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Abstract: Background and aims: Sleep disruptions increase the risk of substance misuse. Substance use-especially stimulants-can increase acute and chronic sleep dysfunction. This study aimed to estimate the associations between sleep disturbance and stimulant use over time among participants with stimulant use disorder (StUD). Design: In this secondary analysis, a Random Intercept Cross-Lagged Panel Model (RI-CLPM) was used to assess sleep disturbance and stimulant use over 8 weeks among participants with StUD. Setting: United States of America. Participants: The analysis included 793 participants with StUD enrolled across 3 randomized controlled trials in the National Institute on Drug Abuse’s Clinical Trials Network (CTN): CTN-0037, CTN-0048 and CTN-0068. Measurements: Self-reported sleep disturbance was harmonized as a binary indicator across trial measures at each week. Stimulant use days per week were captured by Timeline Follow Back. Baseline covariates included age, sex, race/ethnicity, employment status, presence of depressive symptoms, any psychiatric history, treatment arm and trial. Findings: Sleep disturbance was associated with a higher average number of stimulant use days the following week [β = 0.15, 95% confidence interval (CI) = 0.09, 0.22, P < 0.001], and greater stimulant use was linked to increased odds of subsequent sleep disturbance (odds ratio = 1.20, 95% CI = 1.14, 1.26, P < 0.001). Conclusions: Higher-than-usual stimulant use appears to be associated with increased likelihood of sleep disturbance the following week, and vice versa. Related protocols: CTN-0037, CTN-0048, CTN-0068

Abstract:

The Treatment Effectiveness Assessment (TEA) score is derived from a 4-item self-administered assessment utilizing a Likert scale to evaluate changes across four life domains: substance use, personal responsibilities, health, and citizenship. The World Health Organization Quality of Life Brief (WHOQOL-BREF) scale is a shortened version of the original instrument that may be more convenient for use in large research studies or clinical trials. It assesses the individual’s perceptions in the context of their culture and value systems, and their personal goals, standards, and concerns. Cocaine craving is a core symptom of cocaine use disorder and remains a consistent obstacle to achieving sustained reductions in use and relapse prevention.

This secondary analysis of data from CTN-0048 aimed to examine relationships between quality of life and health satisfaction (using the WHO-QOL scale), cocaine use (urine drug screens), and patient ratings of treatment effectiveness, as measured by the TEA over 8 weeks of treatment.

Results found significant negative relationships between cocaine craving and TEA and significant positive relationships between patient quality of life and satisfaction with health. A model including 4 health domains also indicated that there were significant positive relationships between health domains and TEA as well. TEA was not significantly related to longest duration of abstinence (LDA) for cocaine verified by urine drug screens.

Conclusions: Self-reported treatment effectiveness was integrally related to patient level factors, over time, while in treatment for cocaine use disorder and receiving placebo or buprenorphine and extended-release naltrexone, however TEA was not predictive of LDA. Recognizing and providing parallel intervention for these patient level factors during substance use disorder treatment may enhance patient reports of treatment effectiveness, indicating improvement across the patient reported domains of substance use, life satisfaction, health, and community.

Related protocols: CTN-0048

Abstract:

High levels of missing outcome data for biologically confirmed substance use (BCSU) threaten the validity of substance use disorder (SUD) clinical trials. Underlying attributes of clinical trials could explain BCSU missingness and identify targets for improved trial design.

We reviewed 21 clinical trials funded by the NIDA National Drug Abuse Treatment Clinical Trials Network (CTN) and published from 2005 to 2018 that examined pharmacologic and psychosocial interventions for SUD. We used configurational analysis-a Boolean algebra approach that identifies an attribute or combination of attributes predictive of an outcome-to identify trial design features and participant characteristics associated with high levels of BCSU missingness. Associations were identified by configuration complexity, consistency, coverage, and robustness. We limited results using a consistency threshold of 0.75 and summarized model fit using the product of consistency and coverage.

For trial design features, the final solution consisted of two pathways: psychosocial treatment as a trial intervention OR larger trial arm size (complexity=2, consistency=0.79, coverage=0.93, robustness score=0.71). For participant characteristics, the final solution consisted of two pathways: interventions targeting individuals with poly- or nonspecific substance use OR younger age (complexity=2, consistency=0.75, coverage=0.86, robustness score=1.00).

Conclusions: Psychosocial treatments, larger trial arm size, interventions targeting individuals with poly- or nonspecific substance use, and younger age among trial participants were predictive of missing BCSU data in SUD clinical trials. Interventions to mitigate missing data that focus on these attributes may reduce threats to validity and improve utility of SUD clinical trials.

Related protocols: CTN-0002, CTN-0003, CTN-0004, CTN-0006, CTN-0007, CTN-0009. CTN-0013, CTN-0014, CTN-0015, CTN-0017, CTN-0021, CTN-0029, CTN-0030, CTN-0031, CTN-0037, CTN-0044, CTN-0046, CTN-0048, CTN-0051, CTN-0053

Abstract:

The aim of this secondary analysis of CTN-0048 was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP).

Cocaine-dependent participants (N=302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines.

In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P=0.0021). The interactions of genetic variant x treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N=35) had fewer cocaine-positive urines (P=0.0006) than did the PLB group (N=26) and in the rs1997794 A-allele carrier group where the BUP16 group (N=49) had fewer cocaine-positive urines (P=0.0003) than did the PLB group (N=58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response.

Conclusions: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Related protocols: CTN-0048

Abstract:

The purpose of this study was to estimate obesity prevalence among drug-dependent individuals and to compare prevalence across different types of drug dependence.

1596 opioid- and/or stimulant-dependent participants were extracted from six clinical trials within the National Drug Abuse Treatment Clinical Trials Network of the National Institute on Drug Abuse (NIDA CTN) to estimate obesity prevalence among drug-dependent users. Age-, sex-, and race-matched National Health and Nutrition Examination Survey (NHANES) samples were used as a general population reference. Standardized prevalence ratios (SPRs) were calculated to compare the CTN sample to NHANES as well as to compare within the CTN sample. Logistic regression estimated associations between the type of drug dependence and obesity.

The standardized obesity prevalence among the drug-dependent CTN trial participants was 67% of expected for age-, sex- and race-matched NIHANES participants (SPR = 0.67, 95% CI: 0.60-0.74). Obesity was least prevalent among opioid-dependent-only participants (SPR = 0.36, 95% CI: 0.27-0.46 compared to the NHANES, and SPR = 0.33, 95% CI: 0.23-0.46 compared to the stimulant-dependent-only participants). Compared to stimulant-dependent-only users (p < 0.0001), the odds of obesity were 67% lower among opioid-dependent-only users (adjusted odds ratio [AOR] = 0.33, 95% CI: 0.23-0.46) and 33% lower among opioid and stimulant-co-dependent users (AOR = 0.67, 95%CI: 0.49-0.90) after controlling for age, sex, race, education and employment pattern.

Conclusions: The prevalence of obesity among drug-dependent clinical trial participants was lower than the general population, and lowest among opioid-dependent-only users, suggesting an inverse relationship between obesity prevalence and drug dependence, most notable among opioid-dependent-only users.

Related protocols: CTN-0001, CTN-0002, CTN-0003, CTN-0037, CTN-0046, CTN-0048

Abstract:

Qualify of life is an important construct in assessing outcomes of substance use treatment interventions. The goal of the current analysis was to evaluate changes in participants’ quality of life in the Clinical Trials Network multi-site Cocaine Use Reduction with Buprenorphine (CURB) study in cocaine-dependent opioid users. Participants were randomly assigned to 1 of 3 conditions provided with extended-release naltrexone: 16 mg/day buprenorphine+naloxone (BUP) (BUP 16), 4mg/day BUP (BUP 4), 0mg/day BUP (placebo, PLB), plus weekly therapy and extended-release naltrexone (XR-NTX). Participants completed the WHOQOL-BREF at screening, end of medication/treatment, and the 3-month follow-up. This 24-item measure assessed quality of life across physical, psychological, social, and environmental domains. Of the 302 study participants, 219 completed QOL surveys at all time points and were used in the analyses. Baseline Quality of Life scores were lower than the norms established for individuals in a healthy population in all domains. No treatment effects were found, but there were statistically significant differences in mean ratings of QOL across the time points in all domains: physical, psychological, social, and environmental. Despite the significant increase in QOL at end of treatment, compared to the general population, participants were still scoring low in Social and Environmental domains.

Conclusions: The results showed significant improvements in quality of life between the start and end of treatment. However, despite the improvement, participants remained considerably lower than healthy population norms across some domains, suggesting the particular vulnerability of this substance-using population.

Related protocols: CTN-0048

Abstract:

The use of blinding in trials is an established element of study design, intended to minimize bias and expectation effects and strengthen the internal validity of the results. The goal of the current analysis was to assess participants’ perceptions of their blinded treatment assignment and examine whether these perceptions were associated with the primary outcome results of the trial. Perceived treatment assignment was evaluated in the NIDA Clinical Trials Network (CTN) trial “Cocaine Use Reduction with Buprenorphine (CURB)” at the the end of active medication. Participants were randomly assigned to 1 of 3 conditions: 16mg buprenorphine+naloxone (BUP16), 4mg (BUP4), placebo (PLB), plus cognitive behavioral therapy and extended-release naloxone (XR-NTX). Data was available for 281/302 participants (93%). 57% of participants had an opinion regarding their assignment and 43% were unsure. Of those who had an opinion, 46% guessed correctly. There was no association with actual treatment group. In the BUP16 arm, 55% guessed correctly, 44% in the BUP4 arm, and 39% in the PLB arm. Perceived treatment assignment was not related to the primary outcome (self-reported cocaine use combined with urine drug screens during last 30 days of medication) or the number of cocaine-negative UDS collected during that period. The fewest average number of days of cocaine use was 6.4 for participants who believed they got BUP16; the greatest was for PLB at 8.0 days. These differences were not significant. There was no difference in the number of cocaine-negative UDS across perceived treatment.

Conclusions: This secondary analysis showed that the blind was maintained in CURB. Participants who speculated about their arm were no more likely to be correct than by chance. This finding increases the confidence in the validity of trial results. Further examination revealed no association with cocaine abstinence.

Related protocols: CTN-0048

Abstract:

This is the primary outcomes article for CTN-0048.

This study aimed to examine the safety and effectiveness of buprenorphine+naloxone sublingual tablets (BUP, as Suboxone) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse.

This multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the NIDA Clinical Trials Network (CTN-0048), randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York, and Washington D.C. to 1 of 3 conditions provided with XR-NTX: 4mg/day BUP (BUP4, n=100), 16mg/day BUP (BUP16, n=100), or no buprenorphine (placebo, PLB, n=102).

Participants received pharmacotherapy for 8 weeks, with 3 clinic visits per week. Cognitive Behavioral Therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4 weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention, and adverse events.

No group differences were found between groups for the primary outcome (BUP4 vs. PLB, p=0.262; BUP16 vs PLB, p=0.185).). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB (p=0.022, OR=1.71) but not for BUP4 (p=0.105, OR=1.05). No secondary outcome differences across groups were found for adherence, retention, or adverse events.

Conclusions: Although the primary outcome analysis did not detect significant differences in cocaine use between treatment groups, some urine drug screen analyses found that participants randomized to higher dose (16 mg/day) of buprenorphine provided significantly more cocaine-negative urine samples compared to participants randomized to placebo. Furthermore, the medication combination used in this study appeared to be safe with little risk of inducing iatrogenic opioid dependence. The combination of naltrexone and buprenorphine deserves further confirmatory study as pharmacotherapy for cocaine use disorder.

Related protocols: CTN-0048

Abstract:

Treatment satisfaction in research may be associated with treatment retention, engagement, and outcomes. Including a satisfaction measure not only collects data on participants’ attitudes about the treatment provided, but provides an unspoken message that participants’ opinions are valued. The current study examines results of a treatment satisfaction survey administered to participants enrolled in the multi-center National Drug Abuse Treatment Clinical Trials Network (CTN) Cocaine Use Reduction with Buprenorphine (CURB, CTN-0048) trial to assess opinions about study participation. This secondary analysis uses a 9-item satisfaction survey self-administered by cocaine-dependent participants at the end of the 8-week study. All participants received extended-release injectable naltrexone and were randomly assigned to 1 of 3 daily, sublingual buprenorphine/naloxone (BUP) conditions: 16mg BUP (BUP16), 4mg BUP (BUP4), 0mg BUP (placebo, PLB), plus weekly CBT. Satisfaction ratings were based on a 5-point Likert Scale.

Two hundred and seventy-eight (278) surveys were collected for a 92% completion rate. Most participants (93.5%) reported being satisfied or very satisfied with their overall experience in the study, and 84.9% reported that they would definitely participate again if given the opportunity. No difference in overall satisfaction was found between the BUP groups and the PLB group (BUP4 vs PLB, p=0.08; BUP16 vs PLB, p=0.43). Satisfaction was not associated with retention, CBT attendance, or cocaine use outcomes. Participants were also asked to what medication group they thought they were assigned, and 56.8% had an opinion whereas 43.2% were unsure. Of those with an opinion, 26.3% correctly guessed their group assignment. Additional analyses of items addressing participant opinion of the study medication and counseling will be presented.

Conclusions: Given the high rates of treatment satisfaction reported by study participants, it is not surprising that satisfaction is not related to treatment performance and outcome. Interestingly, participant guesses about assigned treatment were no better than chance. This seems to demonstrate the effectiveness of the study blinding process.

Abstract:

Effective medications to treat cocaine dependence have not been identified. Recent pharmacotherapy trials demonstrate the potential efficacy of buprenorphine (BUP) (alone or with naltrexone) for reducing cocaine use. The National Drug Abuse Treatment Clinical Trials Network (CTN) launched CTN-0048, the Cocaine Use Reduction with Buprenorphine (CURB) protocol, to examine the safety and efficacy of sublingual BUP (as Suboxone) in the presence of extended-release injectable naltrexone (XR-NTX) for the treatment of cocaine dependence. This multi-site, double-blind, placebo-controlled study will randomize 300 participants across 11 sites. Participants must meet the DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. Participants are inducted onto XR-NTX after self-reporting at least 7 days of abstinence from opioids and tolerating a naloxone challenge followed by oral naltrexone and are then randomly assigned to one of three medication conditions (4 mg BUP, 16 mg BUP, or placebo) for 8 weeks. Participants receive a second injection of XR-NTX 4 weeks after the initial injection, and follow-up visits are scheduled at 1 and 3 months post-treatment. Participants receive weekly cognitive behavioral therapy (CBT). Recruitment commenced in September, 2011. Enrollment, active medication, and follow-up phases are ongoing, and recruitment is exceeding targeted enrollment rates. The protocol aims to demonstrate whether BUP, administered in the presence of XR-NTS, reduces cocaine use in adults with cocaine dependence and opioid use disorders and to demonstrate if XR-NTS prevents development of physiologic dependence on BUP.

Related protocols: CTN-0048

Abstract:

The National Drug Abuse Treatment Clinical Trials Network (CTN) has faced many challenges over its first eleven years. This review explores some of these challenges and the paths the CTN took to meet these challenges, including: designing clinical trials that reflect the CTN’s mission and changing public health needs, finding the synergies in the varied expertise of clinical treatment providers and academic researchers, promoting evidence-based practices, and expanding the Network into mainstream medical practices to reach a broader patient population. Included in this exploration are specific examples from CTN clinical trials.

CTN studies have shown that quality clinical trials can be successfully implemented into practice settings unfamiliar with research logistics by taking clinicians’ practical needs and research knowledge level into account. The challenges yet to be faced in the CTN’s efforts to expand opportunities to offer existing treatments to the segment of the drug-abusing population that utilizes mainstream health care seem large, but not as large as the potential for improvements in public health.

Related protocols: CTN-0001, CTN-0002, CTN-0003, CTN-0004, CTN-0005, CTN-0006, CTN-0007, CTN-0009, CTN-0010, CTN-0011, CTN-0013, CTN-0014, CTN-0015, CTN-0017, CTN-0018, CTN-0019, CTN-0020, CTN-0021, CTN-0027, CTN-0028, CTN-0029, CTN-0030, CTN-0031, CTN-0032, CTN-0037, CTCN-0044, CTN-0047, CTN-0048, CTN-0049

Abstract:

This protocol-specific training webinar, hosted by the NIDA Clinical Coordinating Center, provides an overview of the National Drug Abuse Treatment Clinical Trials Network (CTN) study, protocol CTN-0048 (Cocaine Use Reduction with Buprenorphine (CURB)). This study is a randomized, double-blind, placebo-controlled trial designed to examine the safety and effectiveness of buprenorphine in the presence of naltrexone for individuals with cocaine dependence and past-year opioid dependence, past-year opioid abuse, or past-year opioid use with a history of opioid dependence during the participant’s lifetime. The chemical mechanisms of both cocaine and opioids are discussed, along with the effects of withdrawal from both substances. Also included are study participant inclusion/exclusion criteria, a list of the screening assessments that will be used, and information about both buprenorphine and naloxone and the dosing specifics that will be used in the trial itself.

Related protocols: CTN-0048