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Comparing Opium Tincture (OT) With Methadone for Medication-assisted Treatment of Opioid Use Disorder (OT-RCT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02502175
Recruitment Status : Completed
First Posted : July 20, 2015
Last Update Posted : July 12, 2019
Sponsor:
Collaborators:
Tehran University of Medical Sciences
Iran National Science Foundation
AJA University of Medical Sciences
Information provided by (Responsible Party):
Michael Krausz, University of British Columbia

Tracking Information
First Submitted Date  ICMJE July 13, 2015
First Posted Date  ICMJE July 20, 2015
Last Update Posted Date July 12, 2019
Actual Study Start Date  ICMJE June 22, 2017
Actual Primary Completion Date March 8, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
Retention in treatment [ Time Frame: three months ]
percent of participants retained in the treatment
Original Primary Outcome Measures  ICMJE
 (submitted: July 16, 2015)
retention in treatment [ Time Frame: three months ]
percent of participants retained in the treatment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • Craving [ Time Frame: Day 1-3/ Twice daily | Day 4-14/ Once daily | Day 15-28/ Three times a week | Day 29-84/ Once weekly ]
    Visual analogue scale (0-10 scale)
  • Withdrawal symptoms [ Time Frame: Day 1-3/ Twice daily | Day 4-14/ Once daily | Day 15-28/ Three times a week | Day 29-84/ Once weekly ]
    Subjective Opioid Withdrawal Scale (SOWS) Questionnaire
  • Physical health [ Time Frame: Baseline, month 1, 2 and 3 ]
    Opiate Treatment Index (OTI)-Health section Questionnaire
  • Mental health [ Time Frame: Baseline, month 1, 2 and 3 ]
    Symptom Checklist-90-Revised (SCL90-R) Questionnaire
  • Cognitive function [ Time Frame: Baseline, month 1, 2 and 3 ]
    Montreal Cognitive Assessment (MOCA) Questionnaire
  • Severity of substance use problem [ Time Frame: Baseline, month 1, 2 and 3 ]
    Addiction Severity Index-5th (ASI-5th) Questionnaire
  • Quality of life score from World Health Organization Quality of Life-BREF Questionnaire [ Time Frame: Baseline, month 1, 2 and 3 ]
    World Health Organization Quality of Life-BREF (WHOQoL-BREF) Questionnaire
  • Client Satisfaction [ Time Frame: month 3 ]
    Treatment Perception Questionnaire (TPQ)
  • Abstinence [ Time Frame: Baseline, month 1, 2 and 3 ]
    Use of illicit opioids: Self-report / Use of amphetamines, methamphetamines, benzodiazepines: Self-report AND urine toxicology
  • Adverse events [ Time Frame: Day 1-3/ Twice daily | Day 4-14/ Once daily | Day 15-28/ Three times a week | Day 29-84/ Once weekly ]
    Spontaneous reports AND checklist included in the Case Report Form (CRF), physical examination and lab data
  • Cost-effectiveness [ Time Frame: three months ]
    Cost per Quality-adjusted life-month (QALM) and Quality-adjusted life-year (QALY) is calculated using Substance Abuse Services Cost Analysis Program (SASCAP).
Original Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2015)
  • Craving [ Time Frame: Day 1-3/ Twice daily | Day 4-14/ Once daily | Day 15-28/ Three times a week | Day 29-84/ Once weekly ]
    Visual analogue scale (0-10 scale)
  • Withdrawal symptoms [ Time Frame: Day 1-3/ Twice daily | Day 4-14/ Once daily | Day 15-28/ Three times a week | Day 29-84/ Once weekly ]
    Subjective Opioid Withdrawal Scale (SOWS) Questionnaire
  • physical health [ Time Frame: Baseline, month 1, 2 and 3 ]
    Opiate Treatment Index (OTI)-Health section Questionnaire
  • mental health [ Time Frame: Baseline, month 1, 2 and 3 ]
    Symptom Checklist-90-Revised (SCL90-R) Questionnaire
  • cognitive function [ Time Frame: Baseline, month 1, 2 and 3 ]
    Montreal Cognitive Assessment (MOCA) Questionnaire
  • severity of substance use problem [ Time Frame: Baseline, month 1, 2 and 3 ]
    Addiction Severity Index-5th (ASI-5th) Questionnaire
  • quality of life [ Time Frame: Baseline, month 1, 2 and 3 ]
    World Health Organization Quality of Life-BREF (WHOQoL-BREF) Questionnaire
  • Client Satisfaction [ Time Frame: month 3 ]
    Treatment Perception Questionnaire (TPQ)
  • Abstinence [ Time Frame: Baseline, month 1, 2 and 3 ]
    Use of illicit opioids: Self-report / Use of amphetamines, methamphetamines, benzodiazepines: Self-report AND urine toxicology
  • adverse events [ Time Frame: Day 1-3/ Twice daily | Day 4-14/ Once daily | Day 15-28/ Three times a week | Day 29-84/ Once weekly ]
    Spontaneous reports AND checklist included in the Case Report Form (CRF), physical examination and lab data
  • Cost- effectiveness [ Time Frame: three months ]
    Quality-adjusted life-month (QALM) and Quality-adjusted life-year (QALY) for quality of life improvement & Drug Abuse Treatment Cost Analysis Program for calculating the associated costs
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparing Opium Tincture (OT) With Methadone for Medication-assisted Treatment of Opioid Use Disorder
Official Title  ICMJE Comparing Opium Tincture (OT) and Methadone for Medication-assisted Treatment of Opioid Use Disorder: A Randomized Double-blind Controlled Clinical Trial
Brief Summary Patients with opioid use disorder seeking medication-assisted treatment will be recruited. Each participant will be allocated to one of the two study groups with the equal chance of receiving either opium tincture (OT) or methadone. Participants, clinical and research staff will not be aware of the medication that each patient receives. This study aims to test whether OT is as equally effective as methadone at retaining participants with opioid use disorder in medication-assisted treatment.
Detailed Description

Purpose:

To compare the efficacy and safety of opium tincture (OT) with methadone syrup for medication-assisted treatment of individuals with opioid use disorder.

Justification:

Currently, methadone is the gold standard for medication-assisted treatment of opioid use disorder. Opium tincture could be a potential alternative treatment for this condition, and a promising solution to address the following issues:

  1. Alternative treatment option As no single treatment is effective for all individuals with opioid use disorder, sufficiently diverse treatment options should be available. Currently, treatment options for opioid use disorder are not always effective.
  2. Avoidance of overdose with methadone:

    The long-acting nature of methadone, its narrow therapeutic window, its high potency and associated lack of standard conversion ratio from and to other drugs, could result in fatal overdose. In contrast, OT has a shorter half-life and lower potency compared to methadone, which can account for a lower incidence of fatal overdose, especially in patients at higher risk of overdose with currently prescribed medications. Thus, OT could be an added treatment option to currently available treatments such as Buprenorphine/ Naloxone for medication-assisted treatment of patients with higher risk of overdose.

  3. Prolonged QT syndrome of methadone:

    Medication-assisted treatment with methadone can cause serious, potentially fatal adverse effects on the cardiac electrical conduction system leading to a prolonged QT interval and predisposing patients to arrhythmias. As such, cardiac conduction co-morbidity is a (relative) contraindication for the use of methadone as a medication-assisted treatment. Thus, OT could be an added treatment option to current available treatments such as buprenorphine or levomethadone for medication-assisted treatment of patients with cardiac conduction defects.

  4. Opium dependence as the dominant pattern of substance use To date, studies on medication-assisted treatment of opioid use disorder have mostly been carried out on populations in which heroin is the predominant substance of use and there is comparatively fewer data on patients with opium use disorder. Opium tincture could be the treatment of choice in geographic areas with higher prevalence of dependence on opium as the predominant pattern of substance use, such as Iran and some other Asian countries.
  5. Traditional medicine and cultural acceptance: Being a traditional herbal remedy for pain, OT appears to be a more culturally acceptable alternative to methadone in some parts of Southeast Asia.
  6. Cost-effectiveness: Possible cost effectiveness of OT for treatment of opioid use disorder can make it a potential treatment of choice if its efficacy and safety profile could be demonstrated through this RCT.

Research methods:

  1. Recruitment strategy: Following methods will be used to recruit participants: 1) Brochures and flyers will be distributed in community outreach, general and mental hospitals, NGO-run communities, colleges and universities, drop-in centers and specialized clinics for treatment of participants with HIV and hepatitis C 2) Posters (same content as a brochures and flyers) of the study will be stuck in the billboard of bus/subway, local stores, hospitals, NGO-run communities, colleges and universities, as well as any specialized health-care center for psychiatry or addiction treatments 3) there are NGO-run communities for treating patients with opioid use disorder in Sari, Isfahan, and Shiraz. Investigators will use the initial contact letter to recruit from new patients attending these communities for receiving treatment.
  2. Randomization and blinding: Randomized to methadone or OT treatment arms will be carried out in a 1:1 allocation ratio using stratified randomization block technique with block sizes of 2. Age and gender distribution of the population with opioid-dependence in Iran is the basis for stratification on sex (F/M ratio = 1/9) and age (younger than 30/ 30-49/ 50 and older ~ 1: 2: 2). The investigators, treatment team (except pharmacist), assessors, and patients will only be aware of the randomization code for each participant, but not the treatment allocation label or randomization tables. Methadone syrup is made similar to OT in terms of smell, color, and taste using an essence.
  3. Sample size: The sample size was calculated using a fixed margin (95%-95%) approach based on the FDA guidelines for non-inferiority clinical trials (Food and Drug Administration, 2016). For the active control effect, a pooled 95% CI for retention ratio of methadone to placebo of 4.44 [3.26, 6.04] was considered (Mattick et al., 2009). The lower bound i.e., 3.26 was considered as M1, with calculated treatment effect of 2.26. M2 equal to 1.25 (11% of M1) was chosen as a conservative non-inferiority margin. Retention rate for participants in medication-assisted treatment with methadone was assumed to be 77.7% at 3 months based on a comprehensive systematic review (Feelemyer et al., 2014). Based on formula by Zhong, 2009, and assuming a power of 90% and Type I error set at 5%, the total sample size was initially calculated to be 240 participants, 120 in each group. Due to financial constraints, recruitment was set to stop at 200 given that it still provides a power more than 80% (a sample size of 174 provides a power of 80%).
  4. Statistical analysis plan: Retention in treatment will be compared between two groups using confidence interval procedure. Secondary outcomes will be compared between two groups using appropriate regression methods.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Opioid Dependence
Intervention  ICMJE
  • Drug: opium
    Opium tincture (10mg/ml), manufactured by Daroupakhsh.co, Tehran, Iran.
    Other Names:
    • tincture of opium
    • laudanum
    • Opium tincture
  • Drug: methadone
    Methadone (5mg/ml), manufactured by Daroupakhsh.co, Tehran, Iran.
Study Arms  ICMJE
  • Experimental: Opium
    patient-centered flexible dosing in line with the national protocol published by Iranian Ministry of Health for maintenance treatment of opioid dependent population
    Intervention: Drug: opium
  • Active Comparator: methadone
    patient-centered flexible dosing in line with the national protocol published by Iranian Ministry of Health for maintenance treatment of opioid dependent population
    Intervention: Drug: methadone
Publications * Nikoo M, Moazen-Zadeh E, Nikoo N, Javidanbardan S, Kazemi A, Choi F, Vogel M, Gholami A, Tavakoli S, Givaki R, Jazani M, Mohammadian F, Markazi Moghaddam N, Goudarzi N, Schutz C, Jang K, Akhondzadeh S, Krausz M. Comparing opium tincture and methadone for medication-assisted treatment of patients with opioid use disorder: Protocol for a multicenter parallel group noninferiority double-blind randomized controlled trial. Int J Methods Psychiatr Res. 2019 Mar;28(1):e1768. doi: 10.1002/mpr.1768. Epub 2019 Feb 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 10, 2019)
204
Original Estimated Enrollment  ICMJE
 (submitted: July 16, 2015)
240
Actual Study Completion Date  ICMJE March 8, 2018
Actual Primary Completion Date March 8, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Opioid dependence as confirmed by DSM V diagnostic criteria
  • Willingness and ability to adhere to study protocol and follow-up schedule as determined through the pre-randomization period
  • Provide written informed consent.
  • Females of childbearing capacity must agree to use an acceptable method of birth control approved by the study investigator throughout the study.

Exclusion Criteria:

  • Active participant in another treatment program for opioid dependence within 14 days before inclusion in the study
  • Severe hepatic impairment (decompensated liver disease), a contraindication for methadone and its potential to precipitate hepatic encephalopathy.
  • Hypersensitivity to methadone syrup or other ingredients in the formulation
  • Pregnancy
  • Severe chronic respiratory disease
  • Head injury and raised intracranial pressure: Respiratory depressant effects (with CO2 retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury, or a preexisting increase in intracranial pressure. May produce effects that obscure the clinical course in participants with head injuries.
  • Biliary tract disease: may cause constriction of sphincter of Oddi.
  • Monoamine oxidase inhibitors use within 14 days of the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Iran, Islamic Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02502175
Other Study ID Numbers  ICMJE H15-00220
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Michael Krausz, University of British Columbia
Study Sponsor  ICMJE University of British Columbia
Collaborators  ICMJE
  • Tehran University of Medical Sciences
  • Iran National Science Foundation
  • AJA University of Medical Sciences
Investigators  ICMJE
Principal Investigator: Michael R Kausz, MD, PhD University of British Columbia
Principal Investigator: Shahin Akhondzadeh, PhD Tehran University of Medical Sciences
PRS Account University of British Columbia
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP