Moreover, many of those who participated in this survey reported being on treatment including methadone, and given high rates of relapse of substance use among those in treatment this suggests many in our survey were at high risk of substance use. When critical services that helped PWUD survive overdose and keep their use under control such as group therapy and MOUD became only virtual during the pandemic, the use of such services declined . Virtual access to care may be particularly challenging for individuals who are unemployed and older as fewer may own and have access to the technology needed for this than younger and employed people. What should also be noted is that fewest of those reporting intermittent use of substances were tested for COVID-19, with more of the daily users getting tested. This may be because reduced social interaction during the pandemic may have lessened situations in which some people use drugs particularly affecting those who used at bars or parties and thereby had less exposure to COVID-19. Some substances are often use for social enhancement particularly by YMSM, and the less social opportunities the less they may have felt like or had opportunities to use drugs reflected in their COVID testing rates. The reduction in social use of substances may also reflect the high rates of overdose that were noted during the pandemic as more people may have used drugs alone without someone to help them or call for help if they did overdose . Higher testing by those reporting daily use may be because these individuals may access services such as needle exchange or MOUD and may have been offered testing through these services.5Stimulant use disorders remain a significant public health concern . For example, cocaine was noted more often than any other illicit drug among emergency department visits in the United States . Currently,vertical cannabis there are no medications that have regulatory approval for cocaine addiction leading to an urgent need for novel therapeutic approaches.
Cocaine is a molecule that, by itself, is too small to elicit an antibody response. However, conjugation to larger, immunogenic protein carriers can enable production of antibodies specific to small molecules. The B subunit of cholera toxin is a highly immunogenic protein known to elicit a potent antibody response. TA-CD vaccine is designed to induce formation of anti-cocaine antibodies. This cocaine vaccine covalently links succinylnorcocaine to cholera toxin B , which has a worldwide safety record for cholera immunization . The anti-drug antibodies elicited by TA-CD bind to cocaine entering the bloodstream, forming antigen-antibody complexes too large to cross the blood-brain barrier. In sufficient quantity and appropriate affinity, such antibodies can therefore prevent high concentrations of cocaine from reaching the mid-brain. The absence of reward stimulus in the brain should reduce the reinforcing psychoactive effects of cocaine. By blocking the pleasurable response to cocaine, it is expected that cocaine usage could be reduced in subjects undergoing treatment for cocaine dependence. The concentration of anti-cocaine antibody in the blood must be sufficient to bind a significant amount of the drug in order to be effective. The peak plasma amount of cocaine that users need to experience pleasure in human laboratory studies is approximately 0.5 μM. , and to bind 90% of this amount of cocaine requires approximately 42 ug/ml of moderately high affinity antibody . We therefore compared reductions in cocaine use for the placebo group to two groups of vaccinated subjects: those with peak IgG antibody levels above versus below 42 ug/ml IgG. We also know from previous work that the window of optimal IgG levels would be after week 8 and that after week 16 these IgG levels would fall. . Thus, we hypothesized that subjects with high IgG levels above 42 ug/ml should have more cocaine-free urines, more sustained abstinence and greater treatment retention than the subjects getting placebo or having low IgG responses to the vaccine.
The primary analysis compared the TA-CD group to placebo. With a two-sided t-test of the difference in the weekly fraction of cocaine-free urines between TA-CD and placebo with a common standard deviation of 0.40, the sample size needed with an 80% power is 113 for TA-CD and 113 for placebo, at a two-sided alpha of 0.05. Thus, the total sample size needed for the study would be 226 subjects in the efficacy evaluable sample. However, assuming approximately 20% of randomized subjects will drop out by the start of the efficacy evaluable period and be excluded from the efficacy evaluable population, a total of 300 subjects were randomized . Although the primary analysis did not use the t-test, it is anticipated that the primary analysis was more powerful than the t-test. The vaccine and placebo subjects were comparable in age, gender and ethnicity, but most were African American preventing ethnic sub-analysis . They had a long history of cocaine use and on average used 13 days in the month prior to treatment . Alcohol use was relatively low with an average of 4 days per month with few subjects reporting use to intoxication. Cannabis use was uncommon. We found no significant differences between the vaccine and placebo groups in an intention to treat analysis using generalized linear mixed modeling. Figure 3 shows the biweekly urine toxicology results for the placebo vs active vaccine groups.In addition to the cut-off of ≥42μg/ml we reanalyzed the data utilizing the 50th, 75th, and 90th percentiles of the whole sample as antibody titre cut-points, and similarly found no differences between the high and low antibody titer groups. Remaining abstinent from cocaine for at least two weeks of treatment occurred more often in the active than placebo vaccine group , but not significantly . Among the vaccinated patients those with the high antibody titer had a greater odds ratio of being cocaine-free for their final 2-weeks in treatment compared to the low antibody titer group , although only 15 patients attained abstinence for their last 2 weeks of treatment. Reanalyzing the data utilizing the 50th, 75th, and 90th percentiles as antibody titre cut-points yielded the same relative odds ratios between the high and low antibody groups.Table 3 shows the number of individuals reporting side-effects from specific body systems.
Also provided are raw p-values and False Discovery Rates evaluating these counts as a function of treatment condition. The only category showing differential reporting as a function of treatment condition is “General disorders and administration site conditions” . Further evaluation of preferred diagnostic terms occurring under “General disorders and administration site conditions” indicated differential reporting for an “Injection Site Reaction” . All these AEs were mild or moderate and none led to dropout from treatment. There were also no differences in side-effects related to peak antibody levels. Treatment-emergent severe AEs among randomized subjects included 29 hospitalizations: 14 in the active vaccine and 15 in the placebo group. Two in the placebo group were considered possibly related to the vaccine, but none in the active vaccine group were considered treatment related. Depression with suicidality was the most common event: 6 in the active vaccine and 5 in the placebo group. Cocaine use accounted for 3 in the vaccine and 2 in the placebo group. Other hospitalizations in the active vaccine group were for a leg ulcer, chronic obstructive lung disease, erectile dysfunction, and alcohol intoxication. Other hospitalizations in the placebo groups were for loss of consciousness, coronary vasospasm, foot pain, leg cellulitis, chest pain and a pelvic bone fracture. In contrast to our previous study with this cocaine vaccine TA-CD , we did not find a significant attenuation of outpatient cocaine use, even when adequate antibody levels were attained. Instead,cannabis drying racks the patients with higher antibody levels had more cocaine positive urines than those with the lower levels of 42 ug/ml or less throughout the first 16 weeks of the study. However, several findings suggested some efficacy for the vaccine. First, treatment dropout was significantly different and almost 3-times lower for the high IgG than for the low IgG or placebo groups . Second, the active vaccine group was more likely than placebo to attain sustained abstinence during the last two weeks of treatment, particularly those with the higher antibody levels . The odds ratio of 3.02 suggests that having more abstinent patients than the 5% obtained in this study or having a greater sample size of 466 would have demonstrated the vaccine efficacy for those attaining the higher antibody levels with a statistical power of 80%. Third, based on the mean antibody levels at weeks 9 and 16 the vaccine showed sufficient immunogenicity with two thirds of the patients attaining peak levels above 42 ug/ml. Thus, the vaccine may have therapeutic value for a portion of cocaine dependent patients, although many will try to override the partial blockade that is possible with this vaccine. Furthermore, it took us 17 months from multiple trial sites to recruit 300 cocaine addicted persons who were nominally motivated to cease using cocaine.
This suggests that even an effective vaccine may not be much more attractive to the cocaine abusing treatment population than are current psychosocial treatments. We are concerned that adequately immunized subjects may have increased their cocaine use to overcome the competitive anti-cocaine antibody blockade. As Haney and colleagues showed, these antibody levels were only sufficient to block modest doses of cocaine. Overall, this vaccine is designed to reduce relapse among cocaine dependent patients who are motivated to stop using cocaine. The high rate of cocaine use and low rate of sustained abstinence shown by these study patients clearly reflected a population that was using cocaine several times per week and rarely attempted abstinence during the clinical trial. In the previous study the high antibody level patients achieved 48% cocaine-free urines during weeks 9 to 16 compared to only 25% in the present study. Having only half the rate of cocaine-free urines in the present Phase III study compared to the previous Phase IIb study in methadone maintained patients may reflect several non-pharmacological differences in design and programmatic structure between the two studies. Some salient differences include first the study setting, which involved a daily methadone program with monitoring 6 days per week vs three times weekly monitoring in the current study. Second, delivery of Cognitive Behavioral Therapy was mandated in the Phase IIb methadone study and optional in this Phase III study. The participation rates in the therapy involved about two-thirds of the sessions in this study. Third, the single study site of opiate addicts who had secondary cocaine use was more homogenous than the primary cocaine users drawn from six sites in different regions of the country. Fourth, financial incentives of $55 per week plus $65 for each of the five vaccinations were approximately three times higher in this Phase III study than the compensation in the previous methadone based study, which may have made more funds available to purchase or trade for cocaine. In view of these differences future studies would benefit from a more structured study setting such as a day-treatment program that helps the patients become motivated for abstinence. This should lead to a more homogeneous population of patients who have been at least 2-weeks cocaine-free prior to starting the TA-CD vaccinations. In this way the study would shift from an abstinence initiation to a relapse-prevention design and potentially greater integration of CBT to facilitate the maintenance of abstinence. Future studies also may benefit from the development of high activity cholinesterase enzymes that will more rapidly metabolize the cocaine to inactive metabolites . Because these enzymes appear to act relatively slowly compared to the rapid entry of cocaine into the brain, the fast kinetics of antibody-drug interactions are ideally suited to being combined with these enhanced enzymes to produce extremely effective blockers of cocaine’s actions on all organ systems including both the brain and heart .The current generation of young people faces the worst labour market prospects in decades . The legacy of the Great Recession, as well as longer term structural changes to the global economy, have disproportionately affected young people . Disengagement from the labour market in young adulthood is particularly concerning because it may lead to long-term negative economic consequences for the individual as well as social problems such as criminal offending .