Safety and Tolerability of Oral Lisdexamfetamine in Adults with Methamphetamine Dependence: a Phase-2 Dose-Escalation Study
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Open access Original research BMJ Open: first published as 10.1136/bmjopen-2020-044696 on 18 May 2021. Downloaded from Safety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence: a phase-2 dose-escalation study Nadine Ezard ,1,2,3,4 Brendan Clifford,1,5 Adrian Dunlop,4,6,7 Raimondo Bruno,8 Andrew Carr,9 Zhixin Liu ,9,10 Krista J Siefried ,1,2,3 Nicholas Lintzeris4,11,12 To cite: Ezard N, Clifford B, ABSTRACT Strengths and limitations of this study Dunlop A, et al. Safety Objectives To examine the safety of an agonist- type and tolerability of oral treatment, lisdexamfetamine (LDX), at 250 mg/day among ► This study is the first to demonstrate the safe- lisdexamfetamine in adults adults with methamphetamine (MA) dependence. with methamphetamine ty, tolerability and acceptability of higher doses of Design A dose- escalating, phase-2, open- label, single- dependence: a phase-2 dose- lisdexamfetamine (LDX) in people with metham- group study of oral LDX at two Australian drug treatment escalation study. BMJ Open phetamine (MA) dependence than those currently services. 2021;11:e044696. doi:10.1136/ approved in the treatment attention deficit/hyperac- Setting The study was conducted at two Australian bmjopen-2020-044696 tivity disorder and binge eating disorder. stimulant use disorder treatment clinics. ► There are currently no pharmacotherapies approved ► Prepublication history for Participants There were 16 participants: at least 18 years this paper is available online. for the treatment of MA dependence, research into old, MA dependent for at least the preceding 2 years using To view these files, please visit medication options could provide a complementary ICD-10 criteria, reporting use of MA on at least 14 of the the journal online (http:// dx. doi. adjunct to the success of psychosocial therapies. preceding 28 days. org/ 10. 1136/ bmjopen- 2020- ► This pilot study demonstrated the safety and tolera- Interventions Daily, supervised LDX of 100–250 mg, 044696). bility of LDX in this population, which may encourage single- blinded to dose, ascending- descending regimen further larger scale trials of LDX as a pharmacother- Received 14 September 2020 over 8 weeks (100–250 mg over 4 weeks; followed by 4- apy for MA dependence. Revised 12 April 2021 week dose reduction regimen, 250–100 mg). Participants Accepted 16 April 2021 ► The small sample size and short duration of treat- were followed through to week 12. http://bmjopen.bmj.com/ ment is typical of pilot safety studies, limiting the Outcomes Primary outcomes were safety, drug tolerability clinical extrapolation of findings. and regimen completion at the end of week 4. Participants ► The study is not powered to explore efficacy of LDX were followed to week 12. Secondary outcomes and this precludes more sophisticated statistical included: change in MA use; craving; withdrawal; analysis. severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non- prescription use; adherence and neurocognitive functioning. second most commonly used illicit drug class. Results Fourteen of 16 participants (87.5%) completed An estimated 29 million people used amphet- on September 30, 2021 by guest. Protected copyright. 1 escalation to 250 mg/day. Two participants withdrew amines in 2019, with 7 million estimated to 2 from the trial in the first week: one relocated away from be dependent. Poor health outcomes are the study site, the other self- withdrew due to a possible, seen particularly among people who use MA known side effect of LDX (agitation). There was one several times a week,3 including psychosis, serious adverse event of suicidal ideation which resolved. depression, anxiety, bloodborne virus trans- All other adverse events were mild or moderate in severity mission, sexually transmitted infections, and and known side effects of LDX. No participant was cardio/cerebral vascular events.4 5 withdrawn due to adverse events. MA use decreased from Currently, treatment for MA dependence is a median of 21 days (IQR: 16–23) to 13 days (IQR: 11–17) © Author(s) (or their based on psychological therapies such as cogni- over the 4- week escalation period (p=0.013). employer(s)) 2021. Re- use tive–behavioural therapy.6 7 Psychological ther- permitted under CC BY-NC. No Conclusions LDX at a dose of up to 250 mg/day was safe commercial re- use. See rights and well tolerated by study participants, warranting larger apies are labour- intensive and predicated on and permissions. Published by trials as a pharmacotherapy for MA dependence. high levels of attendance and participation by BMJ. Trial registration number ACTRN12615000391572. patients. No pharmacotherapy has yet achieved For numbered affiliations see comparable efficacy, and there are as yet none end of article. licensed for the treatment of MA dependence. 8 Correspondence to INTRODUCTION Though agonist therapies show some promise, Dr Nadine Ezard; Amphetamine- type stimulants, including their efficacy for treatment of MA dependence nadine. ezard@ svha. org. au methamphetamine (MA), make up the is uncertain, with one systematic review showing Ezard N, et al. BMJ Open 2021;11:e044696. doi:10.1136/bmjopen-2020-044696 1 Open access BMJ Open: first published as 10.1136/bmjopen-2020-044696 on 18 May 2021. Downloaded from no benefit over placebo, although limitations in retention Recruitment and enrolment and power of published studies were noted.9 Dexamphet- Notices were displayed at clinics at both sites, as well as amine, an MA agonist, has similar neurochemical and at other drug and alcohol services, associated community behavioural effects to MA,10 and has been used off- label for organisations, and local general practice clinics. Inter- both amphetamine and MA dependence in the UK11 12 and ested individuals either approached or were referred Australia.13 to a research nurse who undertook a standardised Lisdexamfetamine (LDX) is a pharmacologically inac- prescreening. If basic inclusion criteria and no exclu- tive prodrug of dexamphetamine approved for the treat- sion criteria were met, potential participants attended a ment of attention deficit/hyperactivity disorder (ADHD) screening visit with a site principal investigator. in Australia, Brazil (in children only), Canada, several Euro- pean countries, the UK and the USA14 and more recently Participants for binge eating disorder (BED) in Australia and the USA. Eligible participants were at least 18 years of age who Potential advantages of LDX over immediate release dexam- had been dependent on MA for at least the preceding phetamine include once- daily dosing, a slower onset, lower 2 years, determined by an addiction medicine physician peak concentration, longer duration of action and lower (AD and NE) using International Statistical Classifica- abuse potential.15 LDX presents a candidate pharmaco- tion of Diseases and Related Health Problems 10th Revi- 21 therapy for MA dependence. sion (ICD-10) criteria. Inclusion additionally required There are no clinical trial data on the effectiveness of reported use of MA on 14 days or more of the previous LDX for the treatment of MA dependence. Chronic use of 28 days at the time of screening, confirmed by two urine high doses of MA may lead to physiological adaptation so samples positive for MA 1 week apart. Patients who had that a dose higher than the licenced therapeutic range of used dexamphetamine in the previous 4 weeks were medication is required.9 For the treatment of ADHD and excluded, as were those with known sensitivity or previous BED in stimulant- naïve populations, LDX is licensed for adverse reaction to LDX or prescribed drugs which may doses ranging from 30 to 70 mg/day. A previous study of interact with LDX (venlafaxine, desvenlafaxine, mono- dexamphetamine has trialled doses up to 110 mg for this amine oxidase inhibitors), known contraindications to 16 LDX (severe and symptomatic peripheral vascular disease population without serious adverse events (SAEs), which or Raynaud’s phenomenon, significant prior or symptom- is approximate to 275 mg of LDX using a mole weight atic cardiovascular disease, moderate to severe hyperten- equivalent of 100 mg LDX to 40 mg dexamphetamine.17 sion, glaucoma, phaeochromocytoma, hyperthyroidism, The highest dose for which safety data of LDX are avail- motor and phonic tics, Tourette’s syndrome, high suicide able is 250 mg/day, equivalent to 100 mg dexamphetamine, risk, voicing suicidal ideation, active psychosis, severe tolerated in a safety and pharmacokinetic study of LDX in agitation or unstable use of alcohol or drugs other than http://bmjopen.bmj.com/ non- MA dependent volunteers18 and in participants with MA as assessed by a specialist in addiction medicine22). clinically stable schizophrenia adherent to antipsychotic Patients with well- controlled mild to moderate hyperten- pharmacotherapy.19 sion on a single antihypertensive agent were permitted, This study aimed to determine the safety of LDX in people and those with a history of psychosis were permitted with MA dependence, at doses higher than those currently on review by a psychiatrist. Pregnant or breastfeeding approved for the treatment of ADHD and BED. The primary women and women not willing to avoid becoming preg- objectives of the study were to describe the safety, tolerability nant during the study were also excluded. and regimen completion of ascending doses of LDX in on September 30, 2021 by guest. Protected copyright. adults with MA dependence. Secondary objectives included Study procedures measures of efficacy, drug- liking and neurocognition. At the screening visit, informed consent was obtained as well as a detailed medical and substance use history, physical and mental state examinations, an ECG and a urine human chorionic gonadotrophin test (for women METHODS of childbearing potential) to verify eligibility. Trial design All participants were commenced on a dose escala- A phase-2, open- label, single- group trial was undertaken tion regimen of supervised daily dispensing of ascending at two stimulant use disorder treatment outpatient clinics 20 doses of LDX from 100 to 250 mg over 4 weeks, followed in New South Wales, Australia.