Rheumatoid Arthritis
Conditions
Brief summary
This 2 arm study will investigate the effects of tocilizumab on lipids, arterial stiffness, and markers of atherogenic risk in patients with moderate to severe active rheumatoid arthritis. In Part 1 of the study, patients will be randomized to receive either tocilizumab 8mg/kg intravenously or placebo every 4 weeks, in combination with methotrexate 7.5-25 mg weekly. In Part 2, all patients will receive open-label treatment with tocilizumab plus methotrexate.
Interventions
DRUGTocilizumab
Administered by intravenous infusion, 8 mg/kg every 4 weeks.
DRUGPlacebo
Placebo to tocilizumab administered by intravenous infusion every 4 weeks.
DRUGMethotrexate
Administered orally or parenterally, 7.5-25 mg weekly.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* adult patients, 18-75 years of age * rheumatoid arthritis (RA) of \>6 months duration * able to receive outpatient treatment * on methotrexate for at least 12 weeks before entering study, at a stable dose of 7.5-25 mg/week for the last 8 weeks * oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDS) permitted, if at a stable dose for 4 weeks before study start
Exclusion criteria
* major surgery (including joint surgery) within 8 weeks prior to screening, or planned surgery within 6 months after entering study * history of, or current inflammatory joint disease or rheumatic autoimmune disease other than RA * inadequate response to anti-tumor necrosis factor (TNF) agent during the 6 months prior to baseline, or inadequate response to \>2 anti-TNF agents * initiation of treatment with lipid lowering agents within 12 weeks prior to baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Baseline and Week 12 | Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology. |
| Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Baseline and Week 12 | Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Baseline and Week 24 | Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology. |
| Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Baseline and Week 24 | Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes. |
| Number of Participants Experiencing Adverse Events (AEs) | Up to Week 24 | A severe AE is an event in which the intensity of the event results in an inability to work or perform normal daily activity. A Serious AE is fatal, life-threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant or requires intervention to prevent one of the above outcomes. AEs of special interest include infection, gastrointestinal, infusion reaction (occurring during or within 24 hours of infusion), hepatic disorder, myocardial infarction and stroke. |
Countries
Canada, Puerto Rico, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TCZ + MTX During Part 1 of the study participants received 8 mg/kg tocilizumab (TCZ) by intravenous (IV) infusion every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 2, from Week 24 to Week 104, participants received open-label 8 mg/kg TCZ every 4 weeks plus 7.5-25 mg MTX weekly. | 69 |
| Placebo + MTX During Part 1 of the study participants received placebo intravenous (IV) infusion every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 2, from Week 24 to Week 104, participants received 8 mg/kg TCZ IV every 4 weeks plus 7.5-25 mg MTX weekly. | 63 |
| Total | 132 |
Baseline characteristics
| Characteristic | TCZ + MTX | Placebo + MTX | Total |
|---|---|---|---|
| Age, Customized <52 years | 23 participants | 20 participants | 43 participants |
| Age, Customized ≥52 years | 46 participants | 43 participants | 89 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Black | 2 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized Other | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized White | 63 participants | 55 participants | 118 participants |
| Region of Enrollment Canada | 23 participants | 16 participants | 39 participants |
| Region of Enrollment United Kingdom | 5 participants | 1 participants | 6 participants |
| Region of Enrollment United States | 41 participants | 46 participants | 87 participants |
| Sex: Female, Male Female | 57 Participants | 47 Participants | 104 Participants |
| Sex: Female, Male Male | 12 Participants | 16 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 59 / 70 | 44 / 62 | 124 / 130 |
| serious Total, serious adverse events | 3 / 70 | 2 / 62 | 30 / 130 |
Outcome results
Primary
Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers
Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology.
Time frame: Baseline and Week 12
Population: Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ + MTX | Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Baseline (n=63, 59) | 737.79 nmol/L | Standard Deviation 467.097 |
| TCZ + MTX | Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Week 12 (n=69, 63) | 768.04 nmol/L | Standard Deviation 628.281 |
| TCZ + MTX | Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Change from Baseline at Week 12 (n=63, 59) | 23.73 nmol/L | Standard Deviation 368.273 |
| Placebo + MTX | Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Baseline (n=63, 59) | 792.78 nmol/L | Standard Deviation 392.051 |
| Placebo + MTX | Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Week 12 (n=69, 63) | 777.71 nmol/L | Standard Deviation 394.527 |
| Placebo + MTX | Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Change from Baseline at Week 12 (n=63, 59) | 22.41 nmol/L | Standard Deviation 237.476 |
Primary
Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV)
Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes.
Time frame: Baseline and Week 12
Population: Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ + MTX | Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Baseline (n=69, 59) | 8.97 meters/second | Standard Deviation 1.97 |
| TCZ + MTX | Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Week 12 (n=69, 62) | 8.94 meters/second | Standard Deviation 2.51 |
| TCZ + MTX | Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Change from Baseline at Week 12 (n=69, 59) | -0.03 meters/second | Standard Deviation 1.97 |
| Placebo + MTX | Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Week 12 (n=69, 62) | 8.39 meters/second | Standard Deviation 1.836 |
| Placebo + MTX | Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Baseline (n=69, 59) | 9.01 meters/second | Standard Deviation 2.519 |
| Placebo + MTX | Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Change from Baseline at Week 12 (n=69, 59) | -0.68 meters/second | Standard Deviation 1.741 |
Secondary
Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV)
Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes.
Time frame: Baseline and Week 24
Population: Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ + MTX | Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Baseline (n=69, 59) | 8.97 meters/second | Standard Deviation 1.97 |
| TCZ + MTX | Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Week 24 (n=69, 62) | 8.98 meters/second | Standard Deviation 2.337 |
| TCZ + MTX | Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Change from Baseline at Week 24 (n=69, 59) | 0.01 meters/second | Standard Deviation 1.946 |
| Placebo + MTX | Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Baseline (n=69, 59) | 9.01 meters/second | Standard Deviation 2.519 |
| Placebo + MTX | Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Week 24 (n=69, 62) | 8.85 meters/second | Standard Deviation 2.014 |
| Placebo + MTX | Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Change from Baseline at Week 24 (n=69, 59) | -0.20 meters/second | Standard Deviation 1.792 |
Secondary
Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers
Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology.
Time frame: Baseline and Week 24
Population: Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ + MTX | Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Baseline (n=63, 59) | 737.79 nmol/L | Standard Deviation 467.097 |
| TCZ + MTX | Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Week 24 (n=69, 63) | 792.78 nmol/L | Standard Deviation 605.485 |
| TCZ + MTX | Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Change from Baseline at Week 24 (n=63, 59) | 39.03 nmol/L | Standard Deviation 367.786 |
| Placebo + MTX | Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Baseline (n=63, 59) | 792.78 nmol/L | Standard Deviation 392.051 |
| Placebo + MTX | Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Week 24 (n=69, 63) | 801.78 nmol/L | Standard Deviation 398.91 |
| Placebo + MTX | Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Change from Baseline at Week 24 (n=63, 59) | 32.41 nmol/L | Standard Deviation 250.576 |
Secondary
Number of Participants Experiencing Adverse Events (AEs)
A severe AE is an event in which the intensity of the event results in an inability to work or perform normal daily activity. A Serious AE is fatal, life-threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant or requires intervention to prevent one of the above outcomes. AEs of special interest include infection, gastrointestinal, infusion reaction (occurring during or within 24 hours of infusion), hepatic disorder, myocardial infarction and stroke.
Time frame: Up to Week 24
Population: The safety population includes all patients who received any part of an infusion of study drug and who provided at least one assessment of safety. Randomized patients who received the incorrect therapy from that intended are summarized in the group according to the therapy actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Infection AEs | 42 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Any AE | 59 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Gastrointestinal AEs | 22 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Serious AE | 3 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Infusion reaction AEs | 12 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Withdrawals due to AE | 2 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Hepatic disorder AEs | 0 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Deaths | 0 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Myocardial infarction | 0 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Pregnancy | 0 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Stroke | 0 participants |
| TCZ + MTX | Number of Participants Experiencing Adverse Events (AEs) | Severe AE | 7 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Stroke | 0 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Deaths | 0 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Any AE | 45 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Severe AE | 4 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Withdrawals due to AE | 1 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Pregnancy | 0 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Infection AEs | 17 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Gastrointestinal AEs | 10 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Infusion reaction AEs | 7 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Hepatic disorder AEs | 0 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Myocardial infarction | 0 participants |
| Placebo + MTX | Number of Participants Experiencing Adverse Events (AEs) | Serious AE | 2 participants |