A Double-blind Randomised Controlled Clinical Trial of Lofexidine Versus Diazepam in the Management of the Opioid Withdrawal Syndrome During Inpatient Detoxification in Singapore

Study Design: This is a randomized, double-blind (double-dummy design) phase IV clinical trial. Patients will be receiving 10 days of Lofexidine plus Diazepam placebo or Diazepam plus Lofexidine placebo. All the patients are expected to complete the 2-weeks inpatient detoxification programme at the NAMS ward. Up to 122 patients (61 in each randomized arm) will be enrolled into the study to ensure that at least 43 patients in each arm complete Day 4 of study treatment programme. Efficacy Assessments: The primary efficacy outcome measure will be the Objective Opiate Withdrawal Scale (OOWS) scores (range = 0-13) on Day 3 and Day 4 of the treatment phase. The second efficacy outcome measure will be the Short Opiate Withdrawal Scale (SOWS), Opiate Craving visual analogue scale and Pupil size on Day 3 and Day 4, time to dropout (length of stay on the ward) and emotional/psychological symptoms measured every 3 days. Our expected study outcomes are as following: Significantly lower mean scores on the Objective Opiate Withdrawal Scale (OOWS) on day 3 and 4 of detox among patients in the lofexidine arm relative to those in the benzodiazepine arm Significantly lower mean scores on the Subjective experience of opiate withdrawal scale (SOWS)on day 3 and 4 of detox among patients in the lofexidine arm relative to those in the benzodiazepine arm Significantly larger pupil size on day 3 and 4 of detox among patients in the lofexidine arm relative to those in the benzodiazepine arm Significantly lower mean craving score on the Visual Analogue Scale on day 3 and 4 of detox among patients in the lofexidine arm relative to those in the benzodiazepine arm Significantly longer stay (days) on the ward among patients in the lofexidine arm relative to those in the benzodiazepine arm Significantly lower anxiety and depression score on the MAP among patients in the lofexidine arm relative to those in the benzodiazepine arm Safety Assessment and Monitoring: After signing the informed consent, the subject will undergo screening assessments to determine eligibility for study enrollment; the screen tests include FBC, LFT, Renal function and 12-lead ECG, and urine pregnancy test if female. A complete physical examination will be performed on the first day of screening. From Day 1 till discharge, Vital Signs (e.g. pulse rate, body temperature, blood pressure and respiratory rate) will be closely monitored by the study nurses at the ward, i.e. immediately prior to each lofexidine dose and in addition, 2 hours after the first dose of each dosing day. Should patients show signs of hypotension, the nurse will inform the investigators and they will determine whether or not it is necessary to terminate the patients' participation in the trial. Patients will be required to repeat a 12-lead ECG test when they complete the study or if they drop out of the study. If there is any significant finding from the repeat ECG, it will be followed through by the investigators until resolved. All the adverse events will be documented and followed through until resolved during the study period. The Regular Study Safety Reports inclusive of patients' recruitment, AE/SAE will be generated periodically and sent to an Independent Date & Safety Monitoring Committee (DSMC) for review, the DSMC comprise addiction medicine experts from outside of IMH. Individual patients or the entire study will be discontinued if there is any major safety finding. Sample Size and Statistical methods: The estimate of 122 subjects (61 per group) for the sample size is based on the following assumptions - mean (SE) OOWS scores on day 4 of 2.4 (0.4000) and 3.9 (2.7713) for the lofexidine and diazepam groups respectively (which implies an expected absolute treatment effect of 1.5), a power of 80%, and allowing for 30% of the patients dropping out before their evaluation on day 4. Thirty percent dropout implies that 86 subjects (43 per group) are required to evaluate the benefit of lofexidine over diazepam. The primary efficacy analysis will be done using the ITT dataset and the safety profile will be described using the safety dataset. All analysis will be conducted by independent statisticians (SCRI).