Combining Varenicline and Bupropion for Smoking Cessation

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00943618
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute on Drug Abuse (NIDA) (NIH), Pfizer (Industry)
• Enrollment: 641
• Location: 1
• Arms: 3
• Actual Duration (Months): 135.8
• Patients Per Site Per Month: 4.7

Study Details

Study Description

Brief Summary

The goal of this clinical research study is learn if the combination of Chantix (varenicline) and Zyban (bupropion) is more effective at helping people to quit smoking than varenicline when given alone. Researchers also want to learn if this drug combination can reduce cravings and other negative symptoms of nicotine withdrawal better than varenicline does alone. The safety of this drug combination will also be tested.

Condition or Disease	Intervention/Treatment	Phase
Smoking Cessation	Drug: Varenicline; Drug: Bupropion; Other: Placebo; Behavioral: Counseling/Phone Calls	Phase 3

Detailed Description

The Study Drugs:

Bupropion and varenicline are designed to imitate the effects that nicotine has on the body. This may reduce cigarette cravings and help patients quit smoking.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of a dice) to 1 of 3 treatment groups.

• If you are in Group 1, you will receive varenicline and bupropion.

• If you are in Group 2, you will receive varenicline and a placebo. A placebo is a substance that looks like the study drug (in this case, bupropion) but that has no active ingredients.

• If you are in Group 3, you will receive a placebo that looks like varenicline and a placebo that looks like bupropion.

You will have a higher chance (5 out of 6) of receiving study drug than receiving just placebo. Equal numbers of patients will be in Groups 1 and 2. Neither you nor the study doctor will know to which group you are assigned. However, if needed for your safety, the study staff will be able to find out which study drug you are receiving.

Study Drug Administration:

You will begin taking the study drugs/placebo 1 to 10 days after the first study visit. A dose of the study drug/placebo combination will be made up of 1 tablet of varenicline or placebo and 1 tablet of bupropion or placebo. You should take each dose of study drugs/placebo with a cup (8 oz.) of water after eating a full meal.

On Days 1-3, you will take 1 dose of the study drug/placebo combination in the morning.

Beginning on Day 4, and then every day after that, you will take 1 dose in the morning and 1 dose in the evening (for a total of 2 doses of the study drug/placebo combination each day). You must return any study drug bottles as well as any unused study drug to a study staff member at each study visit.

You will be given a smoking diary to record how many cigarettes you smoke (if any) each day while you are on study. You must turn in this diary at each study visit.

Study Visits:

About 1 time each week while you are taking the study drugs/placebo, the following tests and procedures will be performed:

• Your weight and blood pressure will be measured.

• Your CO level will be measured.

• You will be asked about any other drugs you may be taking and about any side effects you may be having.

• You will answer 8 questionnaires about several topics, including depression, suicide, your smoking behavior, any effects from the study drugs, and any symptoms of attention-deficit hyperactivity disorder (ADHD). These should take about 30-45 minutes total to complete.

• You will do tasks that will measure your logic and attention. These will take about 15 -20 minutes to complete.

• You will receive counseling about quitting smoking in which you discuss possible "triggers" for smoking and strategies for dealing with quitting smoking. These sessions will take about 15 minutes each time.

During counseling at the first study visit, you will set a "quit date" for stopping smoking for about 1 week after you start taking the study drug. You should not quit smoking before the quit date. You should stay smoke-free after the quit date. Additionally, you will be given a medication instruction sheet, a card with emergency contact information, and a participant manual to help you follow along with the topics discussed during counseling.

At Week 2, saliva will be collected to check your cotinine level.

At Week 4, blood (about 2 teaspoons) will be drawn to assess liver and kidney function.

Lab Sessions:

You may be asked to take part in lab sessions during Visits 1, 2, and 6 to test your brain activity and attention span. You will be asked to watch slides and listen to a series of tones. The slides will include pictures of people, nature, and artwork. Slides showing nude people, medical procedures, and victims of car crashes will also be shown. You will be shown examples of these slides before beginning the procedure and given the opportunity to withdraw from the study.

During the lab sessions, your brain electrical activity (EEG) will be monitored. To do this, small sensors will be placed on your scalp and face. You should not drink more than 2 cups of coffee or other caffeinated drinks for at least 2.5 hours before each session. At the first lab session, you may be asked to smoke a cigarette if the doctor thinks it is needed for you to exhibit your normal smoking behavior.

Length of Study:

You will receive the study drug for up to 12 weeks. However, the entire length of the study is about 13 months (55 weeks), which includes 3, 6, and 12-month post-quit follow up visits. You will be taken off study if the doctor thinks it is in your best interest.

End-of-Study Visit:

After you have finished taking the study drugs/placebo, the following tests and procedures will be performed:

• Your weight and blood pressure will be measured.

• Your CO level will be measured.

• You will be asked about any side effects you may be having and about any other drugs you may be taking.

• Blood (about 2 teaspoons) will be drawn to assess liver and kidney function.

• You will answer the same questionnaires you completed at the regular study visits. These should take about 30-45 minutes total to complete.

• Saliva will be collected to measure your cotinine level.

Follow-Up Visits:

About 3, 6, and 12 months after you have stopped smoking, the following tests and procedures will be performed:

• Your weight, heart rate, and blood pressure will be measured.

• Your CO level will be measured.

• You will be asked about any side effects you may be having and about any other drugs you may be taking.

• You will answer the same questionnaires you completed at the regular study visits. These should take about 30-45 minutes total to complete.

• Saliva will be collected to measure your cotinine level.

You will be called by the study staff 1 day before your quit date, 3 days after your quit date, and at Weeks 14, 20, 34, 42, and 48 weeks after your quit date to check on your progress in quitting smoking. Each call should take about 10-15 minutes.

This is an investigational study. Varenicline and bupropion are both FDA approved and commercially available to help people stop smoking. The use of the drugs in combination is investigational.

Up to 385 participants will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 641 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Effectiveness of Varenicline vs. Varenicline Plus Bupropion or Placebo for Smoking Cessation
• Actual Study Start Date: May 17, 2010
• Actual Primary Completion Date: May 31, 2020
• Actual Study Completion Date: Sep 9, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group 1 Varenicline and Bupropion	Drug: Varenicline; On Days 1-3, .5mg tablet by mouth in the morning. Beginning on Day 4, and then every day after that, .5mg tablet by mouth in the morning and .5mg tablet by mouth in the evening (for a total of 2 doses).; Other Names: Chantix ; Drug: Bupropion; On Days 1-3, 150 mg tablet by mouth in the morning. Beginning on Day 4, and then every day after that, 150 mg tablet by mouth in the morning and 150 mg tablet by mouth in the evening (for a total of 2 doses).; Other Names: Zyban ; Behavioral: Counseling/Phone Calls; Brief-behavioral counseling sessions (10-15 minutes) provided to all participants once per week for 12 weeks. One support phone call conducted 3 days after the target quit date.
Placebo Comparator: Group 2 Varenicline and Placebo	Drug: Varenicline; On Days 1-3, .5mg tablet by mouth in the morning. Beginning on Day 4, and then every day after that, .5mg tablet by mouth in the morning and .5mg tablet by mouth in the evening (for a total of 2 doses).; Other Names: Chantix ; Other: Placebo; On Days 1-3, 1 tablet by mouth of placebo that looks like the study drug in the morning. Beginning on Day 4, and then every day after that, 1 tablet by mouth in the morning and 1 tablet by mouth in the evening for a total of 2 doses of the placebo each day.; Behavioral: Counseling/Phone Calls; Brief-behavioral counseling sessions (10-15 minutes) provided to all participants once per week for 12 weeks. One support phone call conducted 3 days after the target quit date.
Placebo Comparator: Group 3 Placebo that looks like varenicline and a placebo that looks like bupropion.	Other: Placebo; On Days 1-3, 1 tablet by mouth of placebo that looks like the study drug in the morning. Beginning on Day 4, and then every day after that, 1 tablet by mouth in the morning and 1 tablet by mouth in the evening for a total of 2 doses of the placebo each day.; Behavioral: Counseling/Phone Calls; Brief-behavioral counseling sessions (10-15 minutes) provided to all participants once per week for 12 weeks. One support phone call conducted 3 days after the target quit date.

Outcome Measures

Primary Outcome Measures

1. Smoking Abstinence at 12 Months [From quit date to 12 months.]

   Prolonged Abstinence is defined as no smoking from the quit date to 12 Months post quit date.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Age: 25-70 years old

2. Smoking 5 or more cigarettes per day, on average, within the 2 months preceding the screening visit and expired CO of greater than or equal to 6ppm.

3. Able to follow verbal and written instructions in English and complete all aspects of the study

4. Provide informed consent and agree to all assessments and study procedures

5. Have an address and home telephone number where they may be reached

6. Be the only participant in their household

Exclusion Criteria:

1. Within the month immediately preceding the screening visit, use of any form of tobacco products other than cigarettes on 3 or more days within a week if the individual refuses to refrain from such tobacco use during the course of the study.

2. Within the month immediately preceding the screening visit, use of marijuana in any form on 3 or more days within a week

3. Within the two weeks immediately preceding the screening visit, involvement on more than 3 days in any formal smoking cessation activities

4. Treatment on a continuous basis within 2 weeks before the screening visit: any contraindicated medication for Varenicline or Bupropion. Classes of contraindicated medications include, but are not limited to, antiasthmatics, antipsychotics, some antidepressants, antihypertensives, antiarrhythmics, antineoplastics, some antiseizures, and MAO inhibitors (See Appendix U for specific list of excluded and precautionary medications).

5. Uncontrolled hypertension (average reading of systolic blood pressure greater than 150 or diastolic blood pressure greater than 95) or other major contraindications for Bupropion or Varenicline (See section on Screening).

6. Severe renal impairment (Creatinine Clearance less than 30 ml/min/1.73 m2).

7. Laboratory evaluations outside normal limits and of potential clinical significance in the opinion of the investigator.

8. Meet current criteria for psychiatric disorders or substance abuse as assessed by the MINI plus (major depressive episode) and the MINI for items B, D, I, J (Alcohol Addendum-past 6 months only), K, L, M and N including a past manic or hypomanic episode as well as a lifetime psychotic disorder.

9. Individuals rated as moderate (6 - 9) to high (10 or greater) on suicidality as assessed by Module C of the MINI.

10. Psychiatric hospitalization within 1 year of screening date.

11. A positive urine pregnancy test during the screening period. Women who are two years post menopausal, or who have had a tubal ligation or a partial or full hysterectomy will not be subject to a urine pregnancy test.

12. Pregnant, breast-feeding or of childbearing potential and is not protected by a medically acceptable, effective method of birth control while enrolled in the study. Medically acceptable contraceptives include: (1) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, or (3) an intrauterine device (IUD). Contraceptive measures sold for emergency use after unprotected sex, are not acceptable methods for routine use.

13. Use of Varenicline or Bupropion within two weeks before the screening visit.

14. History of hypersensitivity or allergic reaction to Varenicline, tricyclic antidepressant, Bupropion (Wellbutrin, Zyban) or similar chemical classes or any component of these formulations.

15. Current or previous history of a seizure disorder.

16. Current or previous history of anorexia.

17. Subject considered by the investigator as unsuitable candidate for receipt of an investigational drug or unstable to be followed up throughout the entire duration of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Institutes of Health (NIH)
• National Institute on Drug Abuse (NIDA)
• Pfizer

Investigators

• Principal Investigator: Paul M Cinciripini, PhD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 5, 2021

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00943618
• Other Study ID Numbers: 2008-0850; R01DA024709-01A1; NCI-2011-01101
• First Posted: Jul 22, 2009
• Last Update Posted: Dec 7, 2021
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Smoking Cessation; Nicotine Withdrawal; Smoking Reduction; Varenicline; Chantix; Bupropion; Zyban
• Additional relevant MeSH terms: Bupropion; Varenicline

Study Results

Participant Flow

Recruitment Details	Paid and unpaid media advertising from May 2010 to July 2013 recruited volunteer smokers from the Houston, Texas metropolitan area. Inclusion criteria included: 25- 65 years of age; smoke five or more cigarettes per day (CPD); baseline expired carbon monoxide (CO) level greater than 6 parts per million (p.m.); fluent in English; stable residency.
Pre-assignment Detail	641 patients were consented to this study; 250 patients were screen failures.

Arm/Group Title	Varenicline + Bupropion	Varenicline	Placebo
Arm/Group Description	Smokers in varenicline + bupropion took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took 150 mg bupropion (SR once per day for the first 3 days followed by 150mg bid for the next 4 days. From week 2-12 smokers in the VB group will take 1mg of varenicline and one active 150 mg bupropion tablet twice per day.	Smokers in varenicline group took took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took a matching bupropion placebo on the same schedule as those in the varenicline + bupropion group. From week 2-12, smokers in the varenicline group took 1mg of varenicline and one bupropion matching placebo twice per day.	Smokers in the placebo group took a matching varenicline and bupropion placebos on the same schedule as the varenicline group took varenicline and the bupropion group took bupropion, respectively.
Period Title: Overall Study
STARTED	163	166	56
COMPLETED	108	89	25
NOT COMPLETED	55	77	31

Baseline Characteristics

Arm/Group Title	Varenicline + Bupropion	Varenicline	Placebo	Total
Arm/Group Description	Smokers in varenicline + bupropion took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took 150 mg bupropion (SR once per day for the first 3 days followed by 150mg bid for the next 4 days. From week 2-12 smokers in the VB group will take 1mg of varenicline and one active 150 mg bupropion tablet twice per day.	Smokers in varenicline group took took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took a matching bupropion placebo on the same schedule as those in the varenicline + bupropion group. From week 2-12, smokers in the varenicline group took 1mg of varenicline and one bupropion matching placebo twice per day.	Smokers in the placebo group took a matching varenicline and bupropion placebos on the same schedule as the varenicline group took varenicline and the bupropion group took bupropion, respectively.	Total of all reporting groups
Overall Participants	163	166	56	385
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.36 (9.38)	48.75 (10.89)	48.48 (10.33)	48.97 (10.17)
Sex: Female, Male (Count of Participants)
Female	68 41.7%	68 41%	24 42.9%	160 41.6%
Male	95 58.3%	98 59%	32 57.1%	225 58.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 6.1%	14 8.4%	6 10.7%	30 7.8%
Not Hispanic or Latino	146 89.6%	146 88%	48 85.7%	340 88.3%
Unknown or Not Reported	7 4.3%	6 3.6%	2 3.6%	15 3.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	1 0.6%	0 0%	2 0.5%
Asian	1 0.6%	5 3%	1 1.8%	7 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.6%	0 0%	1 0.3%
Black or African American	44 27%	43 25.9%	16 28.6%	103 26.8%
White	106 65%	110 66.3%	36 64.3%	252 65.5%
More than one race	3 1.8%	1 0.6%	2 3.6%	6 1.6%
Unknown or Not Reported	8 4.9%	5 3%	1 1.8%	14 3.6%
Region of Enrollment (participants) [Number]
United States	163 100%	166 100%	56 100%	385 100%
Marital Status (percentage of participants) [Number]
Married or Living with partner	42.94 26.3%	53.01 31.9%	62.50 111.6%	50.13 13%
Other	57.06 35%	46.99 28.3%	37.50 67%	49.87 13%
Employment Status (percentage of participants) [Number]
Employed/Student	82.72 50.7%	80.72 48.6%	78.57 140.3%	81.25 21.1%
Unemployed	17.28 10.6%	19.28 11.6%	21.43 38.3%	18.75 4.9%
Depression History (Count of Participants)
Positive	9 5.5%	10 6%	4 7.1%	23 6%
Negative	154 94.5%	156 94%	52 92.9%	362 94%
Years of education (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.89 (2.11)	13.60 (1.92)	13.80 (1.89)	13.75 (2)
Current Smoking Rate (cigs per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cigs per day]	19.64 (9.49)	19.02 (9.49)	19.71 (11.20)	19.66 (9.45)
Number of Previous Quit Attempts (Number of quit attempts) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of quit attempts]	7.58 (13.51)	5.83 (9.22)	6.12 (13.90)	6.62 (11.94)
Age started smoking (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18.41 (5.15)	18.16 (60.16)	16.48 (3.43)	18.02 (5.44)
Fagerström Test for Nicotine Dependence (FTND) Total Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	4.74 (2.01)	4.65 (2.04)	5.34 (2.24)	4.79 (2.07)
Center for Epidemiologic Studies Depression Scale (CESD) (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	5.82 (5.37)	7.76 (7.07)	6.59 (6.17)	6.73 (6.27)
Positive and Negative Affect Schedule (PANAS) (units on a scale) [Mean (Standard Deviation) ]
PANAS Negative	14.56 (4.93)	14.93 (5.31)	14.44 (4.39)	14.70 (5.02)
PANAS Positive	34.08 (7.64)	33.26 (7.43)	33.84 (8.80)	33.69 (7.72)
Wisconsin Smoking Withdrawal Scale (WSWS) (score on a scale) [Mean (Standard Deviation) ]
Anger	3.57 (2.25)	4.01 (2.48)	3.67 (23.8)	3.77 (2.37)
Anxiety	6.80 (2.74)	6.96 (2.99)	7.15 (2.76)	6.92 (2.84)
Concentration	3.80 (2.05)	3.84 (2.02)	3.69 (1.99)	3.80 (2.02)
Craving	9.40 (2.63)	9.86 (2.94)	9.87 (2.85)	9.67 (2.80)
Hunger	9.67 (3.39)	10.46 (3.50)	10.31 (3.44)	10.10 (3.46)
Sadness	4.38 (2.21)	4.76 (2.48)	4.55 (2.04)	4.57 (2.31)
Sleep	7.91 (4.04)	8.52 (4.48)	8.16 (4.47)	8.21 (4.29)
Wisconsin Index of Smoking Dependence Motives (WISDM) (units on a scale) [Mean (Standard Deviation) ]
WISDM-Affect	4.83 (2.00)	4.75 (2.01)	5.22 (1.97)	4.85 (2.00)
WISDM-Affiliation	4.20 (2.13)	3.87 (2.22)	4.41 (2.42)	4.09 (2.22)
WISDM-Automaticity	6.05 (2.02)	5.57 (2.17)	6.42 (2.11)	5.90 (2.11)
WISDM-Cognitive	4.66 (2.09)	4.37 (2.17)	4.82 (2.05)	4.56 (2.12)
WISDM-Control	6.17 (1.73)	6.32 (1.87)	6.51 (2.09)	6.28 (1.85)
WISDM-Craving	6.11 (1.62)	5.95 (1.78)	6.53 (1.83)	6.11 (1.73)
WISDM-Cue Exposure-Associative Processes	5.36 (1.82)	5.34 (2.02)	5.56 (1.74)	5.38 (1.90)
WISDM-Social-Environmental Goads	4.00 (2.22)	3.77 (2.54)	4.25 (2.59)	3.94 (2.42)
WISDM-Primary Dependence Motives	6.08 (1.53)	5.96 (1.64)	6.43 (1.75)	6.08 (1.61)
WISDM-Secondary Dependence Motives	4.57 (1.36)	4.38 (1.48)	4.71 (1.46)	4.51 (1.43)
WISDM-Taste and Sensory Processes	5.52 (2.06)	5.29 (2.27)	5.50 (2.11)	5.41 (2.16)
WISDM-Tolerance	6.01 (2.04)	6.01 (2.11)	6.26 (2.04)	6.04 (2.07)
WISDM-Weight Control	3.40 (1.93)	3.29 (2.10)	3.18 (2.12)	3.32 (2.03)
WISDM-Total	56.32 (14.11)	54.54 (15.66)	58.65 (15.53)	55.89 (15.03)

Outcome Measures

1. Primary Outcome

Title	Smoking Abstinence at 12 Months
Description	Prolonged Abstinence is defined as no smoking from the quit date to 12 Months post quit date.
Time Frame	From quit date to 12 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline + Bupropion	Varenicline	Placebo
Arm/Group Description	Smokers in varenicline + bupropion took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took 150 mg bupropion (SR once per day for the first 3 days followed by 150mg bid for the next 4 days. From week 2-12 smokers in the VB group will take 1mg of varenicline and one active 150 mg bupropion tablet twice per day.	Smokers in varenicline group took took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took a matching bupropion placebo on the same schedule as those in the varenicline + bupropion group. From week 2-12, smokers in the varenicline group took 1mg of varenicline and one bupropion matching placebo twice per day.	Smokers in the placebo group took a matching varenicline and bupropion placebos on the same schedule as the varenicline group took varenicline and the bupropion group took bupropion, respectively.
Measure Participants	163	166	56
Count of Participants [Participants]	30 18.4%	33 19.9%	2 3.6%

Adverse Events

Time Frame	12 months
Arm/Group Title	Varenicline + Bupropion		Varenicline		Placebo
Arm/Group Description	Smokers in varenicline + bupropion took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took 150 mg bupropion (SR once per day for the first 3 days followed by 150mg bid for the next 4 days. From week 2-12 smokers in the VB group will take 1mg of varenicline and one active 150 mg bupropion tablet twice per day.		Smokers in varenicline group took took 0.5 mg varenicline once per day for the first three days and 0.5 mg bid (am and pm) for the next 4 days. They also took a matching bupropion placebo on the same schedule as those in the varenicline + bupropion group. From week 2-12, smokers in the varenicline group took 1mg of varenicline and one bupropion matching placebo twice per day.		Smokers in the placebo group took a matching varenicline and bupropion placebos on the same schedule as the varenicline group took varenicline and the bupropion group took bupropion, respectively.
All Cause Mortality
	Varenicline + Bupropion		Varenicline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/163 (0%)		0/166 (0%)		0/56 (0%)
Serious Adverse Events
	Varenicline + Bupropion		Varenicline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/163 (4.9%)		4/166 (2.4%)		1/56 (1.8%)
Cardiac disorders
Atrial fibrillation	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Chest pain-cardiac	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Heart failure	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Myocardial infarction	0/163 (0%)		1/166 (0.6%)		1/56 (1.8%)
Supraventricular tachycardia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Tachycardia/Palpitations	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Eye disorders
Blurred vision	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Flashing lights	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Floaters	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Gastrointestinal disorders
Cholecystitis	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Pancreatitis	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
General disorders
Influenza	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Infections and infestations
Infection and infestation - Strep Throat	0/163 (0%)		2/166 (1.2%)		0/56 (0%)
Infection and infestation - Tonsillitis	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Metabolism and nutrition disorders
Dehydration	0/163 (0%)		2/166 (1.2%)		0/56 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	3/163 (1.8%)		1/166 (0.6%)		0/56 (0%)
Neck pain	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Reproductive system and breast disorders-other: uterine cancer	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nervous system disorders
Dizziness	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Presyncope	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Psychiatric disorders
Delerium	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Depressive Symptoms	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Disturbance in attention	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Suicidal ideation	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Pneumonitis	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Shortness of Breath	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Vascular disorders
Thromboembolic event	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Other (Not Including Serious) Adverse Events
	Varenicline + Bupropion		Varenicline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/163 (98.2%)		156/166 (94%)		50/56 (89.3%)
Blood and lymphatic system disorders
Anemia	0/163 (0%)		1/166 (0.6%)		1/56 (1.8%)
Cardiac disorders
Atrial fibrillation	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Atrial flutter	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Cardiac disorders - Other, specify	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Chest pain - cardiac	4/163 (2.5%)		4/166 (2.4%)		2/56 (3.6%)
Conduction disorder	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Heart failure	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Myocardial infarction	0/163 (0%)		1/166 (0.6%)		1/56 (1.8%)
Sinus bradycardia	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Sinus tachycardia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Supraventricular tachycardia	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Tachycardia/Palpitations	3/163 (1.8%)		7/166 (4.2%)		2/56 (3.6%)
Ear and labyrinth disorders
Earache	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Ear and labyrinth disorders - Other, specify	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Tinnitus	6/163 (3.7%)		1/166 (0.6%)		0/56 (0%)
Endocrine disorders
Endocrine disorders, other-excessive thirst	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Eye disorders
Blurred vision	8/163 (4.9%)		5/166 (3%)		2/56 (3.6%)
Conjunctivitis	0/163 (0%)		1/166 (0.6%)		1/56 (1.8%)
Eye irritation	4/163 (2.5%)		12/166 (7.2%)		3/56 (5.4%)
Flashing lights	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Photosensitivity	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
eye disorders, other-eye twitching	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Gastrointestinal disorders
Abdominal Pain	22/163 (13.5%)		16/166 (9.6%)		3/56 (5.4%)
Anal fistula	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Blood in Stool	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Bloating	4/163 (2.5%)		5/166 (3%)		1/56 (1.8%)
Cecal hemorrhage	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Constipation	22/163 (13.5%)		19/166 (11.4%)		3/56 (5.4%)
Diverticulitis	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Diarrhea	9/163 (5.5%)		21/166 (12.7%)		2/56 (3.6%)
Dry mouth	28/163 (17.2%)		7/166 (4.2%)		2/56 (3.6%)
Dyspepsia	11/163 (6.7%)		11/166 (6.6%)		4/56 (7.1%)
Esophageal pain	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Flatulence	12/163 (7.4%)		10/166 (6%)		4/56 (7.1%)
Gallbladder obstruction	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Gastroenteritis	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Gastro-esophageal reflux disease	3/163 (1.8%)		3/166 (1.8%)		0/56 (0%)
Gastrointestinal anastomotic leak	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Gastrointestinal disorders - Other, specify	1/163 (0.6%)		2/166 (1.2%)		1/56 (1.8%)
Gastrointestinal disorders, other-softer stools	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Gastrointestinal disorders, other-increased salivation	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Hemorrhoids	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Hiccups	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nausea	47/163 (28.8%)		64/166 (38.6%)		7/56 (12.5%)
Oral pain	2/163 (1.2%)		2/166 (1.2%)		0/56 (0%)
Pancreatitis	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Periodontal disease	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Toothache	7/163 (4.3%)		7/166 (4.2%)		3/56 (5.4%)
Vomiting	17/163 (10.4%)		18/166 (10.8%)		2/56 (3.6%)
Appetite, decreased	20/163 (12.3%)		9/166 (5.4%)		0/56 (0%)
Appetite, increased	24/163 (14.7%)		29/166 (17.5%)		5/56 (8.9%)
General disorders
Floaters	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Chest Pain - non cardiac	4/163 (2.5%)		9/166 (5.4%)		1/56 (1.8%)
Dehydration	1/163 (0.6%)		5/166 (3%)		1/56 (1.8%)
Dizziness	29/163 (17.8%)		31/166 (18.7%)		10/56 (17.9%)
Face Edema	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Fatigue	22/163 (13.5%)		22/166 (13.3%)		7/56 (12.5%)
General Disorders and administration site conditions - Other, Hyperthermia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
General disorders and administration site conditions, other -blood from throat	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
General disorders and administration site conditions - Other, feeling speedy	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
General disorders and administration site conditions - Other, specify	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Influenza	28/163 (17.2%)		25/166 (15.1%)		11/56 (19.6%)
Vertigo	2/163 (1.2%)		1/166 (0.6%)		0/56 (0%)
Weight gain	18/163 (11%)		28/166 (16.9%)		3/56 (5.4%)
Weight loss	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Alanine aminotransferase increased	12/163 (7.4%)		12/166 (7.2%)		1/56 (1.8%)
Aspartate aminotransferase increased	11/163 (6.7%)		15/166 (9%)		2/56 (3.6%)
Bilirubin Increased	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Blood Bilirubin Increased	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Creatinine increased	17/163 (10.4%)		1/166 (0.6%)		1/56 (1.8%)
GGT increased	16/163 (9.8%)		10/166 (6%)		1/56 (1.8%)
Hepatobiliary disorders - Elevated GGT	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Investigations - Increased Alcohol Consumption	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Investigations, Other - Specify	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Vascular disorders, other-hypercholesterolemia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Hepatobiliary disorders
Cholecystitis	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Immune system disorders
Allergy, Seasonal	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Immune system disorders - Shingles	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Infections and infestations
Bronchial infection	5/163 (3.1%)		3/166 (1.8%)		0/56 (0%)
Gum infection	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Hepatitis viral	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Infection	0/163 (0%)		1/166 (0.6%)		2/56 (3.6%)
Infection and infestation - Other - swollen lymph nodes	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Infection and infestation - Strep Throat	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Infection and infestation - Tonsillitis	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Infections & infestations, other-mycobacterium avium complex)	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Infections and infestations - Other, specify	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Infections and infestations, other-fever blisters	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Infections and infestations, other-infection of R hand	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Kidney infection	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Lip infection	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Mucosal infection	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Mucositis oral	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nail infection	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Pharyngitis - bacterial	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Urinary tract infection	2/163 (1.2%)		2/166 (1.2%)		0/56 (0%)
Vaginal infection	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Wound infection	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Injury, poisoning and procedural complications
Bruising	1/163 (0.6%)		4/166 (2.4%)		1/56 (1.8%)
Injury, poisoning and procedural complications	9/163 (5.5%)		11/166 (6.6%)		4/56 (7.1%)
Investigations
Investigations-other (abnormal EKG)	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Metabolism and nutrition disorders
General disorders & administration site conditions - Diaphoresis	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Metabolism and nutrition disorders - Other, specify	7/163 (4.3%)		2/166 (1.2%)		1/56 (1.8%)
Metabolism and nutrition disorders, other-low B12 levels	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	2/163 (1.2%)		1/166 (0.6%)		0/56 (0%)
Costochondritis	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Edema	16/163 (9.8%)		5/166 (3%)		2/56 (3.6%)
Fracture	4/163 (2.5%)		2/166 (1.2%)		0/56 (0%)
Generalized muscle weakness	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Inflammation Gluteus	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Joint range of motion decreased lumbar spine	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Localized edema	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Musculoskeletal pain	45/163 (27.6%)		50/166 (30.1%)		16/56 (28.6%)
Neck pain	9/163 (5.5%)		4/166 (2.4%)		1/56 (1.8%)
PERIPHERAL EDEMA	2/163 (1.2%)		1/166 (0.6%)		0/56 (0%)
Plantar Fasciitis	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Neoplasms benign, malignant, and unspecified (incl cysts & polyps) - other uterine fibroids	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Neoplasms, benign, malignant, & unspecified, (incl cysts & polyps) other-spot on cervix	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Nervous system disorders
Aphonia	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Dizziness	29/163 (17.8%)		31/166 (18.7%)		10/56 (17.9%)
Dysgeusia	20/163 (12.3%)		6/166 (3.6%)		2/56 (3.6%)
FALL	1/163 (0.6%)		0/166 (0%)		1/56 (1.8%)
Facial nerve disorder	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Headache	33/163 (20.2%)		35/166 (21.1%)		14/56 (25%)
Nervous System disorders, other - Somniloquy	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nervous system disorder other-jittery	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Nervous system disorder, other-feeling heart beating	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nervous system disorder, other-headrushes	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nervous system disorders, other-Migraine	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Nervous system disorders, other-lightheadedness	0/163 (0%)		2/166 (1.2%)		0/56 (0%)
Neurology - other	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Olfactory nerve disorder	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Presyncope	1/163 (0.6%)		1/166 (0.6%)		0/56 (0%)
Sensory disturbance	11/163 (6.7%)		12/166 (7.2%)		1/56 (1.8%)
Slurred Speech	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Tremor	4/163 (2.5%)		2/166 (1.2%)		1/56 (1.8%)
Psychiatric disorders
Asthenia	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Abnormal Dreams	42/163 (25.8%)		57/166 (34.3%)		6/56 (10.7%)
Anxiety symptoms	38/163 (23.3%)		26/166 (15.7%)		10/56 (17.9%)
Depressive Symptoms	39/163 (23.9%)		40/166 (24.1%)		14/56 (25%)
Disturbance in attention	31/163 (19%)		27/166 (16.3%)		10/56 (17.9%)
Hallucinations	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Insomnia	87/163 (53.4%)		60/166 (36.1%)		17/56 (30.4%)
Irritability	32/163 (19.6%)		42/166 (25.3%)		10/56 (17.9%)
Personality change	3/163 (1.8%)		3/166 (1.8%)		0/56 (0%)
Psychiatric disorders, other-emotional lability	1/163 (0.6%)		3/166 (1.8%)		0/56 (0%)
Psychiatric disorders - Other, Self-Injurious Behavior	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Psychiatric disorders - Other, specify	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Psychiatric disorders - other, calmness	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Psychiatric disorders other-altered mental state	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Psychiatric disorders other-psychomotor retardation	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Psychiatric disorders, other- panic attack	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Psychiatric disorders, other-pressured speech	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Psychiatric disorders, other-Nicotine Dependence	8/163 (4.9%)		2/166 (1.2%)		1/56 (1.8%)
Psychiatric disorders-other (crying)	4/163 (2.5%)		1/166 (0.6%)		1/56 (1.8%)
Restlessness	16/163 (9.8%)		14/166 (8.4%)		2/56 (3.6%)
Somnolence	17/163 (10.4%)		26/166 (15.7%)		6/56 (10.7%)
Suicidal ideation	0/163 (0%)		3/166 (1.8%)		0/56 (0%)
other Sleep Disturbances	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Renal and urinary disorders
Hematuria	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Renal and urinary disorders - Other, specify	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Renal and urinary disorders-other hematospermia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Renal calculi	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Urinary frequency	9/163 (5.5%)		9/166 (5.4%)		0/56 (0%)
Urine abnormality	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Urine output decreased	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Reproductive system and breast disorders
Erectile dysfunction	1/163 (0.6%)		1/166 (0.6%)		1/56 (1.8%)
Irregular menstruation	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Libido decreased	4/163 (2.5%)		1/166 (0.6%)		1/56 (1.8%)
Menorrhagia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Prostatic obstruction	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Reproductive system and breast disorders other - Endometrial Hyperplasia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Reproductive system and breast disorders-other: uterine cancer	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Vaginal dryness	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Increased Coughing	24/163 (14.7%)		20/166 (12%)		5/56 (8.9%)
Laryngeal inflammation	0/163 (0%)		0/166 (0%)		1/56 (1.8%)
Pneumonitis	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Respiratory, thoracic and mediastinal disorders - Other, mucopurulent sputum	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Respiratory, thoracic and mediastinal disorders - Other, specify	2/163 (1.2%)		0/166 (0%)		0/56 (0%)
Respiratory, thoracic and mediastinal disorders - Other-Heavy Breathing	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Respiratory, thoracic, & mediastinal disorders, other-exacerbation of COPD	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Rhinitis	37/163 (22.7%)		34/166 (20.5%)		18/56 (32.1%)
Shortness of Breath	15/163 (9.2%)		9/166 (5.4%)		7/56 (12.5%)
Sore throat	12/163 (7.4%)		10/166 (6%)		3/56 (5.4%)
Upper Respiratory Infection	4/163 (2.5%)		9/166 (5.4%)		3/56 (5.4%)
Voice alteration	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Skin and subcutaneous tissue disorders
ACNE	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Eczema	17/163 (10.4%)		13/166 (7.8%)		6/56 (10.7%)
Purpura	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Rash acneiform	0/163 (0%)		2/166 (1.2%)		0/56 (0%)
Rash maculo-papular	1/163 (0.6%)		3/166 (1.8%)		0/56 (0%)
Urticaria	4/163 (2.5%)		1/166 (0.6%)		2/56 (3.6%)
Surgical and medical procedures
Surgical and medical Procedures - Other, Eye Surgery	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Surgical and medical procedures - Other, Eye Surgery (II)	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Surgical and medical procedures - Other, Eye Surgery (III)	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Surgical and medical procedures - Other, exploratory endoscopy	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Surgical and medical procedures - Other, specify	2/163 (1.2%)		2/166 (1.2%)		0/56 (0%)
Surgical and medical procedures - Other, tooth extraction	1/163 (0.6%)		2/166 (1.2%)		0/56 (0%)
Surgical and medical procedures - Tonsillectomy	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Surgical and medical procedures - back surgery	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Surgical and medical procedures -other, biopsy of prostate	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Surgical and medical procedures, other-removal of facial cyst	0/163 (0%)		10/166 (6%)		0/56 (0%)
Surgical and medical procedures, other-Removal of cyst	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Surgical and medical procedures, other-root canal	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Vascular disorders
Flushing	0/163 (0%)		1/166 (0.6%)		0/56 (0%)
Hot flashes	8/163 (4.9%)		3/166 (1.8%)		0/56 (0%)
Hypertension	3/163 (1.8%)		4/166 (2.4%)		1/56 (1.8%)
Hypotension	1/163 (0.6%)		2/166 (1.2%)		0/56 (0%)
Superficial thrombophlebitis	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Thromboembolic event	1/163 (0.6%)		0/166 (0%)		0/56 (0%)
Vascular disorder, other-sweating	3/163 (1.8%)		2/166 (1.2%)		3/56 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.