3.1. Baseline demographics
is a flow diagram of the numbers of study participants, from consent through randomization and on to completion of the study. One participant in each treatment group did not begin the study medication, and was considered to have failed enrollment. In addition, one participant dropped out in the first week of treatment. The screen failure rate (336/546 = 62%) is not unusual for studies in this population. The most common reasons for failure in screening were: (1) did not return to clinic (41%); (2) had a serious medical illness, such as uncontrolled hypertension, significant heart, renal, or hepatic disease or potentially life-threatening or progressive illness (19%); (3) did not provide a cocaine-positive urine during the 3-week screening period (18%); (4) had a psychiatric or neurologic disorder requiring ongoing treatment that would make study participation unsafe, or compliance difficult (9.5%); and (5) had an abnormal lab value that was clinically significant (8%).
Flow chart of participants in the clinical trial of modafinil for cocaine dependence. One pt. in each treatment group dropped out before the first dose of medication, i.e., ‘failed enrollment.’.
Demographics and baseline characteristics of study participants are summarized in . The distribution of race among the treatment groups was not equivalent. The group that received modafinil 200 mg had more African–Americans and fewer Whites than the other two groups (p = 0.01). Also of possible relevance is the nearly significant difference among groups in the number of years using cocaine. Again, the 200 mg modafinil group had used cocaine, on average, about 2.5–3 years longer than the other two groups (p = 0.07).
Baseline characteristics of participants in the modafinil cocaine study.
Not shown in are the frequencies of other illicit drug use. At screening, by self-report about the past 30 days, overall frequency of any alcohol use was 82%, alcohol used to intoxication 49%, nicotine 80%, cannabis 42%, sedative/benzodiazepine 7%, heroin 2%, other opiate/analgesic 6%, methamphetamine 2%, other amphetamines 2%. The treatment groups were not significantly different on these rates.
3.2. Treatment retention and compliance
A total of 125 participants (60%) completed the 12 weeks of treatment, with no significant differences in retention between groups (p = 0.48, log-rank test) (). Retention also did not differ significantly between those who were and were not alcohol dependent [current or lifetime] (p = 0.85, log-rank test). Counseling attendance was similar across all groups, averaging 88% until the participant’s point of study discontinuation, and 72% for the full 12-week treatment period. Medication compliance was also similar across all treatment groups, averaging 93% (range 36–100%) up until the point of discontinuation, and 72% (range 2.4–100%) for the full 12-week treatment period.
Study retention for participants in the placebo, 200 and 400 mg/day modafinil treatment groups. Shown are the percentage remaining from randomization to the day of the last study visit.
3.3. Primary outcome—efficacy by self-report and urine analysis
Our simple GEE model contained only factors for treatment Group (3 levels: placebo, modafinil 200 mg, modafinil 400 mg), Study Week (continuous over 12 weeks), and their interaction, Week × Group (3 levels, which represented the medication effect). The response variable was our primary outcome: average weekly percent of cocaine non-use days, which was based on self-report confirmed by urine BE. This model showed no significant difference between either modafinil group and placebo in the rate of change (slope) in the primary outcome over the 12-week treatment period (see , top panel, p = 0.92 for Week × Group/Modaf 400, and p = 0.79 for Week × Group/Modaf 200, GEE). In the simple model the factor of Study Week, or time in treatment, had a significant effect (p < .0001), while treatment Group did not (p = 0.19). A second model showed significant effects of baseline cocaine use (mean of weekly% non-use days from Study Weeks-1 and -2, p < .0001), and of Study Week (p < .0001) on the primary outcome, but again, non-significant effects of Group (p = 0.24) and Week × Group (p = 0.65 overall). We also tested a secondary outcome ‘maximum number of consecutive cocaine non-use days’ (by self-report and urine BE), and found a significant difference between modafinil groups and placebo (p = 0.05, overall Kruskal–Wallis test). The average maximum number of consecutive cocaine non-use days was 12.6 for modafinil 200 mg, compared to 8.8 days for placebo (p = 0.02, Wilcoxon 2-sample), and 12.0 days for modafinil 400 mg (p = 0.46, Wilcoxon 2-sample).
Fig. 3 Treatment group’s average weekly% of cocaine non-use days (self-report confirmed by urine benzoylecgonine) in: (A) the total sample; and (B) non-alcohol-dependent, and (C) alcohol-dependent (current or lifetime per DSM-IV), by dose of modafinil (more ...)
3.4. Alcohol dependence, current and lifetime
In a post hoc exploratory analysis, each participant’s alcohol dependence, either current (within the past month) or lifetime (ever present), was determined from the SCID interview done at screening. Participants with current or lifetime alcohol dependence were combined, and groups with and without alcohol dependence were tested for an independent association with the primary outcome and/or an interaction with the effect of modafinil treatment. The subgroup that was never alcohol-dependent (i.e., neither current nor lifetime) N = 125, demonstrated a significant difference in average percent of cocaine non-use days between the modafinil groups and placebo (p < 0.02, GEE), where the 200 mg and 400 mg doses of modafinil treatment resulted in an average of 8.9% and 8.5% more cocaine non-use days, respectively, than placebo (see ,middle panel). This subgroup, “non-alcohol-dependent,” also had more consecutive cocaine non-use days in the modafinil treatment groups than in placebo (mean: 15.2 days for 400 mg, 13.5 for 200 mg, 6.6 for placebo; p = 0.01, Kruskal–Wallis). By contrast, in the subgroup with either current or lifetime alcohol dependence, N = 82, the modafinil 400 mg treatment group had an average of 1.3% fewer cocaine non-use days than placebo, although this difference was not significant (see , lower panel, p = 0.92, GEE), and the modafinil 200 mg treatment group had 0.2% more non-use days than placebo. This alcohol-dependent subgroup had baseline differences in weekly percent of non-use days among the treatment groups, which remained roughly parallel throughout the treatment period (i.e., no differential treatment effect) ().
3.5. Major race categories
Because only 9 participants described themselves as a race other than White or African American, we used only the two large categories to test for an interaction of Race with the primary outcome. We found that our GEE model showed a significant effect of race (p = 0.0003), in addition to significant effects of the baseline level of cocaine use (from Study Weeks-1 and -2, p < .0001), and the Study Week (time in treatment, p < .0001). The GEE parameter estimate for African American race, with White as reference, was −11.9 (SE 3.7), i.e., the weekly percent of cocaine non-use days was 12% less for African Americans. The factor of medication dose continued to be non-significant (interaction of Group × Study Week, p = 0.65). Interactions of race with treatment Group and with Study Week were also non-significant (p > 0.9).
3.6. Secondary outcomes
There were no significant differences overall between modafinil and placebo groups in many secondary outcome measures, including:
- For quantitative cocaine use, the (slope) decrease in average weekly log10 median urine benzoylecgonine over the 12-week treatment period (p = 0.34, GEE).
- Any of seven Addiction Severity Index (ASI)-Lite domains, examining the difference in means from baseline to last observation using a two-sample t-test or a Mann–Whitney–Wilcoxon two-sample rank sum test (all p > 0.10).
- Either of the two outcomes (improvement or experience) from the Clinical Global Impression scales, separately regressed on treatment Group and the Group × Week interaction using GEE, for the-Observer (CGI-O, p > 0.35) or for the-Self (CGI-S, p > 0.11).
- For the sexual risk domain of the HIV Risk Behavior Scale (HRBS), examining change from baseline to last visit for each participant (two sample t-test contrasts between each active group and placebo, all p > 0.30). [96% of the changes in injection risk domain scores were zero, therefore, analysis was restricted to sexual risk.]
3.6.1. Cocaine craving
Total scores for the Brief Substance Craving Scale (BSCS) for cocaine (items 1–8) were ordinal interval transformed to reduce skewness prior to regression analysis (Kyomen et al., 1999
). The BSCS total score was tested with factors of treatment Group, Week, and the Group × Week interaction, using GEE. The slope over the treatment period was compared between modafinil 200 or modafinil 400 and placebo. Relative to placebo, we estimated that craving declined on average within each active arm, and this difference from placebo was nominally significant for 200 mg (p
= 0.04) but not for 400 mg (p
= 0.90). However, the attained significance level of p
= 0.04 was not significant after correction for multiple comparisons. Total scores for the Cocaine Craving Questionnaire (CCQ) were examined using means at baseline and end of treatment (Week-12) via a two-sample t
-test. No significant effect on total score was noted, however, the sub-domains “Anticipation” (p
= 0.04) and “Relief” (p
= 0.03) were significant with treatment of 200 mg modafinil.
There were 16 Serious Adverse Events in the entire study, none of which met the criteria for expedited reporting, i.e., serious, unexpected, and possibly related to the study medication. Our non-serious Adverse Events totaled 1507 events among 200 participants. Among the events that had a greater incidence with 400 mg of modafinil than with 200 mg or placebo (p < 0.10), and occurred in participants at a >5% rate, were nausea (26%, p = 0.085), insomnia (20%, p = 0.02), dizziness (11%, p = 0.07), pain in extremity (7%, p = 0.02), irritability (6%, p = 0.04), and the total events from the Psychiatric Disorders Body System (43%, p = 0.04). Decreased appetite was equally more frequent with 200 or 400 mg modafinil than with placebo (p < 0.001). There were 17 participants with at least one AE leading to permanent discontinuation of study drug (placebo: 6, modafinil 200 mg: 1, modafinil 400 mg: 10). The most common category of such AEs was gastrointestinal disorders, with the modafinil 400 mg group having four instances of nausea and two of dry mouth, while the placebo group had one of each. The modafinil 200 mg group had one abnormal liver function test. The modafinil 400 mg group also had one instance each of abnormal electrocardiogram, hypertension, chest discomfort, ‘bitter taste’, irritability, agitation, anxiety, tension, and two instances of insomnia, and in the skin disorders one ‘sweaty palms’ and one ‘upper lip swelling’, with none of these events in the other groups. Aside from the one instance of hypertension requiring discontinuation, average blood pressures remained stable throughout the 12 weeks of treatment. The weekly average change from baseline had no greater increase in any treatment group than 2.6 mmHg systolic and 2.8 mmHg diastolic, with similar size average decreases in some weeks.