Health-Related QOL During Natalizumab Maintenance Therapy - Crohn's
Health-Related QOL During Natalizumab Maintenance Therapy - Crohn's
Objectives: We evaluated the effects of treatment on health-related quality of life (HRQoL) during a randomized controlled trial of natalizumab maintenance therapy (ENACT-2) using both disease-specific and generic measures.
Methods: Crohn's disease patients who received natalizumab as induction therapy in ENACT-1 (N = 724) and responded (N = 339) were re-randomized to ENACT-2 in which they received natalizumab 300 mg (N = 168) or placebo (N = 171) every 4 wk for 48 additional wk. Outcome measures were the change from baseline on the inflammatory bowel disease questionnaire (IBDQ), the short form-36 (SF-36), the EuroQol-5D (EQ-5D), and a subject global assessment.
Results: At entry into ENACT-1, scores indicated substantially impaired HRQoL for both the disease-specific and general measures. Natalizumab responders showed clinically meaningful improvement in HRQoL over the course of the ENACT-1 study. During maintenance therapy, IBDQ and SF-36 scale scores of patients who responded to natalizumab induction and were re-randomized to receive the drug in ENACT-2 (N = 168) remained stable, while those re-randomized to placebo (N = 171) worsened. At week 60, 48 wk after the initiation of maintenance therapy, the mean change from ENACT-1 baseline of all scales of the IBDQ and the SF-36 was significantly higher for those who continued to receive natalizumab (P < 0.001 for all scales). The scores of patients who received maintenance natalizumab treatment were not statistically different from those of a cross-section of the U.S. population for 6 of 8 scales of the SF-36.
Conclusions: The substantial improvement in HRQoL experienced by patients who responded to natalizumab induction therapy was maintained during an additional 48 wk of maintenance therapy.
Crohn's disease is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that is characterized by symptoms of abdominal pain, diarrhea, and rectal bleeding. Crohn's disease is also frequently associated with extraintestinal manifestations, including arthralgias, aphthous stomatitis, and erythema nodosum. Although many patients with mild to moderate disease will experience prolonged remission, approximately 60% will ultimately develop a stricturing or penetrating complication. Surgery is frequently required to manage these complications and to provide symptomatic relief for patients who are refractory to medical therapy. Although effective pharmacological therapy has been available for some time through the use of corticosteroids and immunosuppressants, treatment with these drugs may cause side effects that also negatively affect health-related quality of life (HRQoL).
In summary, symptoms, complications, comorbidities, and therapy all contribute to the poor HRQoL of patients. Previous studies have shown that patients with Crohn's disease have worse HRQoL than members of the general population. Furthermore, the degree of impairment experienced by these individuals may be as severe as, or worse than, other debilitating diseases such as severe angina or ulcerative colitis after colectomy.
Given this situation, a need exists for more effective medical therapy. The chimeric monoclonal antitumor necrosis factor antibody infliximab is typically reserved for patients whose disease is refractory to immunosuppressants or corticosteroids. Infliximab is an effective maintenance therapy in this patient population and has demonstrated long-term HRQoL improvements in patients with moderately to severely active Crohn's disease. However, in the largest trial of infliximab maintenance therapy (ACCENT-1), patients were not demonstrated to have sustained inflammatory bowel disease questionnaire (IBDQ) scores typical of remission (total score > 170) during maintenance therapy with infliximab.
Natalizumab (TYSABRI®, Elan Pharmaceuticals, San Diego, CA and Biogen Idec, Cambridge, MA), a humanized monoclonal IgG4 antibody that binds to the α-4 integrin, selectively inhibits immune cells from leaving the bloodstream and prevents these cells from migrating into the gastrointestinal tract, where they can initiate and sustain inflammation. Data from phase 2 and 3 studies suggest that natalizumab is effective for both induction and maintenance therapy, and that HRQoL improvements occur following treatment for active disease.
In the ENACT-2 (Evaluation of Natalizumab As Continuous Therapy) maintenance study, the primary and contingent primary end points were the proportion of patients who did not lose response or remission achieved in the preceding 12-wk induction study (ENACT-1; Efficacy of Natalizumab as Active Crohn's Therapy) through 36 wk. Determinations of response and remission were made independently of concomitant therapy status. Monthly treatment with natalizumab resulted in significantly greater sustained (month-over-month) response (61% vs 28%, P < 0.001) and remission (CDAI < 150) (44% vs 26%, P = 0.003) than placebo through 36 wk. Response (54% vs 20%, P < 0.001) and remission (39% vs 15%, P < 0.001) remained significantly greater in the natalizumab-treated group compared with placebo through week 60. This manuscript reports the results from ENACT-2 on the effect of maintenance natalizumab treatment on HRQoL improvements that were achieved in patients who responded to natalizumab induction treatment in ENACT-1.
Abstract and Introduction
Abstract
Objectives: We evaluated the effects of treatment on health-related quality of life (HRQoL) during a randomized controlled trial of natalizumab maintenance therapy (ENACT-2) using both disease-specific and generic measures.
Methods: Crohn's disease patients who received natalizumab as induction therapy in ENACT-1 (N = 724) and responded (N = 339) were re-randomized to ENACT-2 in which they received natalizumab 300 mg (N = 168) or placebo (N = 171) every 4 wk for 48 additional wk. Outcome measures were the change from baseline on the inflammatory bowel disease questionnaire (IBDQ), the short form-36 (SF-36), the EuroQol-5D (EQ-5D), and a subject global assessment.
Results: At entry into ENACT-1, scores indicated substantially impaired HRQoL for both the disease-specific and general measures. Natalizumab responders showed clinically meaningful improvement in HRQoL over the course of the ENACT-1 study. During maintenance therapy, IBDQ and SF-36 scale scores of patients who responded to natalizumab induction and were re-randomized to receive the drug in ENACT-2 (N = 168) remained stable, while those re-randomized to placebo (N = 171) worsened. At week 60, 48 wk after the initiation of maintenance therapy, the mean change from ENACT-1 baseline of all scales of the IBDQ and the SF-36 was significantly higher for those who continued to receive natalizumab (P < 0.001 for all scales). The scores of patients who received maintenance natalizumab treatment were not statistically different from those of a cross-section of the U.S. population for 6 of 8 scales of the SF-36.
Conclusions: The substantial improvement in HRQoL experienced by patients who responded to natalizumab induction therapy was maintained during an additional 48 wk of maintenance therapy.
Introduction
Crohn's disease is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that is characterized by symptoms of abdominal pain, diarrhea, and rectal bleeding. Crohn's disease is also frequently associated with extraintestinal manifestations, including arthralgias, aphthous stomatitis, and erythema nodosum. Although many patients with mild to moderate disease will experience prolonged remission, approximately 60% will ultimately develop a stricturing or penetrating complication. Surgery is frequently required to manage these complications and to provide symptomatic relief for patients who are refractory to medical therapy. Although effective pharmacological therapy has been available for some time through the use of corticosteroids and immunosuppressants, treatment with these drugs may cause side effects that also negatively affect health-related quality of life (HRQoL).
In summary, symptoms, complications, comorbidities, and therapy all contribute to the poor HRQoL of patients. Previous studies have shown that patients with Crohn's disease have worse HRQoL than members of the general population. Furthermore, the degree of impairment experienced by these individuals may be as severe as, or worse than, other debilitating diseases such as severe angina or ulcerative colitis after colectomy.
Given this situation, a need exists for more effective medical therapy. The chimeric monoclonal antitumor necrosis factor antibody infliximab is typically reserved for patients whose disease is refractory to immunosuppressants or corticosteroids. Infliximab is an effective maintenance therapy in this patient population and has demonstrated long-term HRQoL improvements in patients with moderately to severely active Crohn's disease. However, in the largest trial of infliximab maintenance therapy (ACCENT-1), patients were not demonstrated to have sustained inflammatory bowel disease questionnaire (IBDQ) scores typical of remission (total score > 170) during maintenance therapy with infliximab.
Natalizumab (TYSABRI®, Elan Pharmaceuticals, San Diego, CA and Biogen Idec, Cambridge, MA), a humanized monoclonal IgG4 antibody that binds to the α-4 integrin, selectively inhibits immune cells from leaving the bloodstream and prevents these cells from migrating into the gastrointestinal tract, where they can initiate and sustain inflammation. Data from phase 2 and 3 studies suggest that natalizumab is effective for both induction and maintenance therapy, and that HRQoL improvements occur following treatment for active disease.
In the ENACT-2 (Evaluation of Natalizumab As Continuous Therapy) maintenance study, the primary and contingent primary end points were the proportion of patients who did not lose response or remission achieved in the preceding 12-wk induction study (ENACT-1; Efficacy of Natalizumab as Active Crohn's Therapy) through 36 wk. Determinations of response and remission were made independently of concomitant therapy status. Monthly treatment with natalizumab resulted in significantly greater sustained (month-over-month) response (61% vs 28%, P < 0.001) and remission (CDAI < 150) (44% vs 26%, P = 0.003) than placebo through 36 wk. Response (54% vs 20%, P < 0.001) and remission (39% vs 15%, P < 0.001) remained significantly greater in the natalizumab-treated group compared with placebo through week 60. This manuscript reports the results from ENACT-2 on the effect of maintenance natalizumab treatment on HRQoL improvements that were achieved in patients who responded to natalizumab induction treatment in ENACT-1.