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What Are the Effects of Varenicline Compared With Nicotine Replacement Therapy on Long Term Smoking Cessation and Clinically Important Outcomes?

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Neil Davies, University of Bristol
ClinicalTrials.gov Identifier:
NCT02681848
First received: November 25, 2015
Last updated: February 11, 2016
Last verified: February 2016
  Purpose

Introduction: Smoking is a major avoidable cause of ill-health and premature death. Treatments that help patients successfully quit smoking have an important effect on health and life expectancy. Varenicline is a medication that can help smokers successfully quit smoking. However, there are concerns that it may cause adverse effects, such as increase in the occurrence of depression, self-harm and suicide and cardiovascular disease. In this study the investigators aim to examine the effects of varenicline versus other smoking cessation pharmacotherapies on smoking cessation, health service use, all-cause and cause-specific mortality and physical and mental health conditions.

Methods: In this project the investigators will investigate the effects of varenicline compared to nicotine replacement therapies on: (1) long-term smoking cessation and whether these effects differ by area level deprivation; and (2) the following clinically-important outcomes: rate of general practice and hospital attendance; all-cause mortality and death due to diseases of the respiratory system and cardiovascular disease; and a primary care diagnosis of respiratory illness, myocardial infarction or depression and anxiety. The study is based on a cohort of patients prescribed these smoking cessation medications from the Clinical Practice Research Datalink (CPRD). The investigators will use three methods to overcome confounding: multivariable adjusted Cox regression, propensity score matched Cox regression, and instrumental variable regression. The total expected sample size for analysis will be at least 180 000. Follow-up will end with the earliest of either an 'event' or censoring due to the end of registration or death.

Ethics and dissemination: Ethics approval was not required for this study. This project has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). The investigators will disseminate the findings via publications in international peer-reviewed journals and presentations at international conferences.


Condition Intervention
Smoking Cessation
Cardiovascular Disease
Respiratory Illness
Myocardial Infarction
Depression
Anxiety
Drug: Varenicline
Drug: Nicotine replacement therapy

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective

Resource links provided by NLM:


Further study details as provided by University of Bristol:

Primary Outcome Measures:
  • Smoking abstinence [ Time Frame: 24 months after first prescription ] [ Designated as safety issue: No ]

    Number of patients who successfully abstain from smoking after treatment.

    The investigators will define a patient as relapsed on the day they have their first record indicating that the patient is a current smoker after their first prescription of a smoking cessation therapy.



Other Outcome Measures:
  • Primary care attendance [ Time Frame: 3, 6, 9, 12, 24 and 48 months after first prescription ] [ Designated as safety issue: No ]
    Number of visits to primary care after first prescription.

  • All-cause and cause specific mortality [ Time Frame: 3, 6, 9, 12, 24 and 48 months after first prescription ] [ Designated as safety issue: No ]
    1. All-cause patient mortality after treatment identified via linked Office of National Statistics data.
    2. Cause specific mortality by respiratory disease (ICD-10=J00-J99) or cardiovascular disease (ICD-10=I00-I52)

  • Respiratory illness [ Time Frame: 3, 6, 9, 12, 24 and 48 months after first prescription ] [ Designated as safety issue: No ]
    Incident primary care diagnosis of respiratory illness identified via Read codes.

  • Myocardial infarction [ Time Frame: 3, 6, 9, 12, 24 and 48 months after first prescription ] [ Designated as safety issue: No ]
    Incident primary care diagnosis of myocardial infarction identified via Read codes.

  • Depression or anxiety. [ Time Frame: 3, 6, 9, 12, 24 and 48 months after first prescription ] [ Designated as safety issue: No ]
    Incident primary care diagnosis of depression or anxiety identified via Read codes.

  • Smoking abstinence [ Time Frame: 3, 6, 9, 12, and 48 months after first prescription ] [ Designated as safety issue: No ]
    Number of patients who successfully abstain from smoking after treatment.

  • Secondary care attendance [ Time Frame: 3, 6, 9, 12, 24 and 48 months after first prescription ] [ Designated as safety issue: No ]
    Number of visits to secondary care after first prescription. The investigators will define a patient as relapsed on the day they have their first record indicating that the patient is a current smoker after their first prescription of a smoking cessation therapy.


Estimated Enrollment: 180000
Study Start Date: July 2015
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Varenicline
    Smoking cessation medication
    Other Names:
    • Champix
    • Chantix
    Drug: Nicotine replacement therapy
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

The investigators will use the CPRD to conduct a cohort study of all patients prescribed varenicline or nicotine replacement products. The study type is "Hypothesis testing". Exposure will be defined as the first prescription of either varenicline or nicotine replacement therapy.

Setting/Context:

Prescriptions of smoking cessation medications issued in primary care.

Target population:

All smokers aged over 18 prescribed smoking cessation treatment in eligible primary care centres contributing to the CPRD after the 1st of September 2006.

Sampling method:

The investigators will sample all individuals prescribed smoking cessation medication at any point after 1st of September 2006 to the most recent release of the CPRD data.

Study population:

The investigators will use patients prescribed other smoking cessation products such as nicotine patches as controls for patients prescribed varenicline.

Criteria

Inclusion Criteria:

Patients:

  • With CPRD records aged 18 and over.
  • Who were prescribed medicines in BNF category 4.10.2 from 1st September 2006, when varenicline was introduced to the UK, to the present.
  • With records that were classified as 'acceptable' by the CPRD from all up to standard practices at least 18 months prior to date of entry of each cohort (1st March 2005).
  • Who have data defined as "acceptable" by the CPRD if they meet minimum quality control standards, for example their registration period with their GP is valid. "Up to standard" practices are GP practices defined by the CPRD to be providing data of sufficient quality for research purposes.

Exclusion Criteria:

  • Patients who registered at a practice less than 365 days before the first recorded prescription to allow for high quality assessment of baseline data and possible confounders.
  • Patients prescribed bupropion in the year before their index prescription will be excluded from the analysis. It is relatively rare for patients to be prescribed both NRT and varenicline on the same day. In the investigators' previous study this only occurred for 0.248% of all prescription events. In the primary analysis for this study the investigators will exclude patients initially prescribed both NRT and varenicline.

Follow-up

* Follow-up will end with the earliest of either an "event" or censoring due to the end of registration or death.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

Publications:
D. of Health, Smoking kills: a White Paper on tobacco (1998), (available at http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4006684).
Action on Smoking and Health, Smoking statistics who smokes and how much (2014), (available at http://www.ash.org.uk/files/documents/ASH_106.pdf).
Drug Safety and Availability > FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of neuropsychiatric adverse events, (available at http://www.fda.gov/Drugs/DrugSafety/ucm276737.htm).
The Pharmacovigilance Expert Advisory Group, Summary report based on the minutes of the Pharmacovigilance Expert Advisory Group meeting held on Wednesday 3 July 2013 (2013), (available at http://www.mhra.gov.uk/home/groups/l-cs-el/documents/committeedocument/con322356.pdf).
B. R. Kirkwood, J. A. . Sterne, Essential medical statistics (Wiley-Blackwell, 2003).
E. Leuven, B. Sianesi, PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing. Stat. Softw. Compon. (2012) (available at http://ideas.repec.org/c/boc/bocode/s432001.html).
P. R. Rosenbaum, D. B. Rubin, Constructing a Control Group Using Multivariate Matched Sampling Methods That Incorporate the Propensity Score. Am. Stat.. 39, 33 (1985).
P. R. Rosenbaum, D. B. Rubin, The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika. 70, 41 (1983).
P. S. Clarke, F. Windmeijer, Instrumental Variable Estimators for Binary Outcomes. J. Am. Stat. Assoc.. 107, 1638-1652 (2012).
L. Hansen, K. Singleton, Generalized instrumental variables estimation of nonlinear rational expectations models. Econometrica. 50, 1269-1286 (1982).
Stata Statistical Software: Release 13. (College Station, TX: StataCorp LP, 2013).
C. Baum, M. Schaffer, S. Stillman, IVREG2: Stata module for extended instrumental variables/2SLS and GMM estimation. Stat. Softw. Compon. (2002).
Office of National Statistics, Do smoking rates vary between more and less advantaged areas? (2014), (available at http://www.ons.gov.uk/ons/rel/disability-and-health-measurement/do-smoking-rates-vary-between-more-and-less-advantaged-areas-/2012/sty-smoking-rates.html).
J. D. Angrist, G. W. Imbens, D. B. Rubin, Identification of causal effects using instrumental variables. J. Am. Stat. Assoc.. 91, 444-455 (1996).

Responsible Party: Neil Davies, Dr, University of Bristol
ClinicalTrials.gov Identifier: NCT02681848     History of Changes
Other Study ID Numbers: 14/49/94 
Study First Received: November 25, 2015
Last Updated: February 11, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Bristol:
Primary care attendance
All-cause
cause specific
hospital attendance

Additional relevant MeSH terms:
Cardiovascular Diseases
Myocardial Infarction
Heart Diseases
Myocardial Ischemia
Vascular Diseases
Nicotine
Varenicline
Autonomic Agents
Cholinergic Agents
Cholinergic Agonists
Ganglionic Stimulants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nicotinic Agonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 11, 2016