Trial Outcomes & Findings for Zoledronate in Preventing Osteoporosis and Bone Fractures in Patients With Locally Advanced Nonmetastatic Prostate Cancer Undergoing Radiation Therapy and Hormone Therapy (NCT NCT00329797)

Last Updated: 2017-11-29

Results Overview

The time of failure was measured from the date of randomization to the date of documented bone fractures, defined as any fracture of the bone. The three-year FABF rate will be estimated by the Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

109 participants

Primary outcome timeframe

From randomization to 3 years

Results posted on

2017-11-29

Participant Flow

Participant milestones

Participant milestones
Measure	Zoledronic Acid Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and luteinizing hormone-releasing hormone (LHRH) therapy.	Control Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Overall Study STARTED	57	52
Overall Study COMPLETED	50	46
Overall Study NOT COMPLETED	7	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and luteinizing hormone-releasing hormone (LHRH) therapy.	Control Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Overall Study Protocol Violation	1	0
Overall Study Withdrawal by Subject	6	6

Baseline Characteristics

Zoledronate in Preventing Osteoporosis and Bone Fractures in Patients With Locally Advanced Nonmetastatic Prostate Cancer Undergoing Radiation Therapy and Hormone Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid n=50 Participants Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Control n=46 Participants Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Total n=96 Participants Total of all reporting groups
Age, Continuous	70 years n=5 Participants	71 years n=7 Participants	71 years n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	50 Participants n=5 Participants	46 Participants n=7 Participants	96 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to 3 years

Population: Eligible patients

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=50 Participants Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Control n=46 Participants Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Freedom From Any Bone Fracture (FABF) Rate at Three Years	98.0 percentage of participants Interval 94.0 to 100.0	97.4 percentage of participants Interval 92.3 to 100.0

SECONDARY outcome

Timeframe: Baseline, 3 years from start of treatment

Population: Eligible patients with baseline and 3-year BMD data at respective location

Bone mineral density (BMD) was measured by DXA scan (Dual X-ray absorptiometry) for five locations: lumbar, right total hip, left total hip, right femoral neck, and left femoral neck. The percent change at 3 years was calculated for each location by the following formula: Percent Change BMD = (BMD\_3 years - BMD\_Baseline)/ BMD\_Baseline \* 100.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=50 Participants Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Control n=46 Participants Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Percent Change in Bone Mineral Density at 3 Years Lumbar	6 percentage of baseline value Interval -5.0 to 15.0	-5 percentage of baseline value Interval -19.0 to -1.0
Percent Change in Bone Mineral Density at 3 Years Hip - Right	-2 percentage of baseline value Interval -17.0 to 3.0	-5 percentage of baseline value Interval -13.0 to 1.0
Percent Change in Bone Mineral Density at 3 Years Hip - Left	1 percentage of baseline value Interval -6.0 to 13.0	-8 percentage of baseline value Interval -18.0 to 3.0
Percent Change in Bone Mineral Density at 3 Years Femoral - Right	1 percentage of baseline value Interval -13.0 to 4.0	-6 percentage of baseline value Interval -9.0 to 0.0
Percent Change in Bone Mineral Density at 3 Years Femoral - Left	3 percentage of baseline value Interval -8.0 to 12.0	-8 percentage of baseline value Interval -26.0 to 3.0

SECONDARY outcome

Timeframe: Baseline, 3 years from start of treatment

Population: Eligible patients with baseline and 3-year FACT-G data

The FACT-G is a validated, 27-item measure. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, with 0=Not a lot and 4=Very much. All items in a subscale are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range from 0-108 for the FACT-G total score, 0-28 for the physical, social and functional subscales, and 0-24 for the emotional subscale. Certain items, identified on the FACT-G scoring guides, must be reversed before it is added by subtracting the response from 4. All subscale totals are added together to form the FACT-G total score. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=29 Participants Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Control n=21 Participants Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years Physical Subscale	-1.03 units on a scale Interval -15.0 to 8.0	0.06 units on a scale Interval -5.0 to 10.0
Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years Social Subscale	-0.69 units on a scale Interval -7.0 to 6.42	-1.13 units on a scale Interval -14.7 to 18.0
Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years Functional Subscale	-1.10 units on a scale Interval -20.8 to 5.0	-2.76 units on a scale Interval -11.0 to 6.0
Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years Total	-1.00 units on a scale Interval -30.7 to 19.0	-2.77 units on a scale Interval -27.7 to 27.0
Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years Emotional Subscale	1.83 units on a scale Interval -4.0 to 10.0	1.15 units on a scale Interval -4.0 to 14.0

SECONDARY outcome

Timeframe: From pre-treatment to 3 years from start of treatment

Population: Eligible patients with baseline and follow-up EQ-5D scores, resulting in only 59 patients (no deaths), less than half of enrolled patients (and less than 5% of planned enrollment), which is extremely problematic as it can lead to selection bias, especially with even fewer patients with follow-up scores. Therefore analysis was not conducted.

The EQ-5D is a standardized instrument for measuring generic health status used to generate health utilities, used to derive quality adjusted survival. Quality adjusted survival is computed using the weighted sum of times in different health states added up to a total quality-adjusted survival time. The log-rank test is used to compare quality-adjusted survivals between the treatment arms.

Outcome measures

Outcome data not reported

Adverse Events

Zoledronic Acid

Serious events: 8 serious events

Other events: 45 other events

Deaths: 0 deaths

Control

Serious events: 5 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Wendy Seiferheld, M.S.

NRG Oncology

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.
Publication restrictions are in place

Restriction type: OTHER

Measure	Zoledronic Acid n=50 participants at risk Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Control n=46 participants at risk Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Cardiac disorders Left ventricular failure	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Cardiac disorders Myocardial ischaemia	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Cardiac disorders Restrictive cardiomyopathy	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Eye disorders Uveitis NOS	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Abdominal pain NOS	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Colonic haemorrhage	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Death NOS	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Gait abnormal NOS	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Injury, poisoning and procedural complications Fracture NOS	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Injury, poisoning and procedural complications Vessel injury-artery: Carotid	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Lymphopenia	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Metabolism and nutrition disorders Glucose tolerance impaired	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Metabolism and nutrition disorders Hypocalcemia	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Metabolism and nutrition disorders Hypokalemia	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Metabolism and nutrition disorders Hyponatremia	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Arthralgia	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Muscle weakness, generalized or specific area (not due to ne	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Cerebral ischaemia	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Psychiatric disorders Confusional state	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Pollakiuria	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Renal/genitourinary - Other:	4.0% 2/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Reproductive system and breast disorders Penile pain	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.

Measure	Zoledronic Acid n=50 participants at risk Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Control n=46 participants at risk Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Blood and lymphatic system disorders Hemoglobin	26.0% 13/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	23.9% 11/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Abdominal pain NOS	2.0% 1/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.5% 3/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Constipation	14.0% 7/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.7% 4/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Diarrhoea NOS	18.0% 9/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	17.4% 8/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Dry mouth	0.00% 0/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.5% 3/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Gastrointestinal - Other:	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Hemorrhoids	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Nausea	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Proctitis NOS	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	10.9% 5/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Rectal hemorrhage	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	19.6% 9/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Constitutional Symptoms - Other:	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Edema: limb:	14.0% 7/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Fatigue	46.0% 23/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	32.6% 15/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Pain - Other:	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Pain NOS	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Aspartate aminotransferase increased	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Blood creatinine increased	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Leukopenia NOS	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Lymphopenia	14.0% 7/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	10.9% 5/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Metabolic/laboratory - Other:	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Platelet count decreased	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Investigations Weight increased	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Metabolism and nutrition disorders Hyperglycaemia NOS	4.0% 2/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	13.0% 6/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Arthralgia	26.0% 13/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	15.2% 7/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Back pain	12.0% 6/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Bone pain	16.0% 8/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Muscle weakness NOS	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Musculoskeletal/soft tissue - Other:	12.0% 6/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Myalgia	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.5% 3/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Pain in extremity	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Dizziness	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Headache	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Peripheral sensory neuropathy	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.5% 3/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Psychiatric disorders Depression	12.0% 6/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.5% 3/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Psychiatric disorders Insomnia	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.3% 2/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Psychiatric disorders Libido decreased	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.7% 4/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Pollakiuria	40.0% 20/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	28.3% 13/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Renal/genitourinary - Other:	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.7% 4/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Urinary incontinence	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.7% 4/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Urinary retention	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	10.9% 5/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Reproductive system and breast disorders Erectile dysfunction NOS	18.0% 9/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	13.0% 6/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Reproductive system and breast disorders Gynaecomastia	14.0% 7/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.7% 4/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Respiratory, thoracic and mediastinal disorders Cough	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.0% 5/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	10.9% 5/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Skin and subcutaneous tissue disorders Dermatitis exfoliative NOS	6.0% 3/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.2% 1/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Skin and subcutaneous tissue disorders Pruritus	8.0% 4/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Vascular disorders Hot flushes NOS	54.0% 27/50 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	54.3% 25/46 Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.