Belsomra + Methylphenidate for Smoking Cessation

Recruiting in Palo Alto (17 mi)

Overseen by Amy Janes, Ph.D.

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: National Institute on Drug Abuse (NIDA)

Must not be taking: CNS depressants, CYP3A inhibitors

Disqualifiers: Psychotic disorders, Neurological disorders, Obesity, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Study Description: Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant s ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant s impact in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. Objectives: The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, suvorexant s impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:\<TAB\> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are using medications that depress the central nervous system or are CYP3A inhibitors/inducers, you may be excluded from the study. It's best to discuss your current medications with the study team.

How does the drug Belsomra combined with Methylphenidate differ from other smoking cessation drugs?

Belsomra (Suvorexant) is unique in smoking cessation as it is primarily used for insomnia, and its combination with Methylphenidate, a stimulant, is novel compared to traditional smoking cessation drugs like nicotine replacement therapy, bupropion, and varenicline, which focus on reducing nicotine withdrawal and cravings.

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Eligibility Criteria

This trial is for daily smokers/vapers aged 18-60 who have been using nicotine consistently for at least a year. They must not use other drugs or alcohol, be pregnant, or have certain health conditions like severe heart disorders, respiratory issues, major depression (unless stable on medication), obesity with BMI over 35, or neurological disorders.

Inclusion Criteria

I can become pregnant and will take pregnancy tests on all study days.

I am willing to follow the study's lifestyle requirements and have given my written consent.

I am between 18 and 60 years old.

Exclusion Criteria

Participants cannot self-report complex sleep behaviors

I have never had a major head injury that affected my thinking, caused seizures, or led to other brain problems.

Participants cannot meet DSM-5 criteria for lifetime and/or current psychotic disorders such as bipolar disorder, schizophrenia, schizoaffective disorder or medical conditions that impact reward function

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive suvorexant and/or methylphenidate to assess neurobiological and behavioral impacts

1-2 months

Multiple visits for drug administration and fMRI scans

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Participant Groups

The study tests the drug suvorexant's impact on brain function and behavior in people with nicotine addiction. It also examines how suvorexant interacts with methylphenidate in non-smokers. Participants will take a single dose of suvorexant and then daily doses for about a week; control subjects will receive various combinations of the drugs and placebo.

Group I: Nicotine Dependence Arm Experimental Treatment 2 Interventions

140 Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days.

Group II: Control Arm Active Control 3 Interventions

80 Volunteers who are between the ages of 18-60 and are non-smokers/vapers. 1. Baseline visit with 1 fMRI scans pre- and post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max)

Belsomra is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as Belsomra for:

• Insomnia characterized by difficulties with sleep onset and/or sleep maintenance

🇪🇺 Approved in European Union as Belsomra for:

• Insomnia characterized by difficulties with sleep onset and/or sleep maintenance

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institute on Drug Abuse Baltimore, MD

Who Is Running the Clinical Trial?

National Institute on Drug Abuse (NIDA) Lead Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice. [2022] Strategies for assisting smoking cessation include behavioural counselling to enhance motivation and to support attempts to quit and pharmacological intervention to reduce nicotine reinforcement and withdrawal from nicotine. Three drugs are currently used as first line pharmacotherapy for smoking cessation, nicotine replacement therapy, bupropion and varenicline. Compared with placebo, the drug effect varies from 2.27 (95% CI 2.02, 2.55) for varenicline, 1.69 (95% CI 1.53, 1.85) for bupropion and 1.60 (95% CI 1.53, 1.68) for any form of nicotine replacement therapy. Despite some controversy regarding the safety of bupropion and varenicline, regulatory agencies consider these drugs as having a favourable benefit/risk profile. However, given the high rate of psychiatric comorbidity in dependent smokers, practitioners should closely monitor patients for neuropsychiatric symptoms. Second-line pharmacotherapies include nortriptyline and clonidine. This review also offers an overview of pipeline developments and issues related to smoking cessation in special populations such as persons with psychiatric comorbidity and pregnant and adolescent smokers.

2. England pubmed.ncbi.nlm.nih.gov

New medications for nicotine dependence treatment. [2019] For several years, nicotine replacement therapy (nicotine gum, patches, and nasal spray) has been the mainstay for the treatment of nicotine dependence. The nicotine vapor inhaler is a new pharmacological adjunct shown to be effective in placebo-controlled trials. It delivers a vaporized form of nicotine to the oral mucosa. Bupropion sustained release (SR) is the first non-nicotine pharmacological treatment approved for smoking cessation and is thought to be effective because of its dopaminergic activity on the pleasure and reward pathways in the mesolimbic system and nucleus accumbens. Though few studies have been reported, there is pharmacological rationale to use combined pharmacotherapies for the treatment of nicotine dependence. While there are a limited number of reported studies with mixed findings using higher than the standard nicotine patch dose, use of higher doses of nicotine patch therapy (i.e., more than one patch at a time) may be appropriate for smokers who previously failed single dose patch therapy or in those whose nicotine withdrawal symptoms were not adequately relieved with standard therapy. The concept of therapeutic drug monitoring can be applied to nicotine replacement therapy. A new product, a sublingual nicotine tablet, has shown efficacy in a double-blind placebo-controlled trial and will likely be approved in the future. The anti-hypertensive, mecamylamine, has been found to have efficacy for smoking cessation in a small trial. Nicotine and mecamylamine both occupy receptors that would otherwise be acted upon by nicotine from cigarettes, thus, when administered in combination, would be expected to occupy more receptors than either drug alone, thereby attenuating smoking reward and facilitating extinction of the smoking behavior. Pivotal trials of this combination are underway. Remaining questions include: (1) what is the optimal dose and duration of treatment using nicotine replacement therapy? (2) What is the optimal duration of treatment using bupropion? (3) What are the best combination treatments and which smokers are best suited for combination treatment? (4) Will other similar pharmacological agents with dopaminergic/noradrenergic activity have efficacy similar to bupropion?

3. United States pubmed.ncbi.nlm.nih.gov

Bupropion sustained release as a smoking cessation treatment in remitted depressed patients maintained on treatment with selective serotonin reuptake inhibitor antidepressants. [2022] Patients with depressive disorders smoke tobacco more often than the population at large and find quitting more difficult. Furthermore, when they quit smoking, they are more likely to suffer a relapse of depression. We evaluated the addition of bupropion sustained release (SR) for smoking cessation among patients with a history of depressive disorders being maintained in a euthymic state with selective serotonin reuptake inhibitor (SSRI) antidepressants.

4. United States pubmed.ncbi.nlm.nih.gov

Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking. [2018] Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventable cause of death in developed countries. Since the development of nicotine replacement therapy (NRT) in 1978, treatment options have continued to evolve and expand. Despite this, currently available treatments remain insufficient, with less than 25% of smokers remaining abstinent 1 year after treatment. In this article, we review existing and emerging smoking cessation pharmacotherapies, with a special emphasis on the most promising agents that are currently being investigated. A search of the Cochrane Database of Systematic Reviews and the PubMed, Ovid, and ClinicalTrials.gov databases (August 2 to September 1, 2017) was undertaken for articles on smoking cessation pharmacotherapies, applying no language restrictions. More than 40 pharmacotherapies were reviewed including conventional pharmacotherapies-NRT, bupropion, and varenicline (all approved by the U.S. Food and Drug Administration as first-line treatment of smoking cessation)-and novel therapies: cytisine, N-acetylcysteine, cycloserine, memantine, baclofen, topiramate, galantamine, and bromocriptine. Studies of combination NRT and varenicline showed the greatest smoking cessation rates. Clonidine and nortriptyline are second-line treatments used when first-line treatments fail or are contraindicated, or by patient preference. Some novel therapies, especially acetylcholinesterase inhibitors, cytisine, and N-acetylcysteine, display promising results. Because the results of randomized clinical trials were reported using varied end points and outcome measures, direct comparisons between different pharmacotherapies cannot easily be evaluated. Additional high-quality randomized double-blind placebo-controlled trials with long-term follow-up, using validated sustained abstinence measures, are needed to find more effective smoking cessation aids.

5. England pubmed.ncbi.nlm.nih.gov

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. [2023] A population pharmacokinetic and pharmacodynamic analysis evaluated the relationships of dose, plasma concentrations of bupropion and metabolites, and patient covariates with the safety and efficacy of bupropion sustained release (SR) for smoking cessation. A total of 519 outpatient chronic cigarette smokers were randomized to one of three bupropion SR doses: 100, 150, or 300 mg/day or placebo. The bupropion plasma concentration time data were fit and subject-specific bayesian estimates of clearance were obtained. Logistic regression analyses evaluated the role of dose, concentrations, and covariates in predicting efficacy and safety endpoints. For the evaluation of efficacy, patients were classified as quitters or non-quitters on the basis of a 4-week quit variable (defined as complete abstinence for weeks 4-7 of the study). For the evaluation of safety, patients were classified into two categories for each adverse event evaluated, corresponding to whether the patient ever experienced the adverse event during the course of the study or never experienced the event, regardless of whether the event was treatment-emergent. The efficacy of bupropion SR in facilitating smoking cessation was found to be related to dose and a mean metabolite concentration, and quitting in general was found to be related to the number of cigarettes smoked per day at baseline. Smoking cessation was 1.42, 1.69, and 2.84 times more likely in patients receiving 100, 150, and 300 mg/day of bupropion SR, respectively, as compared to placebo (p = 0.0001). As the baseline number of cigarettes smoked per day increased, the likelihood of quitting decreased regardless of the treatment condition. Insomnia and dry mouth were positively associated with mean metabolite concentrations, and dry mouth was inversely related to patient weight. Anxiety was inversely related to predicted steady-state concentration (Cpss), suggesting a positive effect on this withdrawal symptom. Bupropion SR exhibits a statistically significant dose/plasma level-response relationship for smoking cessation. Dry mouth and insomnia, related to concentrations, may be managed with dose reduction, with the realization that smoking cessation may be impaired.