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

• ClinicalTrials.gov Identifier: NCT02585024
• Recruitment Status: Terminated
• First Posted: October 23, 2015
• Last Update Posted: March 22, 2019
• Sponsor: University of Auckland, New Zealand
• Information provided by (Responsible Party): Natalie Walker, University of Auckland, New Zealand

Tracking Information

• First Submitted Date: October 21, 2015
• First Posted Date: October 23, 2015
• Last Update Posted Date: March 22, 2019
• Study Start Date: February 2016
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 16, 2017)

Exposure (AUC) [ Time Frame: Arms 1-3: 24 hours; Arms 4-6: 24 hours, and up to Day 5 ]

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.

• Original Primary Outcome Measures (submitted: October 22, 2015): Plasma cytisine concentration [ Time Frame: C-DRAKS 3: Blood samples taken at 0 (just before dosing), 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 and 10 hours ]

Current Secondary Outcome Measures (submitted: May 16, 2017)

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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cytisine Pharmacokinetics and Dose Response (C-DRAKS 3 and C-DRAKS 4)
• Official Title: Cytisine as a Smoking Cessation Agent: Improving Adherence Through a Better Understanding of Pharmacokinetics and Dose Response

Brief Summary

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: see above
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Smoking Cessation

Intervention

Drug: Cytisine

Other Name: Cytisine, Desmoxan

Study Arms

• Experimental: 1.5 mg cytisine
  1.5 mg cytisine given as a single dose
  Intervention: Drug: Cytisine
• Experimental: 3 mg cytisine
  3 mg cytisine given as a single dose
  Intervention: Drug: Cytisine
• Experimental: 4.5 mg cytisine
  4.5 mg cytisine given as a single dose
  Intervention: Drug: Cytisine
• 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
  Intervention: Drug: Cytisine
• 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
  Intervention: Drug: Cytisine
• 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
  Intervention: Drug: Cytisine

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 20, 2019): 35
• Original Estimated Enrollment (submitted: October 22, 2015): 48
• Actual Study Completion Date: March 2019
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: New Zealand

Administrative Information

• NCT Number: NCT02585024
• Other Study ID Numbers: AMRF reference 1 1 15 011
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Natalie Walker, University of Auckland, New Zealand
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Auckland, New Zealand
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: University of Auckland, New Zealand
• Verification Date: March 2019