Lofexidine for Inpatient Opiate Detox in Singapore
Condition: Opiate Dependent Patients Who Are Undergoing Inpatient Detoxification in Singapore
Study type: Interventional
Phase: Phase 4

Summary: 
      In Singapore, opiate substitution medication e.g. methadone is only licensed for use with
      specific population. The standard treatment is one week of detoxification assisted with
      diazepam and symptomatic treatment followed by one week of rehabilitation. However, diazepam
      is highly addictive and widely abused among heroin users and pharmacologically, does not
      reduce the physical and psychological craving for opioids which can trigger relapse. Many
      opiate patients undergoing inpatient detoxification leave prematurely (i.e. PID: patient
      initiated discharge) because of the severity of unpleasant withdrawal symptoms. The purpose
      of the study is to establish an alternative medication to reduce opiate withdrawal symptoms
      for use in Singapore by evaluating the clinical efficacy of Lofexidine versus Diazepam in the
      management of the opiate withdrawal syndrome during inpatient detoxification.
    

Detailed description: 
      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).
    

Intervention name(s): Lofexidine; Diazepam; Placebo for Lofexidine; Placebo for Diazepam
Intervention type(s): Drug; Drug; Drug; Drug
Other intervention name(s): BritLofex 0.2mg; Apo-Diazepam 5mg and 2mg
Intervention MeSH terms: Lofexidine; Clonidine; Diazepam
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Opiate dependent; inpatient detoxification