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Clinical Trial Summary

- Introduction: The Cocaine Base Paste (or Coca Paste or CBP), a highly toxic and addictive smokable drug (a by-product of the cocaine extraction chain), has become in the last years a real social scourge for Chile. Today, there is not a pharmacological treatment approved in Chile neither around the world for the management of the withdrawal syndrome nor the dependence caused by the use of this substance. The N-Acetylcysteine (NAC), a derivative of the amino acid cysteine, with mucolytic and antioxidant properties, used in Chile since several years for bronchopulmonary treatments, as well as a hepatic and renal protector, among others, has shown, in animal and human research, that has benefits to reduce the craving for cocaine and in the management of the withdrawal syndrome of this and other psychoactive substances.

- Objectives: To evaluate whether the use of NAC in patients with problematic CBP consumption reduce the craving for this substance and prolong its abstinence time.

- Methods: will be carried out a randomized, double-blind, controlled, phase II-b clinical trial, with a parallel group design with CBP dependent patients in different outpatient care units in the province of Concepción, Chile. Patients who meet the cocaine (CBP) consumption disorder criteria, who have used of CBP within the last month and who have started to use it one year at least prior to admission to the study, will be selected from among the consulting population. Patients who agree to participate in the study must sign an informed consent form before being clinically evaluated. During the evaluations, semi-structured interviews and standardized questionnaires were used to investigate both consumption habits and symptoms of withdrawal and intensity of CBP craving, among others. All patients in the study will be attended twice weekly to treatment centers for four weeks, reporting their craving for CBP, the use of this substance (as well as urine tests), adverse reactions to the indicated medication, among others.

- Expected results: It is expected that, thanks to the use of NAC, patients with CBP use disorder entered to this study significantly reduce their craving to consume this substance, they can prolong the abstinence time of it and they can reduce their falls in CBP consumption.

Clinical Trial Description

- Quality assurance plan: With the monitoring of our research through the supervision of the Contract Research Organization named South Cone Alliance.

- Data checks: With the monitoring of our research through the supervision of the Contract Research Organization named South Cone Alliance.

- Source data verification: All information of the patients recruited in our study was obtained by the research team directly from each patient, without using to external sources.

- Data dictionary: None

- Standard Operating Procedures: Each patient must attend twice a week (every 3 days approximately) to assessment in her/him mental health center with the research team. The interventions are detailed below:

- Number 1 Visit:

1. Reception by the psychiatrist:

- Explanation of the nature of the study and signing of informed consent.

- Clinical evaluation with Semi-Structured Interview and application of MINI.

- Selection of patients who meet criteria, assignment of the respective entry code to the study and entry to the study with it.

- Delivery of medicine bottle with the first 28 capsules according to previous randomization (treatment for the 1st week)

2. Nursing Reception (initial structured evaluation):

- Application of urine drug test (for detection of cocaine, marijuana, benzodiazepines, opiates, amphetamines.) If positive for opioids, the patient is excluded from this study.

- Anthropometric evaluation (measure, weigh, BMI)

- Hemodynamic evaluation (blood pressure (BP), body temperature (BT), heart rate (HR) and breathing rate (BR)) to each patient.

- Performance of baseline blood test: blood count, glycemia, liver tests and creatininemia.

- Drug administration.

- Observation for 2 hours of the patient, in which progress is made in:

- Application of CCQ-N-10, CSSA and Clinical Global Impression (CGI) scales .

- Record of adverse reactions / side effects of the medication and

- Final hemodynamic evaluation (BP, BT, HR, BR).

- Delivery of card of citations for next assessments (or controls).

Number 2 Visit:

Nursing follow-up (follow-up file):

- Record of Abstinence Days (last use of CBP)

- Urine drug test application (for cocaine detection).

- Anthropometric evaluation (measure, weigh, BMI)

- Hemodynamic evaluation ( BP, BT, HR and BR).

- Asking about withdrawal symptoms (CSSA application)

- Asking about craving (VAS-craving and CCQ-N-10 application)

- Asking about adherence to a treatment: application of Morisky-Green Test

- UKU Scale Application

- CGI application.

- Agreement about time for next assesments (or controls).

Number 3 Visit: Idem to the number 2 visit more delivery of second medicine bottle with 28 capsules for the second week of treatment by the doctor of the research team.

Number 4 Visit: Idem to the visit number 2

Number 5 Visit: Idem to the visit number 2 more delivery of third medicine bottle with 28 capsules for the third week of treatment by the doctor of the research team.

Number 6 Visit: Idem to the visit number 2

Number 7 Visit: Idem to the visit number 2 more delivery of fourth medicine bottle with 28 capsules for the fourth week of treatment by the doctor of the research team.

Number 8 visit: Idem to the visit number 2.

Number 9 visit: Idem to the visit number 2 more the closing of the study.

- Sample size assessment: The minimum size necessary for a definitive trial in this case would be 106 subjects calculated according to a power of β = 0.8 to detect at least one effect size of the treatment of d = 0.55 , which corresponds to effect size calculated with data from previous studies with this drug in cocaine-dependent patients (LaRowe y cols. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. American Journal on Addictions . 2006: 15(1), 105-110). Considering that the analysis of results would be done through a test more powerful than t for independent samples and a level of significance α = 0.05 will be accepted in a two-tailed design.

- Plan for missing data:

First: the missing data pattern will be analyzed Second: The mechanism of missing data will be studied to see if it is possible to predict the loss pattern and evaluate the possible bias for missing data.

Third: If it is found that the missing data mechanism generates bias, multiple imputation will be used for the analyzes.

• Statistical analysis plan:

The main outcomes of this test will be described as follows:

- the proportion of patients who agreed to enter the trial,

- the differences between those who entered and those who refused,

- the characteristics of the sample,

- adherence to treatment, and

- the number and characteristics of dropouts during follow-up.

- The characteristics of the participants in each arm of the trial will be compared, but will not be subjected to statistical tests. The variables to be compared will be sex, age, comorbidity, PBC consumption time, severity of CBP use disorder and baseline CBP craving to verify homogeneity between groups.

- Primary outcomes will be compared at four-week follow-up, as follows:

- After verifying the distribution of the mean duration of CBP abstinence days in both groups, a model will be analyzed by adjusting according to the severity of the CBP use disorder in the baseline (this is the most relevant variable reported in the literature that could influence to the abstinence) and by adjusting according to previous abstinence days, it means, days without coca paste use before to enter this research.

- Differences in primary outcome by group (with severity adjustment and previous abstinence days) will be reported along with their 95% confidence intervals.

- The results will be analyzed using the statistical program SPSS and R. According to the variables of result to be evaluated, the analyzes will be:

- For tolerability assessment: Proportion comparison test (normal approximation, sample sizes allow) for Adverse Drug Reactions (ADR) for each of the 8 post-basal measurement instances.

- For safety assessment: proportion of patients with mild, moderate and severe ADR per group analyzed with the Brunner-Munzel test, extension of the Mann-Whitney U for ordinal data with many repetitions.

- To assess coca paste (CBP) abstinence time: Abstinence days will be compared using a Kaplan-Mier estimator. In the case of finding a signifcant increase in CBP abstinence days in the NAC treatment group, a correlation study (Pearson, if there is normality, Spearman otherwise) will be made between the quantitative variables measured to the individuals and days of abstinence.

- To evaluate the rate of falls in CBP consumption: Fall rates in CBP consumption will be compared using a generalized linear mixed model, with Poisson response and times between exponential relapses. In case of over-dispersion, a model with Negative Binomial response will be considered.

- For Craving evaluation: it will be analyzed by means of test comparisons of means (Student T, under normality verified with Kolmogorov Smirnov, or U Mann Whitney, otherwise) for independent samples, considering the initial measurements (before there is much desertion ).

- A comparison of means between experimental and control groups will be performed using repeated measures ANOVA (if normality is verified with Kolmogorov Smirnov and Fisher homoscedasticity) or non-parametric ANOVA analysis for repeated measures (otherwise).

- It is also important to mention that incomplete data due to abandonment of the study, whether or not there is a return, should be considered for the analysis. ;

Study Design

Related Conditions & MeSH terms

NCT number NCT03556371
Study type Interventional
Source University of Concepcion, Chile
Contact Carmen G Betancur, MD/PhD(c)
Phone +56993182683
Status Recruiting
Phase Phase 2
Start date April 9, 2018
Completion date April 30, 2019

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