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ACCENT I Clinical Trial Overview

ACCENT I Study Background

The FDA approval of REMICADE as maintenance therapy was based on data from the ACCENT I trial. ACCENT I stands for “A Crohn’s disease Clinical trial Evaluating infliximab in a New Long term Treatment regimen.”

ACCENT I was a multi-center, randomized international trial of 545 patients with moderately to severely active CD who failed conventional therapies (e.g. 5-aminosalicylates, immunomodulators, steroids). The objectives of the trial were to determine the efficacy and safety of maintenance treatment with REMICADE versus a single infusion of REMICADE.^1,2

Patients in the study were typical of a Crohn's disease population with moderately to severely active disease. At baseline, the median Crohn's Disease Activity Index (CDAI) score was 295, and the median Inflammatory Bowel Disease Questionnaire score (IBDQ) was 127. Approximately half (51%) of the patients were receiving corticosteroids (median dose, 20 mg) and 31% were receiving immunomodulator therapy. The trial continued through 54 weeks.¹

All patients received an initial infusion of REMICADE 5 mg/kg at Week 0. At Week 2, patients were randomized based on clinical response, defined as a reduction in CDAI ≥ 25% and ≥ 70 points, to one of the following maintenance treatment groups:

Group I: Placebo at Weeks 2, 6, and then placebo every 8 weeks

Group II: REMICADE 5 mg/kg at Weeks 2, 6 and then 5 mg/kg every 8 weeks

Group III: REMICADE 5 mg/kg at Weeks 2, 6 and then 10 mg/kg every 8 weeks

Patients who did not respond to the initial infusion at Week 2 were randomized separately from those who demonstrated a clinical response. Only the Week 2 responders were analyzed for the primary endpoints of the trial. The 2 co-primary endpoints were the proportion of patients in remission (CDAI <150) at Week 30, and the time to loss of response up to Week 54. Patients who initially responded to treatment, but then lost their clinical benefit were eligible to cross over to active episodic retreatment starting at Week 14 with an additional 5 mg/kg of REMICADE added to their maintenance dose. Concomitant Crohn’s disease medications were to be maintained at stable doses, and corticosteroid tapering was permitted beginning at Week 6 in patients who demonstrated a clinical response to initial treatment.¹

ACCENT I Study Findings

At Week 2, 57% (311/545) of patients were in clinical response. At Week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 1).²

Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at Week 54 (Table 1).²

Table 1: Clinical Remission and Steroid Withdrawal²

	Placebo Maintenance Single 5 mg/kg^a	Three dose Induction^b Infliximab Maintenance q 8 weeks
		5 mg/kg	10 mg/kg
Week 30 Clinical Remission P-value^c	25/102 (25%)	41/104 (39%) 0.022	48/105 (46%) 0.001
Week 54 Patients in remission able to discontinue corticosteroid use^d p-value^c	6/54 (11%)	14/56 (25%) 0.059	18/53 (34%) 0.005

^a REMICADE at Week 0

^b REMICADE 5 mg/kg administered at Weeks 0, 2 and 6 and every 8 weeks

^c P-values represent pairwise comparisons to placebo

^d Of those receiving corticosteroids at baseline

Patients in the infliximab maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group. Specifically, median time to loss of response was 19 weeks for the placebo maintenance group, 37 weeks for the 5 mg/kg group, and >54 weeks for the 10 mg/kg. At Weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg infliximab-treated groups compared to the placebo group in the disease specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.²

In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the infliximab maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at Week 10. Of the infliximab-treated patients showing mucosal healing at Week 10, 9 of 12 patients also showed mucosal healing at Week 54.²

Patients who achieved a response and subsequently lost response were eligible to receive infliximab on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at Week 2, 59% (92/157) of infliximab maintenance patients responded by Week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by Week 14, additional therapy did not result in significantly more responses.²

References:

Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.
REMICADE^® (infliximab) Prescribing Information.

Indications

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.

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.

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.

Adult Crohn's Disease
REMICADE^® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult 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.

Pediatric Crohn’s Disease
REMICADE^® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.

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.

Ankylosing Spondylitis
REMICADE^® is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

IMPORTANT SAFETY INFORMATION

SERIOUS 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 in rare cases with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering REMICADE^® in patients with these disorders and consider discontinuation if these disorders develop.

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 occuring 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

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.
See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.

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Last Updated: April 13, 2010

ACCENT I Clinical Trial Overview

ACCENT I Study Background

ACCENT I Study Findings

Table 1: Clinical Remission and Steroid Withdrawal2

References

Table 1: Clinical Remission and Steroid Withdrawal²