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

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 How to cite this paper: Kadric, S., Mohler, H., Kallioniemi, O. and Altmann, K.H. (2019) 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. World Journal of Neuroscience, 9, 113-137. https://doi.org/10.4236/wjns.2019.93008 Received: June 15, 2019 Accepted: July 22, 2019 Published: July 25, 2019 Copyright © 2019 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/


Introduction
Cocaine dependence is a significant public health problem that is characterized by recidivism and associated with serious medical, psychiatric, social, and economic consequences [1]. This highly-addictive drug initially produces euphoria.
Often, users become psychotic, violent, and suicidally depressed [2]. Safe and effective means of counteracting drug abuse are needed. Although proven pharmacotherapies are available for alcohol and heroin dependence none exist for cocaine dependence despite two decades of clinical trials primarily involving antidepressants, anticonvulsants, and dopaminergic medications [3] [4] [5].
Although many compounds have been evaluated for the treatment of cocaine dependence, none has been approved for this indication. Psychosocial and behavioral therapy are currently the treatments of choice for cocaine dependence [6]. Current strategies to treat cocaine dependence include: 1) blocking its effects, 2) restoration of central nervous system homeostasis, 3) reducing craving or enhancing the addict's ability to manage his/her response to craving, 4) treating underlying conditions (or consequences of use) that may predispose targeted subpopulations toward dependence. An effective pharmacotherapy has long been sought to improve treatment outcomes, particularly since this disorder has a significant neurobiological basis. The mesolimbic dopamine is a crucial neurochemical mediator of rewarding behaviors, e.g., eating and sex [7]. In vivo microdialysis studies have demonstrated that the level of extracellular dopamine increases in the nucleus accumbens by people engaged in rewarding behavior, such as or cocaine self-administration. It is believed that the ability of a drug to elevate the level of mesolimbic extracellular dopamine is critical to its abuse and those drugs that inhibit dopamine reuptake, thereby resulting in addictive and euphorogenic effects, are classified as "type 1 blockers" [8]. Increased use of cocaine in the 1980s resulted in a parallel increase in cocaine use by cocaine-dependent and methadone-maintained patients. The increase in the use of cocaine has been further compounded by the link between intravenous drug abuse and the spread of HIV. Consequently, public awareness of drug abuse has increased, leading to drug abuse treatment becoming a national priority in many countries. Accordingly, there is a constant and ever growing need for pharmacotherapies, which enable the treatment of larger numbers of drug abusers than would otherwise be possible with nonpharmacological treatment modalities and which can be coupled with more traditional treatment approaches, such as counseling and rehabilitation [9]. One pharmacotherapeutic approach is to develop a competitive World Journal of Neuroscience cocaine antagonist, i.e., a drug that will bind to the dopamine transporter but will not inhibit dopamine reuptake [10]. Such a cocaine antagonist would be expected to block cocaine from increasing the level of extracellular dopamine. However, a patient could overcome the inhibitory effect of a competitive cocaine antagonist by self-administering more cocaine. Another pharmacotherapeutic approach is to develop a noncompetitive cocaine antagonist. The noncompetitive cocaine antagonist would be one that binds to the dopamine transporter with high affinity and dissociates slowly. The noncompetitive cocaine antagonist would then provide a sustained increase in the level of extracellular dopamine, thereby providing the drug abuser with some relief from cocaine-craving due to dopamine deficiency yet inhibiting cocaine from further elevating the level of extracellular dopamine and increasing the probability of increased toxic side effects [11]. One such noncompetitive cocaine antagonist is the compound 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4- [3-phenylpropyl]piperazine, otherwise known as Vanoxerine. Vanoxerine is a selective inhibitor of dopamine reuptake and is about 700-fold more potent than cocaine in inhibiting dopamine reuptake in vitro. Unlike cocaine, however, vanoxerine-inhibited dopamine reuptake does not result in addictive and euphorogenic effects and, thus, vanoxerine is considered to be a "type-II blocker". In addition, although cocaine and vanoxerine produce equivalent motor-stimulating effects, vanoxerine must occupy the dopamine transporter to a greater extent than cocaine in order to produce equivalent behavioral effects. Similarly, although cocaine and vanoxerine cause dose-related elevations in extracellular dopamine when given alone, cocaine causes a rapid and short-lived increase in dopamine, whereas vanoxerine causes a low and sustained elevation of dopamine [12].
Currently, there are no available drugs that will effectively block the acute ef-  [14]. Vanoxerine has been used as dopamine agonists for the treatment of Parkinsonism, acromegaly, hyperprolactinemia and diseases arising from a hypofunction of the dopaminergic system [15]. However, the method of the study using Vanoxerine and analogs thereof as cocaine antagonists had not been known previously. Methods are disclosed for treating cocaine addiction, acute effects of cocaine, and cocaine craving.
The methods of treatment can counteract cocaine intoxication and prevent relapse into drug use during and after treatment. Safe and effective means of counteracting drug abuse are needed. The studies disclosed herein provides a means for blocking the acute effects of such drugs [16]. By decreasing or limiting the "high" effect World Journal of Neuroscience of dosing with euphoria producing drugs, the method of treatment can counteract cocaine intoxication and prevent relapse into drug use during and after treatment. Although drug treatments for cocaine craving are available, there are currently no drugs available which will effectively block the acute effects of cocaine. The drug, Vanoxerine Consta  , presented in this study acts as a cocaine antagonist. We believe that the ability of Vanoxerine Consta  to bind tightly to, and dissociate slowly from, the dopamine reuptake complex, is the underlying mechanism responsible for its cocaine antagonist activity. It has been demonstrated that Vanoxerine Consta  act as a cocaine antagonist for extended intervals, ranging from a few weeks to 3 months [17]. The present study provides sustained-release derivatives of hydroxylated analogs of substituted compositions comprising the same, and a method of using such sustained-release derivatives to bind the dopamine transporter to achieve a desired effect, such as antagonism of dopamine reuptake inhibitors, such as cocaine, or dopamine releasers or norepinephrine and/or serotonin reuptake inhibitors, such as methamphetamine [18]. Since it is believed that the inhibition of DA reuptake is thought to be the major neurochemical mechanism responsible for the addictive properties of cocaine, PCP, amphetamine and methamphetamine, these agents also interact with the reuptake carriers for serotonin and norepinephrine. The treatment of these addictions is also within the scope of our research wherein treatment effects the DA reuptake complex since these drugs also bind tightly (reversibly or irreversibly) to the serotonin or norepinephrine reuptake carriers [19].
Vanoxerine Consta  is supplied as a microsphere formulation of Vanoxerine [20]. The active ingredient in Vanoxerine Consta  -Vanoxerine-is an anta-  [26]. Several examples in the literature discuss their effectiveness in providing targeted drug levels in vivo, for long periods of time. For this reason, they are popular as delivery vehicles for drugs where the sustained release is desired for extended intervals, ranging from a few weeks to 12 months [27]. The success of PLGA polymers as delivery systems is due to the fact that polymer properties are well understood and can be customized to afford sustained drug release. For instance, selection of copolymers of various lactide: glycolide with variable molecular weights is an effective way to control polymer degradation rate and drug release. By changing the composition of lactide or glycolide in the copolymer, a wide range of degradation rates can be obtained. An increase in the more hydrophobic lactide moiety ensures a slower degradation rate of the PLGA polymer leading to the extended duration of drug release [28]. Similarly, utilization of a higher molecular weight copolymer increases degradation times leading to prolonged drug release. Additional properties that can be varied include polymer crystallinity and glass transition temperature. These physical and chemical properties have been well studied and characterized leading to predictable degradation kinetics of the PLGA polymer, in vitro and/or in vivo [29]. Upon in vivo administration of a PLGA based injectable depot, water interacts with the polymer and hydrolysis of the ester bonds commences. As the polymer degrades, its hydrophobicity decreases and the number of hydrophilic hydroxyl and carboxylic acid end groups in the matrix increases. An accumulation of hydrophilic acidic end groups has a two-fold effect: 1) it increases the amount of water incursion into the polymer and 2) initiates autocatalysis of the polymer matrix. Therefore, polymer degradation and, consequently, drug release from PLGA is a very complex and dynamic process. The study presented a report of the results of a 3-month double-blind phase in terms of the effectiveness and safety of Vanoxerine Consta  for the treatment of cocaine dependence. There was no statistically significant difference between plasma concentrations of Vanoxerine and Central Dopamine transporter receptor occupancy by Vanoxerine between days 1 and 84 (medium limit of quantification).
The depot formulation of Vanoxerine used in the current study provided a safe, effective and long-lasting antagonism of the effects of cocaines.

Methods
This randomized clinical trial received 2600 patients in a clinical setting for treatment with long-acting injection of Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks compared to Placebo injection given intramuscularly once in 12 weeks. The inclusion was discontinued on August 10, 2010, and the last patient monitoring was carried out on July 23, 2011. The study was approved by the State Committee for Medical and Health Ethics, State Medicines Agency and research ethics committees in the participating countries and hospitals. The monitoring study was conducted by publicly funded supervisory authorities in accordance with good clinical practice standards. The participants gave a written informed consent.

Participants and Setting
Patients were recruited from March 10, 2009 to August 10, 2010 by research staff from 17 hospital clinics and detoxification units in 15 countries. Eligible participants were cocaine-dependent (according to DSM-IV criteria) men or women aged 22 to 34 years. Exclusion criteria were dependence on other drugs or alcohol or serious somatic or psychiatric illness that was considered a contraindication or required therapy that would interfere with participation in the research (Table 1).
Women in reproductive age could not be pregnant or breast-feeding and agreed to use effective birth control. Participants were screened for psychiatric disorders and examined for severe somatic illness. Routine blood tests (complete blood cell counts, electrolytes, and levels of ALT/AST) and urinalysis were completed as part of usual treatment before study enrollment. Assessments added for the study included a detailed history of drug use and psychiatric interview to confirm current cocaine dependence; urine testing for cocanie and alcohol breath test; Addiction Severity Index; pregnancy test; monthly measurements of ALT and AST levels while receiving medication; cocaine craving (visual analog scale); Global Assessment of Functioning; Brief Psychiatric Rating Scale; and visual inspection of the site 5 to 7 days after implantation (Table 2). Urine drug testing was performed at biweekly counseling sessions. Eligible participants were referred to the detoxification unit after examination and inclusion. The study took place at the hospital facility, and all participants were discharged from the detoxification unit and are in the process of hospital treatment. Ethnicity is defined by the participants.

Procedure and Outcomes
After detoxification, participants were randomly assigned (1:1) to commence ei-  12) or "cocaine-free" was defined as a negative urine drug test for cocaines and no self-reported cocaine use. The twice a week UDTs were analyzed using specific chromatographic methods and calculated as the number of cocaine-negative urine drug screens divided by the total number of attended tests (group proportion) in accordance with recently revised Cochrane guidelines. Missing UDTs were considered as testing positive for cocaines in all participants. Secondary outcome variables were comparison of retention in the study, number of days in treatment, the degree of cocaine craving (Minnesota Cocaine Craving Scale (MCCS): Composed of five items which correspond to intensity, frequency, duration of craving, changes in relation to previous week and craving response to medication), and mental health (Hopkins Symptom Checklist-25 of anxiety and depression, 25 -100, with 25 indicating very low; 100, very high). Retention in treatment was defined as the number of days until dropout from study medication and by the number of patients completing the study at week 12. Participants who completed this randomized clinical trial were invited to continue or cross over to either treatment for up to 48 weeks. These data will be described in a subsequent publication.

Pharmacokinetic Studies Protocol
Blood samples were collected through an indwelling plastic cannula, inserted into a superficial upper arm vein, into tubes containing anticoagulant Li-heparin.
They were drawn at given time points, centrifuged, and plasma was separated

PET Studies Protocol
Dopamine transporter receptor occupancies were measured at day 2, 12, 36, 60, or 84 after single Vanoxerine administration (by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography). A highly sensitive method has been developed to measure drug occupancy of the dopamine trans-

Statistical Analysis
The target sample size was based on the width of the 95% CI for the hazard ratio

Retention in Treatment
Among the 2800 participants assessed for eligibility, 2600 were included in the study and 1300 were randomized to treatment with Long-acting intramuscular

Secondary Endpoint: Craving
Craving was reported weekly according to a Minnesota Cocaine Craving Scale (MCCS), composed of five items which correspond to intensity, frequency, duration of craving, changes in relation to previous week and craving response to medication (we used the first three items of the scale (none 0 to 10 maximum visual score analogue scale)).
Reduction in craving intensity was observed in baseline and every week to final evaluation, week 12. A statistically significant finding in this study was a decrease in craving intensity, frequency and duration of craving. A statistically and clinically significant reduction in cocaine craving was observed with Vanoxerine tensity, frequency and duration of craving for cocaine than Placebo participants. Patients given Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) had a 75% decrease in craving intensity, 70% decrease in frequency and 75% in duration from baseline to week 12. Patients given a Placebo injection had a 1% increase in craving from baseline to week 12.
Satisfaction with treatment was significantly higher among Vanoxerine Consta 394.2 mg, long-acting depot formulations) participants and they would also recommend their treatment to others to a higher extent compared with Placebo participants. The main clinical implication of this result is that Vanoxerine Consta seems to reduce craving, which is one of the main factors related to relapses in drug dependence.

Pharmacokinetic Assessments: Concentrations of Vanoxerine and 17-Hydroxyl Vanoxerine in Plasma
Analyses

PET Assessments
Very high Central Dopamine transporter receptor occupancy by Vanoxerine was

Discussion
To our knowledge, this is the first study comparing the effectiveness of long-acting There was no reported overdose in the study. This low rate may reflect the high motivation for treatment and good response to regular follow-up by the same study worker in this group of participants. In the present study, several participants used cocaine after receiving the depot injections, but there was no evidence that attempts to override the blockade were successful, and no accidental or intentional cocaine over-doses occurred. It is possible that the gradual dissipation of Vanoxerine from these long-acting injectable formulation (Vanoxerine Consta 394.2 mg) protected these patients from experiencing cocaine overdose.
The results of the study also show the consistency of release of Vanoxerine and on the average level of Vanoxerine between 70.4 and 94.3 ng/mL over the 12, weeks life of the Vanoxerine Consta 394.2 mg. After the administration of long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg), mean Vanoxerine plasma levels ranged from 77 and 94 ng/mL. Across the 12-week study, plasma Vanoxerine levels tended to be fairly constant, with perhaps a slight decline during the twelfth week after drug administration. In general, many investigators agree that doses that maintain Vanoxerine plasma levels of approximately 70 ng/mL are sufficient for antagonizing the effects of high doses of cocaine agonists.
Every single dose of long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) resulted in very high occupancy at the Central Dopamine transporter receptors (94% to 100%) measured 24 hours post-dose. The high Vanoxerine occupancy (95% to 79%) persisted 10 weeks after single dosing of long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and the receptor occupancy was still above 77%, 12 weeks after dosing.
Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) was more effective than Placebo in maintaining short-term abstinence from cocaine and should be considered as a treatment option for cocaine-dependent individuals.
This study demonstrated that a long-acting injectable formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) in conjunction with psychosocial treatment significantly reduced cocaine use in a large geographically varied sample of treatment-seeking patients with cocaine dependence. Long-acting injectable formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) was well tolerated, few serious In summary, the results from this trial, with one of the largest samples ever treated with a medication for cocaine dependence, indicate that long-acting injectable formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) is well tolerated and is associated with a significant reduction in cocaine use in the cocaine-dependent population ( Table 4). The long-acting formulation has the potential to improve intervention strategies for cocaine dependence by providing a predictable pharmacological foundation for treatment. In addition to their utility for cocaine dependence, long-acting formulations may prove to be an important treatment strategy for a variety of addictive disorders. The present results demonstrate that this long-acting injectable formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) is safe, well tolerated, and effective in retaining patients in treatment. An increase in treatment retention is particularly important because it will allow clinicians sufficient time to engage patients in psychotherapy so that they can learn to make other psychological and social adjustments that support life without cocaines.

Contributors
Academic Research Department of AURUM Group, Ludgate Hill, London City, UK designed the study and wrote the protocol. All authors implemented the study protocol and contributed to data collection. Emmes Corporation coordinated the Data Safety Monitoring Board and study monitoring. Emmes Corporation had access to study data, and statistically analysed and interpreted the data. Sead Kadric wrote the first draft of the manuscript. All authors contributed to and approved the final manuscript.

Declaration of Interests
All authors report grant or contract funding from the Aurum Charitable Trust.