3.1. Baseline demographics and drug use
The baseline demographics and drug use characteristics were very similar in the baclofen and the placebo groups (). On average, the subject cohort was 43 years old and 80% male. In both groups, blacks represented the majority of the subjects (63% in the baclofen group and 54% in the placebo group). In the 30 days prior to study participation, subjects used cocaine for an average of 18 - 19 days and spent about $550 - $570 on drugs. The majority of subjects smoked cocaine as opposed to insufflation or other routes of administration.
3.2. Treatment retention
The overall retention for the baclofen trial was 67%, and there was no significant difference (log-rank p-value = 0.84) between the retention rates in the two treatment groups.
3.3. Efficacy as assessed by self-report of cocaine use and confirmed by urine BE levels
The repeated measures analysis of the weekly mean proportions of cocaine non-use days for the 8-week treatment phase indicates that, in the ITT population, baclofen failed to increase the number of cocaine non-use days significantly compared to placebo (p-value = 0.77). shows the mean weekly percentage of cocaine non-use days in both treatment groups over the entire treatment period.
Mean weekly percentage of cocaine non-use days by treatment based on self report confirmed by urine BE.
The same outcome measure was also analyzed with additional model terms to control for variations due to site, gender, cocaine use in the 30 days prior to consent, and the baseline HAM-D score. This GEE analysis again failed to detect any significant difference between the treatment groups (p-value = 0.75).
illustrates the findings for three of the secondary outcome measures, the definitions of which were based on self-report of use and confirmatory urine BE analysis. Fisher's exact test failed to detect a difference between the two treatment groups for the proportions of subjects who reduced cocaine use days to 75% or less (p = 0.75) and to 50% or less (p = 0.67) of baseline rates. Subjects in the baclofen group and in the placebo group showed an average of 6 and 7 days of consecutive cocaine non-use, respectively. This difference was also statistically insignificant (p = 0.37).
Secondary outcome measures based on self-report of cocaine use and confirmed by urine BE
3.4. Efficacy based on urine benzoylecgonine test results
The raw quantitative urine BE values had a very wide range (min. = 0 and max = 2,470,000 ng/ml) and the distribution of these scores was extremely skewed. The log10 transformation of the raw scores resulted in a narrower range (min = 0 and max = 6.39) and a more well-behaved, approximately bell-shaped distribution. Mean weekly log10 transformed urine BE levels were analyzed using GEE with treatment and study week as main effects, the baseline mean as a covariate, and the first order interaction term between treatment and study week. Baclofen did not show any significantly different effect on the urine BE values compared to placebo (p = 0.99).
3.5. CGI results
Mean weekly severity and improvement scores on the CGI-O and CGI-S were analyzed separately with GEE models including treatment and study week as main effects, the baseline mean score as a covariate, and the first order interaction term between treatment and study week. Overall, baclofen did not show any significantly different effect on the weekly severity or improvement scores compared to placebo in any of the models (p = 0.46 - 0.95).
3.6. Results from the CSSA
Mean weekly severity scores on the CSSA were analyzed using GEE with treatment and study week as main effects, the baseline mean severity score as a covariate, and the first order interaction term of treatment and study week. The analysis showed that baclofen failed to lessen the severity in cocaine dependence as assessed by this score (p-value = 0.14).
3.7. Analysis of severity scores on the BSCS
A similar analysis of mean weekly severity scores of the BSCS was done and the analysis suggested that the baclofen subjects did not experience significantly less craving compared to the placebo subjects over the entire length of the trial (p-value = 0.59).
3.8. Analysis of the HAM-D score
GEE analysis of the mean weekly scores of the HAM-D indicated no significant treatment effects (p-value = 0.66).
3.9. Results from the HRBS
The HRBS has two subscale scores-a drug subscale which ranges from 0 to 30, and a sexual behavior subscale, which ranges from 0 to 25-and the overall score which can range from 0 to 55. A lower score overall on each either subscale indicates less risk-taking behavior. The change in HRBS scores from baseline to week 8 was compared between the two treatment groups using t-tests. The change score comparisons on drug subscale scores (p-value = 0.99), sexual behavior subscale scores (p-value = 0.12) and overall scores (p-value = 0.13) show no significant differences in the two treatment groups. The analysis suggests that subjects on baclofen showed no significant difference in their risk-taking behavior.
3.10. ASI results
The ASI has seven distinct components-medical, employment, alcohol, drug, legal, family/social, and psychiatric. Four change scores (baseline and week 4, baseline and week 8, baseline and the last visit, and weeks 4 and weeks 8) are compared between treatment groups for all seven components using t-tests. A positive change score is indicative of improvement and a negative change score is indicative of worsening between the respective time points during the treatment phase of the trial. No significant differences between the two treatment groups were detected when mean change scores in each of the seven components were compared.
Baclofen was safe and well tolerated in this trial. There was no difference between groups in overall incidence of AEs (p=1.00). Ninety-one percent of subjects taking baclofen and 90% of subjects taking placebo experienced AEs. Somnolence, headache, and dizziness were experienced by 45%, 39%, and 20%, respectively, in the baclofen group compared to 35%, 31% and 18% in the placebo group. Nausea was reported by 26% in the baclofen group and 14% in the placebo group (p= 0.07). Vomiting was reported by 14% for baclofen and 6% for placebo. Diarrhea was reported by 11% and 9%, respectively. Dry mouth was reported by 6% for baclofen and 13% for placebo. Other common AEs (baclofen vs placebo) were cough (15% vs 14%), nasal congestion (8% vs 6%), rhinorrhea (6% vs 6%), anxiety (10% vs 4%), depression (5% vs 9%), insomnia (4% vs 6%), back pain (9% vs 11%), myalgia (8% vs 10%), and arthralgia (10% vs 9%). There were no effects on blood chemistries or QTc intervals, and there were no seizures.
Nine serious adverse events (SAEs) were reported during the study. Three were judged to be possibly related to medication. One SAE was in a 46-year-old male who experienced chest pain and was admitted to the hospital in atrial fibrillation. After failing to respond to procainamide he was cardioverted back to sinus rhythm with electrical shock. The incident occurred on his last day of study medication and he returned to the study for follow up. He revealed that he had had two previous episodes of atrial fibrillation in his life; he was taking placebo. A second subject with a possibly related SAE was a 40-year-old male treated in an emergency room for dizziness and disorientation after heavy use of cocaine. After stabilization he was admitted to a detoxification center for 48 hours, after which he returned to the study; he was also taking placebo. A third subject was a 52-year-old male who was hospitalized for attempted overdose with alcohol and the study medication. After recovery, he was discharged from the study at week 6. While this was considered an unrelated SAE at the time of the subject's participation, it was later determined that the subject was taking baclofen. Consequently, and in consultation with the DSMB, this SAE was reclassified as possibly related. Other SAEs that were unrelated to medication were abdominal pain and hematochezia, injury from a motor vehicle, urticaria after albuterol use, hospitalization for suicidal thoughts during the follow-up period, and jaundice and liver enzyme elevation due to hepatitis C.