A Study of the Impact of Methotrexate (MTX) Discontinuati... | NCT01855789

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Non-Randomized Participants (TCZ + MTX)	Experimental	All participants will receive initial treatment with open-label TCZ + MTX. Participants who complete 24-week treatment with open-label TCZ + MTX and did not achieve a DAS28 score \	Drug: Tocilizumab (TCZ) Drug: Methotrexate (MTX)
Randomized Participants (TCZ + MTX)	Experimental	Participants who complete the initial 24-week treatment with open-label TCZ + MTX and achieve a DAS28 score \	Drug: Tocilizumab (TCZ) Drug: Methotrexate (MTX)
Randomized Participants (TCZ + PBO)	Active Comparator	Participants who complete the initial 24-week treatment with open-label TCZ + MTX and achieve a DAS28 score \	Drug: Tocilizumab (TCZ) Drug: Placebo (PBO)

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Tocilizumab (TCZ)	Drug	TCZ will be administered at a dose of 162 milligrams (mg) via SC injection weekly (if body weight is greater than or equal to [>/=] 100 kilograms [kg]) or every 2 weeks (if body weight was less than [<] 100 kg).

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40	The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity.	Week 24, Week 40

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response	The ACR20 response at any time was defined as >/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein [CRP] in milligrams per deciliter [mg/dL]).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Body weight </=150 kg
Active moderate to severe rheumatoid arthritis (DAS28 >/=4.4) according to the revised 1987 ACR criteria at screening and baseline (prior to treatment on Day 1)
Currently receiving oral MTX for at least 24 weeks and on a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1), with the following exception: a stable dose of at least 10 mg/week is allowed for participants with a body weight <50 kg or calculated glomerular filtration rate (or creatinine clearance) <60 milliliters per minute (mL/min)
History of parenteral (SC or intramuscular [IM]) MTX is allowed, but not within 6 weeks prior to treatment (Day 1). Participants must not have a documented, clinically significant intolerance to oral MTX and must be receiving oral MTX at a dose of 15 mg/week for at least 6 weeks prior to treatment (Day 1)
Participants who have received one prior anti-tumor necrosis factor (TNF) must have discontinued etanercept, infliximab, certolizumab, adalimumab, or golimumab for at least 6 months prior to screening
Oral corticosteroids must have been </=10 mg/day prednisone (or equivalent) and stable for at least 25 out of 28 days prior to treatment (Day 1)
Participants receiving treatment on an outpatient basis

Exclusion Criteria:

Documented medical history of significant intolerance to oral MTX >/=15 mg/week
Participants receiving other (non-MTX) disease modifying anti-rheumatic drugs (DMARDs) within 8 weeks of screening
Previous treatment with abatacept, rituximab, tofacitinib, or anakinra
Treatment with parenteral corticosteroids within 4 weeks prior to treatment
Previous treatment with cell-depleting therapies or alkylating agents
Previous treatment with TCZ
Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery during the study
Rheumatic autoimmune disease other than rheumatoid arthritis
Non-rheumatic active autoimmune diseases (for example, inflammatory bowel diseases, psoriasis, multiple sclerosis)
Prior history of or current inflammatory joint disease other than rheumatoid arthritis
Functional Class IV according to the revised (1987) ACR criteria for rheumatoid arthritis
History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
Evidence of significant uncontrolled concomitant diseases; uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids
Active current or history of recurrent infection, or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening
Active tuberculosis requiring treatment within the previous 3 years
History of or currently active primary or secondary immunodeficiency
Pregnant or breast-feeding women
Positive for hepatitis B or hepatitis C infection
For potential MRI substudy participants: the presence of any metal-containing device or object in the body

Name	Affiliation	Role
Clinical Trials	Hoffmann-La Roche	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Pinnacle Research Group; Llc, Central		Anniston	Alabama	36207	United States
Uni Of Alabama,Birmingham; Medicine - Rheumatology

PubMed Identifier	Type	Citation	Retractions
29575803	Derived	Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, Pei J, Michalska M. Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial. Arthritis Rheumatol. 2018 Aug;70(8):1200-1208. doi: 10.1002/art.40493. Epub 2018 Jun 14.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Period 1: All Participants (TCZ + MTX)	All enrolled participants received tocilizumab (TCZ) at a dose of 162 milligrams (mg) via subcutaneous (SC) injection weekly (qw; if body weight was greater than or equal to [>/=] 100 kilograms [kg]) or every 2 weeks (q2w; if body weight was less than [<] 100 kg) along with methotrexate (MTX) at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a disease activity score based on 28 joints (DAS28) less than or equal to (\

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

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

Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40

The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity.

Analysis was performed on randomized group which included participants in ITT population who were randomized and received blinded treatment at Week 24. Missing Week 40 values were imputed using last available assessment obtained after Week 24. Here, 'Number Analyzed' signifies number of participants with assessment at specified time point.

Posted

Mean

Standard Deviation

units on a scale

Week 24, Week 40

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Units	Counts
Participants	OG000147 OG001147

Title

Denominators

Categories

Week 24

- ParticipantsOG000147
- ParticipantsOG001147

Title	Measurements
	OG0002.13± 0.816

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	Analysis of covariance (ANCOVA) model included Week 24 DAS28 as a covariate, treatment group, and the randomization stratification factors: DAS28 remission status at Week 24 (<2.6, >/=2.6 to </=3.2), baseline weight-by-dosing group (<80 kg q2w, <80 kg qw, 80-<100 kg q2w, 80-<100 kg qw, >/=100 kg qw), participant anti-tumor necrosis factor (anti-TNF) exposure (Yes/No).					Estimated Mean Difference	0.318	Standard Error of the Mean	0.139	2-Sided	95	0.045	0.592					Non-Inferiority	Non-inferiority of TCZ + PBO was claimed if the upper bound of the 95% confidence interval (CI) for the mean difference was below 0.6.

Secondary

Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response

The ACR20 response at any time was defined as >/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein [CRP] in milligrams per deciliter [mg/dL]).

Analysis was performed on randomized group. Missing assessments of response were treated as no response.

Posted

Number

percentage of participants

Weeks 24, 40, and 52

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Secondary

Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response

The ACR50 response at any time was defined as >/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).

Analysis was performed on randomized group. Missing assessments of response were treated as no response.

Posted

Number

percentage of participants

Weeks 24, 40, and 52

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Secondary

Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response

The ACR70 response at any time was defined as >/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).

Analysis was performed on randomized group. Missing assessments of response were treated as no response.

Posted

Number

percentage of participants

Weeks 24, 40, and 52

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Secondary

Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52

The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28- score could range from 0 to 10, where higher score represented higher disease activity.

Analysis was performed on randomized group. Missing assessments of DAS28 were treated as worsening.

Posted

Number

percentage of participants

Week 24, 40, and 52

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Secondary

Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission)

The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity.

Analysis was performed on randomized group. Missing assessments of DAS28 were treated as no response.

Posted

Number

percentage of participants

Week 40, Week 52

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Secondary

Percentage of Participants With DAS28 Score </=3.2 (Low DAS28)

The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28-ESR score could range from 0 to 10, where higher score represented higher disease activity.

Analysis was performed on randomized group. Missing assessments of DAS28 were treated as no response.

Posted

Number

percentage of participants

Week 40, Week 52

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \

Secondary

Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy

Bones from the wrist regions (carpal bones, distal radius, distal ulna, and metacarpal bases) and the metacarpophalangeal (MCP) joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranged from 0 (no erosion) to 10 (91-100%). Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value for change from Week 24 in bone erosion score indicated an improvement.

Analysis was performed on MRI subset which included all participants in the randomized group who passed MRI eligibility requirements and who had an MRI performed on or after the Week 24 visit. Here, 'Number Analyzed' signifies participants with assessment at specified time point.

Posted

Mean

Standard Deviation

units on a scale

Weeks 24, Week 40

ID	Title	Description
OG000	Period 2: Randomized Participants (TCZ + MTX)	Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \
OG001	Period 2: Randomized Participants (TCZ + PBO)

Secondary

Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ

Percentage of participants with positive results for ATA against TCZ at Baseline and at any of the post-baseline assessment time-points was reported. Participants positive at any post-baseline time points were participants who had no positivity at baseline for the same assay.

Analysis was performed on safety population which included all participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = participants with ATA assessment at specified time points.

Posted

Number

percentage of participants

Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60])

ID	Title	Description
OG000	Overall Study Population	All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was >/=100 kg) or q2w (if body weight was <100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \

Secondary

Mean TCZ Serum Concentration

Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = number of participants with assessment at specified time points.

Posted

Mean

Standard Deviation

micrograms per milliliter

Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)

ID	Title	Description
OG000	Overall Study Population	All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was >/=100 kg) or q2w (if body weight was <100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \

Units	Counts
Participants	OG000

Secondary

Mean Soluble Interleukin-6 (IL-6) Receptor Concentration

Posted

Mean

Standard Deviation

nanograms per milliliter

Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)

ID	Title	Description
OG000	Overall Study Population	All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was >/=100 kg) or q2w (if body weight was <100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pneumonia	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG00010 affected713 at risk
Cellulitis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0003 affected713 at risk
Arthritis infective	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Diverticulitis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Urosepsis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Abscess neck	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Bronchitis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Encephalitis viral	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Gastritis viral	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Influenza	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Localised infection	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Meningitis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Pyelonephritis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Sepsis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Thrombophlebitis septic	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Myocardial infarction	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0005 affected713 at risk
Angina unstable	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Atrial fibrillation	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Bradycardia	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Bundle branch block right	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Cardiac arrest	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0004 affected713 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Laryngeal oedema	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Lung infiltration	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Respiratory tract oedema	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Colitis	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Colitis ischaemic	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Crohn's disease	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Diverticular perforation	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Hiatus hernia	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Impaired gastric emptying	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Lower gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Chest pain	General disorders	MedDRA v19.1	Non-systematic Assessment	EG0005 affected713 at risk
Death	General disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Non-cardiac chest pain	General disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Pain	General disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Presyncope	Nervous system disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Seizure	Nervous system disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Syncope	Nervous system disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Vertebrobasilar insufficiency	Nervous system disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Benign lung neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Bladder papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Invasive lobular breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Ovarian cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Small cell lung cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Squamous cell carcinoma of lung	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA v19.1	Non-systematic Assessment	EG0002 affected713 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Ankle fracture	Injury, poisoning and procedural complications	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Fall	Injury, poisoning and procedural complications	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Incisional hernia	Injury, poisoning and procedural complications	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Overdose	Injury, poisoning and procedural complications	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Myopathy	Musculoskeletal and connective tissue disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Aortic stenosis	Vascular disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Deep vein thrombosis	Vascular disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Hypotension	Vascular disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Mental status changes	Psychiatric disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Suicide attempt	Psychiatric disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Dysmenorrhoea	Reproductive system and breast disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Menorrhagia	Reproductive system and breast disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Drug hypersensitivity	Immune system disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Hepatic enzyme increased	Investigations	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk
Hyperuricaemia	Metabolism and nutrition disorders	MedDRA v19.1	Non-systematic Assessment	EG0001 affected713 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Alanine aminotransferase increased	Investigations	MedDRA v19.1	Non-systematic Assessment	EG000101 affected713 at risk
Hepatic enzyme increased	Investigations	MedDRA v19.1	Non-systematic Assessment	EG00069 affected713 at risk
Aspartate aminotransferase increased	Investigations	MedDRA v19.1	Non-systematic Assessment	EG00065 affected713 at risk
Liver function test increased	Investigations	MedDRA v19.1	Non-systematic Assessment	EG00052 affected713 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG00093 affected713 at risk
Urinary tract infection	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG00054 affected713 at risk
Sinusitis	Infections and infestations	MedDRA v19.1	Non-systematic Assessment	EG00040 affected713 at risk
Nausea	Gastrointestinal disorders	MedDRA v19.1	Non-systematic Assessment	EG00053 affected713 at risk

ID	Term
D001168	Arthritis
D007592	Joint Diseases
D009140	Musculoskeletal Diseases
D012216	Rheumatic Diseases
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
D000630	Aminopterin
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds