Cytisine Pharmacokinetics and Dose Response (C-DRAKS 3 and C-DRAKS 4)

Study Overview
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Brief Summary
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A number of pharmacotherapies are available for smoking cessation in New Zealand including nicotine replacement therapy, bupropion, an antidepressant medication and varenicline. Of these, varenicline is the most effective, but also the most expensive. Varenicline acts like nicotine and stimulates nicotine receptors in the brain, but to a lesser extent, and simultaneously block nicotine binding to its receptors and thus reduces the rewarding effects of cigarette smoking. Cytisine (Tabex® and Desmoxan®) is a plant alkaloid and also acts in a similar way to varenicline but is significantly cheaper. It has been used for more than 50 years in some parts of eastern and central Europe as an aid to quit smoking, but is not approved for use in many countries such as New Zealand, Australia, the UK or the US. Randomised, placebo-controlled trials have shown that cytisine is more effective than placebo and nicotine replacement therapy (NRT)for smoking cessation. However there is a paucity of pre-clinical data on cytisine. In particular, there are limited data on the pharmacokinetic and the dose response characteristics of cytisine. Furthermore, the current dosing regimen recommended by the manufacturer is complex and has no clear basis in empirical research. Complexity of dosing has been shown to be a key factor in determining adherence. Therefore, a simpler regimen would likely maximise the effectiveness of treatment through improved adherence to the treatment regimen. The investigators therefore propose to undertake two studies to investigate the influence of dose, dosing frequency and dosing duration on the pharmacokinetics and tolerability of cytisine and cigarette craving in smokers.

Detailed Description
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see above

Official Title
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Cytisine as a Smoking Cessation Agent: Improving Adherence Through a Better Understanding of Pharmacokinetics and Dose Response

Conditions
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Smoking Cessation

Intervention / Treatment
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* Drug: Cytisine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: be at least 18 years of age, be able to provide written consent, have no significant medical or psychiatric disorder (see below under exclusion criteria) smoke at least 10 cigarettes a day Exclusion Criteria: they are pregnant or breastfeeding, they are current users of NRT products, they are current users of non-NRT smoking cessation therapies (e.g. bupropion [Zyban®], clonidine, nortriptyline, or varenicline [Champix®]), they are enrolled in another smoking cessation programme (concurrent referral to a face-to-face provider from Quitline is acceptable) or other cessation study they have had a heart attack, stroke, or severe angina within the past three months, they have uncontrolled high blood pressure (> 150 mmHg systolic, > 100 mmHg diastolic), they have phaeochromocytoma, they have been diagnosed with epilepsy they suffer from significant mental health problems they have severe renal impairment they are taking medications which are significantly affected by cessation of smoking (e.g. warfarin, olanzapine, clozapine, therophylline, etc.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.5 mg cytisine<br>1.5 mg cytisine given as a single dose | Drug: Cytisine<br> <br> * Other names: Cytisine, Desmoxan;|
| Experimental: 3 mg cytisine<br>3 mg cytisine given as a single dose | Drug: Cytisine<br> <br> * Other names: Cytisine, Desmoxan;|
| Experimental: 4.5 mg cytisine<br>4.5 mg cytisine given as a single dose | Drug: Cytisine<br> <br> * Other names: Cytisine, Desmoxan;|
| Experimental: 1.5 mg cytisine six times a day<br>1.5 mg (1 capsule) is given six times a day (0, 2, 4, 6, 8 and 10 hours) for 5 days | Drug: Cytisine<br> <br> * Other names: Cytisine, Desmoxan;|
| Experimental: 3 mg cytisine three times a day<br>3 mg (2 capsules) are given three times a day (0, 4 and 8 hours) for 5 days | Drug: Cytisine<br> <br> * Other names: Cytisine, Desmoxan;|
| Experimental: 4.5 mg cytisine two times a day<br>4.5 mg (3 capsules) are given two times a day (0 and 6 hours) for 5 days | Drug: Cytisine<br> <br> * Other names: Cytisine, Desmoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exposure (AUC) | Plasma cytisine concentrations will be measured in all groups for 24 hours. For Arms 4-6, we will continue to take blood samples to measure cytisine concentrations throughout the dosing period (Days 1-5). Days 3-5: one blood sample will be taken before the first dose for the day. On Day 5 an extra blood sample will be taken at 7.5 hours post the first dose for that day. | Arms 1-3: 24 hours; Arms 4-6: 24 hours, and up to Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nicotine and cotinine concentrations | Plasma nicotine and cotinine concentrations will be measured along with cytisine concentrations (from the same plasma samples) | Arms 1-3: 24 hours; Arms 4-6: 24 hours, and up to Day 5 | 
| Craving for cigarettes | The brief Questionnaire on Smoking Urges will be administered | Arms 1-3: 0, 1, 2, 4, 6, 8, 10 and 24 hours. Arms 4-6: 0, 2, 4 ,6, 8, 10, 24 hours; once on Days 3- 5 | 
| Blood pressure | Systolic and diastolic blood pressure (mm Hg) will be measured with a blood pressure monitor | Arms: 1-3: 0, 1, 2, 4, 6, 8, 10, 24 hours. Arms 4-6: 0, 2, 4, 6, 8, 10, 24 hours; once on Days 3- 5 | 
| Heart rate | Heart rate (beats per minute) will be simultaneously measured with blood pressure using a blood pressure monitor | Arms: 1-3: 0, 1, 2, 4, 6, 8, 10, 24 hours. Arms 4-6: 0, 2, 4, 6, 8, 10, 24 hours; once on Days 3- 5 | 
| Respiratory rate | Respiratory rate (breaths per minute) will be measured along with blood pressure and heart rate | Arms: 1-3: 0, 1, 2, 4, 6, 8, 10, 24 hours. Arms 4-6: 0, 2, 4, 6, 8, 10, 24 hours; once on Days 3- 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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smoking, cytisine, Pharmacokinetics