Infuse change in patients with moderately to severely active Crohn’s disease (CD) who had an inadequate response to conventional therapy

Treat beyond symptom control with REMICADE®

Clinical Remicade Remission CD

REMICADE® clinical trials1-5
Targan
SONIC
ACCENT I
ACCENT II

Targan: A registration trial for REMICADE®

Targan study overview6*

  • 12-week, multicenter, randomized, double-blind, placebo-controlled trial (N=108)
  • Patients were randomly assigned to receive a single infusion of
    • Placebo
    • REMICADE® 5 mg/kg
    • REMICADE® 10 mg/kg§ (not an approved induction dose)
    • REMICADE® 20 mg/kg (not an approved dose)
Featured Targan study endpoints—click each endpoint to learn more
Primary endpoint Secondary endpoints

Baseline patient characteristics6

  • Median disease duration: 12 years (calculated from all patient groups)
  • CD (colitis, ileitis, or ileocolitis) ≥6 months' duration
  • CDAI ≥220 and ≤400
  • Previous CD-related surgery (%)
    • Placebo: 52%
    • REMICADE® 5 mg/kg: 44%
    • REMICADE® 10 mg/kg: 50%
    • REMICADE® 20 mg/kg: 50%
  • Patients on corticosteroids ≥20 mg/day
    • Placebo: 24%
    • REMICADE® 5 mg/kg: 26%
    • REMICADE® 10 mg/kg: 29%
    • REMICADE® 20 mg/kg: 25%

Click here for a complete study design of Targan.

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ACCENT I: A Crohn's disease clinical trial evaluating infliximab in a new long-term treatment regimen

ACCENT I study overview2,3II

  • 1-year, multicenter, randomized, double-blind trial (N=545)
  • All patients received initial infusion of REMICADE® 5 mg/kg at Week 0
  • At Week 2, patients were randomized based on clinical response to 1 of 3 maintenance treatment groups through Week 54:
    • Group I: Placebo at Weeks 2, 6, and then every 8 weeks
    • Group II: REMICADE® 5 mg/kg at Weeks 2, 6, and then every 8 weeks
    • Group III: REMICADE® 5 mg/kg at Weeks 2 and 6, and then REMICADE® 10 mg/kg every 8 weeks
Featured ACCENT I study endpoints—click each endpoint to learn more
Co-primary endpoints Secondary endpoints Week 10 endoscopic substudy

Baseline patient characteristics2

  • Median disease duration: 7.9 years
  • CD ≥3 months' duration
  • CDAI ≥220 and ≤400
  • Previous CD-related surgery: 51%
  • Patients on corticosteroids >20 mg/day: 16%

Click here for a complete study design of ACCENT I.

SELECTED IMPORTANT SAFETY INFORMATION

Serious and sometimes fatal side effects have been reported with REMICADE®. Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma (HSTCL), and other malignancies have been reported, including in children and young adult patients. Due to the risk of HSTCL, carefully assess the risk/benefit especially if the patient has Crohn's disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

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SONIC: The study of biologic- and immunomodulator-naïve patients in Crohn's disease

SONIC study overview4,5#

  • Multicenter, randomized, double-blind study (N=508)
  • Primary phase: Primary endpoint analysis at Week 26 (N=508)
    • Study arm I: Azathioprine (AZA) 2.5 mg/kg/day + placebo infusion (n=170)
    • Study arm II: REMICADE® 5 mg/kg + placebo capsules (n=169)
    • Study arm III: REMICADE® 5 mg/kg + AZA 2.5 mg/kg/day (n=169)
  • Extension phase: Patients who completed first 30 weeks, continuing with initial regimen (N=280)
    • Study arm I: AZA 2.5 mg/kg/day + placebo infusion (n=75)
    • Study arm II: REMICADE® 5 mg/kg + placebo capsules (n=97)
    • Study arm III: REMICADE® 5 mg/kg + AZA 2.5 mg/kg/day (n=108)
Featured SONIC study endpoints—click each endpoint to learn more
Primary endpoints Secondary endpoints

Baseline patient characteristics4,5

  • Median disease duration: 2.2 to 2.4 years
  • CD (colitis, ileitis, or ileocolitis) ≥6 weeks' duration
  • Crohn's Disease Activity Index (CDAI) ≥220 and ≤450
  • Previous CD-related surgery (%)
    • Azathioprine (AZA) + placebo: 31.2%
    • REMICADE® + placebo: 27.8%
    • REMICADE® + AZA: 26%
  • Patients on corticosteroids ≥20 mg/day: 18.1% (92/508)
  • Failed conventional therapy with 5-ASAs or budesonide, or required repeated courses of steroids before treatment with an immunomodulator or a biologic

Azathioprine (AZA) is not approved by the Food and Drug Administration (FDA) for the treatment of Crohn's disease and its contribution to the effectiveness of use in combination with REMICADE® has not been established. The use of AZA in combination with REMICADE® should take into account the potential risks associated with combination therapy and monotherapy.

Click here for a complete study design of SONIC.

SELECTED IMPORTANT SAFETY INFORMATION

Serious and sometimes fatal side effects have been reported with REMICADE®. Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma (HSTCL), and other malignancies have been reported, including in children and young adult patients. Due to the risk of HSTCL, carefully assess the risk/benefit especially if the patient has Crohn's disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

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ACCENT II: A Crohn's disease clinical trial evaluating infliximab in a new long-term treatment regimen in patients with fistulizing Crohn's disease

ACCENT II study overview1,3,7

  • Multicenter, randomized, double-blind, international trial evaluating the safety and efficacy of long-term maintenance therapy with REMICADE® (N=282) in patients with fistulizing CD**
  • All patients received an initial induction regimen of REMICADE® 5 mg/kg at Weeks 0, 2, and 6
  • At Week 14 patients were randomized based on clinical response to receive:
    • Maintenance dosing with either REMICADE® 5 mg/kg or placebo every 8 weeks
    • Non-responders to the initial 3-dose induction regimen were randomized separately
  • At Week 22 responders who lost clinical benefit were eligible to cross over to maintenance treatment with REMICADE® 5 mg/kg, if receiving placebo, or to REMICADE® 10 mg/kg, if receiving REMICADE® 5 mg/kg
  • Concomitant CD medications could be maintained at a stable dose
Featured ACCENT II study endpoints—click each endpoint to learn more
Primary endpoints
  • Time from randomization to loss of response among patients in fistula response
Secondary endpoints based on number of draining fistulas:

Baseline patient characteristics7

  • Median disease duration
    • Placebo group (responders): 12.3 years
    • REMICADE® maintenance group (responders): 10.5 years
    • Non-responders: 11.7 years
  • CD with single or multiple perianal fistulas and/or enterocutaneous fistulas for ≥3 months
  • Patients on corticosteroids ≥20 mg/day: 8%

Click here for a complete study design of ACCENT II.

SELECTED IMPORTANT SAFETY INFORMATION

Serious and sometimes fatal side effects have been reported with REMICADE®. Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma (HSTCL), and other malignancies have been reported, including in children and young adult patients. Due to the risk of HSTCL, carefully assess the risk/benefit especially if the patient has Crohn's disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

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 *
Targan et al conducted a 12-week, multicenter, randomized, double-blind, placebo-controlled trial in 108 moderately to severely active CD patients (baseline Crohn's Disease Activity Index [CDAI] ≥220 and ≤400) unresponsive to conventional therapy. Patients were randomized to receive a single infusion of placebo (n=25) or REMICADE® 5 mg/kg (n=27), 10 mg/kg (n=28), or 20 mg/kg (n=28). The primary endpoint was clinical response at Week 4.
 
 †
In Targan: Clinical response was defined as a reduction of ≥70 points in CDAI score that was not accompanied by a change in concomitant medications.
 
 ‡
REMICADE® 10 mg/kg is not an approved induction dose.
 
 §
REMICADE® 20 mg/kg is not an approved dose.
 
 II
Results from ACCENT I, a 1-year, multicenter, randomized, double-blind trial of REMICADE® in 545 patients with moderately to severely active CD (Crohn's Disease Activity Index [CDAI] ≥220 and ≤400). At baseline, median CDAI score was 295. All patients received an initial dose of REMICADE® 5 mg/kg. Patients were then randomized based on clinical response at Week 2 to 1 of 3 treatment groups through Week 54: the placebo maintenance group received placebo infusion at Weeks 2, 6, and every 8 weeks thereafter (n=102); the 5 mg/kg maintenance group received REMICADE® 5 mg/kg at Weeks 2, 6, and every 8 weeks thereafter (n=104); the REMICADE® 10 mg/kg maintenance group received REMICADE® 5 mg/kg at Weeks 2 and 6, followed by REMICADE® 10 mg/kg every 8 weeks thereafter (n=105). The coprimary endpoints of the trial were the proportion of patients responding at Week 2 who were in remission at Week 30 and time to loss of response through Week 54. The median time to loss of response was 37 weeks for the 5 mg/kg group vs 19 weeks in the single infusion group (P=0.004).
 
  ¶
In ACCENT I: Clinical response was defined as a ≥70-point decrease and a ≥25% reduction in baseline CDAI score.
 
 #
Results from SONIC, a multicenter, randomized, double-blind, controlled, phase IIIb trial of 508 patients with moderately to severely active CD (baseline Crohn's Disease Activity Index [CDAI] ≥220 and ≤450). At baseline, mean CDAI score for all patients was 287; median duration of CD ranged from 2.2 to 2.4 years. Patients were randomly assigned to 1 of 3 treatment groups through Week 30: in the primary study phase, patients received REMICADE® 5 mg/kg or placebo infusions at Weeks 0, 2, 6, 14, and 22; patients also received azathioprine (AZA) capsules at a dose of 2.5 mg/kg/day or placebo capsules daily through Week 30. Patients completing treatment through Week 30 (main study) were eligible to enter the study extension if, in the opinion of the investigator, the patient could benefit from continued treatment. Patients eligible for participation in the extension (N=280) continued to receive their initial treatment through Week 50. The Week 50 analysis included patients who did not enter the study extension. These patients were assumed non-responders and not to be in steroid-free remission at Week 50. The primary endpoint of the study was the proportion of patients in corticosteroid-free remission at Week 26. Secondary endpoints included mucosal healing at Week 26 and corticosteroid-free remission at Week 50. Monitoring for adverse events was performed through Week 54.
 
**
Results from ACCENT II, a 1-year randomized, double-blind trial of REMICADE® in 296 patients with at least 1 draining, enterocutaneous fistula. At baseline, approximately 80% of patients were receiving stable doses of 1 or more concomitant Crohn's-related therapies. All patients received an initial 3-dose induction of REMICADE® 5 mg/kg at Weeks 0, 2, and 6. Patients were then randomized based on clinical response at Week 14 to receive REMICADE® 5 mg/kg every 8 weeks or placebo through Week 46. The primary endpoint of the trial was time to loss of fistula response through Week 54 among patients responding at Week 14. Among patients randomized as responders at Week 14, patients receiving REMICADE® maintenance therapy (n=87) had a significantly longer time to loss of fistula response than patients in the control group (n=90) (median >40 weeks vs 14 weeks [P=0.001]). At Week 14, 65% (177/273) of patients were responders. Fistula response was defined as ≥50% reduction in the number of draining fistulas on at least 2 consecutive visits and no increase in Crohn's disease (CD) medication and no surgery for CD.
 
References:
  1. Data on file. Janssen Biotech, Inc.
  2. Hanauer SB, Feagan BG, Lichtenstein GR, et al; and the ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.
  3. REMICADE® (infliximab) Prescribing Information. Janssen Biotech, Inc.
  4. Supplement to: Colombel JF, Sandborn WJ, Reinisch W, et al; Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395. http://www.nejm.org/doi/suppl/10.1056/NEJMoa0904492/suppl_file/nejm_colombel_1383sa1.pdf. Accessed January 18, 2011.
  5. Colombel JF, Sandborn WJ, Reinisch W, et al, for the SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395.
  6. Targan SR, Hanauer SB, van Deventer SJH, et al, for the Crohn's Disease cA2 Study Group. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. N Engl J Med. 1997;337:1029-1035.
  7. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004;350:876-885.

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REMICADE® is indicated for:

Crohn's Disease
  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy
  • Reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD
Pediatric Crohn's Disease
  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age or older with moderately to severely active CD who have had an inadequate response to conventional therapy
Ulcerative Colitis
  • Reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy
Pediatric Ulcerative Colitis
  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy
Rheumatoid Arthritis
  • Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate (MTX)
Psoriatic Arthritis
  • Reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis (PsA)
Ankylosing Spondylitis
  • Reducing signs and symptoms in patients with active ankylosing spondylitis (AS)
Plaque Psoriasis
  • The treatment of adult patients with chronic severe (ie, extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate

 

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, blastomycosis 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, including Legionella and Listeria.

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.

Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant 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).

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including REMICADE®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

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 should be tested for HBV infection before initiating REMICADE®. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. 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 (eg, ≥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 occurring in >10% of patients included infections (eg, upper respiratory, sinusitis, and pharyngitis),
infusion-related reactions, headache, and abdominal pain.

USE WITH OTHER DRUGS

Concomitant use of REMICADE® with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as REMICADE® is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

Live vaccines or therapeutic infectious agents should not be given with REMICADE® due to the possibility of clinical infections, including disseminated infections.

Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE®. Exercise caution in the administration of live vaccines to infants born to female patients treated with REMICADE® during pregnancy.

For more information, please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion. (Requires Adobe® Reader®. Click here to download.)

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.