Baseline Characteristics, Retention and Opioid Use
The vaccine and placebo subjects were comparable in age, gender and ethnicity, but most were white preventing ethnic sub-analysis. Most subjects (89%) considered smoked cocaine their second drug of choice after opioids including prescription opioids. We found no statistically significant baseline demographic or drug use differences between groups, and treatment retention showed no difference; 82% completed 24 weeks ( and ). The full sample of 114 patients showed a significant increase in opioid-free urines from 55% (SEM 0.05) during the first two weeks on methadone maintenance to 68% during week 8 onward on a mean stabilization methadone dose of 83 mg daily (F= 9.9; df = 2,108; P<0.002). The two treatment groups showed no difference in opioid-free urines or methadone dose.
Baseline Clinical Characteristics of Participantsa
Cocaine Vaccine Specific IgG Levels
Of the 58 subjects randomized to receive active vaccine, 55 completed the series of five vaccinations and 98% (54/55) made detectable antibody levels. shows individual serum IgG anti-cocaine levels through week 24. Notably, early antibody responders made antibodies as early as week 2; however, many mounted antibody responses only after week 6. One subject had pre-existing high levels of IgG anti-cocaine antibody and maintained them throughout the study. Of those vaccinated, 21 (38%- high IgG group) attained antibody levels greater than 43 µg/ml, whereas, 34 (62%- low IgG group) had levels below this threshold, including one subject who made no antibodies. Only two subjects mounted antibody responses > 43 ug/ml before week 8, and all subjects’ IgG levels declined after week 16.
IgG responses to the Cocaine-CTB vaccine was highly variable
Cocaine-Free Urines by Treatment Group
The frequency of cocaine-free urines did not differ between treatments in an intention to treat analysis at baseline (weeks 1 to 2) (33% vaccinated vs. 25% placebo) (χ2=0.3) or for the full 20 weeks. However, our HLM analyses of weekly cocaine-free urines for both vaccinated and placebo recipients from weeks 1 through 16 showed significantly more cocaine-free urines as the study progressed (placebo by time: Z=5.4, p<0.001; vaccine by time: Z=8.7, p<0.001). As the difference in Z values over time suggest, the frequency of cocaine-free urines rose faster in the vaccinated than placebo group (treatment by time interaction: Z=2.45, p<0.01). However, after we stopped immunizing these subjects and antibody levels began to fall off during the interval between weeks 16 and 24, HLM analyses showed no significant differences in the frequency of cocaine-free urines between the vaccinated and placebo groups.
Cocaine-Free Urines by IgG Response to Vaccine versus Placebo
shows the mean rates of cocaine-free urines in the high IgG group (>43µg/ml) and both the placebo and low IgG groups (≤43µg/ml). Standard errors (not shown) at each time point were +/− 3%. Between weeks 9 through 16 cocaine-free urines were significantly greater in the High IgG than the Low IgG and Placebo groups (45% vs 35%; t=2.26; df=110; P<0.03). By week 9 most of the 21 high IgG subjects had antibody levels at or above 43 ug/ml and after week 16 these levels declined to levels found in the low IgG subjects.
Mean weekly cocaine-free urines by medication condition for weeks 1–20
Using HLM analyses of weekly cocaine-free urines through week 16, the high IgG and placebo groups showed significantly more cocaine-free urines as the study progressed (placebo by time: Z=5.4, p<0.001; high IgG by time: Z=9.5, p<0.001), while the low IgG group showed no significant change over time. As the difference in Z values over time suggest, the frequency of cocaine-free urines increased faster in the high IgG group than the placebo and low IgG groups (treatment by time interaction: Z=4.8, p<0.01).
As a stronger test of IgG antibody levels and vaccine efficacy, we then examined the results using the 45 vaccinated subjects who remained after excluding three who dropped out before week 15 and seven who did not use cocaine during weeks 8–20 and therefore did not directly test the vaccine’s efficacy. As shown in , the proportion of these subjects whose urinalyses showed no new episodes of cocaine use at least 50% of the time (based on the Preston criteria) was significantly greater in the high IgG as compared to the low IgG subjects (0.53 vs. 0.23) (Fishers test, P<0.04).
Scatter-plot of peak antibody response by % cocaine-negative urines
Adverse Events (AE)
Treatment emergent or associated AEs and subject dropout related to treatment were not significantly different in vaccinated and placebo subjects (). Dropouts were related to incarceration and loss of housing due to cocaine use. All of the reported AEs were considered mild or moderate in intensity. The more frequent AEs recorded for vaccinated subjects as compared with placebo were: injection site induration (3% versus 0), site tenderness (10% versus 6%), feeling cold (12% versus 7%), hot flashes (19% versus 12%), hyperhydrosis (15% versus 10%) and nausea (14% versus 2%). Treatment-emergent severe AEs included: a toothache and tooth abscess in two placebo subjects, and a vaginal hemorrhage in a vaccinated subject. One vaccinated subject left due to an exacerbation of pre-existing, but initially undiagnosed, spondyloarthropathy.
Summary of Adverse Events (AEs)
Six serious AEs were all deemed unrelated to the vaccine. The three for vaccinated subjects were: cocaine-related paranoia, molar pregnancy resulting in spontaneous abortion in a 42 year old, and alcoholic pancreatitis. The three for placebo subjects were: hematuria and kidney stones, facial cellulitis, and right forearm cellulitis from self-injecting drugs.