Trial Outcomes & Findings for Efficacy and Safety Evaluation of AN2690 Topical Solution to Treat Onychomycosis of the Toenail (NCT NCT01270971)

Last Updated: 2019-02-22

Results Overview

No clinical evidence of onychomycosis as evidenced by normal toenail plate, no onycholysis, and no subungual hyperkeratosis, and negative KOH wet mount and negative fungal culture.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

594 participants

Primary outcome timeframe

Week 52

Results posted on

2019-02-22

Participant Flow

Subjects were screened and enrolled at thirty-four investigative centers in the United States and Mexico. The study population included men and women, 18 years of age and older who had distal subungual onychomycosis. The first subject visit occurred on December 1, 2010, and the last subject completed the Post Study Follow Up on January 8, 2013.

Eligible subjects were randomized in a 2:1 ratio to receive AN2690 Topical Solution, 5% or Solution Vehicle to be applied once daily to all affected toenails throughout the 48-week treatment period.

Participant milestones

Participant milestones
Measure	AN2690 Topical Solution, 5% AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Overall Study STARTED	400	194
Overall Study COMPLETED	348	171
Overall Study NOT COMPLETED	52	23

Reasons for withdrawal

Reasons for withdrawal
Measure	AN2690 Topical Solution, 5% AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Overall Study Withdrawal by Subject	24	11
Overall Study Lost to Follow-up	18	5
Overall Study Adverse Event	1	2
Overall Study Non compliance	2	2
Overall Study Non-specific	7	3

Baseline Characteristics

Efficacy and Safety Evaluation of AN2690 Topical Solution to Treat Onychomycosis of the Toenail

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AN2690 Topical Solution, 5% n=399 Participants AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=194 Participants Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks	Total n=593 Participants Total of all reporting groups
Age, Continuous Age	53.6 years STANDARD_DEVIATION 12.5 • n=93 Participants	53.4 years STANDARD_DEVIATION 12.3 • n=4 Participants	53.5 years STANDARD_DEVIATION 12.4 • n=27 Participants
Sex: Female, Male Female	75 Participants n=93 Participants	36 Participants n=4 Participants	111 Participants n=27 Participants
Sex: Female, Male Male	324 Participants n=93 Participants	158 Participants n=4 Participants	482 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	99 Participants n=93 Participants	54 Participants n=4 Participants	153 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	300 Participants n=93 Participants	140 Participants n=4 Participants	440 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	2 Participants n=93 Participants	0 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	19 Participants n=93 Participants	12 Participants n=4 Participants	31 Participants n=27 Participants
Race (NIH/OMB) White	316 Participants n=93 Participants	152 Participants n=4 Participants	468 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	62 Participants n=93 Participants	30 Participants n=4 Participants	92 Participants n=27 Participants
Region of Enrollment United States	340 participants n=93 Participants	164 participants n=4 Participants	504 participants n=27 Participants
Region of Enrollment Mexico	59 participants n=93 Participants	30 participants n=4 Participants	89 participants n=27 Participants

PRIMARY outcome

Timeframe: Week 52

Population: Efficacy analysis was performed using the ITT population. The last observation was carried forward (LOCF) in order to provide a value for efficacy parameters that were missing.

No clinical evidence of onychomycosis as evidenced by normal toenail plate, no onycholysis, and no subungual hyperkeratosis, and negative KOH wet mount and negative fungal culture.

Outcome measures

Outcome measures
Measure	AN2690 Topical Solution, 5% n=399 Participants AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=194 Participants Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Complete Cure (Completely Clear Nail and Negative Mycology) of Target Great Toenail at Week 52 Success	26 participants	1 participants
Complete Cure (Completely Clear Nail and Negative Mycology) of Target Great Toenail at Week 52 Failure	373 participants	193 participants

SECONDARY outcome

Timeframe: Week 52

Population: Efficacy analysis was performed using the ITT population. The LOCF was used in order to provide a value for efficacy parameters that were missing.

No clinical evidence of onychomycosis as evidenced by normal toenail plate, no onycholysis, and no subungual hyperkeratosis, or no more than minimal evidence of onychomycosis as evidenced by toenail plate dystrophic or discolored over ≤ 10% of the distal aspect, with minimally evident onycholysis and subungual hyperkeratosis.

Outcome measures

Outcome measures
Measure	AN2690 Topical Solution, 5% n=399 Participants AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=194 Participants Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Completely Clear or Almost Clear Target Great Toenail at Week 52 Failure	295 participants	176 participants
Completely Clear or Almost Clear Target Great Toenail at Week 52 Success	104 participants	18 participants

SECONDARY outcome

Timeframe: Week 52

Population: Efficacy analysis was performed using the ITT population. The LOCF was used in order to provide a value for efficacy parameters that were missing.

Outcome measures

Outcome measures
Measure	AN2690 Topical Solution, 5% n=399 Participants AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=194 Participants Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Treatment Success (Completely Clear or Almost Clear Nail and Negative Mycology) of Target Great Toenail at Week 52 Success	61 participants	3 participants
Treatment Success (Completely Clear or Almost Clear Nail and Negative Mycology) of Target Great Toenail at Week 52 Failure	338 participants	191 participants

SECONDARY outcome

Timeframe: Week 52

Population: Efficacy analysis was performed using the ITT population. The LOCF was used in order to provide a value for efficacy parameters that were missing.

Negative KOH and negative fungal culture.

Outcome measures

Outcome measures
Measure	AN2690 Topical Solution, 5% n=399 Participants AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=194 Participants Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Negative Mycology of Target Great Toenail at Week 52 Success	124 participants	14 participants
Negative Mycology of Target Great Toenail at Week 52 Failure	275 participants	180 participants

Adverse Events

AN2690 Topical Solution, 5%

Serious events: 12 serious events

Other events: 90 other events

Deaths: 0 deaths

Solution Vehicle

Serious events: 8 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	AN2690 Topical Solution, 5% n=396 participants at risk AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=193 participants at risk Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Infections and infestations Nasopharyngitis	5.8% 23/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	5.2% 10/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Infections and infestations Tinea pedis	10.6% 42/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	18.1% 35/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Infections and infestations Upper respiratory tract infection	5.1% 20/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	4.1% 8/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Infections and infestations Influenza	2.8% 11/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	5.2% 10/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.

Additional Information

Sheryl Baldwin, RN/Associate Director

Anacor Pharmaceuticals, Inc.

Phone: 650-223-8597

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institution or Principal Investigator may only publish Study results after: (i) the results of the multicenter Study in its entirety have been publicly disclosed by the Sponsor in an abstract, manuscript or presentation form, or (ii) two (2) years after conclusion of the Study at all sites, whichever is first to occur.
Publication restrictions are in place

Restriction type: OTHER

Measure	AN2690 Topical Solution, 5% n=396 participants at risk AN2690 Topical Solution, 5% AN2690 Topical Solution, 5%: AN2690 Topical Solution, 5%, applied once daily for 48 weeks	Solution Vehicle n=193 participants at risk Solution Vehicle Solution Vehicle: AN2690 Topical Solution, Vehicle, applied once daily for 48 weeks
Blood and lymphatic system disorders Anaemia (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Acute myocardial infarction (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Angina unstable (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Atrial fibrillation (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Cardiogenic shock (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Coronary artery disease (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Ischaemic cardiomyopathy (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Gastrointestinal disorders Pancreatitis acute (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Infections and infestations Cellulitis (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Infections and infestations Pneumonia (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Infections and infestations Vestibular neuronitis (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Metabolism and nutrition disorders Diabetic ketoacidosis (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Musculoskeletal and connective tissue disorders Intervertebral disc disorder (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Musculoskeletal and connective tissue disorders Osteoarthritis (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Nervous system disorders Syncope (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Psychiatric disorders Drug dependence (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Psychiatric disorders Psychotic disorder (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Psychiatric disorders Suicidal ideation (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Psychiatric disorders Suicide attempt (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Vascular disorders Aortic stenosis (unrelated)	0.00% 0/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.52% 1/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.
Cardiac disorders Coronary artery occlusion (unrelated)	0.25% 1/396 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.	0.00% 0/193 • Up to Week 52 An AE was any unfavorable and unintended sign,symptom,or disease temporally associated with the use of the investigational product. A serious AE resulted in death,was life-threatening, required or prolonged in-patient hospitalization,persistent or significant disability/incapacity, resulted in a congenital anomaly,or was an important medical event.