a Genetically Informed Biomarker For Personalizing Treatment for Tobacco Dependence_Clinical Trial

1. PHASE 3 CLINICALTRIALDESIGN CRITIQUE:A
RANDOMIZED PLACEBO-CONTROLLEDTRIALTO
TESTAGENETICALLYINFORMED BIOMARKER FOR
PERSONALIZING TREATMENT FORTOBACCO
DEPENDENCE
Obumneke Amadi, Dr.PH
September,2020
Lerman, C., Schnoll, R. A., Hawk LW Jr, Cinciripini, P., George, T. P., Wileyto, E. P., . . . PGRN-PNAT
Research Group. (2015). Use of the nicotine metabolite ratio as a genetically informed biomarker of
response to nicotine patch or varenicline for smoking cessation: A randomised, double-blind placebo-
controlled trial. The Lancet.Respiratory Medicine, 3(2), 131-138. doi:10.1016/S2213-2600(14)70294-2
NCT01314001
Pharmacogenetics of Nicotine Addiction Treatment (PNAT)

2. SECTION 1:
CRITICALAPPRAISAL
Section 1, critical appraisal of the trial design and associated
results.
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3. Nicotine Patch Images
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4. Research Question
• What are the Differences In Outcome Measures of Using a
Genetically Informed Biomarker for Personalizing Treatment
for Tobacco Addiction and Help Quit Smoking?
• Phase III Clinical Trial
• Chosen Because of Expanding Cases of Terminal Illness e.g.
Opioid addiction, Terminal illness, Maternal smoking, etc.
(ClinicalTrials.gov, 2016)
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5. STUDY METHODS & RESULTS
Study Type : Interventional (Clinical Trial), Stratified
Multicenter, Randomized, Placebo-controlled Clinical Trial
Actual Enrollment : 1246 Participants
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6. Study Design Schema
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• Masked, placebo-controlled, multicenter, parallel-group, superiority trial.
• Randomization was centralized via computer program.
• To test whether a genetically-informed biomarker of nicotine clearance, the nicotine
metabolite ratio (NMR; 3’hydroxycotinine/cotinine), predicts response to nicotine patch
vs. varenicline for smoking cessation.
• For the NMR assay, cotinine and 3’hydroxycotinine were measured by LC-MS; limits of
quantification were<1 ng/ml whole blood.
Pre-specified Outcome Measure
The primary endpoint was7-day point prevalence abstinence at EOT / week 11
The secondary endpoints to assess whether pharmacogenetic effects
(Lerman et al.,2015,pp.132-137)

7. Patient Disposition
• Patient Disposition
• Retention rates at end of treatment exceeded 70% and retention did not
vary across treatment groups or NMR group
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(Lerman et al.,2015, p.134)

8. Baseline Characteristics
• The article of baseline
demographics/ characteristics.
• No differences in the treatment
groups
• Demographic
• Smoking history variables
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(Lerman et al.,2015, pp.134-135)

9. Results: Primary Endpoint
•Primary Endpoint
•Patient population used: ITT (randomised and
attended pre-quit session)
•1246 participants (662 slow metabolisers of
nicotine, 584 normal metabolisers of
nicotine)
•Statistical findings (p value, HR, and Confidence
Interval):
•End of treatment,
•normal metabolisers:Varenicline was
more effective than nicotine patch in
(OR 2·17, 95% CI 1·38–3·42;
p=0·001),
•slow metabolisers : varenicline was
not effective than nicotine patch (OR
1·13, 0·74–1·71; p=0·56)
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p.135
(Lerman et al.,2015, pp.134-136)

10. Results: Secondary Endpoints
• Patient Population used: ITT (randomised and attended pre-
quit session)
• 1246 participants (662 slow metabolizers of nicotine, 584 normal
metabolizers of nicotine)
• Statistical Findings (p value, HR, and Confidence Interval):
• longitudinal model at all specified times, the NMR-by-treatment
interaction was significant (ratio of odds ratios [ORR] 1·96, 95% CI 1·11–
3·46; p=0·02).
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(Lerman et al.,2015, pp.134-136)

11. Additional Results
• Side Effects
• Varenicline (vs placebo), significant NMR-by treatment interaction was
observed in side-effects (summary from the self-report checklist; β=–1·06,
95% CI–2·08 to –0·03; p=0·044)
• Elevated side-effects described on varenicline (vs placebo) for slow metabolisers
(β=0·61, 95% CI –0·10 to 1·32; p=0·09), but not for normal metabolisers (β=–0·44,
95% CI –1·19 to 0·30; p=0·24).
• Descriptive (post-hoc)
• slow metabolisers, varenicline caused significant increases in nausea (χ²=18·7, p=0·0003) and
abnormal dreams (χ²=13·0, p=0·005);
• Normal metabolisers, varenicline caused significant increases in nausea (χ²=15·7, p=0·01), but
decreases in irritability(χ²=15·4, p=0·001), anxiety (χ²=11·2, p=0·01), and attentional
disturbance (χ²=11·3, p=0·01).
• Nicotine patch (vs placebo), the NMR-by-treatment interaction was not
significant (β=–0·17, 95% CI=–1·21 to
• 0·86; p=0·74).
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(Lerman et al.,2015, p.136)

12. Safety Results
• Varenicline may be superior to nicotine patch for smokers
generally
• The side-effects of varenicline are commonly mild and
tolerable
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(Lerman et al.,2015, p.137)

13. Safety Results
• Adverse Events
• Serious adverse events:
• Placebo-16 (3·9%), , nicotine patch-22 (5·3%), , and varenicline-11 (2·6%)
respectively
• NMR-by-treatment interactions counts were not significant for side-effect
counts by treatment and NMR groups
• NMR-by-treatment interactions for withdrawal symptoms not significant
or medication adherence (p>0·10)
• Recommended Dose usage
• 62% of participants used 80% pill
• 63% used 80% or more of the patches
• comparable with previous reports
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(Lerman et al.,2015, p.136)

14. Author Conclusions
• Study results
• Support the probable clinical validity of the nicotine metabolite ratio as a
biomarker to direct the select of therapy for smoker's individual.
• Quit rate
• Treating normal metabolisers with varenicline, and slow metabolisers with
nicotine patches, may heighten quit rates for all smokers while decreasing
side-effect
(Lerman et al.,2015, pp.136-137)
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15. SECTION 2:
CRITICALAPPRAISAL
Section 1, along with Peer feedback critical appraisal of the
trial design and associated results.
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16. Positive Critique 1: Provide Title
1. Does the study test a stated hypothesis?
• A primary hypothesis was tested of an NMR at end of
treatment by treatment interaction.
2. Is the study question relevant?
• There are significant diverse treatment predictions to
response and effects of tobacco dependent therapies,
optimizing the use of biomarkers for individual treatment
choice can better treatment results.
(Lerman et al., pp.83, 89,134)
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17. Positive Critique 2: Provide Title
1. Was the process of treatment allocation truly random?
• Participants were randomly assigned into three treatment groups: placebo,
nicotine patch or varenicline by baseline NMR status, study site and blocked to
ensure balance in treatment arms.
2. Were participants and researchers ‘blinded’ to participants’ treatment groups.
• Study participants were masked to allocated treatment groups and NMR status,
this will prevent the identification of treatment by patients which may bias their
response to treatment effects.
3. Were all participants’ data analyzed in the group to which they were randomly
assigned?”
• Analysis was conducted by different models, each model used the full sample
of participants. The ITT population was analyzed for the primary endpoint, and
helped to reduce bias by accounting for all participants in support towards a
reliable outcome analysis.
(Lerman et al., pp.83, 89, 132,134)
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18. Threats to Internal Validity (2)
1. Within the procedure section, the study stated that use of the provided pills and
patches was recorded via patient self-reports. Even though unused patches and
pills were collected as a means of confirmation, there is no control of patients who
incorrectly self-report adherence to proper use of the pills and patches if they
simply decided to be untruthful with their use (e.g. participants used the pills or
patches and threw them away or did not return them). It would have be proper to
recommend that both the used and unused patches and pill blister packages be
collected as a means of reinforcing correct adherence to proper patient use. Thus,
this may introduce bias in adherence measurement, thereby giving unreliable data
report that may affect the proper analysis of the potential benefit expected with the
intervention.
2. Patients who treated with two different active drug treatments, nicotine or
varenicline, were counseled for safety use instructions of the medications. There is
the possibility that blinded patients would be able to discern which drug they had
been assigned due to the differences in usage or safety instructions between
nicotine and varenicline. It is a possibility they can understand the different
treatment based on the instructions and able to match the respective medications
with already known facts surrounding the medications effects. This may interfere
with efficacy out come of the study result.
(Lerman et al., pp.132-134)
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19. Threats to External Validity (2)
1. The choice of placebo comparison in the treatment arms may be
appropriate for clinical phase II trial, but in the Phase III trial in real
world setting, e.g. physicians do not offer a placebo as a current
standard of care for smoking cessation, so the comparison of the
placebo results to those of nicotine and varenicline is not
generalizable of a real world setting.
2. It was a requirement that enrolled patients smoked 10 or more
cigarettes a day. The end results may not reflect the real world
population as there may be a different clinical result of the use of the
cessation drugs for those who smoke less than 10 cigarettes a day
compared to those enrolled in the study who generally were smoking
around 18 per day. Those who smoke less than 10 cigarettes a day
may not have the same drive to seek cessation as those who smoke
more, but could also benefit from the drug therapies given and have a
direct impact on reported results.
(Lerman et al., pp.132-134 )
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20. Risk/BenefitAssessment
• What are the key risks
• Varenicline had significant increases of nausea for slow and normal metabolizers compared to
nicotine vs. placebo. With consideration that the placebo also saw a comparable level of
cessation success compared to nicotine and varenicline treatment for normal metabolizing
patients, varenicline may not always be the best first line of cessation treatment despite the
efficacy results due to the side effects when compared to the nicotine or placebo treatments.
More investigation into using a placebo as a suitable standard of care for smoking cessation
may be valid.
• What are the key benefits
• Varenicline proved to be more efficacious than nicotine for normal nicotine metabolizing
patients, there is some concern as to the resulting side effects.
• Do the benefits outweigh risk
• Overall the risk/benefit ratio for performing the study seemed to be within acceptable
considerations.
• Why or why not?
• Precautions were taken to exclude those with underlying cardiovascular or hypertensive
conditions and those at risk for psychiatric events or additional negative drug use risks
and the resulting adverse events reported seemed reasonable although the exact nature of
those categorized as serious adverse events was not specified.
(Lerman et al., pp. 134-137)
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21. Parting Thoughts
• Nicotine addiction and substance abuse are current alarming public health
problem, having greater knowledge to diagnose patients for best treatment is
integral.
• Determining the usefulness of NMR biomarker to accurately help measure
nicotine drug choices best for smoking cessation therapy is appropriate in the
clinical trail.
• The study design enhanced the internal and external validity of this study,
because the generalizability of the study was established with participants from
several regions in multicenter clinicals.
• The study showed adherence to ethical protocols involved in human study
research.
• The result of the study revealed important benefits to support treatment therapy
for the population investigated and showed the level of effectiveness of drug
choices between comparison arms.
• I acknowledge my peer reviewer Kyle Dzwigalski for his concise articulation of
his observed threats to validity and Risk/Benefit Assessment towards the critical
appraisal of this clinical trail presented.
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22. REFERENCE
ClinicalTrials.gov(2016). Pharmacogenetics of Nicotine Addiction.
TreatmentClinicalTrials.gov Identifier: NCT01314001. Retrieved from
https://clinicaltrials.gov/ct2/show/NCT01314001?term=NCT01314001&draw=2&rank=1
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23. I hope you enjoyed my presentation !!!
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24. 24
iThenticate score for Section 1 and 2