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ASSERT Study Shows REMICADE Improves Signs and Symptoms in Patients with Active AS

ASSERT Study background

ASSERT was the first major study of the safety and effectiveness of REMICADE in the treatment of AS. Standing for “Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy,” ASSERT was one of the largest studies ever conducted in patients with AS. FDA acceptance of a Supplemental Biologics License application for the use of REMICADE to treat AS in the United States was based primarily on results from ASSERT.

Patients in the ASSERT study were assigned at random to different treatment groups. Neither the patients nor the researchers giving them treatment were aware of which group would receive REMICADE.
201 patients were given REMICADE alone in 5 mg/kg infusions at Weeks 0, 2, 6, 12, and 18. Seventy-eight patients were given placebo infusions (treatments with no medical effect) at the same intervals.

ASSERT Study findings

The main goal of ASSERT was to find out how many patients would demonstrate a 20% or greater improvement in their signs and symptoms by the 24th week, as measured by a scale called the ASsessments in AS (ASAS).

At Week 24, a significantly greater number of patients treated with REMICADE achieved 20% or greater improvement in signs and symptoms compared to patients who received a placebo (60% vs. 18%, respectively).
The most commonly reported adverse events were upper respiratory tract infections, which occurred at a slightly higher rate in the placebo group (15%) compared to the REMICADE group (14%). Serious adverse events were noted in 3.5% of REMICADE-treated patients compared to 2.7% of patients receiving placebo.

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