001

P=0,046

0 2 4 6 8 10 12 14 16 18 20 22 240%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PO+PI

ON+PI

PO+NI

**

* *

**

*

*

** *

*

* - P<0,01 Fisher's Exact Test

WEEKS

Average TES per group

Genetic Analysis Thomas Kosten, MDDavid Nielsen, PhD

Baylor College of Medicine

I). Gens of µ-opiate receptors:1) 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

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

Cu m u la ti ve P ro p o rti o n S u rvi vi n g (K a p la n -M e ie r)[O P RM 1 3 ,CO M T ,O P RK 1 ] p =0 .0 3 7 (Co x's F-te st)

Co m p le te Ce n so re d

A A A G T T A G A G T T

th e o th e rs0 5 1 0 1 5 2 0 2 5 3 0

T im e

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Cu

mu

lativ

e P

rop

ort

ion

Su

rviv

ing

Cu m u la ti ve P ro p o rti o n S u rvi v i n g (K a p la n -M e ie r)[O P RM 1 1 ,CO M T ,O P RK 1 ] p =0 .0 2 (Co x's F-te st)

Co m p le te Ce n so re d

CCA G T T CT A G T T

th e o th e rs 0 5 1 0 1 5 2 0 2 5 3 0

T im e

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Cu

mu

lativ

e P

rop

ort

ion

Su

rviv

ing

(p=0.02) (p=0.03)

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

p=0.063 p=0.043

Use of other drugs

Fisher's Exact Test P=0,003

Benzos Amphetamines

THC

Physical Anhedonia Social Anhedonia

Anhedonia (Chapman at al.)

Anhedonia (J. Ferguson et al.)

LACK OF INTEREST LACK OF PLEASURE

PO+PI ON+PI PO+NI0%

1%

2%

3%

4%

5%

6%

1%

0%

5%

n

AE (non-surgical) (% visits)

AE (surgical) (% implants)

POP+IP=0.02

PON+IP=0.002

PO+PI ON+PI PO+NI0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

3%

1%

3%

PON+IP=0.002

No SAE in either group

ALT & AST

SummaryImplantable 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

1. Surgical procedure2. Wound infections (particularly in HIV+

individuals)3. Cosmetic defects 4. Relatively easy to take out within the

first few weeks after implantation5. Dos not provide 2 months long

blockade in some patients (small proportion)