TITLE:
A Multicenter, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Long-Acting Injectable Formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for Cocaine Relapse Prevention
AUTHORS:
Sead Kadric, Hanns Mohler, Olli Kallioniemi, Karl Heinz Altmann
KEYWORDS:
Vanoxerine Consta, Long-Acting Depot Formulations of Vanoxerine, Cocaine Dependence, Long-Term Delivery, PLGA Polymers
JOURNAL NAME:
World Journal of Neuroscience,
Vol.9 No.3,
July
25,
2019
ABSTRACT: Objective: To determine the efficacy and tolerability of a
long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2
mg) for treatment of cocaine-dependent patients. Design, Setting, and
Participants: A 12-week, A multicenter, randomized, placebo-controlled trial
conducted between June 2009-July 2011, at 17 Hospital-based drug clinics, in
the 15 countries. Participants were 18 years or older, had Diagnostic and
Statistical Manual of Mental Disorders-5 cocaine use disorder. Of the 2800 patients
who were assessed between March 10, 2009 to August 10, 2010, 2600 (93%) were
eligible and willing to take part in the trial and were enrolled: 1300 were
randomly assigned to receive injections of Long-acting depot formulations of
Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks
and 1300 to receive Placebo injections, given intramuscularly once in 12 weeks.
Only 100 of 2800 patients (3.6%) did not meet the inclusion criteria. Main
Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Cocaine
abstinence (percentage i.e. the number of patients who achieved complete
abstinence during 12 weeks). Confirmed abstinence or “cocaine-free” was defined
as a negative urine drug test for cocaines and no self-reported cocaine use.
Secondary end points included a number of days in treatment, treatment
retention and craving. The study also investigated, on 275 participants, degree
and time course of Central Dopamine transporter receptor occupancy following
single doses of long-acting intramuscular formulation of Vanoxerine (Vanoxerine
Consta 394.2 mg) as well as the plasma concentration of Vanoxerine and
17-hydroxyl Vanoxerine. Safety was assessed by adverse event reporting. Results: Of 2600 participants, mean (SD) age was 28.5 (±5.5) years and 598
(23%) were women. 1300 individuals were randomized to receive injections of
Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and
1300 to receive injections of Placebo. 1417 participants (54.5.0%) completed
the trial. Primary Endpoints: Confirmed Cocaine Abstinence: Complete abstinence
was sustained by 72% (n = 936) of Vanoxerine patients (patients treated with
Vanoxerine Consta 394.2 mg, long-acting depot formulations) compared with 37%
(n = 481) of patients treated with Placebo, during weeks 5 - 12. The difference
was significant as evaluated using a Chi-square test (χ2 = 672.34, P Secondary Endpoint: Craving: A statistically and clinically
significant reduction in cocaine craving was observed with Vanoxerine
(Vanoxerine Consta 394.2 mg, long-acting depot formulations) vs. Placeboby week
4 (P = 0.0048), which persisted every week through 12 (P Secondary
Endpoint: Treatment Retention: Long-acting intramuscular formulation of
Vanoxerine (Vanoxerine Consta 394.2 mg) helped significantly more patients
complete 12 weeks treatment (n = 936, 72%) compared with Placebo (n = 481, 37%)
(χ2 = 635.53, P Concentrations of Vanoxerine and
17-Hydroxyl Vanoxerinein Plasma: Analyses were made of 275 study samples. There
was no statistically significant difference for plasma Vanoxerine
concentrations between days 2 and 84 (p = 0.416). The plasma concentration of
Vanoxerine were 70.4 and 94.3 ng/ml and concentrations of 17-hydroxyl
Vanoxerine were 10.5 and 13.2 ng/ml, respectively. Plasma levels of Vanoxerine
remained above 70 ng/ml for approximately 12 weeks after administration of
Vanoxerine, long-acting depot formulations (Vanoxerine Consta 394.2 mg). PET
Assessments: Very high central dopamine transporter receptor occupancy by
Vanoxerine was detected 1 day after treatments, at which time point the
occupancy was 100.0% after Vanoxerine injection (Vanoxerine Consta 394.2 mg).
At days 7, 28, 56 and 84 post-Vanoxerine Consta 394.2 mg administration,
occupancies were 95% to 79%. Vanoxerine Consta 394.2 mg injection (long-acting
intramuscular formulation of Vanoxerine) led to very high occupancy of Central
Dopamine transporter receptors in all brain areas examined; nucleus accumbens,
caudate nucleus and putamen. Depending on the brain area Central Dopamine
transporter receptor occupancy varied between 95.0% and 79% at days 7, 28, 56
and 84 after dosing. High Vanoxerine occupancy (77%) persisted at 12 weeks
after the dosings. Adverse Reactions: Adverse events were similar in
cocaine-dependent patients treated with the long-acting intramuscular
formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) vs. patients treated
with Placebo. Conclusions and Relevance: Long-acting depot formulations of
Vanoxerine (Vanoxerine Consta 394.2 mg) were more effective than Placebo
injection in maintaining short-term abstinence from cocaine and should be
considered as a treatment option for cocaine-dependent individuals.