Trial Outcomes & Findings for Clinical Study of Cefiderocol (S-649266) for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens (NCT NCT03032380)

Last Updated: 2020-11-13

Results Overview

The all-cause mortality (ACM) rate at Day 14 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from the first infusion of study drug up to Day 14. The Modified Intent-to-Treat Population included all randomized participants who met either of the following criteria: * Evidence of Gram-negative infection of the lower respiratory tract based on a culture, Gram-stain, or other diagnostic test * Evidence of a lower respiratory tract infection but culture or other diagnostic tests did not provide a microbiologic diagnosis

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

300 participants

Primary outcome timeframe

From first dose of study drug to Day 14

Results posted on

2020-11-13

Participant Flow

The study population included participants with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative bacteria.

Participants were randomized in a 1:1 ratio to either cefiderocol or meropenem. Randomization was performed by the stratified randomization method using infection diagnosis (HABP, VABP, and HCABP) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤ 15 and ≥ 16) as allocation factors.

Participant milestones

Participant milestones
Measure	Cefiderocol Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Overall Study STARTED	148	152
Overall Study Received Treatment	148	150
Overall Study COMPLETED	106	112
Overall Study NOT COMPLETED	42	40

Reasons for withdrawal

Reasons for withdrawal
Measure	Cefiderocol Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Overall Study Adverse Event	0	1
Overall Study Lack of Efficacy	1	0
Overall Study Withdrawal by Subject	2	3
Overall Study Recovery	0	1
Overall Study Death	39	34
Overall Study Other - Miscellaneous	0	1

Baseline Characteristics

Clinical Study of Cefiderocol (S-649266) for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cefiderocol n=148 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=150 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Total n=298 Participants Total of all reporting groups
Age, Continuous	64.7 years STANDARD_DEVIATION 14.5 • n=5 Participants	65.6 years STANDARD_DEVIATION 15.1 • n=7 Participants	65.2 years STANDARD_DEVIATION 14.8 • n=5 Participants
Age, Customized < 65 years	65 Participants n=5 Participants	58 Participants n=7 Participants	123 Participants n=5 Participants
Age, Customized >= 65 years	83 Participants n=5 Participants	92 Participants n=7 Participants	175 Participants n=5 Participants
Sex: Female, Male Female	47 Participants n=5 Participants	46 Participants n=7 Participants	93 Participants n=5 Participants
Sex: Female, Male Male	101 Participants n=5 Participants	104 Participants n=7 Participants	205 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	140 Participants n=5 Participants	139 Participants n=7 Participants	279 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	8 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized White	102 Participants n=5 Participants	100 Participants n=7 Participants	202 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	44 Participants n=5 Participants	44 Participants n=7 Participants	88 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Missing	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region North America	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Region South America	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region Europe	99 Participants n=5 Participants	100 Participants n=7 Participants	199 Participants n=5 Participants
Region Asia-Pacific	43 Participants n=5 Participants	44 Participants n=7 Participants	87 Participants n=5 Participants
Clinical Diagnosis VABP	60 Participants n=5 Participants	65 Participants n=7 Participants	125 Participants n=5 Participants
Clinical Diagnosis HABP	60 Participants n=5 Participants	61 Participants n=7 Participants	121 Participants n=5 Participants
Clinical Diagnosis HCABP	28 Participants n=5 Participants	24 Participants n=7 Participants	52 Participants n=5 Participants
Acute Physiology and Chronic Health Evaluation II (APACHE II) Score <= 15	75 Participants n=5 Participants	78 Participants n=7 Participants	153 Participants n=5 Participants
Acute Physiology and Chronic Health Evaluation II (APACHE II) Score 16 - 19	32 Participants n=5 Participants	26 Participants n=7 Participants	58 Participants n=5 Participants
Acute Physiology and Chronic Health Evaluation II (APACHE II) Score >= 20	41 Participants n=5 Participants	46 Participants n=7 Participants	87 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first dose of study drug to Day 14

Population: Modified Intent-to-Treat Population; participants with known survival status.

Outcome measures

Outcome measures
Measure	Cefiderocol n=145 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=146 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
All-cause Mortality Rate at Day 14	12.4 percentage of participants	11.6 percentage of participants

SECONDARY outcome

Timeframe: Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21)

Population: Modified Intent-to-Treat Population; participants with non-missing Baseline pathogen data

Lower respiratory tract specimens (eg, sputum, endotracheal aspiration \[ETA\], endobronchial culture specimens collected by bronchoalveolar lavage \[BAL\], or protected specimen brush \[PSB\], lung biopsy tissue, pleural effusions, etc) were sent to the local microbiology laboratory for isolation and identification of pathogens. Microbiological outcome by Baseline pathogen at TOC was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, bronchoalveolar lavage (BAL) fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.

Outcome measures

Outcome measures
Measure	Cefiderocol n=124 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=127 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC)	47.6 percentage of participants	48.0 percentage of participants

SECONDARY outcome

Timeframe: Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21)

Population: Modified Intent-to-Treat Population

Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.

Outcome measures

Outcome measures
Measure	Cefiderocol n=145 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=147 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Clinical Cure at Test of Cure	64.8 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: Early assessment (Day 3-4 after the start of treatment)

Population: Modified Intent-to-Treat Population

Outcome measures

Outcome measures
Measure	Cefiderocol n=145 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=147 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Clinical Cure at Early Assessment (EA)	82.8 percentage of participants	83.0 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (Day 7 to 14)

Population: Modified Intent-to-Treat Population

Outcome measures

Outcome measures
Measure	Cefiderocol n=145 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=147 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Clinical Cure at End of Treatment (EOT)	77.2 percentage of participants	81.0 percentage of participants

SECONDARY outcome

Timeframe: Follow-up (14 days after the end of treatment; Day 21 to 28)

Population: Modified Intent-to-Treat Population

Clinical outcome was assessed by the investigator at follow-up as either Sustained Clinical Cure, Relapse, or Indeterminate. Sustained Clinical Cure: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC.

Outcome measures

Outcome measures
Measure	Cefiderocol n=145 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=147 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Sustained Clinical Cure at Follow-up (FU)	57.9 percentage of participants	57.8 percentage of participants

SECONDARY outcome

Timeframe: Early Assessment, Days 3 to 4

Population: Modified Intent-to-Treat Population; participants with non-missing Baseline pathogens

Microbiological outcome by Baseline pathogen at Early Assessment was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.

Outcome measures

Outcome measures
Measure	Cefiderocol n=124 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=127 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Microbiologic Eradication at Early Assessment	41.9 percentage of participants	53.5 percentage of participants

SECONDARY outcome

Timeframe: End of treatment, Day 7 to 14

Population: Modified Intent to-Treat Population; participants with non-missing Baseline pathogens

Microbiological outcome by Baseline pathogen at End of Treatment was determined by the sponsor as either: Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.

Outcome measures

Outcome measures
Measure	Cefiderocol n=124 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=127 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Microbiologic Eradication at End of Treatment	63.7 percentage of participants	66.9 percentage of participants

SECONDARY outcome

Timeframe: Follow-up (14 days after the end of treatment, Days 21 to 28)

Population: Modified Intent-to-Treat Population; participants with non-missing Baseline pathogens

Microbiological outcome by Baseline pathogen at Follow-up was determined by the sponsor as either Sustained Eradication, Persistence, Recurrence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Sustained eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy) after TOC. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical response after TOC, the response was presumed to be eradication.

Outcome measures

Outcome measures
Measure	Cefiderocol n=124 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=127 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up	43.5 percentage of participants	38.6 percentage of participants

SECONDARY outcome

Timeframe: From first dose of study drug to Day 28

Population: Modified Intent-to-Treat Population; participants with known survival status.

The all-cause mortality (ACM) rate at Day 28 was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first dose of study drug up to Day 28.

Outcome measures

Outcome measures
Measure	Cefiderocol n=143 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=146 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
All-cause Mortality Rate at Day 28	21.0 percentage of participants	20.5 percentage of participants

SECONDARY outcome

Timeframe: From first dose of study drug through end of study (28 days after end of treatment, up to 42 days)

Population: Modified Intent-to-Treat Population; participants with known survival status.

The all-cause mortality rate during both the treatment and follow-up period (up to the end of study \[EOS\] visit) was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first infusion of study drug up to EOS. If a participant discontinued from the study before EOS and survival information was not available, then the survival status for this endpoint for the participant was considered unknown.

Outcome measures

Outcome measures
Measure	Cefiderocol n=142 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=146 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
All-cause Mortality Rate at the End of Study	26.8 percentage of participants	23.3 percentage of participants

SECONDARY outcome

Timeframe: From first dose of study drug to test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21) and to follow-up (14 days after the end of treatment; Day 21 to 28)

Population: Modified Intent-to-Treat Population

The length of hospital stay attributable to the study-qualifying infection.

Outcome measures

Outcome measures
Measure	Cefiderocol n=145 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=147 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Total Hospitalization Time Test of Cure	11.54 days Standard Deviation 7.81	11.47 days Standard Deviation 7.32
Total Hospitalization Time Follow-up	13.49 days Standard Deviation 10.06	12.98 days Standard Deviation 9.59

SECONDARY outcome

Timeframe: From first dose of study drug through the end of study, up to 42 days.

Population: The safety population included all randomized participants who received at least 1 dose of study treatment.

The severity of each adverse event (AE) was graded by the investigator according to the following definitions: * Mild: A finding or symptom is minor and does not interfere with usual daily activities. * Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical status. * Severe: The event causes an interruption of the participant's usual daily activities or has a clinically significant effect. The relationship of each AE to the study treatment was determined by the investigator based on whether the AE could be reasonably explained as having been caused by the study drug (treatment related AE \[TRAE\]). An SAE is defined as any AE occurring at any dose that resulted in any of the following outcomes: * Death * Life-threatening condition * Hospitalization or prolongation of existing hospitalization for treatment * Persistent or significant disability/incapacity * Congenital anomaly/birth defect * Other medically important condition

Outcome measures

Outcome measures
Measure	Cefiderocol n=148 Participants Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=150 Participants Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Number of Participants With Treatment-Emergent Adverse Events Any adverse event	130 Participants	129 Participants
Number of Participants With Treatment-Emergent Adverse Events Mild adverse events	33 Participants	37 Participants
Number of Participants With Treatment-Emergent Adverse Events Moderate adverse events	41 Participants	47 Participants
Number of Participants With Treatment-Emergent Adverse Events Severe adverse events	56 Participants	45 Participants
Number of Participants With Treatment-Emergent Adverse Events Treatment-related adverse events	14 Participants	17 Participants
Number of Participants With Treatment-Emergent Adverse Events Serious adverse events	54 Participants	45 Participants
Number of Participants With Treatment-Emergent Adverse Events Treatment-related serious adverse events	3 Participants	5 Participants
Number of Participants With Treatment-Emergent Adverse Events AEs leading to discontinuation of study drug	12 Participants	14 Participants
Number of Participants With Treatment-Emergent Adverse Events TRAE leading to discontinuation of study drug	2 Participants	2 Participants
Number of Participants With Treatment-Emergent Adverse Events Adverse events leading to death	39 Participants	35 Participants

Adverse Events

Cefiderocol

Serious events: 54 serious events

Other events: 119 other events

Deaths: 39 deaths

Meropenem

Serious events: 45 serious events

Other events: 123 other events

Deaths: 35 deaths

Serious adverse events

Other adverse events

Additional Information

Shionogi Clinical Trials Administrator

Shionogi Inc.

Phone: 800-849-9707

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cefiderocol n=148 participants at risk Participants received 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.	Meropenem n=150 participants at risk Participants received 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Blood and lymphatic system disorders Anaemia	8.1% 12/148 • From first dose of study drug through the end of study, up to 42 days.	8.0% 12/150 • From first dose of study drug through the end of study, up to 42 days.
Blood and lymphatic system disorders Thrombocytosis	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Blood and lymphatic system disorders Iron deficiency anaemia	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	0.00% 0/150 • From first dose of study drug through the end of study, up to 42 days.
Blood and lymphatic system disorders Thrombocytopenia	0.68% 1/148 • From first dose of study drug through the end of study, up to 42 days.	4.0% 6/150 • From first dose of study drug through the end of study, up to 42 days.
Cardiac disorders Atrial fibrillation	4.7% 7/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
Cardiac disorders Bradycardia	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	1.3% 2/150 • From first dose of study drug through the end of study, up to 42 days.
Gastrointestinal disorders Diarrhoea	8.8% 13/148 • From first dose of study drug through the end of study, up to 42 days.	8.7% 13/150 • From first dose of study drug through the end of study, up to 42 days.
Gastrointestinal disorders Constipation	4.7% 7/148 • From first dose of study drug through the end of study, up to 42 days.	4.0% 6/150 • From first dose of study drug through the end of study, up to 42 days.
Gastrointestinal disorders Nausea	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	1.3% 2/150 • From first dose of study drug through the end of study, up to 42 days.
Gastrointestinal disorders Vomiting	0.68% 1/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
General disorders Pyrexia	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	3.3% 5/150 • From first dose of study drug through the end of study, up to 42 days.
General disorders Oedema peripheral	1.4% 2/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Hepatobiliary disorders Hepatocellular injury	0.00% 0/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Infections and infestations Urinary tract infection	14.9% 22/148 • From first dose of study drug through the end of study, up to 42 days.	10.0% 15/150 • From first dose of study drug through the end of study, up to 42 days.
Infections and infestations Pneumonia	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	3.3% 5/150 • From first dose of study drug through the end of study, up to 42 days.
Infections and infestations Clostridium difficile infection	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Infections and infestations Urinary tract infection fungal	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	1.3% 2/150 • From first dose of study drug through the end of study, up to 42 days.
Infections and infestations Tracheobronchitis	1.4% 2/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
Infections and infestations Bronchitis	1.4% 2/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Injury, poisoning and procedural complications Post procedural haemorrhage	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	0.67% 1/150 • From first dose of study drug through the end of study, up to 42 days.
Investigations Aspartate aminotransferase increased	6.1% 9/148 • From first dose of study drug through the end of study, up to 42 days.	3.3% 5/150 • From first dose of study drug through the end of study, up to 42 days.
Investigations Alanine aminotransferase increased	5.4% 8/148 • From first dose of study drug through the end of study, up to 42 days.	4.0% 6/150 • From first dose of study drug through the end of study, up to 42 days.
Investigations Gamma-glutamyltransferase increased	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	1.3% 2/150 • From first dose of study drug through the end of study, up to 42 days.
Investigations Transaminases increased	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Investigations Hepatic enzyme increased	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	3.3% 5/150 • From first dose of study drug through the end of study, up to 42 days.
Investigations Amylase increased	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	0.00% 0/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hypokalaemia	10.8% 16/148 • From first dose of study drug through the end of study, up to 42 days.	15.3% 23/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hypomagnesaemia	5.4% 8/148 • From first dose of study drug through the end of study, up to 42 days.	0.67% 1/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hypoglycaemia	4.1% 6/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hypoalbuminaemia	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	5.3% 8/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hyponatraemia	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	6.7% 10/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hyperglycaemia	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	1.3% 2/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hypocalcaemia	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	0.67% 1/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hyperkalaemia	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	0.00% 0/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hypoproteinaemia	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Hyperuricaemia	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	0.67% 1/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Gout	0.68% 1/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Metabolic alkalosis	0.68% 1/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
Nervous system disorders Headache	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	0.67% 1/150 • From first dose of study drug through the end of study, up to 42 days.
Psychiatric disorders Delirium	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
Psychiatric disorders Insomnia	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Psychiatric disorders Anxiety	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	0.00% 0/150 • From first dose of study drug through the end of study, up to 42 days.
Psychiatric disorders Agitation	0.68% 1/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Respiratory, thoracic and mediastinal disorders Pleural effusion	6.1% 9/148 • From first dose of study drug through the end of study, up to 42 days.	3.3% 5/150 • From first dose of study drug through the end of study, up to 42 days.
Respiratory, thoracic and mediastinal disorders Hydrothorax	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	4.0% 6/150 • From first dose of study drug through the end of study, up to 42 days.
Respiratory, thoracic and mediastinal disorders Pulmonary congestion	1.4% 2/148 • From first dose of study drug through the end of study, up to 42 days.	2.0% 3/150 • From first dose of study drug through the end of study, up to 42 days.
Skin and subcutaneous tissue disorders Decubitus ulcer	2.7% 4/148 • From first dose of study drug through the end of study, up to 42 days.	6.7% 10/150 • From first dose of study drug through the end of study, up to 42 days.
Vascular disorders Hypertension	3.4% 5/148 • From first dose of study drug through the end of study, up to 42 days.	4.7% 7/150 • From first dose of study drug through the end of study, up to 42 days.
Vascular disorders Phlebitis	2.0% 3/148 • From first dose of study drug through the end of study, up to 42 days.	2.7% 4/150 • From first dose of study drug through the end of study, up to 42 days.
Vascular disorders Hypotension	1.4% 2/148 • From first dose of study drug through the end of study, up to 42 days.	6.0% 9/150 • From first dose of study drug through the end of study, up to 42 days.