New pharmacotherapeutic treatment options for crack-cocaine dependent people in the Netherlands: A double-blind, placebo-controlled randomized feasibility study of sustained release dexamphetamine

Cocaine, particularly in its base form ('crack'), has become one of the drugs
of most concern in the Netherlands, being associated with a wide range of
medical, psychiatric and social problems for the individual, and with
significant public order consequences for society. Despite this status as one
of the most problematic addictions, available treatment options for cocaine
dependent patients are limited at best. To date, there are no proven effective
pharmacotherapies for cocaine dependence (De Lima et al., 2002; O*Brien, 2005;
Kampman et al., 2005; Dürsteler-MacFarland et al., 2013), despite the wide
range of medications tested for this specific type of dependence, including:
direct and indirect agonists (Amato et al., 2011; Pérez-Maná et al., 2011),
antidepressants (Pani et al., 2011), antipsychotics (Amato et al., 2007),
anticonvulsants (Minozzie et al., 2008; Alvarez et al., 2010), psychostimulants
(Castells et al, 2010), and disulfiram (Pani et al., 2010). In addition,
psychosocial interventions for cocaine dependence have generally produced
modest results (Knapp et al., 2007; Shearer, 2007). From these, one of the more
promising interventions * contingency management * has recently been
investigated in the Netherlands by our research group in the context of the
medical prescription of heroin to chronic heroin dependent patients with
concurrent cocaine use. In this study (the results of which are yet to be
published), we found that contingency management resulted in significant but
small reductions in cocaine use (Blanken et al., in preparation).
Given the limited success of psychosocial interventions and lack of
proven effective pharmacological treatment options, the testing of new
medications for cocaine dependence should be high on the research agenda. In
this testing program, two basic pharmacological strategies can be
distinguished, one directed at substantial reduction or total abstinence from
all stimulants and the other directed at the replacement of illegal,
short-acting stimulants that are smoked (i.e. crack-cocaine) or injected by
medically prescribed, long-acting stimulants that can be taken orally.
Concerning the first strategy, the anticonvulsant topiramate and the
alpha-adrenergic/glutamate agonist modafinil are currently under investigation
in the context of the wider pharmacotherapeutic study of our research group
(see Preface). Concerning the second strategy, a growing number of pre-clinical
and human studies suggest that the monoamine releaser dexamphetamine should be
the prime candidate for replacement therapy (Grabowski et al., 2004a; Castells
et al., 2010; Van den Brink 2012). Several controlled studies have shown
significant improvements in treatment retention and reduced cocaine use in
cocaine addicts receiving sustained release dexamphetamine (Grabowski et al.,
2001; Grabowski et al., 2004b; Shearer et al., 2003), without serious adverse
events (including no serious cardiovascular complications).
Hence, the pharmacotherapy proposed in the present study will consist
of sustained release dexamphetamine. The basic rationale for substitution
treatment for cocaine dependence is similar to that for other addictions: it
aims to replace uncontrolled and harmful drug use with regulated and safer use,
in terms of dose, route of administration and adverse effects, and it
facilitates engagement with health care services by attracting and retaining
addicted individuals in treatment (Shearer & Gowing, 2004). In addition, the
regular supervised prescription regimen may by itself help the patient to
structure his daily life. Oral application of sustained release dexamphetamine,
with a much slower onset and limited peak effect than crack-cocaine, clearly
meets the rationale for substitution treatment. As in any medication study, the
primary focus of our study will be on the balance between (potential) benefit
and harm produced by the medication, taking into consideration the personal and
societal damage associated with continued illicit use of cocaine, in a
situation without effective pharmacological treatment options.

The overall objective of this feasibility study is to investigate the
usefulness of sustained release dexamphetamine in the treatment of cocaine
dependence, and * dependent upon the results of both this study and the
parallel studies of topiramate and modafinil (see Preface) * to yield one or
more candidate medications for future investigation in a large-scale
confirmatory controlled trial. Specifically, the study aims to evaluate, in
crack dependent patients with comorbid heroin dependence, the response to
medically prescribed oral dexamphetamine SR (60 mg/day) as an add-on to
heroin-assisted treatment, in terms of potential efficacy, acceptance,
compliance, safety, and patient satisfaction.

The study will be conducted using a multicenter, double-blind,
placebo-controlled, randomized treatment design. Following screening and
baseline assessment, eligible patients in a heroin-assisted maintenance
treatment program will be randomly allocated (ratio: 1:1) by the collaborating
pharmacist to (continued) heroin-assisted treatment plus 12 weeks treatment
with placebo (control group; n=36) or to (continued) heroin-assisted treatment
plus 12 weeks treatment with sustained release dexamphetamine 60 mg/day
(experimental group; n=36). Randomization will be concealed, using a
computer-generated randomization list, and will be prestratified by treatment
center (4 treatment centers). Study assessments will take place at baseline,
and 4, 8, and 12 weeks after baseline. The primary time point at which
treatment outcome will be determined is 12 weeks after baseline.
A placebo-controlled design is deemed feasible, given that cocaine
dependent patients in an earlier study using sustained release dexamphetamine
60 mg/day were not able to distinguish placebo from dexamphetamine (Grabowski,
personal communication). Hence, selection bias due to drop-out resulting from
recognition of placebo is not expected.
The addiction treatment organizations that participate in the present
study are: Brijder Verslavingszorg (The Hague: 1 study site), BoumanGGZ/Antes
(Rotterdam: 1 study site), and GGD Amsterdam (Amsterdam: 2 study sites).

As described before, study participants will be recruited from the population
of patients who already receive (ongoing) heroin-assisted treatment for their
concurrent heroin dependency. Hence, heroin-assisted treatment will be the
underlying treatment (*treatment as usual*) for all patients, in both the
control and experimental group. In heroin-assisted treatment, patients have the
possibility to receive * dependent upon their usual route of heroin
administration * oral or injectable heroin (pharmaceutical grade
diacetylmorphine; max. single dose 400 mg; max. daily dose 1000 mg) three times
a day (morning, afternoon, evening), during seven days a week in designated
treatment centers, and oral methadone once a day (max. daily dose 150 mg). Both
heroin and methadone have to be taken under supervision at the treatment site.
On a yearly basis, the treating physician and other treatment staff evaluate
whether continuation of heroin-assisted treatment is indicated, based on the
patient*s health and social functioning. Diacetylmorphine was registered in the
Netherlands for the treatment of chronic, treatment-resistant heroin dependence
in December 2006, and has since then been prescribed for this indication in 17
designated treatment programs throughout the Netherlands.

Control treatment consists of ongoing heroin-assisted treatment (as described
above) plus 12 weeks treatment with placebo. Placebo (2 tablets/day) will be
matched to sustained release dexamphetamine tablets, and will be dispensed once
daily during the patient*s morning visit at the treatment center. For the
purpose of the present study, the placebo tablets were manufactured by the
Slotervaart pharmacist (group of prof.dr. Jos Beijnen), in compliance with the
principles and guidelines of good manufacturing practice (see appendix:
IMP-dossier, July 2013).

Experimental treatment consists of ongoing heroin-assisted treatment (as
described above) plus 12 weeks treatment with sustained release dexamphetamine
sulfate, prescribed in a fixed, single oral dose of 60 mg/day (2 tablets of 30
mg each). Oral sustained release dexamphetamine dose-levels of 30-60 up to 110
mg/day have been used in several studies in methamphetamine (Galloway et al.,
2011; Longo et al. 2010) and cocaine dependent (Grabowski et al., 2001, 2004b)
patients. In addition, oral dexamphetamine is prescribed to amphetamine users
with heavy, problematic use in the United Kingdom at doses ranging from 5-200
mg/day (Bradbeer et al., 1998). Sustained release dexamphetamine has an average
elimination half-life of approx. 12 hours, will be dispensed once daily during
the patient*s morning visit at the treatment centre, and * to allow intensive
safety monitoring * must be taken under supervision at the treatment site. In
addition, weekly assessments of heart rate and blood pressure will be conducted
during the entire study period of 12 weeks. For the purpose of the present
study, sustained release dexamphetamine sulfate tablets of 30 mg each were
manufactured by the Slotervaart pharmacist (group of prof.dr. Jos Beijnen), in
compliance with the principles and guidelines of good manufacturing practice
(see appendix: IMP-dossier, July 2013).

In case a patient terminates his/her study treatment before week 12, or is
withdrawn from the study for medical reasons, he/she will not be replaced by
another patient. Following the end of the 12 weeks trial period, patients will
continue their heroin-assisted treatment, but the study medication (either
placebo or sustained release dexamphetamine; due to blinding unknown to both
the treatment physician and research staff) will be terminated in all patients,
and all usual treatment options in Dutch addiction care will be available to
the patients, if indicated.

In both the control and experimental group, study assessments will take place
at baseline, and 4, 8, and 12 weeks after baseline. The assessments will be
conducted by trained research-assistants who are independent from the treatment
staff, using standardized instruments to minimize information bias. At
baseline, the treating physician will conduct a thorough medical examination to
determine whether the patient should be excluded from the study due to the
presence of contraindications. The duration of these study assessments amounts
to a maximum of approximately 5 hours in total (during a study period of 12
weeks).
Additional assessments include blood sampling (laboratory screen: BSE, MCH,
MCV, MCHC, GGT, ALAT, ASAT, alkalase phospate, leucocytes, thrombocytes)
(screening/baseline assessment and 12 weeks assessment; 2 x 16 ml), ECG
(screening/baseline assessment and 12 weeks assessment), weekly medical
screening (adverse and serious adverse events); weekly check on heart rate and
blood pressure; two times/week urine sampling (cocaine metabolites) during the
4 weeks preceding the 12 weeks assessment; monthly pregnancy testing (females).

Given the described safety profile of sustained release dexamphetamine sulfate
preparations, the few (serious) adverse events and mild and often transient
adverse reactions observed in studies in stimulant dependent patients, and
since the patients in the present study will be thoroughly screened (medical
screening, including blood pallet and ECG at baseline and 12 weeks follow-up)
and monitored ((S)AEs weekly; heart rate and blood pressure weekly), with
medication intake under direct supervision of the treatment centers' medical
staff, safety risks are expected to be small and manageable.