Study of Romosozumab (AMG 785) in Tibial Diaphyseal Fract... | NCT00907296

NCT00907296

ID	Type	Description	Link
2008-008392-34	EudraCT Number

Status Module

Name	Class
UCB Pharma	INDUSTRY

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
Placebo	Placebo Comparator	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.	Drug: Placebo
Romosozumab 70 mg: 2 Doses	Experimental	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.	Biological: Romosozumab
Romosozumab 70 mg: 3 Doses	Experimental	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.	Biological: Romosozumab
Romosozumab 70 mg: 4 Doses	Experimental	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2, 6, and 12.	Biological: Romosozumab
Romosozumab 140 mg: 2 Doses	Experimental	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.	Biological: Romosozumab

Name	Type	Description	Arm Group Labels	Other Names
Romosozumab	Biological	Administered by subcutaneous injection	Romosozumab 140 mg: 2 Doses Romosozumab 140 mg: 3 Doses Romosozumab 140 mg: 4 Doses

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Time to Radiographic Healing	Time to radiographic healing was defined as the time from intramedullary (IM) nailing to the first occurrence of bridging of 3 out of 4 cortices. Radiographic fracture healing was determined by a panel of independent reviewers (orthopedic/trauma surgeons and radiologists) blinded to treatment. The cumulative incidence function (CIF) method was used to estimate the median time to radiographic healing and the confidence intervals. Unplanned revision surgery to promote healing was considered a competing risk in CIF estimate.	52 weeks

Secondary Outcomes

Measure	Description	Time Frame
Change From Week 8 in Short Form (36) Health Survey Physical Functioning Domain	The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2, is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical functioning domain includes 10 questions that assess limitations in physical activities because of health problems. Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. The range of SF-36 physical functioning is 14.94 - 57.03. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement in physical functioning.

Eligibility Module

Name	Affiliation	Role
MD	Amgen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Birmingham	Alabama	35294	United States
Research Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
32358413	Background	Bhandari M, Schemitsch EH, Karachalios T, Sancheti P, Poolman RW, Caminis J, Daizadeh N, Dent-Acosta RE, Egbuna O, Chines A, Miclau T. Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study. J Bone Joint Surg Am. 2020 Aug 19;102(16):1416-1426. doi: 10.2106/JBJS.19.01008.

Label	URL
AmgenTrials clinical trials website	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.
FG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.
BG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
BG002	Romosozumab 70 mg: 3 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
BG003	Romosozumab 70 mg: 4 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2, 6, and 12.
BG004	Romosozumab 140 mg: 2 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
BG005	Romosozumab 140 mg: 3 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
BG006	Romosozumab 140 mg: 4 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2, 6, and 12.
BG007	Romosozumab 210 mg: 2 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
BG008	Romosozumab 210 mg: 3 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
BG009	Romosozumab 210 mg: 4 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2, 6, and 12.
BG010	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
	BG00040.3± 13.8 BG00138.6± 13.8 BG00243.2± 17.7 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00029 BG0017 BG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
White	BG00080 BG00120 BG002

Randomization Stratification

Randomization was stratified according to

Gustilo-Anderson System for classifying open tibial fractures:

Gustilo type I open fracture: Open tibial fracture with a puncture wound smaller than 1 cm.

Gustilo type II open fracture: Open tibial fracture with a wound of 1-10 cm.
Definitive fracture fixation: with reamed or unreamed intramedullary (IM) nailing.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Closed with reamed IM nail	BG00088 BG001

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

Time to Radiographic Healing

Time to radiographic healing was defined as the time from intramedullary (IM) nailing to the first occurrence of bridging of 3 out of 4 cortices. Radiographic fracture healing was determined by a panel of independent reviewers (orthopedic/trauma surgeons and radiologists) blinded to treatment.

The cumulative incidence function (CIF) method was used to estimate the median time to radiographic healing and the confidence intervals. Unplanned revision surgery to promote healing was considered a competing risk in CIF estimate.

Participants who received at least 1 dose of study drug.

Posted

Median

95% Confidence Interval

weeks

52 weeks

ID	Title	Description
OG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.
OG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
OG002	Romosozumab 70 mg: 3 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
OG003	Romosozumab 70 mg: 4 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2, 6, and 12.
OG004	Romosozumab 140 mg: 2 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
OG005	Romosozumab 140 mg: 3 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
OG006	Romosozumab 140 mg: 4 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2, 6, and 12.
OG007	Romosozumab 210 mg: 2 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
OG008	Romosozumab 210 mg: 3 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
OG009	Romosozumab 210 mg: 4 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2, 6, and 12.

Units	Counts
Participants	OG000100 OG00134 OG00234 OG003

Title

Denominators

Categories

Title	Measurements
	OG00016.4(14.6 to 18.0) OG00118.6(14.0 to 24.4) OG00218.3(13.0 to 21.0) OG003

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	The cause-specific hazard was modeled using a Cox proportional hazards model with 10 treatment groups as the independent variable, stratified by type of fracture and definitive fracture fixation (closed with reamed IM nail, Gustilo type I/II open with reamed IM nail, Gustilo type I/II open with unreamed IM nail) and adjusting for quality of surgical fixation.	Cox proportional hazard model		0.3598		Hazard Ratio (HR)	0.82			2-Sided	95	0.53	1.26			A hazard ratio > 1 favors romosozumab.		Superiority

Secondary

Change From Week 8 in Short Form (36) Health Survey Physical Functioning Domain

The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2, is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical functioning domain includes 10 questions that assess limitations in physical activities because of health problems.

Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. The range of SF-36 physical functioning is 14.94 - 57.03. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement in physical functioning.

Participants who received at least 1 dose of study drug and with available data at each time point.

Posted

Mean

Standard Deviation

units on a scale

Week 8 and weeks 12, 16, 20, 24, 36, and 52

ID	Title	Description
OG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.
OG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.

Secondary

Number of Participants With Unplanned Revision Surgeries

Participants who received at least 1 dose of study drug

Posted

Count of Participants

Participants

52 weeks

ID	Title	Description
OG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.
OG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.
OG002	Romosozumab 70 mg: 3 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.
OG003	Romosozumab 70 mg: 4 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2, 6, and 12.
OG004	Romosozumab 140 mg: 2 Doses

Secondary

Time to Clinical Healing

Time to clinical healing was defined as the time from the IM nailing surgery date to the first date that both the score for ability to bear weight on the fractured limb and the score for absence of pain at the fracture site were equal to 6.

The score for the ability to bear weight on the fractured limb was based on the ability to stand on affected leg without assistive device and the ability to walk without assistive device. The score ranges from 0 (unable to bear full body weight on the fractured limb) to 6 (able to bear full body weight on the fractured limb). Absence of pain at the fracture site was based on the absence of pain at the fracture site when applying direct pressure to the fracture site and applying a stress to the fracture site. The score ranges from 0 (pain without palpation at fracture site) to 6 (total absence of pain at fracture site).

Time to clinical healing was estimated using CIF; unplanned revision surgery was considered a competing risk in CIF estimate.

Participants who received at least 1 dose of study drug

Posted

Median

95% Confidence Interval

weeks

52 weeks

ID	Title	Description
OG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.
OG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Participants received subcutaneous injections of matching placebo on day 1 and at weeks 2, 6, and 12.	10	100	38	100
EG001	Romosozumab 70 mg: 2 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.	4	34	9	34
EG002	Romosozumab 70 mg: 3 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.	2	34	17	34
EG003	Romosozumab 70 mg: 4 Doses	Participants received subcutaneous injections of 70 mg romosozumab on day 1 and weeks 2, 6, and 12.	3	32	12	32
EG004	Romosozumab 140 mg: 2 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12	3	33	16	33
EG005	Romosozumab 140 mg: 3 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12	4	32	7	32
EG006	Romosozumab 140 mg: 4 Doses	Participants received subcutaneous injections of 140 mg romosozumab on day 1 and weeks 2, 6, and 12.	2	31	9	31
EG007	Romosozumab 210 mg: 2 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and week 2, and matching placebo at weeks 6 and 12.	3	32	10	32
EG008	Romosozumab 210 mg: 3 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2 and 6, and matching placebo at week 12.	3	30	9	30
EG009	Romosozumab 210 mg: 4 Doses	Participants received subcutaneous injections of 210 mg romosozumab on day 1 and weeks 2, 6, and 12.	0	35	6	35

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain upper	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG0030 affected32 at risk EG0040 affected33 at risk EG0050 affected32 at risk EG0060 affected31 at risk EG0070 affected32 at risk EG0080 affected30 at risk EG0090 affected35 at risk
Chest pain	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Chills	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Device breakage	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Inflammation	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Malaise	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Oedema peripheral	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Cellulitis	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Device related infection	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Infection	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0021 affected34 at risk EG003
Localised infection	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Malaria	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Pneumonia	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0021 affected34 at risk EG003
Post procedural infection	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0021 affected34 at risk EG003
Wound infection	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Bone fissure	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Femur fracture	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Fracture displacement	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Loss of anatomical alignment after fracture reduction	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Lower limb fracture	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Ulna fracture	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Wound	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0002 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Oxygen saturation decreased	Investigations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Exostosis	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Rotator cuff syndrome	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Cholesteatoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Cerebral ischaemia	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Paraplegia	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Transient ischaemic attack	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Delirium	Psychiatric disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Calculus ureteric	Renal and urinary disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Medical device removal	Surgical and medical procedures	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Haematoma	Vascular disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Vascular insufficiency	Vascular disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected100 at risk EG0010 affected34 at risk EG0022 affected34 at risk EG0030 affected32 at risk EG0042 affected33 at risk EG0050 affected32 at risk EG0060 affected31 at risk EG0071 affected32 at risk EG0083 affected30 at risk EG0090 affected35 at risk
Vomiting	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0004 affected100 at risk EG0010 affected34 at risk EG0021 affected34 at risk EG003
Asthenia	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Medical device discomfort	General disorders	MedDRA 16.0	Systematic Assessment	EG0003 affected100 at risk EG0012 affected34 at risk EG0021 affected34 at risk EG003
Oedema peripheral	General disorders	MedDRA 16.0	Systematic Assessment	EG0006 affected100 at risk EG0010 affected34 at risk EG0024 affected34 at risk EG003
Pain	General disorders	MedDRA 16.0	Systematic Assessment	EG0007 affected100 at risk EG0010 affected34 at risk EG0022 affected34 at risk EG003
Pyrexia	General disorders	MedDRA 16.0	Systematic Assessment	EG0005 affected100 at risk EG0012 affected34 at risk EG0021 affected34 at risk EG003
Influenza	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0012 affected34 at risk EG0021 affected34 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0004 affected100 at risk EG0012 affected34 at risk EG0022 affected34 at risk EG003
Rhinitis	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0012 affected34 at risk EG0020 affected34 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0003 affected100 at risk EG0011 affected34 at risk EG0024 affected34 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0003 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Limb injury	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Procedural pain	Injury, poisoning and procedural complications	MedDRA 16.0	Systematic Assessment	EG0002 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0006 affected100 at risk EG0011 affected34 at risk EG0021 affected34 at risk EG003
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0003 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0006 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Headache	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0003 affected100 at risk EG0010 affected34 at risk EG0022 affected34 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0003 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Depressed mood	Psychiatric disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 16.0	Systematic Assessment	EG0005 affected100 at risk EG0011 affected34 at risk EG0022 affected34 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected100 at risk EG0011 affected34 at risk EG0020 affected34 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected100 at risk EG0010 affected34 at risk EG0020 affected34 at risk EG003
Blister	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected100 at risk EG0010 affected34 at risk EG0022 affected34 at risk EG003