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ACT 1 Clinical Trial Overview

ACT 1 Study Background

The FDA approval of REMICADE for induction of response and maintenance of remission in ulcerative colitis was based on data from the ACT 1 trial. ACT stands for Active Ulcerative Colitis Trial.

ACT 1 was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 364 patients with moderately to severely active UC who had an inadequate response or were intolerant to conventional therapy. The objectives of the trial were to determine the safety and efficacy of REMICADE versus placebo (1).

Patients presented with a Mayo score between 6 and 12, and an endoscopy subscore of ≥2. Prior failed or intolerable therapies in ACT 1 included oral corticosteroids, 6-mercaptopurine (6-MP), or azathioprine (AZA). At baseline, 46% of patients presented with extensive disease (e.g., pancolitis), the median disease duration was 4.7 years, and the median Mayo score was 8. The proportion of patients receiving concomitant therapy at baseline was reported as follows: corticosteroids, 61%; 6-MP/AZA, 49%; 5-aminosalicylates, 70%; 5-aminosalicylates alone, 11%. Thirty-one percent of patients receiving corticosteroids were refractory to treatment (1).

Patients were randomized to one of the following treatment groups:

Group I: Placebo at Weeks 0, 2, 6, and then placebo every 8 weeks thereafter through Week 46

Group II: REMICADE 5 mg/kg at Weeks 0, 2, 6, and then 5 mg/kg every 8 weeks thereafter through Week 46

Group III: REMICADE 10 mg/kg at Weeks 0, 2, 6, and then 10 mg/kg every 8 weeks thereafter through Week 46

Induction of clinical response, the primary endpoint, was evaluated 8 weeks following the initial infusion. Major secondary endpoints were evaluated at Week 30. Clinical response was defined by a ≥30% and ≥3 point reduction in the Mayo score accompanied by a decrease in rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. Clinical remission (Mayo score of ≤2 points with no individual subscore >1) and mucosal healing (endoscopy subscore of 0 or 1) were also evaluated as secondary endpoints. Concomitant treatment with stable doses of 5-ASA, corticosteroids, and/or immunomodulators was permitted throughout the studies. Of patients receiving steroids at baseline, tapering was allowed beginning at Week 8 (1).

ACT 1 Study Findings

A significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab groups achieved clinical response, clinical remission, and mucosal healing compared to patients in the placebo group (Table 1) (1).

Additionally, at Week 30, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo group (21.7% vs. 10.1%; p<0.039). This effect was maintained through Week 54, (21% in the infliximab groups compared to 9% in the placebo group) (1).

Table 1: Response, Remission, and Mucosal Healing (1).

	Placebo	Infliximab
		5 mg/kg	10 mg/kg
Patients randomized	121	121	122
Clinical Response*^†
Week 8	37%	69%^‡	62%^‡
Week 30	30%	52%^‡	51%^§
Week 54	20%	45%^‡	44%^‡
Sustained Response^†
(Clinical response at both Week 8 and 30)	23%	49%^‡	46%^‡
(Clinical response at Weeks 8, 30, and 54)	14%	39%^‡	37%^‡
Clinical Remission^†\|\|
Week 8	15%	39%^‡	32%^§
Week 30	16%	34%^§	37%^‡
Week 54	17%	35%^§	34%^§
Sustained Remission^†
(Clinical remission at both Week 8 and 30)	8%	23%^§	26%^‡
(Clinical remission at Weeks 8, 30, and 54)	7%	20%^§	20%^§
Mucosal Healing^†¶
Week 8	34%	62%^‡	59%^‡
Week 30	25%	50%^‡	49%^‡
Week 54	18%	45%^‡	47%^‡


*	Defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. (The Mayo score consists of the sum of four subscores: stool frequency, rectal bleeding, physician’s global assessment and endoscopy findings.)

†	Patients who had a prohibited change in medication, had an ostomy or colectomy, or discontinued study infusions due to lack of efficacy are considered to not be in clinical response, clinical remission, or mucosal healing from the time of the event onward.

‡	P<0.001

§	P<0.01

ll	Defined as a Mayo score ≤2 points, no individual subscore >1.

¶	Defined as a 0 or 1 on the endoscopy subscore of the Mayo score.

Please see Full Prescribing Information and Medication Guide for REMICADE.

Reference:
1. Data on file. Centocor, Inc.

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

RISK OF INFECTIONS
Tuberculosis (TB) (frequently disseminated or extrapulmonary at clinical presentation), bacterial infections including sepsis, invasive fungal infections, and other opportunistic infections have been observed in patients receiving REMICADE. Some of these infections have led to hospitalizations and death. Patients should be evaluated for TB risk factors and tested for latent TB.^1,2 Treatment of latent TB infection should be initiated prior to therapy with REMICADE. Some patients who received treatment for latent or active TB or who tested negative for latent TB prior to receiving REMICADE have developed active TB. In consultation with a physician with expertise in the treatment of TB, consider anti-TB treatment prior to REMICADE therapy in patients with a history of latent or active TB, when adequate treatment cannot be confirmed, or in patients who have a negative test for latent TB, but have several or highly significant risk factors.³ Monitor all patients receiving REMICADE for signs and symptoms of active TB.

Serious infections have occurred in patients on REMICADE alone or on concomitant immunosuppressive therapy that, in addition to their disease, could predispose them to infections. Cases of pneumonia, histoplasmosis, coccidioidomycosis, listeriosis, and pneumocystosis have been reported. For patients who have resided in regions where histoplasmosis or coccidioidomycosis is endemic, the benefits and risks of REMICADE should be considered before initiation of therapy. REMICADE should not be given to patients with a clinically important, active infection. Use with caution in patients with a history of infection. Monitor and educate patients for infection during or after treatment. Discontinue REMICADE if a patient develops a serious infection.

MALIGNANCIES
HEPATOSPLENIC T-CELL LYMPHOMAS
Rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with REMICADE. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. All of these hepatosplenic T-cell lymphomas with REMICADE have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine.

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 REMICADE-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected. 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 REMICADE infusions. 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.

Please see Full Prescribing Information and Medication Guide for REMICADE.

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 Centers for Disease Control for latest guidelines and recommendations for latent tuberculosis testing in immunocompromised patients.
Gardam MA, et al. Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-155

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Last Updated: October 31, 2008