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  
Number of Participants  
[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 )  
Gender [2]
[units: Year¬†1¬†participants]
     
Female     194     204     398  
Male     74     70     144  
[1] Year 1 Overall Number of Baseline Participants is 542
[2] 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
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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
  Hide Limitations and Caveats

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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