Trial Outcomes & Findings for Bevacizumab + Endocrine Treatment vs Endocrine Treatment as First Line in Postmenopausal Women (NCT NCT00545077)

Last Updated: 2023-03-31

Results Overview

PFS was defined as the time elapsed from randomization until the date in which the progression of the disease or the death for any reason (whichever occurs first) is documented.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

380 participants

Primary outcome timeframe

Up to 2 years

Results posted on

2023-03-31

Participant Flow

Participant milestones

Participant milestones
Measure	Arm A: Endocrine Therapy (ET) Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Overall Study STARTED	189	191
Overall Study COMPLETED	41	36
Overall Study NOT COMPLETED	148	155

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: Endocrine Therapy (ET) Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Overall Study Treatment not received	5	1
Overall Study Disease Progression	131	98
Overall Study Withdrawal by Subject	3	14
Overall Study Physician Decision	6	3
Overall Study Lost to Follow-up	2	0
Overall Study Protocol Violation	1	0
Overall Study Adverse Event	0	31
Overall Study Death	0	8

Baseline Characteristics

Bevacizumab + Endocrine Treatment vs Endocrine Treatment as First Line in Postmenopausal Women

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Endocrine Therapy (ET) n=184 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=190 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant	Total n=374 Participants Total of all reporting groups
Age, Continuous	66 years n=5 Participants	64 years n=7 Participants	65 years n=5 Participants
Sex: Female, Male Female	184 Participants n=5 Participants	190 Participants n=7 Participants	374 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Germany	53 participants n=5 Participants	55 participants n=7 Participants	110 participants n=5 Participants
Region of Enrollment Spain	131 participants n=5 Participants	135 participants n=7 Participants	270 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) status ECOG 0	131 Participants n=5 Participants	139 Participants n=7 Participants	270 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) status ECOG 1	53 Participants n=5 Participants	51 Participants n=7 Participants	104 Participants n=5 Participants
Previous (neo)adjuvant chemotherapy Taxanes, anthracyclines, or both	66 Participants n=5 Participants	65 Participants n=7 Participants	131 Participants n=5 Participants
Previous (neo)adjuvant chemotherapy Cyclophosphamide+methotrexate+fluorouracil (CMF)	21 Participants n=5 Participants	18 Participants n=7 Participants	39 Participants n=5 Participants
Previous (neo)adjuvant chemotherapy Other	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Previous (neo)adjuvant chemotherapy No previous (neo)adjuvant chemotherapy	96 Participants n=5 Participants	107 Participants n=7 Participants	203 Participants n=5 Participants
Previous (neo)adjuvant endocrine therapy Previous (neo)adjuvant therapy: Antiestrogens	58 Participants n=5 Participants	64 Participants n=7 Participants	122 Participants n=5 Participants
Previous (neo)adjuvant endocrine therapy Previous (neo)adjuvant therapy:Aromatase inhibitor	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Previous (neo)adjuvant endocrine therapy Previous (neo)adjuvant therapy: Both	24 Participants n=5 Participants	28 Participants n=7 Participants	52 Participants n=5 Participants
Previous (neo)adjuvant endocrine therapy No previous (neo)adjuvant endocrine therapy	89 Participants n=5 Participants	90 Participants n=7 Participants	179 Participants n=5 Participants
Stage of disease at study entry Locally advanced	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Stage of disease at study entry Metastatic	178 Participants n=5 Participants	185 Participants n=7 Participants	363 Participants n=5 Participants
Number of metastatic sites Single	67 Participants n=5 Participants	80 Participants n=7 Participants	147 Participants n=5 Participants
Number of metastatic sites Multiple	117 Participants n=5 Participants	110 Participants n=7 Participants	227 Participants n=5 Participants
Visceral disease Visceral	88 Participants n=5 Participants	90 Participants n=7 Participants	178 Participants n=5 Participants
Visceral disease Non visceral	96 Participants n=5 Participants	100 Participants n=7 Participants	196 Participants n=5 Participants
Bone disease Not present	66 Participants n=5 Participants	66 Participants n=7 Participants	132 Participants n=5 Participants
Bone disease Present	118 Participants n=5 Participants	124 Participants n=7 Participants	242 Participants n=5 Participants
Measurable disease Measurable	146 Participants n=5 Participants	142 Participants n=7 Participants	288 Participants n=5 Participants
Measurable disease Non measurable	38 Participants n=5 Participants	48 Participants n=7 Participants	86 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 2 years

Population: Arm A: 189 patients were randomized, but only 184 started treatment due to patient´s wish. Arm B: 191 patients were randomized, but only 190 started treatment due to patient´s wish.

PFS was defined as the time elapsed from randomization until the date in which the progression of the disease or the death for any reason (whichever occurs first) is documented.

Outcome measures

Outcome measures
Measure	Arm A: Endocrine Therapy (ET) n=184 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=190 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Progression-free Survival (PFS)	14.4 Months Interval 11.4 to 17.5	19.3 Months Interval 16.5 to 22.1

SECONDARY outcome

Timeframe: Up to 2 years

Population: Arm A: 189 patients were randomized, but only 184 started treatment due to patient´s wish. Arm B: 191 patients were randomized, but only 190 started treatment due to patient´s wish.

OS was defined as the time elapsed since randomization, until the time in which death occurs for any reason. The patients lost in the follow-up will be censured at the date of the last follow-up.

Outcome measures

Outcome measures
Measure	Arm A: Endocrine Therapy (ET) n=184 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=190 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Overall Survival (OS)	51.8 Months Interval 38.82 to 64.75	52.1 Months Interval 35.79 to 68.49

SECONDARY outcome

Timeframe: Up to 2 years

Population: Arm A: 189 patients were randomized, but only 184 started treatment due to patient´s wish. Arm B: 191 patients were randomized, but only 190 started treatment due to patient´s wish.

TTF was defined as the time elapsed since randomization until the date the treatment is discontinued for any reason (progression disease, treatment toxicity or death).

Outcome measures

Outcome measures
Measure	Arm A: Endocrine Therapy (ET) n=184 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=190 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Time to Treatment Failure (TTF)	14.4 Months Interval 11.31 to 17.56	15.1 Months Interval 12.66 to 17.52

SECONDARY outcome

Timeframe: 2 years

Population: Only patients with measurable lesions were taken into account

ORR to treatment is reflected by a frequency table containing the data of the best overall response (Complete Response, Partial Response,Stable Disease or Progressive Disease) experienced for each patient during treatment (recorded from the start of the treatment until disease progression) per arm.

Outcome measures

Outcome measures
Measure	Arm A: Endocrine Therapy (ET) n=146 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=142 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Overall Response Rate (ORR)	32 Participants	58 Participants

SECONDARY outcome

Timeframe: Up to 2 years

Population: Only patients with partial or complete response were taken into account

RD was defined as the time elapsed from when a partial or complete response is verified until the time in which progression or death occurs.

Outcome measures

Outcome measures
Measure	Arm A: Endocrine Therapy (ET) n=32 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=58 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Response Duration (RD)	13.32 Months Interval 11.19 to 15.45	17.59 Months Interval 8.9 to 26.28

SECONDARY outcome

Timeframe: Up to 2 years

Population: Arm A: 189 patients were randomized, but only 184 started treatment due to patient´s wish. Arm B: 191 patients were randomized, but only 190 started treatment due to patient´s wish.

CBR was defined as the percentage of patients achieving a Complete Response (CR), a Partial Response (PR) or a stabilization of the disease (SD) \> 6 months: the response will be evaluated according to the RECIST criteria. In the patients without measurable disease at the baseline time, the clinical benefit will be defined as the absence of progression \> 6 months.

Outcome measures

Outcome measures
Measure	Arm A: Endocrine Therapy (ET) n=184 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=190 Participants Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Clinical Benefit Rate (CBR)	124 Participants	146 Participants

Adverse Events

Arm A: Endocrine Therapy (ET)

Serious events: 21 serious events

Other events: 184 other events

Deaths: 0 deaths

Arm B: ET With Bevacizumab (ET-B)

Serious events: 64 serious events

Other events: 190 other events

Deaths: 8 deaths

Serious adverse events

Other adverse events

Additional Information

Scientific Director / Medical Lead / Project Manager

Spanish Breast Cancer Research Group

Phone: +34916592870

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Arm A: Endocrine Therapy (ET) n=184 participants at risk Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Fulvestrant	Arm B: ET With Bevacizumab (ET-B) n=190 participants at risk Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent. Letrozole Bevacizumab Fulvestrant
Infections and infestations Abscess right breast	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Infections and infestations Appendicitis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Infections and infestations Erysipela arm	1.1% 2/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Infections and infestations Infection	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Promyelocytic leukemia	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Blood and lymphatic system disorders Lymphangitis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Metabolism and nutrition disorders Hyperkalemia	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Psychiatric disorders Depression	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Nervous system disorders Cerebellum infarction	5.4% 10/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Nervous system disorders Cerebrovascular ischemia	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Nervous system disorders Headache	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Nervous system disorders Hemi-hyperesthesia right	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Nervous system disorders Ischemic insult	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Nervous system disorders Syncope vagovagal	5.4% 10/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Cardiac disorders Angina pectoris	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Cardiac disorders Cardiac infarction	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Cardiac disorders Heart failure	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Cardiac disorders Infarction	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Vascular disorders Hypertension	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	3.2% 6/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Vascular disorders Thrombosis lower leg left	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Aspiration pneumonia	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 2/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.1% 2/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Pneumonia	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	2.6% 5/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Acute pancreatitis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Anal fistula	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Colitis	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Diarrhoea	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	1.1% 2/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Diverticulitis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Hemorrhoids	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Inguinal hernia surgery	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Intestinal perforation	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Mucositis	0.54% 1/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.00% 0/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Pancreatitis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Parodontitis	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.
Gastrointestinal disorders Subileus	0.00% 0/184 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.	0.53% 1/190 • Through study treatment, average of 14 months. The adverse events will be recorded throughout the study. The events that are not related with the study medication will be followed up for 30 days and the related ones until their resolution or stabilization; the selected target adverse events, regardless of their causality, will be followed up until their resolution or stabilization, as specified in the protocol. Arm A: 189 patients randomized, but 184 started treatment. Arm B: 191 patients randomized, but 190 started treatment.