Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Study Comparing Etanercept and Methotrexate vs. Methotrexate Alone in Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Wyeth is now a wholly owned subsidiary of Pfizer
ClinicalTrials.gov Identifier:
NCT00195494
First received: September 13, 2005
Last updated: August 1, 2012
Last verified: August 2012
Results First Received: March 31, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Rheumatoid Arthritis
Interventions: Drug: Etanercept
Drug: Methotrexate
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were recruited worldwide from November 2004 to February 2006.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were randomly assigned equally to 1 of 4 blinded treatment groups: Group (G) 1a received the combination of etanercept (E) and methotrexate (M) in year Y1 and Y2. G1b received the combination of E and M in Y1 and E alone in Y2. G2a received M alone in Y1 and the combination of E and M in Y2. G2b received M alone in Y1 and Y2.

Reporting Groups
  Description
Year 1 E+M / Year 2 E+M

Following a blinded transition from year one- Etanercept injection- two injections 25 mg weekly (given at the same time at different sites)+ oral Methotrexate capsules weekly (same day as injection).

Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.

Year 1 M / Year 2 E+M

Following a blinded transition from year one- Etanercept two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection).

Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.

Year 1 E+M / Year 2 E Following a blinded transition from year one-Etanercept two injections 25 mg weekly (given at the same time at different sites).
Year 1 M / Year 2 M

Following a blinded transition from year one- Methotrexate dose consistent with the ending dose of year one (usually 20 mgs).

No reduction of MTX dose is permitted in year two.

Year 1 M+Placebo

Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites.

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Year 1 E+M

Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection).

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.


Participant Flow for 2 periods

Period 1:   Year 1
    Year 1 E+M / Year 2 E+M   Year 1 M / Year 2 E+M   Year 1 E+M / Year 2 E   Year 1 M / Year 2 M   Year 1 M+Placebo   Year 1 E+M
STARTED   0   0   0   0   268   274 
COMPLETED   0   0   0   0   189   221 
NOT COMPLETED   0   0   0   0   79   53 
Adverse Event                0                0                0                0                34                27 
System Toxicity                0                0                0                0                0                1 
Lack of Efficacy                0                0                0                0                24                9 
Compliance                0                0                0                0                5                1 
Lost to Follow-up                0                0                0                0                1                0 
Missed >4 consecutive doses                0                0                0                0                3                2 
Protocol deviation                0                0                0                0                2                3 
Physician Decision                0                0                0                0                1                0 
Withdrawal by Subject                0                0                0                0                8                9 
Protocol Violation                0                0                0                0                1                1 

Period 2:   Year 2
    Year 1 E+M / Year 2 E+M   Year 1 M / Year 2 E+M   Year 1 E+M / Year 2 E   Year 1 M / Year 2 M   Year 1 M+Placebo   Year 1 E+M
STARTED   111 [1]   90   111 [1]   99   0   0 
COMPLETED   104   74   93   76   0   0 
NOT COMPLETED   7   16   18   23   0   0 
Adverse Event                3                7                5                9                0                0 
Lack of Efficacy                0                1                7                7                0                0 
Compliance                1                0                0                2                0                0 
Lost to Follow-up                0                0                1                1                0                0 
Missed >4 consecutive doses                1                1                1                0                0                0 
Protocol deviation                0                1                0                0                0                0 
Physician Decision                1                1                0                0                0                0 
Withdrawal by Subject                1                5                4                3                0                0 
System toxicity                0                0                0                1                0                0 
[1] A patient with Year 1 termination had taken drug briefly during Year 2 and thus counted in the data.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Year 1 M+Placebo

Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites.

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Year 1 E+M

Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection).

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Total Total of all reporting groups

Baseline Measures
   Year 1 M+Placebo   Year 1 E+M   Total 
Overall Participants Analyzed 
[Units: Participants]
 268   274   542 
Age [1] 
[Units: Years]
Median (Full Range)
 51.50 
 (20.00 to 84.00) 
 52.50 
 (18.00 to 82.00) 
 52.00 
 (18.00 to 84.00) 
[1] Year 1 Overall Number of Baseline Participants is 542
Gender [1] 
[Units: Year 1 participants]
     
Female   194   204   398 
Male   74   70   144 
[1] Year 1 participants collected from Arms M and E+M equal the stated overall participant population of 542. 411 of those participants were then entered into Year 2 Arms E+M/E+M, M/M+E, E+M/E, M/M. This measure provides the gender population for Year 1 only in order to accurately reflect the overall baseline population of 542.


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   The Number of Participants Achieving Remission As Measured by a Disease Activity Score for 28 Joints (DAS 28) < 2.6.   [ Time Frame: 12 months ]

2.  Primary:   Year 1 Participants Having an Annualized Modified Total Sharp Score (mTSS) < 0.5.   [ Time Frame: 12 months ]

3.  Secondary:   Safety Measured by Number of Participants Reporting a Serious Adverse Event That Led to Death   [ Time Frame: 12 and 24 months ]


  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
Year 1 E+M / Year 2 E+M

Following a blinded transition from year one- Etanercept injection- two injections 25 mg weekly (given at the same time at different sites)+ oral Methotrexate capsules weekly (same day as injection).

Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.

Year 1 M / Year 2 E+M

Following a blinded transition from year one- Etanercept two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection).

Dose consistent with the ending dose at year one (usually 20 mgs). No reduction of MTX dose is permitted in year two.

Year 1 E+M / Year 2 E Following a blinded transition from year one-Etanercept two injections 25 mg weekly (given at the same time at different sites).
Year 1 M / Year 2 M

Following a blinded transition from year one- Methotrexate dose consistent with the ending dose of year one (usually 20 mgs).

No reduction of MTX dose is permitted in year two.

Year 1 M+Placebo

Oral Methotrexate capsules once weekly + two injections of placebo given at the same time at different sites.

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.

Year 1 E+M

Etanercept injection- two injections 25 mg weekly (given at the same time at different sites) + oral Methotrexate capsules weekly (same day as injection).

MTX dose is a forced titration from 7.5mg (3 capsules) to 20 mg weekly (8 capsules) by week 8.


Serious Adverse Events
    Year 1 E+M / Year 2 E+M   Year 1 M / Year 2 E+M   Year 1 E+M / Year 2 E   Year 1 M / Year 2 M   Year 1 M+Placebo   Year 1 E+M
Total, serious adverse events             
# participants affected   8   11   10   12   34   33 
Cardiac disorders             
Angina unstable             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Arrhythmia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Aterial fibrillation             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Myocardial infarction             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Pericarditis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Ventricular tachycardia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Aortic valve stenosis             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Atrio ventricular block             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Mitral valve incompetence             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Ear and labyrinth disorders             
Vertigo             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Eye disorders             
Photophobia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Gastrointestinal disorders             
Appendicitis perforated             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Gastritis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   1/274 (0.36%) 
General gastrointestinal disorder             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Gastrointestinal haemorrhage             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Mechanical ileus             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Vomiting             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Abdominal pain upper             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Inguinal hernia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
General disorders             
Chest pain             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   1/274 (0.36%) 
General physical health deterioration             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Systemic inflammatory response system             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Hepatobiliary disorders             
Cholelithiasis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   2/274 (0.73%) 
Gallbladder disorder             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Infections and infestations             
Acute sinusitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   1/268 (0.37%)   0/274 (0.00%) 
Bronchitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Chronic sinusitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Diverticulitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Gastroenteritis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Herpes zoster             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Lung infection             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Lyme disease             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Nasopharyngitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Pneumonia             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   1/99 (1.01%)   1/268 (0.37%)   1/274 (0.36%) 
Septic athritis staphylococcal             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Skin infection             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Streptococcal infection             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Bursitis infected staphylococcal             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Pneumonia streptococcal             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Tonsillitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Injury, poisoning and procedural complications             
Accidental overdose             
# participants affected / at risk   2/111 (1.80%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Joint injury             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Overdose             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Pelvic fracture             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Procedural pain             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Radius fracture             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Spinal fracture             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Concussion             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Device failure             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Fall             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Ligament injury             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Skull fractured base             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Investigations             
Blood alkaline phosphatase increased             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Hepatic enzyme increased             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Transaminases increased             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Metabolism and nutrition disorders             
Diabetes mellitus             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Hyponatraemia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Musculoskeletal and connective tissue disorders             
Arthritis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Haemarthrosis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Intervertebral disc disorder             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Intervetebral disc protrusion             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   2/274 (0.73%) 
Osteoarthritis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   2/268 (0.75%)   0/274 (0.00%) 
Rheumatoid arthritis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   5/268 (1.87%)   2/274 (0.73%) 
Arthropathy             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Spondylolisthesis acquired             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Basal cell carcinoma             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   1/111 (0.90%)   1/99 (1.01%)   1/268 (0.37%)   0/274 (0.00%) 
Bowen's disease             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Breast cancer             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   3/268 (1.12%)   0/274 (0.00%) 
Chronic lymphocytic leukamia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Prostate cancer             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Tongue neoplasm             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Gastrointestinal carcinoma             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Lung cancer metastatic             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Malignant melanoma of sights other than skin             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Metastases to lung             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Pancreatic carcinoma             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Transitional cell carcinoma             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Nervous system disorders             
Cerebral haemorrhage             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Headache             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Paraesthesia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Syncope             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Syncope vasovagal             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Cerebellar infarction             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Cerebral infarction             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Cerebrovascular accident             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Hydrocephalus             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Sciatica             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Psychiatric disorders             
Anxiety             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Sleep disorder             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Confusional state             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Renal and urinary disorders             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Renal colic             
# participants affected / at risk   1/111 (0.90%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Renal and urinary disorders             
Renal failure             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Urinary retention             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Reproductive system and breast disorders             
Testicular torsion             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Vaginal prolapse             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Idiopathic pulmonary fibrosis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Interstitial lung disease             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   2/274 (0.73%) 
Pneumonitis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Pneumothorax             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Dyspnoea             
# participants affected / at risk   0/111 (0.00%)   1/90 (1.11%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Pulmonary embolism             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Skin and subcutaneous tissue disorders             
Hyperhidrosis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Surgical and medical procedures             
Hip arthroplasty             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   2/268 (0.75%)   0/274 (0.00%) 
Hospitalisation             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Cholecystectomy             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
Haemorrhoid operation             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   1/111 (0.90%)   0/99 (0.00%)   0/268 (0.00%)   0/274 (0.00%) 
Vascular disorders             
Deep vein thrombosis             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Infarction             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   0/268 (0.00%)   1/274 (0.36%) 
Ischaemia             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   0/99 (0.00%)   1/268 (0.37%)   0/274 (0.00%) 
Aneurysm             
# participants affected / at risk   0/111 (0.00%)   0/90 (0.00%)   0/111 (0.00%)   1/99 (1.01%)   0/268 (0.00%)   0/274 (0.00%) 
* Events were collected by non-systematic assessment




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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