Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) With XELOX or FOLFOX in Patients With Metastatic Colorectal Cancer and Disease Progression Under First-line FOLFIRI and Avastin (NCT NCT01077739)

Last Updated: 2014-12-15

Results Overview

PFS from the start of treatment beyond progression was defined as the interval between the start of beyond-progression therapy and the date at which disease progression was documented. Progression of disease was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and abdominal/pelvic computerized tomography (CT) or magnetic resonance imaging (MRI) scanning as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

75 participants

Primary outcome timeframe

Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months

Results posted on

2014-12-15

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab + Oxaliplatin + Capecitabine Participants received bevacizumab 7.5 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1; oxaliplatin 130 mg per square meter (mg/m\^2) IV on Day 1; and capecitabine 1000 mg/m\^2, orally (PO), twice daily (BID) on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + 5-fluorouracil/Oxaliplatin/Leucovorin (FOLFOX) Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-fluorouracil \[5-FU\] plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
Overall Study STARTED	25	50
Overall Study COMPLETED	20	40
Overall Study NOT COMPLETED	5	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab + Oxaliplatin + Capecitabine Participants received bevacizumab 7.5 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1; oxaliplatin 130 mg per square meter (mg/m\^2) IV on Day 1; and capecitabine 1000 mg/m\^2, orally (PO), twice daily (BID) on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + 5-fluorouracil/Oxaliplatin/Leucovorin (FOLFOX) Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-fluorouracil \[5-FU\] plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
Overall Study Premature withdrawal	1	3
Overall Study Withdrawal by Subject	1	0
Overall Study Death	0	3
Overall Study Unacceptable toxicity	1	2
Overall Study Other	2	2

Baseline Characteristics

A Study of Avastin (Bevacizumab) With XELOX or FOLFOX in Patients With Metastatic Colorectal Cancer and Disease Progression Under First-line FOLFIRI and Avastin

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab + Oxaliplatin + Capecitabine n=25 Participants Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + FOLFOX n=50 Participants Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.	Total n=75 Participants Total of all reporting groups
Age, Continuous	59.6 years STANDARD_DEVIATION 8.9 • n=5 Participants	64.9 years STANDARD_DEVIATION 8.7 • n=7 Participants	63.1 years STANDARD_DEVIATION 9.0 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	21 Participants n=7 Participants	29 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	29 Participants n=7 Participants	46 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months

Population: ITT population

Outcome measures

Outcome measures
Measure	Bevacizumab + Oxaliplatin + Capecitabine n=25 Participants Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + FOLFOX n=50 Participants Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
Progression-Free Survival (PFS) From the Start of Treatment Beyond Progression	6.3 months Interval 4.1 to 7.6	5.1 months Interval 3.8 to 6.0

SECONDARY outcome

Timeframe: Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months

Population: ITT population.

PFS from the start of first-line therapy was defined as the interval between the start of first-line therapy and the date at which second disease progression (after the start of beyond progression therapy) was documented. Progression of disease was evaluated using RECIST version 1.1 and abdominal/pelvic CT or MRI scanning. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Bevacizumab + Oxaliplatin + Capecitabine n=25 Participants Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + FOLFOX n=50 Participants Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
PFS From the Start of First-Line Therapy	17.8 months Interval 14.1 to 19.4	18.0 months Interval 15.0 to 19.9

SECONDARY outcome

Timeframe: Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months

Population: ITT population; only participants with RECIST evaluations were included in the analysis.

Percentage of participants with an overall response of CR or PR according to RECIST criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis less than \[\<\]10 millimeters \[mm\]). No new lesions. PR was defined as greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

Outcome measures

Outcome measures
Measure	Bevacizumab + Oxaliplatin + Capecitabine n=22 Participants Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + FOLFOX n=47 Participants Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
Percentage of Participants With an Overall Response of Complete Response (CR) or Partial Response (PR)	27.3 percentage of participants	6.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks until disease progression, at final visit or at withdrawal, for up to 24 months

Population: ITT Population. Number (n) equals (=) number of participants assessed for the given parameter at the specified visit.

Pro-angiogenic cytokine concentrations of placental growth factor (PlGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in participant sera were measured and reported in units of picograms/milliliter (pg/mL). The geometric mean was calculated as exp10 (mean of log10 transformed concentration) and the standard deviation (SD) is SD of log10 transformed concentration.

Outcome measures

Outcome measures
Measure	Bevacizumab + Oxaliplatin + Capecitabine n=13 Participants Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + FOLFOX n=23 Participants Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression Baseline bFGF (n=13,23)	6.8 pg/mL Standard Deviation 0.7	6.1 pg/mL Standard Deviation 0.6
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression bFGF, Prior to progression levels (n=12,18)	3.6 pg/mL Standard Deviation 0.9	4.2 pg/mL Standard Deviation 0.7
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression Baseline HGF (n=13,23)	133.0 pg/mL Standard Deviation 0.3	186.0 pg/mL Standard Deviation 0.4
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression HGF, Prior to progression levels (n=12,18)	187.3 pg/mL Standard Deviation 0.4	230.3 pg/mL Standard Deviation 0.4
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression Baseline PIGF (n=13,23)	29.8 pg/mL Standard Deviation 0.1	26.3 pg/mL Standard Deviation 0.2
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression PIGF, Prior to progression levels (n=12,18)	34.7 pg/mL Standard Deviation 0.1	37.1 pg/mL Standard Deviation 0.2

Adverse Events

Bevacizumab + Oxaliplatin + Capecitabine

Serious events: 12 serious events

Other events: 24 other events

Deaths: 0 deaths

Bevacizumab + FOLFOX

Serious events: 18 serious events

Other events: 49 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request the Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Bevacizumab + Oxaliplatin + Capecitabine n=25 participants at risk Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression.	Bevacizumab + FOLFOX n=50 participants at risk Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Abdominal pain	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Abdominal pain upper	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Anal fistula	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Colonic obstruction	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Diarrhoea	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	4.0% 2/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Enteritis	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Ileus	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Intestinal perforation	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Nausea	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Gastrointestinal disorders Vomiting	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Asthenia	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Device dislocation	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Disease progression	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Drug intolerance	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders General physical health deterioration	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	6.0% 3/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Idiosyncratic drug reaction	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Obstruction	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
General disorders Pain	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Infections and infestations Necrotising fasciitis	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Infections and infestations Perirectal abscess	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Infections and infestations Sepsis	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Infections and infestations Vaginal abscess	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Injury, poisoning and procedural complications Drug toxicity	8.0% 2/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Injury, poisoning and procedural complications Fall	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Injury, poisoning and procedural complications Jaw fracture	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Metabolism and nutrition disorders Decreased appetite	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Metabolism and nutrition disorders Dehydration	8.0% 2/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Nervous system disorders Epilepsy	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Psychiatric disorders Confusional state	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Psychiatric disorders Depression	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Respiratory, thoracic and mediastinal disorders Hiccups	4.0% 1/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	0.00% 0/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/25 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.	2.0% 1/50 • Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 24 months. The safety population included all participants who received at least 1 dose of the investigational or non-investigational products.