Smoking Cessation
Conditions
Brief summary
The primary purpose of this study is to determine whether or not varenicline will help people with cardiovascular disease quit smoking and to confirm it is safe in these patients.
Interventions
DRUGplacebo
1 mg placebo twice daily by mouth for 12 weeks
DRUGVarenicline
1 mg twice daily by mouth for 12 weeks
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants must have stable, documented cardiovascular disease (including at least one of the following diagnosed \> 2 months prior to the Screening visit - angina, myocardial infarction (MI), revascularization, transient ischemic attack (TIA), and peripheral vascular disease (PVD). * Participants that smoke \> 10 cigarettes / day.
Exclusion criteria
* Participants with unstable cardiovascular disease * Cardiovascular events in the past 2 months * Moderate or severe chronic obstructive pulmonary disease (COPD)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders With Carbon Monoxide (CO) Confirmed 4-week Continuous Quit Rate (CQR) for Last 4 Weeks of Treatment (Trtmt) | weeks 9 through 12 | Participants considered Responders (4-week CQR \<=10 parts per million \<ppm\>) through reports of cigarette or other nicotine use since last study visit, confirmed by measurement of end-expiratory exhaled carbon monoxide (CO). If any CO measurement at a particular timepoint was \>10 ppm, subject was considered to be Non-Responder at that timepoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Long-Term Quit Responders | Week 9 through Week 52 | Responders: participants were considered Long Term Quit responders if 1) they were responders for the primary endpoint (the 4-week CQR for Weeks 9-12) and 2) had no more than 6 days of smoking from Week 12 through the given visit. |
| Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 12 | Week 12 | Responders: abstinence in previous seven days, defined in the non-treatment follow-up as: 1) Has the participant smoked any cigarettes in the last 7 days? = No AND 2) Has the participant used any other tobacco products in the last 7 days? = No. Participant a non-responder if expired CO \> 10 ppm. |
| Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 24 | Week 24 | Responders: abstinence in previous seven days, defined in the non-treatment follow-up as: 1) Has the participant smoked any cigarettes in the last 7 days? = No AND 2) Has the participant used any other tobacco products in the last 7 days? = No. Participant a non-responder if expired CO \> 10 ppm. |
| Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 52 | Week 52 | Responders: abstinence in previous seven days, defined in the non-treatment follow-up as: 1) Has the participant smoked any cigarettes in the last 7 days? = No AND 2) Has the participant used any other tobacco products in the last 7 days? = No. Participant a non-responder if expired CO \> 10 ppm. |
| Number of Responders With Continuous Abstinence (CA) Through Week 52 | Week 9 through Week 52 | Responders: participants who remained abstinent based on 'since the last contact' question in Nicotine Use Inventory 1) Has participant smoked any cigarettes (even a puff) since last contact? = No AND 2) Has participant used any other tobacco products… since last contact? = No. Participant a non-responder if expired CO \> 10 ppm. |
| Number of Responders With Continuous Abstinence (CA) Through Week 24 | Week 9 through Week 24 | Responders: participants who remained abstinent based on 'since the last contact' question in Nicotine Use Inventory 1) Has participant smoked any cigarettes (even a puff) since the last contact? = No AND 2) Has participant used any other tobacco products… since the last contact? = No. Non- responder if the expired CO \> 10 ppm at any given timepoint. |
| Cigarettes Smoked Per Day | Day 21 | Cigarettes smoked each day during the first 3 weeks of the treatment phase. |
| Number of Long-Term Quit Responders From Week 9 Through Week 24 | Week 9 through Week 24 | Responders: participants were considered Long Term Quit Responders if 1) they were responders for the primary endpoint (the 4-week CQR for Weeks 9-12) and 2) had no more than 6 days of smoking from Week 12 through the given visit. |
| Number of Participants With a 4 Week Point Prevalence of Smoking Cessation | Week 48 through Week 52 (final 4 weeks of non-treatment period [pd]) | Responders: participants with abstinence during the last 4 weeks of non-treatment based on answering 'no' to both of the two 'last 4 week' questions in the Nicotine Use Inventory (NUI). NUI collected information of cigarette or other nicotine use during the study. |
Countries
Argentina, Australia, Brazil, Canada, Czechia, Denmark, France, Germany, Greece, Mexico, Netherlands, South Korea, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in outpatients. The target population was cigarette smokers with cardiovascular disease drawn from the communities surrounding the participating clinics.
Pre-assignment details
714 smokers were randomized (ie, assigned to study treatment), 11 participants were randomized, but not treated. The reasons for participants being randomized, not treated included no longer willing to participate in the study (5 participants), protocol violation (3 participants), lost to follow-up (1 participant), and other (2 participants).
Participants by arm
| Arm | Count |
|---|---|
| Varenicline (Var) 1 week titration followed by 11 weeks of 1 milligram (mg) twice daily (BID) dosing. Study medication was discontinued at the Week 12 visit and participants' smoking status was followed through the non-treatment period to Week 52. | 353 |
| Placebo (Pbo) 1 week titration followed by 11 weeks of placebo (pbo). Study medication was discontinued at the Week 12 visit and participants' smoking status was followed through the non-treatment period to Week 52. | 350 |
| Total | 703 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 |
| Overall Study | Death | 2 | 5 |
| Overall Study | in prison | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | lack of motivation | 1 | 0 |
| Overall Study | Lost to Follow-up | 14 | 10 |
| Overall Study | Participant only allowed phone follow-up | 0 | 1 |
| Overall Study | Participant stopped study medication | 2 | 2 |
| Overall Study | Participant used antipsychosis meds | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Participant | 22 | 34 |
Baseline characteristics
| Characteristic | Varenicline (Var) | Placebo (Pbo) | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 8.6 | 56.0 years STANDARD_DEVIATION 8.4 | 56.5 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 87 Participants | 63 Participants | 150 Participants |
| Sex: Female, Male Male | 266 Participants | 287 Participants | 553 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 253 / — | 179 / — |
| serious Total, serious adverse events | 23 / — | 21 / — |
Outcome results
Primary
Number of Responders With Carbon Monoxide (CO) Confirmed 4-week Continuous Quit Rate (CQR) for Last 4 Weeks of Treatment (Trtmt)
Participants considered Responders (4-week CQR \<=10 parts per million \<ppm\>) through reports of cigarette or other nicotine use since last study visit, confirmed by measurement of end-expiratory exhaled carbon monoxide (CO). If any CO measurement at a particular timepoint was \>10 ppm, subject was considered to be Non-Responder at that timepoint.
Time frame: weeks 9 through 12
Population: Primary analysis population (Modified Intent-to-Treat) included all participants who took at least 1 dose randomized study medication. Participants who discontinued study were assumed smokers from timepoint of discontinuation through end of study. Modified Intent-to-Treat population is referred to as All Participants population in this report.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Responders With Carbon Monoxide (CO) Confirmed 4-week Continuous Quit Rate (CQR) for Last 4 Weeks of Treatment (Trtmt) | responders | 167 participants |
| Varenicline (Var) | Number of Responders With Carbon Monoxide (CO) Confirmed 4-week Continuous Quit Rate (CQR) for Last 4 Weeks of Treatment (Trtmt) | non-responders | 186 participants |
| Placebo (Pbo) | Number of Responders With Carbon Monoxide (CO) Confirmed 4-week Continuous Quit Rate (CQR) for Last 4 Weeks of Treatment (Trtmt) | responders | 50 participants |
| Placebo (Pbo) | Number of Responders With Carbon Monoxide (CO) Confirmed 4-week Continuous Quit Rate (CQR) for Last 4 Weeks of Treatment (Trtmt) | non-responders | 300 participants |
Comparison: Estimates for expected \& clinically meaningful var \& pbo 4-week CQR for Week 9 - 12 of trtmt based on response rates \& corresponding 95% OR confidence interval (CI) from A30510285 \& A30510366 study results. Total n=700 randomized var or pbo 1:1 should have provided at least 99% power to detect difference in primary endpoint (endpt) between (b/w) var \& pbo, assuming true 4-week CQR of 0.18 for pbo \& 0.40 for var (OR of at least 3.04), and 84% power for 2 key secondary endpts.p-value: <0.000195% CI: [4.13, 8.86]Regression, Logistic
Secondary
Cigarettes Smoked Per Day
Cigarettes smoked each day during the first 3 weeks of the treatment phase.
Time frame: Day 21
Population: All Participants population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 11 | 8.9 cigarettes per day | Standard Deviation 7.3 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 6 | 14.4 cigarettes per day | Standard Deviation 8.4 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 12 | 8.7 cigarettes per day | Standard Deviation 7.5 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 2 | 16.8 cigarettes per day | Standard Deviation 8.8 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 13 | 8.8 cigarettes per day | Standard Deviation 7.1 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 7 | 13.8 cigarettes per day | Standard Deviation 8.6 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 14 | 9.3 cigarettes per day | Standard Deviation 7.4 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 4 | 15.7 cigarettes per day | Standard Deviation 8.9 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 15 | 8.9 cigarettes per day | Standard Deviation 7.6 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 8 | 11.7 cigarettes per day | Standard Deviation 9.2 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 16 | 8.8 cigarettes per day | Standard Deviation 7.1 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 1 | 17.6 cigarettes per day | Standard Deviation 9.4 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 17 | 8.3 cigarettes per day | Standard Deviation 6.4 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 9 | 9.5 cigarettes per day | Standard Deviation 7.5 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 18 | 8.2 cigarettes per day | Standard Deviation 6.9 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 19 | 7.8 cigarettes per day | Standard Deviation 6.7 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 5 | 15.1 cigarettes per day | Standard Deviation 8.8 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 20 | 7.9 cigarettes per day | Standard Deviation 6.1 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 10 | 8.9 cigarettes per day | Standard Deviation 7.2 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 21 | 7.2 cigarettes per day | Standard Deviation 6.3 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Day 3 | 15.8 cigarettes per day | Standard Deviation 9.2 |
| Varenicline (Var) | Cigarettes Smoked Per Day | Baseline | 22.2 cigarettes per day | Standard Deviation 10 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 18 | 10.3 cigarettes per day | Standard Deviation 8.8 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Baseline | 22.9 cigarettes per day | Standard Deviation 10.9 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 1 | 19.1 cigarettes per day | Standard Deviation 10 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 2 | 18.4 cigarettes per day | Standard Deviation 9.6 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 3 | 18.0 cigarettes per day | Standard Deviation 10 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 4 | 17.1 cigarettes per day | Standard Deviation 9.6 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 5 | 16.3 cigarettes per day | Standard Deviation 8.9 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 6 | 16.0 cigarettes per day | Standard Deviation 8.9 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 7 | 15.1 cigarettes per day | Standard Deviation 8.8 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 8 | 12.3 cigarettes per day | Standard Deviation 10.5 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 9 | 10.9 cigarettes per day | Standard Deviation 9.5 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 10 | 10.6 cigarettes per day | Standard Deviation 8.6 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 11 | 10.4 cigarettes per day | Standard Deviation 8.4 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 12 | 10.5 cigarettes per day | Standard Deviation 8.3 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 13 | 10.3 cigarettes per day | Standard Deviation 8.2 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 14 | 10.7 cigarettes per day | Standard Deviation 8.6 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 15 | 11.2 cigarettes per day | Standard Deviation 9.1 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 16 | 11.0 cigarettes per day | Standard Deviation 8.7 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 17 | 10.6 cigarettes per day | Standard Deviation 8.2 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 19 | 10.3 cigarettes per day | Standard Deviation 8.4 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 20 | 10.6 cigarettes per day | Standard Deviation 8.3 |
| Placebo (Pbo) | Cigarettes Smoked Per Day | Day 21 | 9.3 cigarettes per day | Standard Deviation 8.1 |
Secondary
Number of Long-Term Quit Responders
Responders: participants were considered Long Term Quit responders if 1) they were responders for the primary endpoint (the 4-week CQR for Weeks 9-12) and 2) had no more than 6 days of smoking from Week 12 through the given visit.
Time frame: Week 9 through Week 52
Population: All participants population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Long-Term Quit Responders | responders | 80 participants |
| Varenicline (Var) | Number of Long-Term Quit Responders | non-responders | 273 participants |
| Placebo (Pbo) | Number of Long-Term Quit Responders | responders | 34 participants |
| Placebo (Pbo) | Number of Long-Term Quit Responders | non-responders | 316 participants |
Comparison: Estimates for expected and clinically meaningful varenicline (var) \& pbo 4-week CQR for Weeks 9 - 12 of treatment were based on response rates \& corresponding 95% odds ratio CI from A30510285 and A30510366 study results. Total n=700 randomized var or pbo 1:1 should have provided at least 99% power to detect difference in primary endpt b/w varenicline \& pbo, assuming true 4-week CQR of 0.18 for pbo \& 0.40 for var (odds ratio of at least 3.04), and a power of 84% for the 2 key secondary endpts.p-value: <0.000195% CI: [1.82, 4.38]Regression, Logistic
Secondary
Number of Long-Term Quit Responders From Week 9 Through Week 24
Responders: participants were considered Long Term Quit Responders if 1) they were responders for the primary endpoint (the 4-week CQR for Weeks 9-12) and 2) had no more than 6 days of smoking from Week 12 through the given visit.
Time frame: Week 9 through Week 24
Population: All Participants population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Long-Term Quit Responders From Week 9 Through Week 24 | non-responders | 236 participants |
| Varenicline (Var) | Number of Long-Term Quit Responders From Week 9 Through Week 24 | responders | 117 participants |
| Placebo (Pbo) | Number of Long-Term Quit Responders From Week 9 Through Week 24 | non-responders | 308 participants |
| Placebo (Pbo) | Number of Long-Term Quit Responders From Week 9 Through Week 24 | responders | 42 participants |
p-value: <0.000195% CI: [2.58, 5.75]Regression, Logistic
Secondary
Number of Participants With a 4 Week Point Prevalence of Smoking Cessation
Responders: participants with abstinence during the last 4 weeks of non-treatment based on answering 'no' to both of the two 'last 4 week' questions in the Nicotine Use Inventory (NUI). NUI collected information of cigarette or other nicotine use during the study.
Time frame: Week 48 through Week 52 (final 4 weeks of non-treatment period [pd])
Population: All Participants population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline (Var) | Number of Participants With a 4 Week Point Prevalence of Smoking Cessation | 99 participants |
| Placebo (Pbo) | Number of Participants With a 4 Week Point Prevalence of Smoking Cessation | 57 participants |
p-value: 0.000195% CI: [1.41, 2.97]Regression, Logistic
Secondary
Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 12
Responders: abstinence in previous seven days, defined in the non-treatment follow-up as: 1) Has the participant smoked any cigarettes in the last 7 days? = No AND 2) Has the participant used any other tobacco products in the last 7 days? = No. Participant a non-responder if expired CO \> 10 ppm.
Time frame: Week 12
Population: All Participants population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 12 | responders | 192 participants |
| Varenicline (Var) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 12 | non-responders | 161 participants |
| Placebo (Pbo) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 12 | responders | 65 participants |
| Placebo (Pbo) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 12 | non-responders | 285 participants |
Comparison: Week 12 analysisp-value: <0.000195% CI: [4.17, 8.56]Regression, Logistic
Secondary
Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 24
Responders: abstinence in previous seven days, defined in the non-treatment follow-up as: 1) Has the participant smoked any cigarettes in the last 7 days? = No AND 2) Has the participant used any other tobacco products in the last 7 days? = No. Participant a non-responder if expired CO \> 10 ppm.
Time frame: Week 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 24 | responders | 124 participants |
| Varenicline (Var) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 24 | non-responders | 229 participants |
| Placebo (Pbo) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 24 | responders | 57 participants |
| Placebo (Pbo) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 24 | non-responders | 293 participants |
Comparison: 24 Week analysisp-value: <0.000195% CI: [2.03, 4.23]Regression, Logistic
Secondary
Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 52
Responders: abstinence in previous seven days, defined in the non-treatment follow-up as: 1) Has the participant smoked any cigarettes in the last 7 days? = No AND 2) Has the participant used any other tobacco products in the last 7 days? = No. Participant a non-responder if expired CO \> 10 ppm.
Time frame: Week 52
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 52 | responders | 102 participants |
| Varenicline (Var) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 52 | non-responders | 251 participants |
| Placebo (Pbo) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 52 | responders | 62 participants |
| Placebo (Pbo) | Number of Participants With a Seven-Day Point Prevalence of Abstinence at Week 52 | non-responders | 288 participants |
Comparison: 52 Week analysisp-value: 0.000395% CI: [1.34, 2.77]Regression, Logistic
Secondary
Number of Responders With Continuous Abstinence (CA) Through Week 24
Responders: participants who remained abstinent based on 'since the last contact' question in Nicotine Use Inventory 1) Has participant smoked any cigarettes (even a puff) since the last contact? = No AND 2) Has participant used any other tobacco products… since the last contact? = No. Non- responder if the expired CO \> 10 ppm at any given timepoint.
Time frame: Week 9 through Week 24
Population: All Participants population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline (Var) | Number of Responders With Continuous Abstinence (CA) Through Week 24 | 100 participants |
| Placebo (Pbo) | Number of Responders With Continuous Abstinence (CA) Through Week 24 | 34 participants |
p-value: <0.000195% CI: [2.51, 5.93]Regression, Logistic
Secondary
Number of Responders With Continuous Abstinence (CA) Through Week 52
Responders: participants who remained abstinent based on 'since the last contact' question in Nicotine Use Inventory 1) Has participant smoked any cigarettes (even a puff) since last contact? = No AND 2) Has participant used any other tobacco products… since last contact? = No. Participant a non-responder if expired CO \> 10 ppm.
Time frame: Week 9 through Week 52
Population: All participants population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Varenicline (Var) | Number of Responders With Continuous Abstinence (CA) Through Week 52 | responders | 70 participants |
| Varenicline (Var) | Number of Responders With Continuous Abstinence (CA) Through Week 52 | non-responders | 283 participants |
| Placebo (Pbo) | Number of Responders With Continuous Abstinence (CA) Through Week 52 | responders | 26 participants |
| Placebo (Pbo) | Number of Responders With Continuous Abstinence (CA) Through Week 52 | non-responders | 324 participants |
Comparison: Estimates for expected and clinically meaningful var \& pbo 4-week CQR for Weeks 9 - 12 of trtmt were based on response rates \& corresponding 95% odds ratio CI from A30510285 and A30510366 study results. Total n=700 randomized var or pbo 1:1 should have provided at least 99% power to detect difference in primary endpt b/w var \& pbo, assuming true 4-week CQR of 0.18 for pbo \& 0.40 for var (odds ratio of at least 3.04) \& a power of 84% for the 2 key secondary endpts.p-value: <0.000195% CI: [1.97, 5.18]Regression, Logistic