Zoledronic Acid - Letrozole Adjuvant Synergy Trial (ZFAST... | NCT00050011

Label	Type	Description	Intervention Names
Zoledronic Acid upfront	Experimental	Participants in the upfront arm received zoledronate 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence) or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily.	Drug: Zoledronic Acid Drug: Letrozole
Zoledronate delayed-start	Experimental	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronate 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily.	Drug: Zoledronic Acid Drug: Letrozole

Name	Type	Description	Arm Group Labels	Other Names
Zoledronic Acid	Drug	Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.	Zoledronate delayed-start Zoledronic Acid upfront

Measure	Description	Time Frame
Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD)	Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Month 12 - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the last observation carried forward (LOCF) method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.	Baseline, 12 months

Measure	Description	Time Frame
Percent Change From Baseline in Lumbar Spine (L1-L4) BMD	Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Time Frame - Baseline BMD)/Baseline BMD)). Missing data beyond month 12 were not imputed by LOCF.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Signed informed consent
Postmenopausal status defined by one of the following :
- women equal to or greater than 55 years with cessation of menses
- spontaneous cessation of menses within the past 1 year, but amenorrheic in women less than or equal to 55 years (e.g., spontaneous or secondary to hysterectomy), and with postmenopausal gonadotrophin levels (follicle stimulating hormone levels >40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved
- bilateral oophorectomy (prior to the diagnosis of breast cancer).
Adequately diagnosed and treated breast cancer defined as:
- Patients with breast cancer whose tumor can be removed by an appropriate surgical procedure such as mastectomy or breast conserving surgery and who receive appropriate additional local treatments such as radiotherapy according to best practice.
- Patients must be at the end of their local treatment without evidence of local residual disease.
- Patients must have no clinical or radiological evidence of distant metastasis.
Hormone receptor positive defined as:
- ER and/or PR greater than or equal to1 0 fmol/mg cytosol protein; or greater than or equal to 10% of the tumor cells positive by
- immunohistochemical evaluation.
Patients with a baseline lumbar spine and total hip BMD T-score at or above -2.0 SD are eligible.
Patients who will receive adjuvant chemotherapy are eligible for participation. Adjuvant chemotherapy must be completed prior to randomization.
The date of randomization must not be more than the following:
- 12 weeks from completion of surgery;
- 12 weeks after completion of adjuvant chemotherapy;
- 12 weeks after completion of surgery and radiation therapy; however the patient may be randomized while receiving radiation therapy - this decision is at the Investigator's discretion.
- 12 weeks after completion of chemotherapy and radiation therapy; however, the patient may be randomized while receiving radiation therapy - this decision is at the Investigator's discretion.
Patients who have undergone neoadjuvant chemotherapy are eligible.
No prior treatment with Femara.

Exclusion criteria:

Patients with any clinical or radiological evidence of distant spread of their disease at any point before randomization.
Patients with clinical or radiological evidence of existing fracture in the lumbar spine and/or total hip.
Patients with a history of fracture with low-intensity or no associated trauma.
Patients who have started adjuvant hormonal therapy or who have completed adjuvant hormonal therapy prior to randomization.
Patients who have received any endocrine therapy within the past 12 months (other than neoadjuvant tamoxifen or toremifene, insulin and/or oral anti-diabetic medications, and thyroid hormone replacement). Hormone replacement therapy must be discontinued prior to randomization.
Patients who have received prior treatment with intravenous bisphosphonates within the past 12 months.
Patients currently receiving oral bisphosphonates. Oral bisphosphonates must be discontinued within 3 weeks of baseline evaluations.
Patients who have received prior treatment with systemic corticosteroids within the past 12 months (short term corticosteroid therapy, e.g. to prevent/treat chemotherapy-induced nausea/vomiting, is acceptable).
Patients with prior exposure to anabolic steroids or growth hormone within the past 6 months.
Patients with prior use of Tibolone within the last 6 months.
Any prior use of PTH for more than 1 week.
Prior use of systemic sodium fluoride for > 3 months during the past 2 years.
Patients currently treated with any drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate) within 2 weeks prior to randomization.
Patients with previous or concomitant malignancy (not breast cancer) within the past 5 years EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a previous other malignancy must have been disease free for five years.
Patients with other non-malignant systemic diseases including uncontrolled infections, uncontrolled type 2 diabetes mellitus, uncontrolled thyroid dysfunction, cardiovascular, renal, hepatic, and lung diseases which would prevent prolonged follow-up. Patients with previous history of thrombosis or thromboembolism can be included only if medically suitable. Patients with a known history of HIV are excluded.
Uncontrolled seizure disorders associated with falls.
Patients with abnormal renal function as evidenced by a serum creatinine equal to or greater than 3 mg/dL (265.2 mmol/L).
History of diseases with influence on bone metabolism, such as Paget's disease, Osteogenesis Imperfecta, and primary or secondary hyperthyroidism within 12 months prior to study entry.
Patients with baseline lumber spine or total hip BMD T-score below -2.0 SD.
Patients treated with systemic investigational drug(s) and/or device(s) within the past 30 days or topical investigational drugs within the past 7 days.

Additional Exclusion Criteria: (for Spine DXA)

History of surgery at the lumbosacral spine, with or without implantable devices.
Scoliosis with a Cobb angle >15 degree at the lumbar spine.
Immobility, hyperostosis or sclerotic changes at the lumbar spine, or evidence of sclerotic abdominal aorta sufficient to interfere with DXA scan.
Any disease of the spine that would preclude the proper acquisition of a lumbar spine DXA.

Additional protocol-defined inclusion/exclusion criteria may apply.

Name	Affiliation	Role
Novartis Pharmaceuticals, MD	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Highlands Oncology Group		Springdale	Arkansas	72764	United States
East Valley Hematology & Oncology

PubMed Identifier	Type	Citation	Retractions
38979716	Derived	Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

ID	Title	Description
FG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence) or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD)

Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100*((BMD at Month 12 - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the last observation carried forward (LOCF) method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.

Intent to treat (ITT population) was used. The ITT population contained all patients in the safety population for whom at least one post-baseline efficacy measurement was collected.

Posted

Mean

Standard Deviation

Percentage of BMD

Baseline, 12 months

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed-start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronic acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Units	Counts
Participants	OG000253 OG001256

Title

Denominators

Categories

Title	Measurements
	OG0001.955± 3.3658 OG001-2.325± 3.9542

Secondary

Percent Change From Baseline in Lumbar Spine (L1-L4) BMD

Percent change = 100*((BMD at Time Frame - Baseline BMD)/Baseline BMD)). Missing data beyond month 12 were not imputed by LOCF.

ITT population

Posted

Mean

Standard Deviation

Percentage of BMD

Baseline, 2 years, 3 years, 5 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Secondary

Percent Change From Baseline in Total Hip BMD

Percent change = 100*((BMD at Time Frame - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the LOCF method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.

ITT population

Posted

Mean

Standard Deviation

Percentage of BMD

Baseline, 12 months, 2 years, 3 years, 5 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Secondary

Percent Change From Baseline in Biochemical Markers of Bone Turnover, Serum N-Telopeptide (sNTX) and Bone-specific Alkaline Phosphatase (BSAP)

Blood samples from a subset of participants (231 participants in total) were collected to measure the sNTX and BSAP. Missing data at month 12 were imputed by using the LOCF method. Post-baseline non-missing data from months 6 and 9 were carried forward to month 12. Data prior to month 6 were not carried forward. Missing data beyond month 12 were not imputed by LOCF.

ITT population

Posted

Mean

Standard Deviation

Percentage of biochemical markers

Baseline, 12 months, 2 years, 3 years, 5 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Secondary

Incidence Rate of All Clinical Fractures

The number of participants who experienced a clinical fracture at month 36 was assessed. Initial x-ray (both AP and lateral views) of the lumbar and thoracic spine were performed at baseline to exclude participants with evidence of fracture. In addition, repeated bone scan and/or x-ray were performed at the Principal Investigator's discretion during the course of the study to confirm evidence of clinical fracture, or at month 36 if there was no evidence of clinical fracture (lumbar and thoracic spine - lateral view). X-ray films were sent to a central reader.

ITT population

Posted

Number

Participants

3 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Secondary

Time to Disease Recurrence/Relapse

The median time to disease progression was assessed by Kaplan-Meier analysis. The Principal Investigator assessed each participant for disease recurrence at each visit. Further testing was performed at the discretion of the Principal Investigator and as clinically indicated. Disease progression was defined as chest wall and/or regional recurrence confirmed by positive cytology or biopsy, and/or distance recurrence of the 1) skin, subcutaneous tissue, and lymph nodes (other than local or regional), 2) bone marrow, 3) lung, 4) skeleton 5) liver and 6) central nervous system confirmed by positive cytology, biopsy, aspirate or radiology as appropriate.

ITT population

Posted

Median

95% Confidence Interval

months

over 5 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Secondary

Rate of Change From Baseline in Lumbar Spine (L1-L4) BMD

The rate of change from baseline in BMD was assessed.

ITT population

Posted

Mean

95% Confidence Interval

g/sq cm/month

Baseline, 5 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Secondary

Rate of Change From Baseline in Total Hip BMD

The rate of change from baseline in BMD was assessed.

ITT population

Posted

Mean

95% Confidence Interval

g/sq. cm/month

Baseline, 5 years

ID	Title	Description
OG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.
OG001	Zoledronic Acid Delayed Start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0010 affected300 at risk
Granulocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Iron deficiency anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Acute coronary syndrome	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0011 affected300 at risk
Angina pectoris	Cardiac disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0011 affected300 at risk
Aortic valve stenosis	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Atrial fibrillation	Cardiac disorders	MedDRA	Systematic Assessment	EG0004 affected300 at risk EG0014 affected300 at risk
Cardiac failure	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Cardiac failure chronic	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0012 affected300 at risk
Cardio-respiratory arrest	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Cardiomyopathy	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Cardiomyopathy acute	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Coronary artery disease	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0014 affected300 at risk
Coronary artery occlusion	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0014 affected300 at risk
Coronary artery stenosis	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Dilatation ventricular	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Ischaemic cardiomyopathy	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Left ventricular dysfunction	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Myocardial infarction	Cardiac disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0011 affected300 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Sinus bradycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Blindness unilateral	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Retinal artery occlusion	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Visual acuity reduced	Eye disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Aphthous stomatitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Colitis ulcerative	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0010 affected300 at risk
Crohn's disease	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Duodenal ulcer perforation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Enterovesical fistula	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Large intestine perforation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0010 affected300 at risk
Oesophageal mass	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Oesophageal spasm	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Peritonitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Rectal haemorrhage	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Adverse drug reaction	General disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Asthenia	General disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Chest discomfort	General disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Chest pain	General disorders	MedDRA	Systematic Assessment	EG0003 affected300 at risk EG0011 affected300 at risk
Non-cardiac chest pain	General disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0010 affected300 at risk
Pain	General disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0004 affected300 at risk EG0012 affected300 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0011 affected300 at risk
Cholelithiasis obstructive	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Ischaemic hepatitis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Drug hypersensitivity	Immune system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Abdominal wall abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Abscess limb	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Appendicitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0013 affected300 at risk
Arthritis bacterial	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Breast abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Breast cellulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0012 affected300 at risk
Cellulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0012 affected300 at risk
Gastroenteritis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Helicobacter infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Incision site infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Liver abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Mastitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Osteomyelitis chronic	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG0004 affected300 at risk EG0013 affected300 at risk
Postoperative wound infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Pyelonephritis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Septic shock	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Skin bacterial infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Staphylococcal infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0012 affected300 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Urinary tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Urosepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Viral infection	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0010 affected300 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Accident	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Accidental overdose	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Ankle fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Arthropod bite	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Brain contusion	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Breast injury	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Device breakage	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Fall	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG00010 affected300 at risk EG0017 affected300 at risk
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Fibula fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Foot fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Hand fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Head injury	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Intentional overdose	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Joint dislocation	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Joint sprain	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Meniscus lesion	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Multiple fractures	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Post procedural complication	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Post procedural haematoma	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Postoperative ileus	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Procedural nausea	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Procedural vomiting	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Radius fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0012 affected300 at risk
Skull fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Thoracic vertebral fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Tibia fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Traumatic brain injury	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Traumatic intracranial haemorrhage	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Ulna fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Upper limb fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Wrist fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Bone density decreased	Investigations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Electrocardiogram T wave inversion	Investigations	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Foot deformity	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0009 affected300 at risk EG0019 affected300 at risk
Osteonecrosis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0012 affected300 at risk
Osteoporosis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Pain in jaw	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Rhabdomyolysis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Rotator cuff syndrome	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Scoliosis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Spinal column stenosis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Spondylolisthesis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Acute lymphocytic leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Acute myelomonocytic leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Benign lung neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Bladder cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Bladder neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Bladder transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Degeneration of uterine fibroid	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Lung carcinoma cell type unspecified stage I	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Meningioma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Ovarian cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0011 affected300 at risk
Pancreatic carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Spindle cell sarcoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Ureteric cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Altered state of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Amyotrophic lateral sclerosis	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Ataxia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0013 affected300 at risk
Dementia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Haemorrhage intracranial	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Hepatic encephalopathy	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Loss of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Lumbar radiculopathy	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Multiple sclerosis	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Subdural hygroma	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Syncope	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0011 affected300 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Alcoholism	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Confusional state	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Depression	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Suicide attempt	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Calculus ureteric	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Cystitis haemorrhagic	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Renal failure	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Breast cyst	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Cystocele	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0012 affected300 at risk
Ovarian cyst	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Rectocele	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected300 at risk EG0011 affected300 at risk
Mediastinal mass	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Pleurisy	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0013 affected300 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0012 affected300 at risk
Pulmonary mass	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Subcutaneous emphysema	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0000 affected300 at risk EG0011 affected300 at risk
Deep vein thrombosis	Vascular disorders	MedDRA	Systematic Assessment	EG0003 affected300 at risk EG0014 affected300 at risk
Haemorrhage	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Hypertension	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk
Jugular vein distension	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected300 at risk EG0010 affected300 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG00013 affected300 at risk EG00120 affected300 at risk
Constipation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00029 affected300 at risk EG00128 affected300 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00025 affected300 at risk EG00131 affected300 at risk
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00016 affected300 at risk EG00115 affected300 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00039 affected300 at risk EG00140 affected300 at risk
Chest pain	General disorders	MedDRA	Systematic Assessment	EG00018 affected300 at risk EG0019 affected300 at risk
Fatigue	General disorders	MedDRA	Systematic Assessment	EG000101 affected300 at risk EG00188 affected300 at risk
Oedema peripheral	General disorders	MedDRA	Systematic Assessment	EG00036 affected300 at risk EG00130 affected300 at risk
Pain	General disorders	MedDRA	Systematic Assessment	EG00016 affected300 at risk EG00114 affected300 at risk
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG00028 affected300 at risk EG00114 affected300 at risk
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG00017 affected300 at risk EG0016 affected300 at risk
Sinusitis	Infections and infestations	MedDRA	Systematic Assessment	EG00019 affected300 at risk EG00115 affected300 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG00026 affected300 at risk EG00126 affected300 at risk
Urinary tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG00037 affected300 at risk EG00126 affected300 at risk
Hypercholesterolaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00021 affected300 at risk EG00117 affected300 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG000141 affected300 at risk EG001136 affected300 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00022 affected300 at risk EG00119 affected300 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00044 affected300 at risk EG00152 affected300 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00048 affected300 at risk EG00124 affected300 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00015 affected300 at risk EG00117 affected300 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00017 affected300 at risk EG0018 affected300 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00033 affected300 at risk EG00122 affected300 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00061 affected300 at risk EG00147 affected300 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00016 affected300 at risk EG0018 affected300 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00045 affected300 at risk EG00140 affected300 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG00029 affected300 at risk EG00122 affected300 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG00039 affected300 at risk EG00137 affected300 at risk
Hypoaesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG00017 affected300 at risk EG00117 affected300 at risk
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG00017 affected300 at risk EG0016 affected300 at risk
Anxiety	Psychiatric disorders	MedDRA	Systematic Assessment	EG00024 affected300 at risk EG00125 affected300 at risk
Depression	Psychiatric disorders	MedDRA	Systematic Assessment	EG00035 affected300 at risk EG00142 affected300 at risk
Insomnia	Psychiatric disorders	MedDRA	Systematic Assessment	EG00041 affected300 at risk EG00129 affected300 at risk
Breast pain	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG00019 affected300 at risk EG00118 affected300 at risk
Vulvovaginal dryness	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG00024 affected300 at risk EG00122 affected300 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00030 affected300 at risk EG00138 affected300 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00026 affected300 at risk EG00125 affected300 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00024 affected300 at risk EG00118 affected300 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00019 affected300 at risk EG00117 affected300 at risk
Hot flush	Vascular disorders	MedDRA	Systematic Assessment	EG000122 affected300 at risk EG001118 affected300 at risk
Hypertension	Vascular disorders	MedDRA	Systematic Assessment	EG00030 affected300 at risk EG00124 affected300 at risk
Lymphoedema	Vascular disorders	MedDRA	Systematic Assessment	EG00019 affected300 at risk EG00120 affected300 at risk

ID	Term
D001943	Breast Neoplasms
D010024	Osteoporosis
D001851	Bone Diseases, Metabolic

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases
D001847	Bone Diseases
D009140	Musculoskeletal Diseases
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases

ID	Term
D004164	Diphosphonates
D063065	Organophosphonates
D009943	Organophosphorus Compounds
D009930	Organic Chemicals
D007093	Imidazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D009570	Nitriles
D014230	Triazoles

ID	Title	Description
BG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid upfront 4 mg IV 15-minute infusion every 6 months.
BG001	Zoledronic Acid Delayed-start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on Zoledronic Acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid upfront 4 mg IV 15-minute infusion every 6 months.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Zoledronic Acid Upfront	Participants in the upfront arm received Zoledronic Acid 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence)or the end of study. Participants also received Femara 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic Acid 4 mg IV 15-minute infusion every 6 months.			83	300	283	300
EG001	Zoledronic Acid Delayed-start	In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronic acid 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily. Letrozole : Participants received 2.5 mg daily. Zoledronic Acid : Participants received Zoledronic acid 4 mg IV 15-minute infusion every 6 months.			71	300	275	300