Opiate Dependent Patients Who Are Undergoing Inpatient Detoxification in Singapore Clinical Trial
Official title:
A Double-blind Randomised Controlled Clinical Trial of Lofexidine Versus Diazepam in the Management of the Opioid Withdrawal Syndrome During Inpatient Detoxification in Singapore
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.
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).
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment