A phase-2, open label, single-group trial was undertaken at two stimulant treatment outpatient clinics in New South Wales, Australia (18). Ethical approval was granted by the St Vincent’s Hospital Human Research Ethics Committee for both study sites (HREC/14/SVH/202). All participants provided written, informed consent prior to undergoing study assessments. An independent data safety and monitoring board reviewed safety data during and at completion of the study.
Recruitment and enrolment
Notices were displayed at clinics at both sites, as well as at other drug and alcohol services, associated community organisations, and local general practice clinics. Interested participants either approached or were referred to a research nurse who undertook a standardised pre-screening. If basic inclusion criteria and no exclusion criteria were met, potential participants attended a screening visit with a site principal investigator. Recruitment continued at all sites until the available number of potential participants was exhausted within the study frame.
Eligible participants were at least 18 years of age who had been dependent on methamphetamine for at least the preceding two years, determined by an Addiction Medicine physician (AD, NE) using ICD-10 criteria (19). Inclusion additionally required reported use of MA on 14 days or more of the previous 28 days at the time of screening, confirmed by two urine samples positive for MA one week apart. Patients who had used dexamphetamine in the previous four weeks were excluded, as were those with known sensitivity or previous adverse reaction to LDX or prescribed drugs which may interact with LDX (venlafaxine, desvenlafaxine, monoamine oxidase inhibitors), known contraindications to LDX (severe and symptomatic peripheral vascular disease or Raynaud’s phenomenon, significant prior or symptomatic cardiovascular disease, moderate to severe hypertension, glaucoma, phaeochromocytoma, hyperthyroidism, motor and phonic tics, Tourette’s syndrome, high suicide risk, voicing suicidal ideation, active psychosis, severe agitation or unstable use of alcohol or drugs other than MA as assessed by a specialist in addiction medicine (20)). Patients with well-controlled mild to moderate hypertension on a single antihypertensive agent were permitted, and those with a past history of psychosis were permitted on review by a psychiatrist. Pregnant or breastfeeding women, and women not willing to avoid becoming pregnant during the study were also excluded.
At the screening visit, informed consent was obtained as well as a detailed medical and substance use history, physical and mental state examinations, an electrocardiogram (ECG), and a urine human chorionic gonadotrophin (HCG) test (for women of childbearing potential) to verify eligibility.
All participants were commenced on a dose escalation regimen of supervised daily dispensing of ascending doses of LDX from 100mg to 250mg over four weeks, followed by a four week dose reduction regimen from 250mg to 100mg, and attended a follow-up visit four weeks after ceasing the study drug (see Figure 1). All participants were supervised at the point of administration by a dispensing nurse. Both participants and dispensing nurses were aware that the dose would first be escalated and then reduced, and of the dose range (100mg to 250mg); but they were blinded to the time points at which the doses changed. To achieve this, the dose comprised 5 identical size 0 capsules, each containing either 50 mg LDX or placebo according to the dose escalation phase. Participants received each dose for 7 days, based on the data that steady state for LDX is achieved after five days (21), and were reviewed by a medical officer weekly.
Participants not already engaged with psychological therapy were offered concurrent weekly counselling, although attendance was not mandatory. Participants were offered supermarket vouchers with a value of AUD $80 at the end of each of six visits: Baseline; Weeks 1 to 4 (escalation phase); and follow-up (Week 12) (total possible value of $480).
Criteria for withdrawing participants were: resting heart rate greater than 120 beats per minute (BPM) for more than 60 minutes; hypertension (two consecutive readings within one hour of each other where the systolic blood pressure [SBP] was greater than 160mmHg, or the diastolic blood pressure [DBP] greater than 100mmHg); clinically significant psychosis; or significant or serious adverse event related to the study drug. Other withdrawal criteria were diversion of study medication, missing more than one planned medical review, and missing three or more doses of study drug over a 7-day period. Full details of the study protocol were published prior to study completion (18), and the study was listed on the Australian and New Zealand Clinical Trials Registry (ACTRN12615000391572).
The primary outcomes of the study were the safety, tolerability, and regimen completion of ascending doses of LDX in adults with MA dependence.
Safety was assessed with a number of measures. Blood pressure, pulse, and temperature were recorded daily. Participants were assessed weekly by a physician and had treatment emergent adverse events (TEAEs) recorded. TEAEs were volunteered by the participants during or between visits, as well through physical examination, laboratory test, or other assessments. Severity of TEAEs was determined by a site principal investigator (both addiction medicine specialists). Severity of symptoms was graded as mild if they caused no or minimal interference with usual social and function activities and required no intervention. Moderate TEAEs were those which caused greater than minimal interference with usual social and functional activities, requiring only minimal intervention. Severe TEAEs were classified as those which resulted in an inability to perform usual social and functional activities and medically significant events which required intervention. Serious adverse events (SAEs) were medically significant events that were; fatal or life-threatening; resulted in persistent or significant disability or incapacity; or required unplanned inpatient hospitalisation. The Psychosis and Hostility items of the Brief Psychiatric Rating Scale (BPRS) (22) were administered weekly. The Insomnia Severity Index (ISI) (23), Patient Health Questionnaire 9 (PHQ9) (24) and the Generalised Anxiety Disorder 7 (GAD7) scale (25) were administered every two weeks and at Follow-up, measuring insomnia, depression, and anxiety respectively. The Patient Health Questionnaire 15 (26) was administered to assess for changes to somatic symptoms and weight in kilograms measured every four weeks. ECGs were recorded at Baseline and at Weeks 2 and 4.
Tolerability of LDX was assessed by the side-effects item of the Treatment Satisfaction Questionnaire for Medication (TSQM) (27), administered weekly from Week 1, and at Follow-up.
Regimen completion was defined as the proportion of participants enrolled who completed the escalation phase to the end of Week 4, at which point they would have received at least five days of 250mg of LDX.
Secondary outcomes were: efficacy measures; change in other substance use; medication acceptability; potential for non-prescription use; adherence; and neurocognitive functioning. Efficacy measures comprised changes in MA use (self-reported and urine screen), withdrawal, craving, severity of dependence, HIV transmission risk and criminal behaviours as well as participant-reported effectiveness measures. MA and other substance use was recorded weekly with a validated self-report tool, the Time Line Follow Back Questionnaire (TLFB) (28, 29). Urine samples were obtained weekly, and tested for the presence of MA. Craving and withdrawal were measured weekly from Baseline and at Follow-up. Craving was measured with a single item 0-100 Visual Analogue Scale (VAS) (30) and withdrawal with the Amphetamine Withdrawal Scale (AWS) (31). Severity of dependence was measured with the Severity of Dependence Scale (SDS) (32) at Baseline, Week 8 and Follow-up. The HIV risk behaviour and crime sections of the Opiate Treatment Index (OTI) (33) were completed at Baseline, Weeks 4 and 8, and at Follow-up. The TSQM Questionnaire (27) was administered weekly from Week 1 and at Follow-up to measure self-rated medication effectiveness, convenience and global satisfaction. Potential for non-prescription drug use was measured weekly from Baseline until Week 4 using the Drug Effects Questionnaire 5 (DEQ5) (34), the Acute Subjective Response to Substances questionnaire (ASRS) for amphetamines (35), a VAS to measure similarity to methamphetamine, and asking participants what price they would pay for the drug (PWP) (36).
General cognition was assessed using the Wechsler test of adult reading (37) and the Montreal Cognitive Assessment (38) at Baseline. Paper-based neurocognitive tests were administered at Baseline, Week 2, Week 4, and at Follow-up 4 weeks after drug discontinuation assessing switching (Trail making test (39, 40)), working memory (Digit-sequencing (41)) and verbal learning and memory (Rey Auditory Verbal Learning Task (42)). Electronic neurocognitive testing was conducted using the Penscreen Six software (43) on an Android 7” tablet assessing: processing speed (Digit-symbol test (41)), sustained attention (Rapid Visual Information Processing), attention/focus (Arrow flankers (44)) and inhibition (go/no-go (44)) weekly from Baseline until Week 4 and at Follow-up (45).
Adverse events were described by the proportion of participants who experienced TEAE by type, severity and dose. Non-parametric tests of paired data (Wilcoxon rank-sum test) were performed for measures taken at the beginning of Week 1 (Baseline), and compared to those taken at the primary endpoint, the end of Week 4 (at presumed steady state of 250 mg/day of LDX). Mixed Models for Repeated Measures (MMRM) were performed for primary cardiovascular (SBP, DBP, and heart rate) and neurocognitive outcomes. MMRM analyses makes use of all available data and is reliable for effect estimates under missing at random (MAR) assumption. The secondary outcomes of does adequacy, medication acceptability, and potential for non-prescription use are described using median scores and interquartile ranges at each dose. Missing urine drug results are assumed positive for methamphetamine. As per protocol, change in days of MA use were analysed separately for participants who partook in at least four sessions of counselling over the eight week trial period. Other secondary outcomes were tested for statistical significance with Wilcoxon rank-sum test for non-parametric data.