ATTRACT Trial (Study of Efficacy and Safety in Rheumatoid Arthritis with Methotrexate Treatment)
The efficacy of infliximab in the treatment of rheumatoid arthritis (RA) has been investigated in a number of pivotal controlled trials. The Anti-Tumor Necrosis Factor Trial In Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) was a Phase 3, randomized, double-blind, placebo-controlled study that evaluated the safety and efficacy of infliximab in 428 patients who continued to have active RA despite treatment with methotrexate (MTX). Patients enrolled had a median age range of 51-56 years, median disease duration of 7.2-9.0 years, and median swollen joint and tender joint counts ranging from 19-23 and 24-35, respectively. Approximately half of the study patients were classified as functional class stage 3, indicating progressive and advanced disease, with more than one-third having had previous joint surgery.1944, 3209, 6467
All patients (n=428) received treatment with
methotrexate (MTX), (median dose of
Of the 428 randomized patients, 259 (61% of the original study population) continued into the second year of treatment, and 216 (approximately 50% of the original study population) completed the second year of therapy. At Week 30, an analysis of the primary end point (proportion of patients achieving an ACR20 score) was performed in the intent-to-treat (ITT) patients who discontinued treatment, because of lack of efficacy, considered as nonresponders from the time of their withdrawal forward. At Week 54, patients who had missing radiographs at baseline or at Week 54 and who had undergone joint surgery before enrollment were not included in the analysis. The pre-specified analyses for both the HAQ and SF-36 measurements mandated that visits after discontinuation of the study and evaluations indicating a worsening (those patients with a negative HAQ or SF-36 score compared to baseline) were treated as having a change from baseline of 0 as a way of imputing the missing results.6467, 3211
Clinical Response
Treatment with infliximab resulted in statistically
significant improvement in signs and symptoms, as measured by ACR20
(
Figure 691 – American College of Rheumatology Response Rates
Centocor. Data on file. 2001.
Some figures may not display clearly when rendered as a PDF or printed.
As shown in the next figure, median percent improvement in individual parameters of clinical response at Week 102 after treatment with infliximab was associated with statistically significant improvements, specifically in tender joint pain, swollen joint counts, morning stiffness, pain, patient and physician global assessments, and levels of inflammatory markers in the blood (CRP). Data collected through the 102-week period demonstrated that treatment with infliximab in combination with methotrexate (MTX) resulted in sustained clinical benefit at all doses and frequencies over 2 years.6467, 3211
Figure 692 – Median Percent Improvement in Parameters of Clinical Response at 102 Weeks
Centocor. Data on file. 2001.
Some figures may not display clearly when rendered as a PDF or printed.
At the lowest dose (
Radiographic Results
Radiographs of the hands and feet were performed
at Weeks 30, 54, and 102 and were compared with those performed at
baseline using the van der Heijde modification of the Sharp scoring
method
Of the 340 patients treated with infliximab,
259 patients (76%) had complete radiographs taken at baseline and
at Week 102 for analysis. In patients treated with all doses and dosing
intervals of infliximab plus (MTX), evaluation of radiographic data
at Week 102 demonstrated less progression of structural damage compared
with those patients who had taken only methotrexate. As shown in
Fig.693, the median change from baseline to Week 102 in the total
Figure 693 – Change in Modified Sharp Score at Week 102
Centocor. Data on file. 2001.
Some figures may not display clearly when rendered as a PDF or printed.
Similar results were observed at Weeks 30 and
54 for all doses of infliximab, compared with methotrexate (MTX) alone
Additional end points at Week 102 included the
individual results for the 2 components of the modified Sharp score,
bone erosions and JSN. Patients treated with infliximab plus MTX had
significantly fewer newly eroded joints and erosive damage than patients
treated with MTX alone. For both bone erosions and joint space narrowing
(JSN), inhibition of structural damage was observed
Figure 694 – Change in Joint Space Narrowing Scores at Week 102
Centocor. Data on file. 2001.
Some figures may not display clearly when rendered as a PDF or printed.
Figure 695 – Change in Erosion Score at Week 102
Centocor. Data on file. 2001.
Some figures may not display clearly when rendered as a PDF or printed.
Correlating Radiographic and Clinical Response
Smolen, et al, evaluated clinical response and
radiographic progression in American College of Rheumatology ACR20
responders (n=176) receiving infliximab plus methotrexate (MTX) vs.
ACR20 nonresponders (n=164) receiving infliximab plus MTX. At Week
54, ACR20 nonresponders receiving infliximab plus MTX (dosage groups
combined) demonstrated greater Disease Activity Score in 28 joints
(DAS28) compared with patients receiving MTX only (n=73;
This analysis also included an evaluation of radiographic progression in responders and nonresponders. Treatment with infliximab plus MTX significantly inhibited total radiographic progression in patients who achieved an ACR20 response at Week 54, as well as in patients who did not achieve an ACR20 response, compared with MTX treatment alone. The results through Week 102, like those observed through Week 54, demonstrated that patients treated with infliximab plus MTX had significantly less progression of structural damage, compared with patients treated with MTX alone, regardless of ACR20 clinical response. Therefore, infliximab provided significant benefit in inhibiting structural damage, regardless of whether an ACR clinical response was observed or not.3213
Figure 696 – Mean Change from Baseline to Week 54 in Total Radiological Scores Among ACR20 Responders (solid bar) and ACR20 Nonresponders (open bars)
Figure 3, Page 1026, Arthritis Rheum. 2005 52:(4):1020-1030; reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
Some figures may not display clearly when rendered as a PDF or printed.
Physical Function
In the ATTRACT trial, improvement in physical
function was assessed by measuring the change from baseline to Week
102 in the disability index score from the Health Assessment Questionnaire
(HAQ). The HAQ index assesses the degree of difficulty a patient has
in accomplishing tasks in 8 functional areas over the previous week:
dressing and grooming, arising, eating, walking, hygiene, reach, grip,
and activities. HAQ scores range from 0 to 3, with higher scores indicating
greater functional impairment. At Week 102, treatment with infliximab
plus methotrexate (MTX) resulted in statistically significant improvement
in physical function, compared with placebo
Results demonstrated that clinically meaningful improvements across the 5 ACR components were associated with an average change of 0.19 in HAQ score (range, 0.13 to 0.24). Similarly, a study by Wells, et al, found that a minimum change of 0.22 in HAQ correlated with a clinically important improvement in physical ability, pain, and overall disease condition.3215 The change in HAQ averaged over time among infliximab-treated patients represented clinically meaningful improvement in physical function. Results at Week 102 were similar to those observed at Week 54, indicating that the response to infliximab was sustained through Week 102.6467, 3211
Figure 697 – Improvement in Health Assessment Questionnaire Score Averaged Over Time through 102 Weeks
Centocor. Data on file. 2001.
Some figures may not display clearly when rendered as a PDF or printed.
Therefore, in the ATTRACT study, the improvement in health assessment questionnaire (HAQ) score averaged over time among patients in each of the infliximab treatment groups represents clinically meaningful improvement in physical function; this improvement was evident as early as Week 54 and was sustained through Week 102.3209, 6467
In addition to the improvement in HAQ scores,
significant improvement was demonstrated in health-related Quality
of Life (QoL) in patients receiving infliximab, as measured by the
Short-Form Health Survey (SF-36) physical component summary scores
at Week 102
Content on this page was last reviewed on March 31, 2008.
Content on this page was last changed on March 19, 2009.
References:| 1944. | Maini R, St Clair EW, Breedveld F, et al; ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999;354(9194):1932-1939. |
| 3209. | Lipsky PE, van der Heijde DM, St Clair EW, et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and MTX in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343(22):1594-1602. |
| 3211. | Centocor. Data on file. 2004. |
| 3213. | Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment with infliximab plus MTX in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum. 2005;52(4):1020-1030. |
| 3215. | Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier DA. Minimum important difference between patients with rheumatoid arthritis: the patient’s perspective. J Rheumatol. 1993;20(3):557-560. |
| 6467. | Maini RN, Breedveld FC, Kalden JR, et al.; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum . 2004;50(4):1051-1065. |
| 8269. | Centocor. Data on file. 2001. |
| 8272. | Centocor. Data on file. 2001. |
| 8273. | Centocor. Data on file. 2001. |
| 8274. | Centocor. Data on file. 2001. |
| 8280. | Centocor. Data on file. 2001. |
| 8285. | Centocor. Data on file. 2001. |
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Prescribing Information and Medication Guide
REMICADE® (infliximab) Indications and Important Safety Information
INDICATIONS AND USAGE
Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
Ulcerative Colitis
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
IMPORTANT SAFETY INFORMATION
RISK OF INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®. 1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE®. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE® in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and anakinra was associated with a higher risk of serious infections, therefore the use of REMICADE® in combination with anakinra is not recommended. Live vaccines should not be given with REMICADE®. Bring pediatric Crohn's patients up to date with all vaccinations prior to initiating REMICADE®.
Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.