Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2017-020723 on 19 July 2018. Downloaded from LiMA: a study protocol for a randomised, double-blind, placebo controlled trial of lisdexamfetamine for the treatment of methamphetamine dependence Nadine Ezard,1,2 Adrian Dunlop,3,4 Michelle Hall,3 Robert Ali,2,5 Rebecca McKetin,6 Raimondo Bruno,7,8 Nghi Phung,9 Andrew Carr,1,2 Jason White,7 Brendan Clifford,1,10 Zhixin Liu,2 Marian Shanahan,11 Kate Dolan,11 Amanda L Baker,4 Nicholas Lintzeris10,12 To cite: Ezard N, Dunlop A, ABSTRACT Strengths and limitations of this study Hall M, et al. LiMA: a study Introduction Methamphetamine dependence is a protocol for a randomised, growing public health concern. There is currently no double-blind, placebo controlled ► The study design is a prospective, randomised con- pharmacotherapy approved for methamphetamine trial of lisdexamfetamine for the trolled trial. dependence. Lisdexamfetamine (LDX) dimesylate, used treatment of methamphetamine ► Strength in methods includes allocation conceal- dependence. BMJ Open in the treatment of attention-deficit hyperactivity disorder ment, blinding, compliance measuring, drop-out 2018;8:e020723. doi:10.1136/ and binge eating disorder, has potential as an agonist measuring and analyses of results by intention to bmjopen-2017-020723 therapy for methamphetamine dependence, and possible treat. ► Prepublication history for benefits of reduced risk of aberrant use due to its novel ► The fixed-dose design is a limitation; if efficacious, this paper is available online. formulation. further dose–response relationship studies may be To view these files, please visit Methods and analysis A double-blind randomised indicated. the journal online (http:// dx. doi. controlled trial will be used to evaluate the efficacy of LDX ► The duration of active treatment is limited to 12 org/ 10. 1136/ bmjopen- 2017- in reducing methamphetamine use. The target sample weeks; if efficacious, further studies will be needed http://bmjopen.bmj.com/ 020723). is 180 participants with methamphetamine dependence to explore optimum duration of treatment and a re- ducing regimen. Received 15 March 2018 of ≥2 years, using ≥14 days out of the previous 28, who Revised 25 May 2018 have previously attempted but not responded to treatment Accepted 19 June 2018 for methamphetamine use. Participants will be randomly The study has been approved assigned to receive either a 15-week intervention Ethics and dissemination by the Human Research Ethics Committee of St. Vincent’s consisting of induction (1 week of 150 mg LDX or placebo), Hospital, Sydney, Australia (HREC/16/SVH/222). Contact the maintenance (12 weeks of 250 mg LDX or placebo) and corresponding author for the full trial protocol. reduction (1 week of 150 mg LDX or placebo and 1 week Trial registration number ACTRN12617000657325; Pre- on 17 September 2018 by guest. Protected copyright. of 50 mg LDX or placebo). All participants will be given results. access to four sessions of cognitive–behavioural therapy as treatment as usual and receive a 4-week follow-up appointment. The primary outcomes are efficacy (change BACkground from baseline in days of methamphetamine use by self- Methamphetamine is a synthetic stimulant report for the last 28 days at week 13 and urinalyses of growing global public health importance confirmation of methamphetamine use) and safety and an important contributor to the global (treatment-related adverse events). Secondary outcomes © Author(s) (or their 1 are total number of days of self-report methamphetamine burden of disease. There are an estimated employer(s)) 2018. Re-use 34 million people worldwide who use the permitted under CC BY-NC. No use over the 12-week active treatment, longest period of abstinence during treatment period, percentage of drug, and an estimated 17 million who are commercial re-use. See rights 2 and permissions. Published by achieving ≥21 days abstinence, craving, withdrawal, dependent on methamphetamine. BMJ. dependence, retention, bloodborne virus transmission Australia has one of the highest documented For numbered affiliations see risk behaviour, criminal behaviour, as well measures of rates of methamphetamine dependence in end of article. abuse liability, physical and mental health, other substance the world, with 160 000 people estimated to 1 use, cognitive performance, psychosocial functioning, be dependent during 2013/2014. Meth- Correspondence to Michelle Hall; treatment retention and satisfaction. Additionally, the study amphetamine dependence is estimated to michelle. hall@ hnehealth. nsw. will assess the cost-effectiveness of LDX relative to the cost Australia around $A5 billion a year, an gov. au placebo control. economic impact which could be reduced by Ezard N, et al. BMJ Open 2018;8:e020723. doi:10.1136/bmjopen-2017-020723 1 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020723 on 19 July 2018. Downloaded from effective treatments.3 4 Methamphetamine dependence from methamphetamine dependent19–21 subjects found is associated with a range of negative health outcomes no serious consequences of DXA in doses from 30 to including psychosis, depression, anxiety, bloodborne 110 mg/day.22 virus transmission, sexually transmissible infections, and While a statistically significant benefit on methamphet- cardiovascular and cerebrovascular events.5 These prob- amine use has not been established with DXA pharma- lems are most prevalent among people who use metham- cotherapy, feasibility has been demonstrated with 60 mg phetamine on a heavy or regular basis,6 highlighting the DXA/day (equivalent to 150 mg lisdexamfetamine).19 need for effective treatments for this group. Studies with sustained-release (SR)-DXA formulations There is no approved medication for the treatment have shown increased retention in treatment at up to of methamphetamine dependence. The current stan- 110 mg SR-DXA/daily (mean dose of 80 mg SR-DXA dard treatment for methamphetamine dependence daily),20 and decreased craving and withdrawal symp- relies on psychosocial interventions, primarily cogni- toms in a study using 60 mg SR-DXA.21 This latter study 7 tive–behavioural therapy (CBT)-based approaches. Such (n=60) with a treatment duration of 8 weeks concluded approaches produce small to medium reductions in that further studies should test a longer treatment dura- 8 methamphetamine use in controlled studies (d=0.53 ). tion, that higher doses of DXA could be warranted due to However, CBT approaches require a substantial invest- possible physiological tolerance, and that larger sample ment by trained therapists, there is often poor engage- sizes are required.21 ment with counselling by methamphetamine users, and Lisdexamfetamine, a pharmacologically inactive cognitive impairment associated with severe methamphet- 7 prodrug, is absorbed after oral administration and is amine dependence may limit CBT effectiveness. Poorer hydrolysed to inactive l-lysine and active DXA by red treatment outcomes are seen in methamphetamine users blood cells.23 It has a slower onset, lower peak concen- who use frequently (those using methamphetamine at tration and longer duration of action than DXA.24 It is least 15 days out of the previous 30 days at treatment metabolised rapidly to DXA: the peak plasma concen- entry), than in less frequent users,9 highlighting the tration occurs 3 hours after dosing. The plasma half-life need for more effective treatment approaches for such 25 (t½) of DXA is 10 hours, with plasma DXA concen- individuals. trations reaching steady state at day 5 of once daily Many authors have highlighted the potential role of lisdexamfetamine dosing.24 There is no plasma accumu- substitution agonist treatment for methamphetamine lation of lisdexamfetamine.24 The conversion time from dependence.10 The theoretical base for agonist prescrip- lisdexamfetamine to DXA results in a more blunted tion is consistent with the rationale for existing agonist effect on brain dopamine than immediate release substitution for nicotine and opioid dependence. Agonist DXA26 and, as a consequence, it has a more moderate substitution therapies aim to replace harmful drug use http://bmjopen.bmj.com/ reinforcing effect in self-administration studies due to with safer alternatives in terms of dose, route of admin- the slower onset of peak effects than other stimulant istration and adverse effects. Long-acting agonists 27 11 12 drugs. can reduce amphetamine withdrawal, craving and decrease the euphoriant and reinforcing effects of extra Abuse liability studies of lisdexamfetamine with doses (illicit) stimulant use due to cross-tolerance.13 Agonist of up to 150 mg indicate it has significantly less propensity for abuse-related ‘liking’ when compared with DXA or treatment also provides a framework for regular ongoing 28 healthcare and psychosocial interventions with this high- diethylpropion. The lower abuse liability of lisdexamfet- amine, due to its rate-limited hydrolysis, attenuated onset risk population, enabling patients to distance themselves on 17 September 2018 by guest. Protected copyright. from illicit drug networks and related crime. and intensity of amphetamine-like effects, and more Agonist therapies for methamphetamine depen- moderate reinforcing properties thus reduce the need dence show promise. A number of ‘weak’ stimulant for supervised dosing. agonist therapies have been studied, including methyl- There have been no published randomised controlled phenidate and modafinil.14 A recent systematic