- 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
- 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:
- 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
- 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
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
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
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 = 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 = 0.05 will be accepted in a two-tailed
- 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
- 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
- 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
- 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.