Evaluation of Varenicline and Accelerated TMS for Reduction of Nicotine Use
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Resting State Functional Connectivity (rsFC)
研究概览
简要总结
The goal of this clinical trial is to learn if a combination of varenicline and enhanced accelerated Transcranial Magnetic Stimulation (aTMS) works to help adults quit using nicotine products. Researchers will compare varenicline + active aTMS with a single dose of D-Clycloserine to varenicline + sham (inactive) aTMS with a placebo pill to see the effect of enhanced aTMS on reaching abstinence. The main question it aims to answer is: Does receiving active enhanced aTMS + varenicline lead to higher abstinence rates and lower nicotine craving?
Participants will be asked to:
- Complete 2 brain MRI scans
- Take varenicline every day for 12 weeks
- Quit using nicotine products at the end of the second week of varenicline
- Complete one day of up to 20 TMS treatments
- Take a single dose of D-Cycloserine medication on the day of TMS treatment
- Complete 12 brief, weekly study visits
- Complete 6 brief, monthly follow up visits
- Complete a brief daily survey each day that they take the study drug
详细描述
This is a 9-month randomized parallel design, double-blind, 2-arm clinical trial consisting of a combination of circuit-targeted TMS and varenicline in 30 adults aged 18-65 with nicotine use disorder who would like to reduce or stop nicotine use.
Eligible participants will complete a baseline assessment of questionnaires and laboratory assessments. They will be randomized to receive varenicline and either active enhanced or sham TMS. Participants will be randomized at their baseline scan visit, during which they will undergo urinalysis, an fMRI scan, and a task and questionnaire battery.
Shortly after, participants will complete a TMS treatment preparation visit during which the treatment target is located and stimulation intensity of the TMS is determined. This target is used in the subsequent TMS Treatment visit of up to 20 TMS treatments. Participants' quit date will be set following their TMS treatment day.
Participants will receive varenicline medication the week of the TMS treatment preparation visit and will be instructed to take it for 12 weeks titrated to 1mg twice daily over seven days.
At the TMS treatment visit, those assigned to active enhanced aTMS will receive a single dose of D-Cycloserine medication while those assigned to sham TMS will receive placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 and ≤65;
- •The ability to give written, informed consent;
- •Fluency in English;
- •Reported interest in quitting nicotine vaping or smoking within the next month;
- •Nicotine dependence, as defined by a score of ≥4 on the 10-question E-cigarette Dependence Inventory (ECDI) or Fagerström Test for Nicotine Dependence (FTND);
- •Smoke or vape nicotine daily for at least the past 90 days, as confirmed by self-report and timeline follow-back methods;
- •Saliva cotinine >30ng/mL;
排除标准
- •Pregnancy or breastfeeding;
- •Use of smoking cessation pharmacotherapy in the past month;
- •Unwilling to abstain during the study from using smoking cessation aids other than those provided by the study;
- •Prior adverse drug reaction to varenicline;
- •Contraindication to D-Cycloserine (including allergy to D-Cycloserine, significant renal impairment or known kidney disease, pregnancy)
- •Receiving or planning to receive other TMS treatments or investigational drugs during course of participation
- •Contraindications to TMS (including seizures, metallic implants, severe existing tinnitus, etc.);
- •Contraindications to MRI (including presence of a cardiac pacemaker or pacemaker wires, metallic particles in the body, vascular clips in the head or previous neurosurgery, prosthetic heart valves, claustrophobia);
- •Inpatient psychiatric hospitalization or suicide attempts in the past six months, or recent active suicidal ideation or suicidal behavior identified at enrollment or baseline visits;
- •History of seizures and/or history of TBI subtypes associated with elevated seizure risk (e.g. penetrating injury and intraparenchymal hemorrhage)
- •History of unstable neurological illness or major medical illness, such as epilepsy or renal impairment, in the past six months, unless clearly resolved;
- •In the opinion of the investigators, evidence of active problem substance use severe enough to compromise ability to safely participate;
- •In the opinion of the investigators, unable to safely participate in this study and/or provide reliable data (e.g., claustrophobia, unable to tolerate TMS or MRI procedures, etc.).
研究组 & 干预措施
Varenicine + Sham TMS
In this arm, participants will receive 12 weeks of varenicline and instructions on how to take it. They will also receive one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. However, the sham setting will deliver no magnetic field to the brain; instead, it will deliver electrical current to the scalp to mimic the feel of active treatment. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: Nicotine Cessation Counseling (Behavioral)
Varenicine + Sham TMS
In this arm, participants will receive 12 weeks of varenicline and instructions on how to take it. They will also receive one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. However, the sham setting will deliver no magnetic field to the brain; instead, it will deliver electrical current to the scalp to mimic the feel of active treatment. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: Transcranial Magnetic Stimulation Sham (Device)
Varenicline + Active Enhanced TMS
In this arm, participants will take 12 weeks of varenicline. They will also receive a single dose of 125 mg D-Cycloserine and one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: Transcranial Magnetic Stimulation (Device)
Varenicline + Active Enhanced TMS
In this arm, participants will take 12 weeks of varenicline. They will also receive a single dose of 125 mg D-Cycloserine and one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: Nicotine Cessation Counseling (Behavioral)
Varenicline + Active Enhanced TMS
In this arm, participants will take 12 weeks of varenicline. They will also receive a single dose of 125 mg D-Cycloserine and one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: D-cycloserine (Drug)
Varenicline + Active Enhanced TMS
In this arm, participants will take 12 weeks of varenicline. They will also receive a single dose of 125 mg D-Cycloserine and one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: Varenicline (Drug)
Varenicine + Sham TMS
In this arm, participants will receive 12 weeks of varenicline and instructions on how to take it. They will also receive one day of up to 20 TMS treatments, adjusted to an individualized target specific to the participant based on their brain MRI collected at the baseline imaging visit. However, the sham setting will deliver no magnetic field to the brain; instead, it will deliver electrical current to the scalp to mimic the feel of active treatment. Participants will also receive 12 brief nicotine cessation counseling sessions.
干预措施: Varenicline (Drug)
结局指标
主要结局
Resting State Functional Connectivity (rsFC)
时间窗: Baseline, Week 12
Within-network resting state Functional Connectivity (rsFC) will be computed by extracting the mean BOLD time series from each region of interest comprising the addiction circuit and calculating pairwise Pearson correlations, which will then be Fisher z-transformed and averaged across all ROI pairs to derive a single within-network rsFC metric per participant at each time point. To isolate effects at the circuit level rather than changes induced by stimulation of the medial prefrontal cortex (mPFC) target site itself, the mPFC stimulation region will be excluded from the connectivity analyses. The primary analytic approach will use a linear mixed-effects model with fixed effects for time (baseline vs. post-treatment), treatment group (TMS vs. sham TMS), and their interaction, as well as a random intercept for each participant.
Change in Insula Activation to Nicotine Cues During a Cue Reactivity Task Measured by fMRI
时间窗: Baseline, Week 12
Neural responses to nicotine and neutral cues will be modeled, convolved with the canonical hemodynamic response function, and contrast images for nicotine \> neutral cues will be generated for each participant at each time point. These contrast images will be entered into second-level analyses to test group-level effects. The primary region of interest (ROI) will be the bilateral anterior insula, defined using an anatomical mask from the Harvard-Oxford atlas. The main analytic model will be a mixed-effects repeated-measures ANOVA or linear mixed-effects model with fixed effects of time (pre vs. post), treatment group (TMS + varenicline vs. sham TMS + varenicline), and their interaction, with subject-level random intercepts. The key test of our hypothesis is the time × treatment interaction within the anterior insula ROI, which reflects whether treatment modulates cue-elicited insula activity.
Biochemically-confirmed continuous nicotine abstinence across study weeks 9-12
时间窗: Week 9-Week 12
Point-prevalence abstinence from e-cigarette use was defined as self-report of no e-cigarette use since the last visit, bioverified by saliva cotinine \<30 ng/ml. Continuous abstinence is defined as observed point-prevalence abstinence over specified study visits at weeks 9, 10, 11 and 12. The primary analysis will compare the proportion of participants achieving continuous abstinence in the enhanced aTMS + varenicline group versus the Sham + varenicline group using a chi-square test. If expected cell counts are low (\<5 in any cell), Fisher's exact test will be used instead.
次要结局
- 7-day point prevalence abstinence at Week 12(Week 12)
- Nicotine withdrawal symptoms(Baseline, Week 12)
- Nicotine Craving (vaping)(Baseline, Week 12)
- Nicotine Craving (smoking)(Baseline, Week 12)
- Change in Depressive Symptoms(Baseline, Week 12)
- Change in Anxiety Symptoms(Baseline, Week 12)
研究者
Jodi Gilman
Associate Professor, Harvard Medical School; Director of Neuroscience, Center for Addiction Medicine, Massachusetts General Hospital
Massachusetts General Hospital