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Clinical Trial Results:
An open-label, randomised, multicentre, phase III study of irinotecan liposome injection, oxaliplatin, 5-fluorouracil/leucovorin versus nab-paclitaxel plus gemcitabine in subjects who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas

Summary
EudraCT number	2018-003585-14
Trial protocol	DE ES GB HU BE CZ AT FR PT GR IT
Global end of trial date

Results information
Results version number	v1(current)
This version publication date	06 Apr 2024
First version publication date	06 Apr 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

D-US-60010-001

ISRCTN number

-

US NCT number

NCT04083235

WHO universal trial number (UTN)

-

Sponsor organisation name

Ipsen Bioscience

Sponsor organisation address

One Main Street, Cambridge, MA, United States, 02142

Public contact

Medical Director, Ipsen Bioscience, clinical.trials@ipsen.com

Scientific contact

Medical Director, Ipsen Bioscience, clinical.trials@ipsen.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Interim

Date of interim/final analysis

23 Jul 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Jul 2022

Global end of trial reached?

No

Main objective of the trial

To evaluate the efficacy of the regimen of irinotecan liposome injection + oxaliplatin + 5-fluorouracil (5-FU)/leucovorin (LV) [NALIRIFOX] versus nab-paclitaxel + gemcitabine in improving overall survival (OS) in participants who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas.

Protection of trial subjects

The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Council for Harmonization Good Clinical Practice and in compliance with independent ethics committees/institutional review boards and informed consent regulations. This study adhered to the United States of America Food and Drug Administration regulations and all applicable local regulations.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

11 Feb 2020

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Portugal: 10

Country: Number of subjects enrolled

Spain: 143

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Austria: 17

Country: Number of subjects enrolled

Belgium: 19

Country: Number of subjects enrolled

Czechia: 38

Country: Number of subjects enrolled

France: 50

Country: Number of subjects enrolled

Germany: 44

Country: Number of subjects enrolled

Greece: 4

Country: Number of subjects enrolled

Hungary: 18

Country: Number of subjects enrolled

Italy: 55

Country: Number of subjects enrolled

Korea, Republic of: 22

Country: Number of subjects enrolled

United States: 230

Country: Number of subjects enrolled

Canada: 12

Country: Number of subjects enrolled

Australia: 25

Country: Number of subjects enrolled

Brazil: 40

Country: Number of subjects enrolled

Israel: 5

Country: Number of subjects enrolled

Russian Federation: 25

Worldwide total number of subjects

770

EEA total number of subjects

398

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

384

From 65 to 84 years

385

85 years and over

1

Subject disposition

Top of page

Recruitment details

This Phase 3, open-label study was conducted in participants with metastatic adenocarcinoma of the pancreas at 187 investigational sites in 18 countries. First participant was recruited on 11 February 2020 and data cut-off (DCO) date 23 July 2022.

Screening details

The study had screening period (up to 28 days), treatment period: 28-day cycles until radiologically determined disease progression per RECIST Version 1.1, unacceptable treatment related toxicity/withdrawal; survival follow-up (until death/study closure). Participants were randomized in 1:1 ratio using an interactive web response system (IWRS).

Period 1 title

Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

NALIRIFOX

Arm description

Participants were treated with irinotecan liposome injection 50 milligram per square meter (mg/m^2) followed by oxaliplatin 60 mg/m^2, followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

Irinotecan liposome injection

Investigational medicinal product code

IPN60010

Other name

Onivyde®

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan liposome injection was administered as IV infusion over 90 minutes (±10 minutes).

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Eloxatin®

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered as IV infusion over 120 minutes (±10 minutes).

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

LV

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

LV was administered as IV infusion over 30 minutes (±5 minutes).

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

5-FU, Adrucil®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

5-FU was administered as IV infusion over 46-hours (±120 minutes).

Nab-paclitaxel+Gemcitabine

Arm description

Participants were treated with nab-paclitaxel 125 mg/m^2 followed by gemcitabine 1000 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Arm type

Active comparator

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane®

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel was administered as IV infusion over 35 minutes (±5 minutes).

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar®

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as IV infusion over 30 minutes (±5 minutes).

Number of subjects in period 1	NALIRIFOX	Nab-paclitaxel+Gemcitabine
Started	383	387
Received Treatment	370	379
Completed	59	77
Not completed	324	310
Consent withdrawn by subject	13	17
Death	252	277
Ongoing at the time of DCO	44	7
Lost to follow-up	1	1
Did not receive treatment	13	8
Does not meet entry criteria	1	-

Baseline characteristics

Top of page

Reporting group title

NALIRIFOX

Reporting group description

Participants were treated with irinotecan liposome injection 50 milligram per square meter (mg/m^2) followed by oxaliplatin 60 mg/m^2, followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Reporting group title

Nab-paclitaxel+Gemcitabine

Reporting group description

Participants were treated with nab-paclitaxel 125 mg/m^2 followed by gemcitabine 1000 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Reporting group values	NALIRIFOX	Nab-paclitaxel+Gemcitabine	Total
Number of subjects	383	387	770
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	62.8 ( 9.71 )	64.0 ( 8.34 )	-
Gender categorical
Units: Subjects
Female	179	157	336
Male	204	230	434
Ethnicity
Units: Subjects
Hispanic or Latino	49	30	79
Not Hispanic or Latino	305	328	633
Not Reported	29	29	58
Race
Units: Subjects
White	315	324	639
Not Reported	26	29	55
Asian	20	18	38
Black or African American	12	7	19
Other	7	6	13
Multiple	3	0	3
American Indian or Alaska Native	0	2	2
Native Hawaiian or Other Pacific Islander	0	1	1

End points

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Reporting group title

NALIRIFOX

Reporting group description

Participants were treated with irinotecan liposome injection 50 milligram per square meter (mg/m^2) followed by oxaliplatin 60 mg/m^2, followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Reporting group title

Nab-paclitaxel+Gemcitabine

Reporting group description

Participants were treated with nab-paclitaxel 125 mg/m^2 followed by gemcitabine 1000 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Primary: OS

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End point title

OS

End point description

The OS was defined as time from the date of randomization to the date of death due to any cause. Participants who did not have a date of death recorded at the time of the final analysis were censored at the last known time that the participant was alive. The median OS was measured using Kaplan-Meier technique. The Intent-to-Treat (ITT) population consisted of all randomized participants to whom study treatment was assigned by randomization.

End point type

Primary

End point timeframe

Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter up to DCO date of 23 July 2022 (maximum of 893 days)

End point values	NALIRIFOX	Nab-paclitaxel+Gemcitabine
Number of subjects analysed	383	387
Units: months
median (confidence interval 95%)	11.1 (10.0 to 12.1)	9.2 (8.3 to 10.6)

Treatment difference in OS

Comparison groups

NALIRIFOX v Nab-paclitaxel+Gemcitabine

Number of subjects included in analysis

770

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.04

Method

Stratified log-rank test

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

0.99

Notes
[1] - The HR and 95% confidence interval (CI) was based on a stratified Cox proportional hazards regression model, stratified by baseline Eastern Cooperative Oncology Group (ECOG) performance status, region and liver metastases as per IWRS.

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

PFS was defined as the time from the date of randomization to the first documented disease progression using response evaluation criteria in solid tumors (RECIST Version 1.1) as per Investigator assessment or death due to any cause. The median PFS was measured using Kaplan-Meier technique. The ITT population consisted of all randomized participants to whom study treatment was assigned by randomization. Only participants with PFS event are reported.

End point type

Secondary

End point timeframe

Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose until EoT visit (maximum of 893 days)

End point values	NALIRIFOX	Nab-paclitaxel+Gemcitabine
Number of subjects analysed	249	259
Units: months
median (confidence interval 95%)	7.4 (6.0 to 7.7)	5.6 (5.3 to 5.8)

Treatment difference in PFS

Comparison groups

NALIRIFOX v Nab-paclitaxel+Gemcitabine

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

< 0.0001

Method

Stratified log-rank test

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

0.83

Notes
[2] - The HR and 95% CI was based on a stratified Cox proportional hazards regression model, stratified by baseline ECOG performance status, region and liver metastases as per IWRS.

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

The ORR was defined as the percentage of participants with a best overall response (BOR) characterized as either a complete response or partial response per RECIST Version 1.1. BOR was defined as the best response as recorded from randomization until documented objective disease progression using RECIST Version 1.1. The ORR was calculated using Clopper-Pearson method. The ITT population consisted of all randomized participants to whom study treatment was assigned by randomization.

End point type

Secondary

End point timeframe

Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose until EoT visit (maximum of 893 days)

End point values	NALIRIFOX	Nab-paclitaxel+Gemcitabine
Number of subjects analysed	383	387
Units: percentage of participants
number (confidence interval 95%)	41.8 (36.8 to 46.9)	36.2 (31.4 to 41.2)

Comparison of odds ratio (OR)

Comparison groups

NALIRIFOX v Nab-paclitaxel+Gemcitabine

Number of subjects included in analysis

770

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.1131

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.69

Notes
[3] - OR, 95% CI and p-value were obtained from the Cochran-Mantel-Haenszel test adjusting by baseline ECOG performance status, region and liver metastases as per IWRS.

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment-emergent adverse events are reported from the time of first study treatment administration (Day 1) up to DCO date of 23 July 2022 (maximum of 893 days)

Adverse event reporting additional description

The Safety population was a subset of the ITT population that received at least 1 dose (including a partial dose) of any component of the study medication in the combination.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

NALIRIFOX

Reporting group description

Participants were treated with irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2, followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Reporting group title

Nab-paclitaxel+Gemcitabine

Reporting group description

Participants were treated with nab-paclitaxel 125 mg/m^2 followed by gemcitabine 1000 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Serious adverse events	NALIRIFOX	Nab-paclitaxel+Gemcitabine
Total subjects affected by serious adverse events
subjects affected / exposed	201 / 370 (54.32%)	195 / 379 (51.45%)
number of deaths (all causes)	252	277
number of deaths resulting from adverse events	22	23
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Peritumoural oedema
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Tumour pain
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	4 / 370 (1.08%)	8 / 379 (2.11%)
occurrences causally related to treatment / all	1 / 4	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 370 (0.27%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Embolism arterial
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 370 (0.00%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Hypertension
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 370 (0.54%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Iliac vein occlusion
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral embolism
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	7 / 370 (1.89%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	3 / 7	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site inflammation
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Condition aggravated
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Fatigue
subjects affected / exposed	7 / 370 (1.89%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	4 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 370 (0.27%)	6 / 379 (1.58%)
occurrences causally related to treatment / all	1 / 1	3 / 6
deaths causally related to treatment / all	1 / 1	1 / 1
Generalised oedema
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inadequate analgesia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inflammation
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	3 / 370 (0.81%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 370 (0.00%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	8 / 370 (2.16%)	12 / 379 (3.17%)
occurrences causally related to treatment / all	1 / 9	4 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sudden death
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Reproductive system and breast disorders
Penile vein thrombosis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Priapism
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspiration
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	2 / 370 (0.54%)	5 / 379 (1.32%)
occurrences causally related to treatment / all	0 / 2	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 370 (0.54%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Pneumonitis aspiration
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Productive cough
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	10 / 370 (2.70%)	7 / 379 (1.85%)
occurrences causally related to treatment / all	3 / 10	1 / 7
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 370 (0.27%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Thrombosis in device
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	5 / 370 (1.35%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	1 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood glucose abnormal
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	2 / 370 (0.54%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SARS-CoV-2 test positive
subjects affected / exposed	1 / 370 (0.27%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Exposure to SARS-CoV-2
subjects affected / exposed	0 / 370 (0.00%)	4 / 379 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hip fracture
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 370 (0.00%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Cardiac failure
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac flutter
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 370 (1.08%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 4	1 / 2
deaths causally related to treatment / all	0 / 2	0 / 0
Embolic stroke
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	4 / 370 (1.08%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	1 / 4	0 / 2
deaths causally related to treatment / all	1 / 2	0 / 0
Metabolic encephalopathy
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myoclonus
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pineal gland cyst
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tremor
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 370 (1.35%)	8 / 379 (2.11%)
occurrences causally related to treatment / all	4 / 6	7 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Febrile neutropenia
subjects affected / exposed	7 / 370 (1.89%)	6 / 379 (1.58%)
occurrences causally related to treatment / all	7 / 9	6 / 6
deaths causally related to treatment / all	1 / 1	1 / 1
Neutropenia
subjects affected / exposed	2 / 370 (0.54%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal vein occlusion
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	9 / 370 (2.43%)	8 / 379 (2.11%)
occurrences causally related to treatment / all	2 / 10	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	6 / 370 (1.62%)	5 / 379 (1.32%)
occurrences causally related to treatment / all	0 / 7	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 0
Colitis
subjects affected / exposed	7 / 370 (1.89%)	4 / 379 (1.06%)
occurrences causally related to treatment / all	6 / 7	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 370 (0.27%)	6 / 379 (1.58%)
occurrences causally related to treatment / all	0 / 1	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	23 / 370 (6.22%)	9 / 379 (2.37%)
occurrences causally related to treatment / all	22 / 28	6 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal obstruction
subjects affected / exposed	2 / 370 (0.54%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal stenosis
subjects affected / exposed	2 / 370 (0.54%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	3 / 370 (0.81%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer perforation
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric fistula
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 370 (0.81%)	4 / 379 (1.06%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	3 / 370 (0.81%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	3 / 370 (0.81%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal pseudo-obstruction
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mesenteric vein thrombosis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	18 / 370 (4.86%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	15 / 24	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	2 / 370 (0.54%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 370 (0.27%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Terminal ileitis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 370 (0.27%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	22 / 370 (5.95%)	6 / 379 (1.58%)
occurrences causally related to treatment / all	15 / 26	4 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	6 / 370 (1.62%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	4 / 370 (1.08%)	6 / 379 (1.58%)
occurrences causally related to treatment / all	1 / 4	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Cholecystitis
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	1 / 370 (0.27%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	2 / 370 (0.54%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Decubitus ulcer
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pruritus
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 370 (0.81%)	9 / 379 (2.37%)
occurrences causally related to treatment / all	2 / 3	5 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 370 (0.00%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Renal impairment
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest wall haematoma
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asymptomatic COVID-19
subjects affected / exposed	0 / 370 (0.00%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	2 / 370 (0.54%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	18 / 370 (4.86%)	14 / 379 (3.69%)
occurrences causally related to treatment / all	0 / 18	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 1
COVID-19 pneumonia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter colitis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 370 (0.00%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis infective
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related bacteraemia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal infection
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 370 (0.27%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder abscess
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 370 (0.81%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic infection
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis E
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Implant site cellulitis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infective spondylitis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine infection
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	7 / 370 (1.89%)	13 / 379 (3.43%)
occurrences causally related to treatment / all	0 / 7	3 / 13
deaths causally related to treatment / all	0 / 2	0 / 3
Pneumonia aspiration
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Post procedural cellulitis
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	6 / 370 (1.62%)	16 / 379 (4.22%)
occurrences causally related to treatment / all	4 / 6	9 / 18
deaths causally related to treatment / all	1 / 2	5 / 8
Septic shock
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suspected COVID-19
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 370 (0.81%)	4 / 379 (1.06%)
occurrences causally related to treatment / all	2 / 3	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Adult failure to thrive
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	5 / 370 (1.35%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	2 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	10 / 370 (2.70%)	4 / 379 (1.06%)
occurrences causally related to treatment / all	8 / 11	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 370 (0.00%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 370 (0.00%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 370 (0.27%)	4 / 379 (1.06%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	6 / 370 (1.62%)	3 / 379 (0.79%)
occurrences causally related to treatment / all	4 / 7	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 370 (0.27%)	2 / 379 (0.53%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 370 (0.27%)	1 / 379 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 370 (0.27%)	0 / 379 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	NALIRIFOX	Nab-paclitaxel+Gemcitabine
Total subjects affected by non serious adverse events
subjects affected / exposed	364 / 370 (98.38%)	371 / 379 (97.89%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	45 / 370 (12.16%)	48 / 379 (12.66%)
occurrences all number	64	64
Aspartate aminotransferase increased
subjects affected / exposed	40 / 370 (10.81%)	40 / 379 (10.55%)
occurrences all number	58	55
Blood alkaline phosphatase increased
subjects affected / exposed	39 / 370 (10.54%)	31 / 379 (8.18%)
occurrences all number	42	33
Blood bilirubin increased
subjects affected / exposed	21 / 370 (5.68%)	22 / 379 (5.80%)
occurrences all number	23	23
Gamma-glutamyltransferase increased
subjects affected / exposed	44 / 370 (11.89%)	34 / 379 (8.97%)
occurrences all number	54	35
Neutrophil count decreased
subjects affected / exposed	73 / 370 (19.73%)	69 / 379 (18.21%)
occurrences all number	208	112
Platelet count decreased
subjects affected / exposed	39 / 370 (10.54%)	67 / 379 (17.68%)
occurrences all number	71	109
Weight decreased
subjects affected / exposed	82 / 370 (22.16%)	33 / 379 (8.71%)
occurrences all number	92	34
White blood cell count decreased
subjects affected / exposed	16 / 370 (4.32%)	32 / 379 (8.44%)
occurrences all number	24	54
Vascular disorders
Hypertension
subjects affected / exposed	21 / 370 (5.68%)	15 / 379 (3.96%)
occurrences all number	24	19
Hypotension
subjects affected / exposed	21 / 370 (5.68%)	25 / 379 (6.60%)
occurrences all number	27	26
Nervous system disorders
Dizziness
subjects affected / exposed	24 / 370 (6.49%)	40 / 379 (10.55%)
occurrences all number	25	44
Dysgeusia
subjects affected / exposed	63 / 370 (17.03%)	58 / 379 (15.30%)
occurrences all number	74	67
Headache
subjects affected / exposed	23 / 370 (6.22%)	19 / 379 (5.01%)
occurrences all number	37	24
Neuropathy peripheral
subjects affected / exposed	66 / 370 (17.84%)	66 / 379 (17.41%)
occurrences all number	89	92
Neurotoxicity
subjects affected / exposed	21 / 370 (5.68%)	13 / 379 (3.43%)
occurrences all number	35	22
Paraesthesia
subjects affected / exposed	44 / 370 (11.89%)	33 / 379 (8.71%)
occurrences all number	53	41
Peripheral sensory neuropathy
subjects affected / exposed	56 / 370 (15.14%)	51 / 379 (13.46%)
occurrences all number	79	60
Polyneuropathy
subjects affected / exposed	16 / 370 (4.32%)	19 / 379 (5.01%)
occurrences all number	19	20
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	94 / 370 (25.41%)	151 / 379 (39.84%)
occurrences all number	134	196
Leukopenia
subjects affected / exposed	18 / 370 (4.86%)	40 / 379 (10.55%)
occurrences all number	24	43
Neutropenia
subjects affected / exposed	108 / 370 (29.19%)	121 / 379 (31.93%)
occurrences all number	264	278
Thrombocytopenia
subjects affected / exposed	50 / 370 (13.51%)	93 / 379 (24.54%)
occurrences all number	84	173
General disorders and administration site conditions
Asthenia
subjects affected / exposed	110 / 370 (29.73%)	101 / 379 (26.65%)
occurrences all number	164	166
Chills
subjects affected / exposed	6 / 370 (1.62%)	19 / 379 (5.01%)
occurrences all number	6	20
Fatigue
subjects affected / exposed	120 / 370 (32.43%)	143 / 379 (37.73%)
occurrences all number	173	183
Mucosal inflammation
subjects affected / exposed	50 / 370 (13.51%)	16 / 379 (4.22%)
occurrences all number	60	20
Oedema peripheral
subjects affected / exposed	52 / 370 (14.05%)	107 / 379 (28.23%)
occurrences all number	60	134
Pyrexia
subjects affected / exposed	33 / 370 (8.92%)	84 / 379 (22.16%)
occurrences all number	43	129
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	22 / 370 (5.95%)	13 / 379 (3.43%)
occurrences all number	26	15
Abdominal pain
subjects affected / exposed	92 / 370 (24.86%)	75 / 379 (19.79%)
occurrences all number	110	80
Abdominal pain upper
subjects affected / exposed	27 / 370 (7.30%)	21 / 379 (5.54%)
occurrences all number	34	29
Constipation
subjects affected / exposed	93 / 370 (25.14%)	113 / 379 (29.82%)
occurrences all number	115	141
Diarrhoea
subjects affected / exposed	258 / 370 (69.73%)	135 / 379 (35.62%)
occurrences all number	566	221
Dry mouth
subjects affected / exposed	28 / 370 (7.57%)	14 / 379 (3.69%)
occurrences all number	29	16
Dyspepsia
subjects affected / exposed	23 / 370 (6.22%)	18 / 379 (4.75%)
occurrences all number	32	20
Flatulence
subjects affected / exposed	30 / 370 (8.11%)	18 / 379 (4.75%)
occurrences all number	33	21
Haemorrhoids
subjects affected / exposed	19 / 370 (5.14%)	12 / 379 (3.17%)
occurrences all number	22	13
Nausea
subjects affected / exposed	215 / 370 (58.11%)	162 / 379 (42.74%)
occurrences all number	406	216
Stomatitis
subjects affected / exposed	50 / 370 (13.51%)	45 / 379 (11.87%)
occurrences all number	81	54
Vomiting
subjects affected / exposed	139 / 370 (37.57%)	96 / 379 (25.33%)
occurrences all number	222	168
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	14 / 370 (3.78%)	30 / 379 (7.92%)
occurrences all number	18	31
Dyspnoea
subjects affected / exposed	24 / 370 (6.49%)	45 / 379 (11.87%)
occurrences all number	28	48
Epistaxis
subjects affected / exposed	14 / 370 (3.78%)	43 / 379 (11.35%)
occurrences all number	15	49
Pulmonary embolism
subjects affected / exposed	20 / 370 (5.41%)	24 / 379 (6.33%)
occurrences all number	20	24
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	52 / 370 (14.05%)	119 / 379 (31.40%)
occurrences all number	53	120
Pruritus
subjects affected / exposed	12 / 370 (3.24%)	22 / 379 (5.80%)
occurrences all number	14	26
Rash
subjects affected / exposed	11 / 370 (2.97%)	34 / 379 (8.97%)
occurrences all number	12	37
Rash maculo-papular
subjects affected / exposed	3 / 370 (0.81%)	25 / 379 (6.60%)
occurrences all number	3	30
Psychiatric disorders
Anxiety
subjects affected / exposed	10 / 370 (2.70%)	24 / 379 (6.33%)
occurrences all number	10	25
Insomnia
subjects affected / exposed	28 / 370 (7.57%)	32 / 379 (8.44%)
occurrences all number	28	32
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	13 / 370 (3.51%)	30 / 379 (7.92%)
occurrences all number	16	41
Back pain
subjects affected / exposed	28 / 370 (7.57%)	33 / 379 (8.71%)
occurrences all number	37	36
Muscular weakness
subjects affected / exposed	17 / 370 (4.59%)	21 / 379 (5.54%)
occurrences all number	22	24
Myalgia
subjects affected / exposed	13 / 370 (3.51%)	31 / 379 (8.18%)
occurrences all number	15	43
Pain in extremity
subjects affected / exposed	7 / 370 (1.89%)	30 / 379 (7.92%)
occurrences all number	8	35
Infections and infestations
Urinary tract infection
subjects affected / exposed	27 / 370 (7.30%)	23 / 379 (6.07%)
occurrences all number	29	29
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	132 / 370 (35.68%)	68 / 379 (17.94%)
occurrences all number	157	136
Dehydration
subjects affected / exposed	35 / 370 (9.46%)	29 / 379 (7.65%)
occurrences all number	40	31
Hypoalbuminaemia
subjects affected / exposed	26 / 370 (7.03%)	30 / 379 (7.92%)
occurrences all number	33	31
Hypokalaemia
subjects affected / exposed	116 / 370 (31.35%)	49 / 379 (12.93%)
occurrences all number	190	70
Hypomagnesaemia
subjects affected / exposed	34 / 370 (9.19%)	16 / 379 (4.22%)
occurrences all number	44	22
Hyponatraemia
subjects affected / exposed	18 / 370 (4.86%)	20 / 379 (5.28%)
occurrences all number	21	21

More information

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Were there any global substantial amendments to the protocol? Yes

28 Nov 2019

The study name was updated with the branding logo. Study duration was clarified. Adverse event causality assessment clarified by the investigator. Adverse events of special interest were defined as thromboembolic disease. Collection of electronic serious adverse events (SAE) were clarified. Clarification that disease progression was not classified as an SAE. The use of contraceptive were aligned with all packaging information in all localities of the study. Minor editorial changes to provide additional details.

03 Jun 2020

The electrocardiogram assessment timepoint were clarified.

19 Aug 2021

Eligibility criterion and protocol procedures were clarified. Details specific to conduct of the study during the COVID-19 pandemic were added. Secondary endpoint analysis was updated to refine the interim analysis of OS.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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