IMPACT 2 Trial (Study of Safety and Efficacy of Infliximab in Psoriatic Arthritis)
IMPACT 2 (theInduction and Maintenance Psoriatic Arthritis Clinical Trial) was a 24-week, Phase III, double-blind trial that further evaluated the efficacy of infliximab in patients with active psoriatic arthritis.11616
Study Design in the IMPACT 2 Trial
The efficacy of infliximab in patients with active psoriatic arthritis was evaluated, along with an analysis of 2 characteristic features of psoriatic arthritis, dactylitis and enthesopathy. In addition, the effect of treatment on the quality of life in patients with psoriatic arthritis was assessed. This larger trial contained 200 patients and was conducted in 36 centers across the US, Canada, and Europe.
Exclusion criteria included the presence of latent or active tuberculosis, chronic or clinically significant infection, malignancy, congestive heart failure (CHF), or previous use of TNF-α inhibitors. Concomitant methotrexate (MTX) use of up to 25 mg/week was allowed at least 3 months before the first infusion and was maintained at a stable dose for at least 4 weeks prior to the first infusion. DMARD use other than MTX was not permitted during the trial. Oral corticosteroids at a stable dose equivalent to no more than 10 mg prednisone a day was allowed, but the use of other DMARDs or intra-articular corticosteroids was not permitted within 4 weeks before the first infusion. Low potency topical steroids for face or groin lesions was permitted during the trial, but no other topical or systemic treatments for psoriasis was allowed.11616
Study End Points in the IMPACT 2 Trial
The primary efficacy end point was the achievement of ACR response, assessed at Weeks 2, 6, 14, and 24. Additional efficacy response evaluations assessed at most visits from screening through Week 24, included PsARC and duration of morning stiffness (minutes) during the previous week. Additional assessments were performed at Weeks 0, 14, and 24:
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Presence of dactylitis in the hands and feet
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Presence/absence of enthesopathy in the feet
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Short Form-36 (SF-36) Questionnaire
Severity of psoriasis at baseline was assessed using the percentage of body surface area affected; mild, moderate, and severe psoriasis were defined as <5% BSA, 5 to <10% BSA, and >10% BSA. Psoriasis activity was assessed at baseline and Weeks 2, 6, 14, and 24 using the PASI for patients with at least 3% BSA at baseline. In addition, assessment of target lesion score (erythema, plaque induration, and scaling rated on a score of 0-4 each) at Weeks 0, 14, and 24 was rated in all patients, regardless of baseline PASI scores.11616
Results in the IMPACT 2 Trial
A total of 200 patients were enrolled for this study in a 1:1 ratio, and 185 (93%) completed the study at Week 24. A summary of patient disposition and treatment groups is shown in Fig.3131. Baseline demographic and disease characteristics were similar in both the infliximab and placebo groups, and a substantial proportion of patients had dactylitis and/or enthesopathy. Most patients had at least 3% BSA, with a vast majority of patients having moderate to severe psoriasis. Reduced health-related, quality-of-life scores was noted in the enrolled patients compared to the general American population, as noted by baseline physical and mental component summary scores of the SF-36.11616 HAQ scores indicated impaired physical function. Both the infliximab and placebo groups were receiving similar mean doses of MTX at baseline.
Figure 3131 – Summary of Patient Disposition
Antoni C, Krueger GG, de Vlam K, et al. Ann Rheum Dis. 2005;64(8):1150-1157, Reproduced with permission from the BMJ Publishing Group. http://group.bmj.com/products/journals
Some figures may not display clearly when rendered as a PDF or printed.
Efficacy Results in the IMPACT 2 Trial
The ACR response to infliximab treatment was evident as early as Week 2 and responses were maintained throughout the study seen in Fig.3132. At Weeks 14 and 24, 58% and 54% of infliximab patients achieved ACR20 response respectively, a result which was significant (P<0.001) when compared to placebo-treated patients (11% and 16% at Weeks 14 and 24, respectively). An ACR50 response was achieved in 36% of infliximab-treated patients at Week 14, compared with 3% in placebo-treated patients, while ACR70 responses in each group was 15% and 1%, respectively (P<0.001). Week 24 results were again significantly better in the infliximab-treated group: 41% and 27% achieved ACR50 and ACR70 responses, compared to 4% and 2%, respectively in the placebo-treated groups. For individual components of the ACR20, improvements from baseline to Week 14 and Week 24 were seen in patients in the infliximab group compared to those in the placebo group.1953, 11566
Figure 3132 – Time Pattern of Arthritis Response
Antoni C, Krueger GG, de Vlam K, et al., Ann Rheum Dis. 2005;64(8):1150-1157, Reproduced with permission from the BMJ Publishing Group. http://group.bmj.com/products/journals
Some figures may not display clearly when rendered as a PDF or printed.
In patients with at least 3% BSA psoriasis involvement at baseline, psoriasis activity was assessed using the PASI. Among the 170 patients with psoriasis affecting at least 3% of BSA at baseline [infliximab (n=83) vs. placebo (n=87)], significantly higher proportions of patients treated with infliximab had at least 50%, 75%, and 90% improvement in PASI scores from baseline to Week 14 compared to placebo patients.
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PASI >50% Improvement: Infliximab (82%) vs. Placebo (9%); (P<0.001)
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PASI >75% Improvement: Infliximab with 3% BSA (64%) vs. Placebo (2%); (P<0.001)
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PASI >90% Improvement: Infliximab (41%) vs. Placebo (0%); (P<0.001)
As early as Week 2, skin response to infliximab treatment was evident in some patients and was maintained through Week 24. Patients in the infliximab-treated group also had a significant improvement in target lesion score from baseline to Week 14 compared to the placebo group (65.6% vs. -0.3%, P<0.001), with response maintained at Week 24. as seen in Fig.3133.1953 At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving infliximab compared to 1% and 0%, respectively, of patients receiving placebo.11567
Figure 3133 – Skin Response Over Time
Antoni C, Krueger GG, de Vlam K, et al. Ann Rheum Dis. 2005;64(8):1150-1157, Reproduced with permission from the BMJ Publishing Group. http://group.bmj.com/products/journals
Some figures may not display clearly when rendered as a PDF or printed.
Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, infliximab-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, P<0.001). Infliximab-treated patients also had less progression in their erosion scores (-0.56 vs. 0.51) and JSN scores (-0.14 vs. 0.31).
Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Infliximab-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to Week 14 and 24 of 43% for infliximab-treated patients vs. 0% for placebo-treated patients). During the placebo-controlled portion of the trial (24 weeks), 54% of infliximab-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥0.3 unit decrease) compared to 22% of placebo-treated patients. Infliximab-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients.11567
One-year Efficacy Data From the IMPACT 2 Trial
The efficacy and safety after 1 year of infliximab treatment was measured in patients with psoriatic arthritis enrolled in the IMPACT 2 trial.11627 The findings from the Phase III, multicenter, double-blind, placebo-controlled study expanded the published data from the original 24-week trial.1953, 11627 The results are displayed below.
Figure 3149 – Clinical Responses at Week 24 and Week 54
Kavanaugh A, Krueger GG, Beutler A, et al., Ann Rheum Dis. 2007;66(4):498-505, Table 2 page 501. Reproduced with permission from the BMJ Publishing Group.
Some figures may not display clearly when rendered as a PDF or printed.
Through Week 54, ACR20, ACR50, and ACR70 responses were maintained with continued infliximab treatment. At Week 54, a major clinical response defined as ACR70 improvement for 24 consecutive weeks, was achieved by 12.1% of infliximab patients. The PASI 75 and PASI 90 responses seen at Week 24 were generally maintained in the infliximab group through Week 54 and can be seen in Fig.3151. Across treatment groups, similar proportions of patients achieved both PASI 75 and PASI 90 by Week 54. Patients receiving MTX at baseline had similar PASI scores to those not receiving MTX at baseline.
Figure 3150 – Joint Response Over Time Through Week 54
Kavanaugh A, Krueger GG, Beutler A, et al., Ann Rheum Dis. 2007;66(4):498-505, Table 2 page 501. Reproduced with permission from the BMJ Publishing Group.
Some figures may not display clearly when rendered as a PDF or printed.
Figure 3151 – Skin Response Over Time Through Week 54
Kavanaugh A, Krueger GG, Beutler A, et al., Ann Rheum Dis. 2007;66(4):498-505, Figure 3 page 502. Reproduced with permission from the BMJ Publishing Group.
Some figures may not display clearly when rendered as a PDF or printed.
The patients in the infliximab group demonstrated continued inhibition of structural damage at Week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received infliximab or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the infliximab group (3%).11567
This concludes the discussion of the topic Psoriatic Arthritis ―Benefits With Infliximab Therapy. We encourage you to read other topics on the MEDVERSATIONTM website.
Content on this page was last reviewed on March 31, 2008.
Content on this page was last changed on March 19, 2009.
References:| 1953. | Antoni C, Krueger GG, de Vlam K, et al; IMPACT 2 Trial Investigators. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005;64(8):1150-1157. |
| 11566. | Centocor, Inc. Remicade-Infliximab. Available at: http://www.remicade.com/remicade/psa/psa_index.html . Accessed November 14, 2008. |
| 11567. | Remicade [prescribing information]. Malvern, PA: Centocor, Inc.; December 2008. |
| 11616. | Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005;64(8):1150-1157. |
| 11627. | Kavanaugh A, Krueger GG, Beutler A, et al. Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis . 2007;66(4):498-505. |
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.