A Study Comparing Trametinib and Dabrafenib Combination T... | NCT01584648

ID	Type	Description	Link
2011-006087-49	EudraCT Number
CDRB436B2301	Other Identifier	Novartis

Status Module

Oversight Module

Description Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dabrafenib + Trametinib	Experimental	Dabrafenib and Trametinib combination	Drug: Dabrafenib Drug: Trametinib
Dabrafenib + Placebo	Active Comparator	Dabrafenib and Trametinib placebo	Drug: Dabrafenib Drug: Trametinib placebo

Name	Type	Description	Arm Group Labels	Other Names
Dabrafenib	Drug	Dabrafenib 150 mg twice daily	Dabrafenib + Placebo Dabrafenib + Trametinib

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Progression-Free Survival (PFS) as Assessed by the Investigator	PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.	From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)

Secondary Outcomes

Measure	Description	Time Frame
Overall Survival (OS)	OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.	From the date of randomization until date of death due to any cause (up to approximately 6 years)

Eligibility Module

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Scottsdale	Arizona	85258	United States
Novartis Investigative Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
34225229	Derived	Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
33587894	Derived

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
BG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00055.1± 13.33 BG00155.3± 13.75 BG00255.2± 13.52

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000100 BG00198 BG002

Race/Ethnicity, Customized

Number

Participants

Title

Denominators

Categories

African American/African Heritage

Title	Measurements
	BG0000 BG0011 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Progression-Free Survival (PFS) as Assessed by the Investigator

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.

Intent-to-Treat (ITT) Population was considered.

Posted

Median

95% Confidence Interval

Months

From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Units	Counts
Participants	OG000211 OG001212

Title

Denominators

Categories

Title	Measurements
	OG00010.2(8.1 to 12.8) OG0018.8(5.9 to 9.3)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001						Hazard Ratio (HR)	0.73			2-Sided	95	0.59	0.91			Hazard ratios (HRs) were estimated using a Pike estimator.		Superiority or Other (legacy)

Secondary

Overall Survival (OS)

OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.

Intent-to-Treat (ITT) Population was considered.

Posted

Median

95% Confidence Interval

Months

From the date of randomization until date of death due to any cause (up to approximately 6 years)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Secondary

Objective Response Rate (ORR) as Assessed by the Investigator

ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm). Only descriptive analysis performed.

Intent-to-Treat (ITT) Population was considered. Only participants with measurable disease at Baseline per RECIST were analyzed.

Posted

Count of Participants

Participants

From randomization until the first documented complete response or partial response (up to approximately 6 years)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo

Secondary

Duration of Response (DoR)

Duration of response is defined as the time from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator. Only descriptive analysis performed.

ITT population. Only those participants with a confirmed CR or PR were analyzed (with or without measurabe disease at Baseline).

Posted

Median

95% Confidence Interval

Months

From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.

Secondary

Trametinib Pharmacokinetic Concentrations

Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Only descriptive analysis performed.

Pharmacokinetic (PK) Population: all participants included in the safety population for whom a PK sample was obtained and analyzed. Only participants with data available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Nanogram per Milliliter (ng/mL)

Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Secondary

Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations

Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of Dabrafenib (GSK2118436) and its metabolites (Hydroxy-Dabrafenib (GSK2285403), Carboxy-Dabrafenib (GSK2298683), and Desmethyl-Dabrafenib (GSK2167542)) were determined using the currently approved analytical methodology. Only descriptive analysis performed.

PK Population.

Posted

Mean

Standard Deviation

Nanogram per Milliliter (ng/mL)

Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Secondary

Number of Participants With Adverse Events and Serious Adverse Events

Analysis of absolute and relative frequencies for Adverse Event (AE) and Serious Adverse Event (SAE) by primary System Organ Class (SOC) to characterize the safety of dabrafenib and trametinib combination therapy through the monitoring of relevant clinical and laboratory safety parameters. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment. Only descriptive analysis performed.

Safety Population: all randomized participants who received at least one dose of study medication and were based on the actual treatment received if this differed from that to which the participant was randomized.

Posted

Count of Participants

Participants

From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (up to approximately 6 years).

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Post-Hoc

All Collected Deaths

Pre-treatment deaths were collected from screening visit up to the first day of treatment, for a maximum duration of 28 days. Patients who died during the screening period are considered as screen failure.

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 77.4 months (treatment duration ranged from 0.1 to 76.4 months).

Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 6 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

Clinical database population; all treated patients and patients who died during screening.

Posted

Count of Participants

Participants

up to 28 days before Day 1 (Screening), up to 77.4 months (on-treatment), up to approximately 6 years (study duration)

ID	Title	Description
OG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.
OG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dabrafenib + Trametinib	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	135	209	100	209	194	209
EG001	Dabrafenib + Placebo	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.	146	211	80	211	200	211
EG002	Crossover Dabrafenib + Trametinib	Crossover Dabrafenib + Trametinib	5	28	8	28	23	28
EG003	All Patients	All Patients	286	420	183	420	394	420

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected209 at risk EG0013 affected211 at risk EG0020 affected28 at risk EG0038 affected420 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Haemolytic uraemic syndrome	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hypochromic anaemia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pancytopenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Acute coronary syndrome	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0012 affected211 at risk EG0021 affected28 at risk EG003
Cardiovascular insufficiency	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Myocardial infarction	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Supraventricular tachycardia	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Tachycardia	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Chorioretinopathy	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Iridocyclitis	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Uveitis	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Visual impairment	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Acute abdomen	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Colitis	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Gastrointestinal disorder	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Intestinal perforation	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Jejunal perforation	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Melaena	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pancreatitis acute	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Peritoneal haemorrhage	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Chest pain	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Chills	General disorders	MedDRA (19.0)	Systematic Assessment	EG00010 affected209 at risk EG0013 affected211 at risk EG0020 affected28 at risk EG003
Drowning	General disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Fatigue	General disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
General physical health deterioration	General disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Influenza like illness	General disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Malaise	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Pyrexia	General disorders	MedDRA (19.0)	Systematic Assessment	EG00036 affected209 at risk EG00115 affected211 at risk EG0022 affected28 at risk EG003
Cholecystitis	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Hepatic haematoma	Hepatobiliary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Contrast media allergy	Immune system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Bacteraemia	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Cellulitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Clostridium difficile colitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Cystitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Diverticulitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Febrile infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Herpes zoster	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Kidney infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Laryngitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Neutropenic sepsis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Peritonitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Pneumonia	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Pseudomonas infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pyelonephritis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Sepsis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Septic shock	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Staphylococcal sepsis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Superinfection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Urosepsis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Humerus fracture	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Joint dislocation	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Ligament rupture	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Ligament sprain	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Meniscus injury	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Post procedural persistent drain fluid	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Radius fracture	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Subarachnoid haemorrhage	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Upper limb fracture	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Ejection fraction decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG00013 affected209 at risk EG0015 affected211 at risk EG0021 affected28 at risk EG003
Forced expiratory volume decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Haemoglobin decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hepatic enzyme increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Neutrophil count decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Oxygen saturation decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Renal function test abnormal	Investigations	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Transaminases increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
White blood cell count decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0012 affected211 at risk EG0021 affected28 at risk EG003
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0021 affected28 at risk EG003
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Type 2 diabetes mellitus	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Compartment syndrome	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Haemarthrosis	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hypercreatinaemia	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Immunoglobulin G4 related disease	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Intervertebral disc degeneration	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Muscle haemorrhage	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Adenocarcinoma gastric	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0008 affected209 at risk EG00114 affected211 at risk EG0020 affected28 at risk EG003
Bile duct adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Bowen's disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0012 affected211 at risk EG0021 affected28 at risk EG003
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Hodgkin's disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Invasive ductal breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Keratoacanthoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Lipofibroma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Malignant melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Osteosarcoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Papillary thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Phaeochromocytoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Schwannoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0017 affected211 at risk EG0021 affected28 at risk EG003
Squamous cell carcinoma of skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG00115 affected211 at risk EG0021 affected28 at risk EG003
Superficial spreading melanoma stage unspecified	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Aphasia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Brain oedema	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Central nervous system lesion	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Cerebral haemorrhage	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Cerebral infarction	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Cerebrovascular accident	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Dizziness	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Epilepsy	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Facial paralysis	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hemiplegia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Nervous system disorder	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Presyncope	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Sciatica	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Seizure	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Syncope	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Tremor	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Confusional state	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Delirium	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Mania	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Organic brain syndrome	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Azotaemia	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Hydronephrosis	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Nephritis	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pelvi-ureteric obstruction	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Renal colic	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Renal failure	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Urinary retention	Renal and urinary disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Uterine prolapse	Reproductive system and breast disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0010 affected211 at risk EG0021 affected28 at risk EG003
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Nasal polyps	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Respiratory depression	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Dermatitis allergic	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Dermatosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hyperkeratosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Skin lesion	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Skin ulcer	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Hypertension	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0010 affected211 at risk EG0020 affected28 at risk EG003
Hypotension	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG0012 affected211 at risk EG0021 affected28 at risk EG003
Hypovolaemic shock	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Peripheral ischaemia	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003
Thrombophlebitis superficial	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0020 affected28 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG00016 affected209 at risk EG00122 affected211 at risk EG0023 affected28 at risk EG00338 affected420 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0007 affected209 at risk EG0011 affected211 at risk EG0022 affected28 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG00020 affected209 at risk EG0015 affected211 at risk EG0023 affected28 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (19.0)	Systematic Assessment	EG0009 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Tachycardia	Cardiac disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG00113 affected211 at risk EG0023 affected28 at risk EG003
Tinnitus	Ear and labyrinth disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected209 at risk EG0012 affected211 at risk EG0023 affected28 at risk EG003
Hypothyroidism	Endocrine disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Blepharitis	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0010 affected211 at risk EG0022 affected28 at risk EG003
Cataract	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG0014 affected211 at risk EG0023 affected28 at risk EG003
Dry eye	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG00011 affected209 at risk EG0014 affected211 at risk EG0021 affected28 at risk EG003
Vision blurred	Eye disorders	MedDRA (19.0)	Systematic Assessment	EG00010 affected209 at risk EG0015 affected211 at risk EG0023 affected28 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00029 affected209 at risk EG00117 affected211 at risk EG0021 affected28 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00020 affected209 at risk EG00112 affected211 at risk EG0023 affected28 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00027 affected209 at risk EG00122 affected211 at risk EG0023 affected28 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00067 affected209 at risk EG00134 affected211 at risk EG0029 affected28 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00018 affected209 at risk EG0016 affected211 at risk EG0021 affected28 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00079 affected209 at risk EG00157 affected211 at risk EG0027 affected28 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00057 affected209 at risk EG00131 affected211 at risk EG0023 affected28 at risk EG003
Asthenia	General disorders	MedDRA (19.0)	Systematic Assessment	EG00029 affected209 at risk EG00130 affected211 at risk EG0024 affected28 at risk EG003
Chest pain	General disorders	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG0015 affected211 at risk EG0020 affected28 at risk EG003
Chills	General disorders	MedDRA (19.0)	Systematic Assessment	EG00063 affected209 at risk EG00134 affected211 at risk EG0023 affected28 at risk EG003
Fatigue	General disorders	MedDRA (19.0)	Systematic Assessment	EG00079 affected209 at risk EG00179 affected211 at risk EG0027 affected28 at risk EG003
Influenza like illness	General disorders	MedDRA (19.0)	Systematic Assessment	EG00017 affected209 at risk EG00112 affected211 at risk EG0023 affected28 at risk EG003
Oedema peripheral	General disorders	MedDRA (19.0)	Systematic Assessment	EG00048 affected209 at risk EG00117 affected211 at risk EG0022 affected28 at risk EG003
Pain	General disorders	MedDRA (19.0)	Systematic Assessment	EG00014 affected209 at risk EG0019 affected211 at risk EG0021 affected28 at risk EG003
Pyrexia	General disorders	MedDRA (19.0)	Systematic Assessment	EG000118 affected209 at risk EG00163 affected211 at risk EG00210 affected28 at risk EG003
Hypersensitivity	Immune system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Bronchitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG0018 affected211 at risk EG0021 affected28 at risk EG003
Cystitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00011 affected209 at risk EG0012 affected211 at risk EG0020 affected28 at risk EG003
Folliculitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG00111 affected211 at risk EG0022 affected28 at risk EG003
Influenza	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00017 affected209 at risk EG0017 affected211 at risk EG0025 affected28 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00028 affected209 at risk EG00121 affected211 at risk EG0024 affected28 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00016 affected209 at risk EG0017 affected211 at risk EG0021 affected28 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG00029 affected209 at risk EG0017 affected211 at risk EG0022 affected28 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Tendon rupture	Injury, poisoning and procedural complications	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG0011 affected211 at risk EG0022 affected28 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG00025 affected209 at risk EG00112 affected211 at risk EG0021 affected28 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG00029 affected209 at risk EG0018 affected211 at risk EG0020 affected28 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG00018 affected209 at risk EG0018 affected211 at risk EG0023 affected28 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0008 affected209 at risk EG0010 affected211 at risk EG0022 affected28 at risk EG003
Blood creatinine increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0008 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Blood lactate dehydrogenase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0008 affected209 at risk EG0012 affected211 at risk EG0022 affected28 at risk EG003
Ejection fraction decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0007 affected209 at risk EG0012 affected211 at risk EG0023 affected28 at risk EG003
Gamma-glutamyltransferase increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG0015 affected211 at risk EG0024 affected28 at risk EG003
Neutrophil count decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0007 affected209 at risk EG0010 affected211 at risk EG0022 affected28 at risk EG003
Weight decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG00013 affected209 at risk EG00119 affected211 at risk EG0020 affected28 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG00030 affected209 at risk EG00128 affected211 at risk EG0025 affected28 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected209 at risk EG0011 affected211 at risk EG0022 affected28 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00057 affected209 at risk EG00168 affected211 at risk EG0026 affected28 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00030 affected209 at risk EG00134 affected211 at risk EG0023 affected28 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00019 affected209 at risk EG0017 affected211 at risk EG0023 affected28 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected209 at risk EG0014 affected211 at risk EG0022 affected28 at risk EG003
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00014 affected209 at risk EG00111 affected211 at risk EG0020 affected28 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG00119 affected211 at risk EG0021 affected28 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00027 affected209 at risk EG00128 affected211 at risk EG0023 affected28 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00034 affected209 at risk EG00138 affected211 at risk EG0023 affected28 at risk EG003
Melanocytic naevus	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0002 affected209 at risk EG00116 affected211 at risk EG0020 affected28 at risk EG003
Seborrhoeic keratosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG00122 affected211 at risk EG0020 affected28 at risk EG003
Skin papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG00146 affected211 at risk EG0021 affected28 at risk EG003
Dizziness	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG00032 affected209 at risk EG00115 affected211 at risk EG0021 affected28 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected209 at risk EG00113 affected211 at risk EG0022 affected28 at risk EG003
Headache	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG00071 affected209 at risk EG00163 affected211 at risk EG0026 affected28 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0009 affected209 at risk EG00112 affected211 at risk EG0021 affected28 at risk EG003
Anxiety	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG0016 affected211 at risk EG0023 affected28 at risk EG003
Depression	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0009 affected209 at risk EG00112 affected211 at risk EG0021 affected28 at risk EG003
Insomnia	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG00011 affected209 at risk EG00118 affected211 at risk EG0021 affected28 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG00051 affected209 at risk EG00146 affected211 at risk EG0023 affected28 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG00016 affected209 at risk EG00119 affected211 at risk EG0021 affected28 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG00021 affected209 at risk EG00111 affected211 at risk EG0021 affected28 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (19.0)	Systematic Assessment	EG00024 affected209 at risk EG00111 affected211 at risk EG0020 affected28 at risk EG003
Actinic keratosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG00115 affected211 at risk EG0021 affected28 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00019 affected209 at risk EG00161 affected211 at risk EG0020 affected28 at risk EG003
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00021 affected209 at risk EG0018 affected211 at risk EG0020 affected28 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00030 affected209 at risk EG00133 affected211 at risk EG0023 affected28 at risk EG003
Eczema	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00019 affected209 at risk EG0018 affected211 at risk EG0022 affected28 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00024 affected209 at risk EG00116 affected211 at risk EG0021 affected28 at risk EG003
Hair texture abnormal	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected209 at risk EG00118 affected211 at risk EG0020 affected28 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00014 affected209 at risk EG0019 affected211 at risk EG0021 affected28 at risk EG003
Hyperkeratosis	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00018 affected209 at risk EG00179 affected211 at risk EG0023 affected28 at risk EG003
Night sweats	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00012 affected209 at risk EG0015 affected211 at risk EG0021 affected28 at risk EG003
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00011 affected209 at risk EG00139 affected211 at risk EG0022 affected28 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00028 affected209 at risk EG00130 affected211 at risk EG0022 affected28 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00062 affected209 at risk EG00145 affected211 at risk EG0023 affected28 at risk EG003
Rash maculo-papular	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00013 affected209 at risk EG0018 affected211 at risk EG0023 affected28 at risk EG003
Skin lesion	Skin and subcutaneous tissue disorders	MedDRA (19.0)	Systematic Assessment	EG00013 affected209 at risk EG00110 affected211 at risk EG0020 affected28 at risk EG003
Hot flush	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG0008 affected209 at risk EG0015 affected211 at risk EG0022 affected28 at risk EG003
Hypertension	Vascular disorders	MedDRA (19.0)	Systematic Assessment	EG00051 affected209 at risk EG00133 affected211 at risk EG0022 affected28 at risk EG003

Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

ID	Term
D018358	Neuroendocrine Tumors
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D009380	Neoplasms, Nerve Tissue
D018326	Nevi and Melanomas
D012878	Skin Neoplasms
D009371	Neoplasms by Site
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases