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

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

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.

Study Overview

• Status: Terminated
• Conditions: Smoking Cessation
• Intervention / Treatment: Drug: Cytisine

Detailed Description

see above

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand, 1072
    • Soo Hee Jeong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Auckland, New Zealand
• Investigators: Principal Investigator: Soo Hee Jeong, Phd, University of Auckland, New Zealand

Publications and helpful links

General Publications

• Jeong SH, Sheridan J, Bullen C, Newcombe D, Walker N, Tingle M. Ascending single dose pharmacokinetics of cytisine in healthy adult smokers. Xenobiotica. 2019 Nov;49(11):1332-1337. doi: 10.1080/00498254.2018.1557760. Epub 2019 Jun 19.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: October 21, 2015
• First Submitted That Met QC Criteria: October 22, 2015
• First Posted (Estimate): October 23, 2015

Study Record Updates

• Last Update Posted (Actual): March 22, 2019
• Last Update Submitted That Met QC Criteria: March 20, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; smoking; cytisine
• Other Study ID Numbers: AMRF reference 1 1 15 011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No