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Methotrexate (Rheumatrex) High Dose Special Investigation (Regulatory Post Marketing Commitment Plan)

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ClinicalTrials.gov Identifier: NCT01414257
Recruitment Status : Completed
First Posted : August 11, 2011
Results First Posted : August 6, 2018
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Observational
Study Design Observational Model: Case-Only;   Time Perspective: Prospective
Conditions Arthritis
Rheumatoid
High Dose
Intervention Drug: Methotrexate (MTX)
Enrollment 2860
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Methotrexate
Hide Arm/Group Description [Not Specified]
Period Title: Overall Study
Started 2860
Completed 2838
Not Completed 22
Reason Not Completed
No Visit After First Day of Treatment             12
Protocol Violation             10
Arm/Group Title Methotrexate
Hide Arm/Group Description [Not Specified]
Overall Number of Baseline Participants 2838
Hide Baseline Analysis Population Description
Not in particular
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2838 participants
≥15 to <65 years 2014
≥65 years 804
Unknown 20
Sex/Gender, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2838 participants
Female 2176
Male 659
Unknown 3
Steinbrocker Stage   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2838 participants
Stage I (Initial) 695
Stage II (Medium) 948
Stage III (Progressive) 613
Stage IV (Terminal) 524
Unknown 58
[1]
Measure Description:

Stage was classified into four-grade based on below criteria by doctor at beginning. StageI:No radiological finding of osteolysis. StageII:1.Radiological finding of osteoporosis with or without mild fracture of subchondral bone. There may be mild cartilage destruction.

2. Articular movement may be restricted, but no joint deformity StageIII:1.Osteoporosis and radiological finding of bone and cartilage destruction 2.Joint deformity such as subluxation, ulnar malposition or extension is present. There is no fibrous or osseous ankylosis.

StageIV:Fibrous or osseous ankylosis is present.

Steinbrocker Class   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2838 participants
Class 1 794
Class 2 1641
Class 3 301
Class 4 16
Unknown 86
[1]
Measure Description:

Class was classified into four-grade based on below criteria by doctor at beginning.

Class1:Complete ability to carry out all the usual duties without handicaps Class2:Adequate for normal activities despite handicap of discomfort or limited motion of one of the joints Class3:Limited to little or none of the duties of usual occupation or self-care Class4:Incapacitated, largely or wholly bed-ridden or confined to a wheelchair with little or no self-care

Morbidity Period  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2838 participants
<1 year 443
1 to ˂3 years 512
3 to ˂5 years 313
≥5 years 1148
Unknown 422
History of Methotrexate Therapy  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2838 participants
˂0.5 year 737
0.5 to ˂1 year 254
1 to ˂3 years 547
3 to ˂5 years 300
≥5 years 436
Unknown 554
Not used Methotrexate Previously 10
1.Primary Outcome
Title Number of Participants With Treatment-Related Adverse Events
Hide Description A treatment-related adverse event was any untoward medical occurrence attributed to methotrexate in a participant who received methotrexate.
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of participants who satisfied the inclusion criteria and had received methotrexate at least once.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 2838
Measure Type: Number
Unit of Measure: Participants
608
2.Primary Outcome
Title Disease Activity Score (DAS28)-4ESR
Hide Description Disease activity score based on 28-joint count and erythrocyte sedimentation rate (4 variables) (DAS28-4 [ESR]) was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, ESR (mm/hour) and visual analogue scale (VAS) of general health assessed by participant or investigator. Higher score indicated more disease activity. The total scale range of DAS28-4 (ESR) , minimum is 0.0 and maximum can not be specified. DAS28-4 (ESR) >5.1 indicated high disease activity, ?3.2 to ?5.1 indicated moderate disease activity, <3.2 indicated low disease activity, and <2.6 indicated remission.
Time Frame Baseline and 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The effectiveness analysis set comprised of participants in the safety analysis set who had effectiveness evaluation (ESR) at least once. Participants with observed DAS28-4(ESR) were included in table.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 1526
Mean (Standard Deviation)
Unit of Measure: Score
At Baseline 4.09  (1.235)
At 24 Weeks 3.21  (1.235)
3.Primary Outcome
Title Disease Activity Score (DAS28)-4CRP
Hide Description Disease activity score based on 28-joint count and C-reactive protein (4 variables) (DAS28-4 [CRP]) was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, C-reactive protein (CRP, mg/dL) and VAS of general health. The total scale range of DAS28-4 (ESR) , minimum is 0.0 and maximum can not be specified. DAS28-4 (CRP) >4.1 indicated high disease activity, ≥2.7 to 4.1 indicated moderate disease activity, <2.7 indicated low disease activity, and <2.3 indicated remission.
Time Frame Baseline and 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The effectiveness analysis set comprised of participants in the safety analysis set who had effectiveness evaluation (CRP) at least once. Participants with observed DAS28-4(CRP) were included in table.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 1818
Mean (Standard Deviation)
Unit of Measure: Score
At Baseline 3.55  (1.148)
At 24 Weeks 2.66  (1.076)
4.Primary Outcome
Title Change From Baseline in Disease Activity Score (DAS28)-4ESR
Hide Description Disease activity score based on 28-joint count and erythrocyte sedimentation rate (4 variables) (DAS28-4 [ESR]) was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, ESR (mm/hour) and visual analogue scale (VAS) of general health assessed by participant or investigator. Mean change from baseline in the DAS28-4 (ESR) at Week 24 is calculated. The total scale range can not be specified.
Time Frame Baseline and 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The effectiveness analysis set comprised of participants in the safety analysis set who had effectiveness evaluation (ESR) at least once. Participants with observed change in DAS28-4(ESR) were included in table.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 1526
Mean (Standard Deviation)
Unit of Measure: Score
-0.88  (1.156)
5.Primary Outcome
Title Change From Baseline in Disease Activity Score (DAS28)-4CRP
Hide Description Disease activity score based on 28-joint count and C-reactive protein (4 variables) (DAS28-4 [CRP]) was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, C-reactive protein (CRP, mg/dL) and VAS of general health. Mean change from baseline in the DAS28-4 (CRP) at Week 24 is calculated. The total scale range can not be specified.
Time Frame Baseline and 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The effectiveness analysis set comprised of participants in the safety analysis set who had effectiveness evaluation (CRP) at least once. Participants with observed change in DAS28-4 (CRP) were included in table.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 1818
Mean (Standard Deviation)
Unit of Measure: Score
-0.89  (1.117)
6.Secondary Outcome
Title Number of Participants With Treatment-Related Serious Adverse Events
Hide Description A treatment-related adverse event was any untoward medical occurrence attributed to methotrexate in a participant who received methotrexate. A treatment-related serious adverse event was a treatment-related adverse event resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness to methotrexate was assessed by the investigator.
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of participants who satisfied the inclusion criteria and had received methotrexate at least once.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 2838
Measure Type: Number
Unit of Measure: Participants
47
7.Secondary Outcome
Title Number of Participants With Treatment Related Pre-specified Important Serious Adverse Events
Hide Description Pre-specified important adverse events were 1) Interstitial pneumonia, 2) Pulmonary fibrosis, 3) Hepatic impairment, 4) Renal impairment, 5) Hematopoietic disorder, 6) Infection, and 7) Lymphoma. A treatment-related adverse event was any untoward medical occurrence attributed to methotrexate in a participant who received methotrexate. A treatment-related serious adverse event was a treatment-related adverse event resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness to methotrexate was assessed by the investigator.
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set comprised of participants who satisfied the inclusion criteria and had received methotrexate at least once.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 2838
Measure Type: Number
Unit of Measure: Participants
Interstitial Pneumonia 7
Pulmonary Fibrosis 0
Hepatic Impairment 1
Renal Impairment 1
Hematopoietic Disorder 3
Infection 28
Lymphoma 4
8.Secondary Outcome
Title Clinical Efficacy Rate
Hide Description Clinical efficacy rate, which was defined as the percentage of participants who achieved clinical effectiveness over the total number of assesable effectiveness analysis population, was presented along with the corresponding 2-sided 95% CI. Clinical effectiveness of methotrexate was assessed as “effective” or “ineffective” by the investigator. The assessment was based on the baseline condition of disease control and degree of alleviation from baseline in clinical symptoms and laboratory data.
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The effectiveness analysis set comprised of participants in the safety analysis set who had effectiveness evaluation (clinical efficacy rate) at least once. Participants with observed effectiveness data were included in table.
Arm/Group Title Methotrexate
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 2190
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
80.2
(78.5 to 81.9)
Time Frame [Not Specified]
Adverse Event Reporting Description The frequency of adverse events. The same event may appear as both an adverse event and a serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
 
Arm/Group Title Methotrexate
Hide Arm/Group Description [Not Specified]
All-Cause Mortality
Methotrexate
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Methotrexate
Affected / at Risk (%)
Total   69/2838 (2.43%) 
Blood and lymphatic system disorders   
Lymphadenopathy * 1  1/2838 (0.04%) 
Haemorrhagic anaemia * 1  1/2838 (0.04%) 
Disseminated intravascular coagulation * 1  1/2838 (0.04%) 
Pancytopenia * 1  1/2838 (0.04%) 
Cardiac disorders   
Aortic valve incompetence * 1  1/2838 (0.04%) 
Congenital, familial and genetic disorders   
Cerebrovascular arteriovenous malformation * 1  1/2838 (0.04%) 
Ear and labyrinth disorders   
Vertigo * 1  1/2838 (0.04%) 
Gastrointestinal disorders   
Gastric polyps * 1  1/2838 (0.04%) 
Duodenal ulcer * 1  1/2838 (0.04%) 
Gastric ulcer haemorrhage * 1  1/2838 (0.04%) 
Large intestine polyp * 1  1/2838 (0.04%) 
Enterocolitis * 1  1/2838 (0.04%) 
Intestinal obstruction * 1  1/2838 (0.04%) 
General disorders   
Pyrexia * 1  2/2838 (0.07%) 
Administration site reaction * 1  1/2838 (0.04%) 
Hepatobiliary disorders   
Liver disorder * 1  1/2838 (0.04%) 
Infections and infestations   
Pneumonia * 1  10/2838 (0.35%) 
Pneumocystis jirovecii pneumonia * 1  5/2838 (0.18%) 
Urinary tract infection * 1  2/2838 (0.07%) 
Pneumonia mycoplasmal * 1  1/2838 (0.04%) 
Liver abscess * 1  1/2838 (0.04%) 
Bronchopneumonia * 1  1/2838 (0.04%) 
Acute tonsillitis * 1  1/2838 (0.04%) 
Tuberculous pleurisy * 1  1/2838 (0.04%) 
Ear infection * 1  1/2838 (0.04%) 
Pyelonephritis * 1  1/2838 (0.04%) 
Sepsis * 1  1/2838 (0.04%) 
Pneumonia pneumococcal * 1  1/2838 (0.04%) 
Lung infection * 1  1/2838 (0.04%) 
Cellulitis * 1  1/2838 (0.04%) 
Injury, poisoning and procedural complications   
Airway burns * 1  1/2838 (0.04%) 
Lumbar vertebral fracture * 1  1/2838 (0.04%) 
Fracture * 1  1/2838 (0.04%) 
Heat illness * 1  1/2838 (0.04%) 
Tendon rupture * 1  1/2838 (0.04%) 
Investigations   
Platelet count decreased * 1  2/2838 (0.07%) 
Helicobacter test positive * 1  1/2838 (0.04%) 
White blood cell count decreased * 1  1/2838 (0.04%) 
Metabolism and nutrition disorders   
Hyponatraemia * 1  1/2838 (0.04%) 
Musculoskeletal and connective tissue disorders   
Osteoarthritis * 1  1/2838 (0.04%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Lymphoma * 1  4/2838 (0.14%) 
Gastric cancer * 1  2/2838 (0.07%) 
Lung neoplasm malignant * 1  2/2838 (0.07%) 
Colon cancer * 1  1/2838 (0.04%) 
Lung adenocarcinoma recurrent * 1  1/2838 (0.04%) 
Breast cancer * 1  1/2838 (0.04%) 
Bladder cancer * 1  1/2838 (0.04%) 
Nervous system disorders   
Subarachnoid haemorrhage * 1  1/2838 (0.04%) 
Cerebral haemorrhage * 1  1/2838 (0.04%) 
Renal and urinary disorders   
Renal failure acute * 1  2/2838 (0.07%) 
Respiratory, thoracic and mediastinal disorders   
Pleurisy * 1  1/2838 (0.04%) 
Pulmonary embolism * 1  1/2838 (0.04%) 
Pulmonary mass * 1  1/2838 (0.04%) 
Interstitial lung disease * 1  7/2838 (0.25%) 
Skin and subcutaneous tissue disorders   
Skin ulcer * 1  1/2838 (0.04%) 
Surgical and medical procedures   
Hip arthroplasty * 1  1/2838 (0.04%) 
Vascular disorders   
Deep vein thrombosis * 1  1/2838 (0.04%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1.0%
Methotrexate
Affected / at Risk (%)
Total   340/2838 (11.98%) 
Gastrointestinal disorders   
Stomatitis * 1  37/2838 (1.30%) 
Hepatobiliary disorders   
Hepatic function abnormal * 1  217/2838 (7.65%) 
Liver disorder * 1  57/2838 (2.01%) 
Investigations   
White blood cell count decreased * 1  29/2838 (1.02%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01414257     History of Changes
Other Study ID Numbers: B3211003
First Submitted: August 9, 2011
First Posted: August 11, 2011
Results First Submitted: January 9, 2017
Results First Posted: August 6, 2018
Last Update Posted: August 6, 2018