Trial Outcomes & Findings for Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans (NCT NCT04313634)

Last Updated: 2024-07-22

Results Overview

Percent change in serum bone turnover markers C-terminal telopeptide of type I collagen \[CTX\]. The C-terminal telopeptide (CTX), also known as carboxy-terminal collagen crosslinks, is a biomarker used to measure the rate of bone turnover. It provides valuable information for assessing bone health and evaluating treatment responses.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

74 participants

Primary outcome timeframe

Baseline, 20 weeks

Results posted on

2024-07-22

Participant Flow

Participant milestones

Participant milestones
Measure	Dasatinib Plus Quercetin Treatment Goup Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group Subjects did not receive any intervention
Overall Study STARTED	30	14	30
Overall Study COMPLETED	27	12	28
Overall Study NOT COMPLETED	3	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Dasatinib Plus Quercetin Treatment Goup Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group Subjects did not receive any intervention
Overall Study Adverse Event	2	2	0
Overall Study Withdrawal by Subject	1	0	1
Overall Study Protocol Violation	0	0	1

Baseline Characteristics

Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dasatinib Plus Quercetin Treatment Goup n=30 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=14 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=30 Participants Subjects did not receive any intervention	Total n=74 Participants Total of all reporting groups
Age, Continuous	71.2 years STANDARD_DEVIATION 4.9 • n=5 Participants	75.9 years STANDARD_DEVIATION 3.7 • n=7 Participants	74.4 years STANDARD_DEVIATION 6.7 • n=5 Participants	73.7 years STANDARD_DEVIATION 5.7 • n=4 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	14 Participants n=7 Participants	30 Participants n=5 Participants	74 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	30 Participants n=5 Participants	14 Participants n=7 Participants	30 Participants n=5 Participants	74 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	29 Participants n=5 Participants	14 Participants n=7 Participants	30 Participants n=5 Participants	73 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	30 participants n=5 Participants	14 participants n=7 Participants	30 participants n=5 Participants	74 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline, 20 weeks

Outcome measures

Outcome measures
Measure	Dasatinib Plus Quercetin Treatment Goup n=28 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=11 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=28 Participants Subjects did not receive any intervention
Change in C-terminal Telopeptide of Type I Collagen [CTX]	-4.1 percent change Interval -28.1 to 114.6	13.7 percent change Interval -42.7 to 61.0	-7.7 percent change Interval -42.4 to 22.5

SECONDARY outcome

Timeframe: Baseline, 2 weeks

Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Quercetin Treatment Goup n=30 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=11 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=30 Participants Subjects did not receive any intervention
Change in Bone Turnover Markers	0.8 percentage change of P1NP Interval -39.6 to 113.5	-31.9 percentage change of P1NP Interval -74.0 to 23.3	-15.2 percentage change of P1NP Interval -55.0 to 59.8

SECONDARY outcome

Timeframe: Baseline, 4 weeks

Population: Outcome measure was only collected and reported for Dasatinib plus Quercetin Treatment arm and Untreated Control group arm

Outcome measures

Outcome measures
Measure	Dasatinib Plus Quercetin Treatment Goup n=29 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=30 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group Subjects did not receive any intervention
Change in Bone Turnover Markers	4.2 percentage change of P1NP Interval -61.4 to 1480.0	-12.1 percentage change of P1NP Interval -58.0 to 95.9	—

SECONDARY outcome

Timeframe: Baseline, 20 weeks

Outcome measures

Outcome measures
Measure	Dasatinib Plus Quercetin Treatment Goup n=28 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=11 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=28 Participants Subjects did not receive any intervention
Change in Bone Turnover Markers	-8.6 percentage change of P1NP Interval -48.1 to 130.9	4.5 percentage change of P1NP Interval -34.8 to 29.7	0.1 percentage change of P1NP Interval -49.2 to 95.2

SECONDARY outcome

Timeframe: Baseline, 20 weeks

Population: Each skeletal site was measured and assessed separately. As such, some sites (which are influenced by osteoarthritis) did not provide interpretable scans. This occurred due to motion artifacts or other issues. Therefore, the number of participants analyzed differ by skeletal site.

Percent change in BMD by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, hip ((total and femoral neck (FN), and radius (total and ultra-distal)).

Outcome measures

Outcome measures
Measure	Dasatinib Plus Quercetin Treatment Goup n=28 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=12 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=29 Participants Subjects did not receive any intervention
Change in Bone Mineral Density (BMD) Lumbar Spine	-0.2 percentage of change in BMD Interval -3.1 to 6.2	0 percentage of change in BMD Interval -1.5 to 8.9	0.5 percentage of change in BMD Interval -10.4 to 6.8
Change in Bone Mineral Density (BMD) Hip (Femoral neck )	-0.3 percentage of change in BMD Interval -4.8 to 4.0	-0.9 percentage of change in BMD Interval -3.7 to 2.0	-0.5 percentage of change in BMD Interval -6.0 to 19.2
Change in Bone Mineral Density (BMD) Radius	0.4 percentage of change in BMD Interval -3.0 to 6.9	0.7 percentage of change in BMD Interval -12.1 to 5.7	0.2 percentage of change in BMD Interval -4.7 to 12.9

SECONDARY outcome

Timeframe: Baseline, 2 weeks

Percent change in SASP cells (representing the total senescence cell burden) present. Assessment of senescence markers in bone at baseline and 2 weeks.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Quercetin Treatment Goup n=30 Participants Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=11 Participants Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=30 Participants Subjects did not receive any intervention
Change in Plasma Senescence-associated Secretory Phenotype (SASP)	-2.6 percent change Interval -187.7 to 16.4	-0.9 percent change Interval -41.8 to 3.7	-2.5 percent change Interval -110.4 to 91.5

Adverse Events

Dasatinib Plus Quercetin Treatment Goup

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Fisetin Treatment Group

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

Untreated Control Group

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dasatinib Plus Quercetin Treatment Goup n=30 participants at risk Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=14 participants at risk Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=30 participants at risk Subjects did not receive any intervention
Gastrointestinal disorders Gastric hemorrhage	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks

Other adverse events

Additional Information

Sundeep Khosla, M.D.

Mayo Clinic

Phone: 507-255-6663

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Dasatinib Plus Quercetin Treatment Goup n=30 participants at risk Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg	Fisetin Treatment Group n=14 participants at risk Subjects received Fisetin (F; \~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally	Untreated Control Group n=30 participants at risk Subjects did not receive any intervention
Gastrointestinal disorders Abdominal distention	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Gastrointestinal disorders Abdominal pain	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Gastrointestinal disorders Constipation	10.0% 3/30 • Number of events 3 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Gastrointestinal disorders Diarrhea	23.3% 7/30 • Number of events 14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Gastrointestinal disorders Dry Mouth	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Gastrointestinal disorders Gastroesophageal reflux disease	6.7% 2/30 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
General disorders Nausea	16.7% 5/30 • Number of events 8 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Respiratory, thoracic and mediastinal disorders Cough	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Respiratory, thoracic and mediastinal disorders Covid	6.7% 2/30 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - other	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Metabolism and nutrition disorders Anorexia	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Metabolism and nutrition disorders Dehydration	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Metabolism and nutrition disorders Metabolism and nutrition disorders - other	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Musculoskeletal and connective tissue disorders Arthritis	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Musculoskeletal and connective tissue disorders Back pain	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Musculoskeletal and connective tissue disorders Neck pain	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Cardiac disorders Cardiac disorders - other	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Psychiatric disorders Depression	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Psychiatric disorders Insomnia	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Nervous system disorders Dizziness	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Nervous system disorders Extrapyramidal disorder	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Nervous system disorders Headache	53.3% 16/30 • Number of events 36 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Nervous system disorders Muscle weakness	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Nervous system disorders Neuralgia	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Skin and subcutaneous tissue disorders Dry Skin	3.3% 1/30 • Number of events 3 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Skin and subcutaneous tissue disorders Hyperhidrosis	3.3% 1/30 • Number of events 3 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - other	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
General disorders Facial pain	3.3% 1/30 • Number of events 4 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
General disorders Fatigue	13.3% 4/30 • Number of events 8 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
General disorders Flu like symptoms	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
General disorders Pain	10.0% 3/30 • Number of events 4 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Vascular disorders Flushing	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Reproductive system and breast disorders Hot flashes	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Reproductive system and breast disorders Menorrhagia	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Renal and urinary disorders Renal and urinary disorders - other	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Renal and urinary disorders Urinary frequency	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Skin and subcutaneous tissue disorders Skin infection	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/14 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Ear and labyrinth disorders Vertigo	6.7% 2/30 • Number of events 4 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	3.3% 1/30 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Eye disorders Cataract surgery	3.3% 1/30 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Musculoskeletal and connective tissue disorders Fracture	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	7.1% 1/14 • Number of events 1 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	0.00% 0/30 • Adverse Events were collected from baseline to end of study, approximately 20 weeks
Musculoskeletal and connective tissue disorders Pain in extremity	6.7% 2/30 • Number of events 2 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	35.7% 5/14 • Number of events 10 • Adverse Events were collected from baseline to end of study, approximately 20 weeks	10.0% 3/30 • Number of events 3 • Adverse Events were collected from baseline to end of study, approximately 20 weeks