The Doctor's Channel - Allergy & Clinical Immunology

Long-term abatacept safe, usually effective for juvenile idiopathic arthritis

2010-03-12T21:01:30+00:00

NEW YORK (Reuters Health) - Four out of five children with juvenile idiopathic arthritis had a good clinical response to abatacept during a long-term open-label extension trial. The safety profile was good, and the level of response often increased as treatment went on, the researchers report.

Lead author Dr. Nicolino Ruperto, from Universita di Genova, Italy, and associates report these findings in Arthritis & Rheumatism published online February 26th.

Abatacept is a soluble fusion protein that selectively modulates the costimulatory signal required for full T cell activation, the authors explain.

Their trial had three phases: a 4-month open-label lead-in in which all patients took abatacept; a 6-month randomized, double-blind, placebo-controlled withdrawal phase (in which patients with a flare discontinued treatment); and the open-label long-term extension that's the focus of the current report.

The researchers enrolled 153 children from Europe, Latin America, and the U.S. who ranged in age from 6 to 17 years. Their median disease duration was 4.1 years. In addition to abatacept 10 mg/kg (maximum, 1000 mg) given every 28 days, the children could also receive oral or intra-articular steroids and methotrexate.

For the efficacy analysis at day 589 of the open extension, the investigators divided patients into three groups:
-- 51 children continuously treated with abatacept during all three phases -- 47 children randomized to placebo who resumed treatment with abatacept during the extension phase
-- 22 children without an ACR (American College of Rheumatology) Pedi 30 response during the open-label lead-in who continued treatment with abatacept in the extension phase.

Total treatment time ranged from 21 to 52 months.

Among the 51 children who took abatacept for all three phases, 88% achieved at least an ACR Pedi 50, 57% achieved at least an ACR Pedi 90, and 43% achieved inactive disease status.

Among the 47 placebo-group children who resumed abatacept in the extension phase, 83% achieved an ACR Pedi 50, 40% an ACR Pedi 90 and 23% achieved inactive disease.

Finally, among the children who could not achieve ACR Pedi 30 in the lead phase, 64% had an ACR Pedi 50 in the extension phase, and 18% had an ACR Pedi 90. One child (2.8%) achieved inactive disease status.

Given that most patients who did not respond during the lead-in phase did respond during the extension, the authors suggest that 4 months may not be a sufficient therapeutic trial with abatacept for some patients.

"The clinical benefit of abatacept treatment is maintained or progressively improves with time," and treatment is safe and well tolerated, the researchers conclude. There were no cases of tuberculosis, opportunistic infections, or malignancies during open-label treatment, although one 12-year-old boy developed multiple sclerosis.

Furthermore, interruptions in therapy were well tolerated and not associated with adverse events or infusion reactions when therapy was re-introduced. Seventeen patients developed anti-abatacept or anti-CTLA-4 antibodies, which did not affect efficacy or elicit safety concerns.

However, the authors note, the number of patients and extent of treatment was not sufficient to detect rare safety events, so they plan to continue following this cohort and to establish a registry.

Bristol-Myers Squibb, which manufactures abatacept under the brand name Orencia, provided funds for the study.

Reference:
Arthritis Rheum 2010.

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Montelukast cuts recurrent wheezing with RSV bronchiolitis

2010-03-02T20:08:06+00:00

NEW YORK (Reuters Health) - Montelukast (Singulair), a leukotriene receptor antagonist, can help prevent recurrent wheezing episodes after respiratory syncytial virus (RSV) bronchiolitis, new research shows.

From earlier work, the researchers knew that airway levels of cysteinyl leukotriene correlated with eosinophil numbers in RSV bronchiolitis. The goal of the present study was to see if reduction of leukotriene levels with montelukast might reduce eosinophil degranulation, which in turn would help reduce recurrent wheezing.

To this end, Dr. Chang-Keun Kim, from Inje University Sanggye Paik Hospital in Seoul, Korea, and colleagues conducted a randomized trial in 200 infants, 6 to 24 months of age, who were hospitalized with a first episode of acute RSV bronchiolitis. Daily for three months, the babies received either oral montelukast 4 mg or placebo. Eosinophil degranulation was assessed by serum levels of eosinophil-derived neurotoxin.

The researchers report their findings in the February 22nd online issue of the Journal of Pediatrics.

At the end of the treatment period, eosinophil-derived neurotoxin levels had decreased significantly in the montelukast group (p < 0.01) and increased significantly in the placebo group (p < 0.0001), the researchers report. Neurotoxin levels remained significantly lower in the montelukast group at 12 months. (Twelve-month data was available for 79 babies in the treatment group and 71 in the placebo group.)

Infants in the montelukast group had significantly fewer recurrent wheezing episodes (p = 0.039), but the significant difference between the groups only emerged after 9 to 12 months. Although this may not seem like strong supporting evidence for montelukast, the authors note this is likely because of the short observation period.

The results "suggest that eosinophil degranulation is important in the pathogenesis of severe RSV disease and that therapies that inhibit degranulation of eosinophils warrant further investigation," the authors said.

Also, they point out, infants with high levels of eosinophil-derived neurotoxin at 3 months seems to be at increased risk for recurrent wheezing. "Although subsequent wheezing may also be caused by other acute viral infections, we suggest 3-month eosinophil-derived neurotoxin levels may be a useful biomarker for predicting recurrent wheezing in children with post-RSV bronchiolitis," the researchers conclude.

The study was funded, in part, by Merck, the maker of Singulair.

Reference:
J Pediatr 2010.

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Belatacept-based immunosuppression spares renal function in kidney recipients

2010-03-01T17:28:28+00:00

NEW YORK (Reuters Health) – Belatacept-based immunosuppression after kidney transplantation allows for better renal function compared to cyclosporine, with similar graft and patient survival, phase III trial results suggest.

In kidney allograft recipients, “the leading causes of death and graft loss are cardiovascular disease and chronic allograft nephropathy, respectively,” Dr. Flavio Vincenti and co-researchers note.

Cyclosporine – perhaps the most commonly used immunosuppressive in kidney recipients -- is a calcineurin inhibitor. This class of drugs has a wide range of severe side effects, including nephrotoxicity. Their toxicity is thought to relate to their broad range of nonimmunologic targets, Dr. Vincenti, from the University of California, San Francisco, and colleagues note. Thus, a drug with greater specificity, such as the selective T-cell activation blocker belatacept, would be expected to have fewer toxicities.

In the 3-year international BENEFIT trial, 686 patients were randomized to receive a belatacept- or cyclosporine-based regimen. Belatacept-treated patients were further divided to receive a more or less intensive regimen, based on how long the drug was given at a 10-mg/kg dose versus a 5-mg/kg dose.

All patients received induction therapy with basiliximab, mycophenolate mofetil, and steroids.

At 12 months, the composite endpoint of patient and graft survival was similar in all three groups, hovering around 95%.

The composite renal endpoint – measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m2 at month 12, or mGFR decrease of at least 10 mL/min/1.73 m2 between months 3 and 12 – occurred in 55% in the belatacept groups versus 78% in the cyclosporine group (p < 0.001).

Episodes of acute rejection occurred in 22% of patients on the more intensive regimen, 17% on the less intensive regimen, and 7% in the cyclosporine group. Grade of rejection was also higher with the belatacept regimens.

Commenting on their finding that “the overall impact of acute rejection episodes did not negate the…benefits of belatacept,” the authors suggest that “the immune-selectivity of betalacept may affect the composition of rejection infiltrate differently from cyclosporine, resulting in reduced graft damage.”

Side effects were common and generally similar in each group. There were two cases of post-transplant lymphoproliferative disorder in the belatacept group but none in the cyclosporine group.

In a related study, BENEFIT-EXT, Dr. Antoine Durrbach, from Bicetre Hospital, Paris, and colleagues compared belatacept versus cyclosporine in recipients of kidney transplants from extended criteria cadaveric donors. These donors were 60 years of age or older, or 50 years or older with at least two risk factors (stroke, hypertension, or serum creatinine >1.5 mg/dL), or their kidneys had at least 24 hours of cold ischemia, or their organs were procured after cardiac death.

Recipients of grafts from these donors are “challenging to immunosuppress, as they tend to be older and are at increased risk for cardiovascular events and mortality compared with nonextended criteria donor recipients,” the authors note. Nonetheless, the results of BENEFIT-EXT, which featured 578 randomized patients, were similar to those of BENEFIT.

Both studies are reported in the March issue of the American Journal of Transplantation.

BENEFIT and BENEFIT-EXT were funded by Bristol-Myers Squibb, the developer of belatacept.

Reference:
Am J Transpl 2010;10:535-557.

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Avoid diphenhydramine, ranitidine after perforated appendicitis: study

2010-02-19T18:52:45+00:00

NEW YORK (Reuters Health) – Giving the antihistamines ranitidine or diphenhydramine to patients with perforated appendicitis dramatically increases their risk of an intra-abdominal abscess, according to a new study.

Giving one or the other agent doubled the risk, while giving both drugs increased the risk four-fold.

“Anybody not having an indication for these meds probably shouldn’t get them,” lead researcher Dr. Shawn D. St. Peter told Reuters Health by phone.

He and his coauthors note that clinicians often treat the pain of perforated appendicitis with ketorolac tromethamine, which can lead to gastritis, or narcotics, which can cause itching. Ranitidine, a histamine-2 (HR) receptor blocker that suppresses gastric acid, and diphenhydramine, an H1 receptor blocker than stops itching and induces sleep, are prescribed, often prophylactically, to counter these side effects.

In the February Archives of Surgery, Dr. St. Peter and his colleagues at Children’s Mercy Hospital in Kansas City, Missouri explain that during a prospective trial of two antibiotic regimens for perforated appendicitis, they saw that patients on ranitidine seemed to have a higher rate of intra-abdominal abscess.

The trial included 98 children (mean age, 8.6 years). The 41 children who didn’t receive either ranitidine or diphenhydramine had an abscess rate of 10%. In contrast, the researchers found abscess rates of 17% in the 24 children who received ranitidine only, 18% in the 17 who received diphenhydramine only, and 44% in the 16 children who took both medications.

On multivariate analysis, the abscess rate was significantly higher with ranitidine (p = 0.05) and diphenhydramine (p = 0.03). Ranitidine also had a significant dose-related effect on abscess rate (p = 0.003).

By contrast, there was no link between abscess rates and use of ketorolac, naloxone, ondansetron or narcotics.

“The effect of blocking (histamine) receptors is diffusely integral to the inflammatory response,” the authors write. They explain that both H1 and H2 receptors are expressed in neutrophils, eosinophils, monocytes, dendritic cells, and T and B cells.

Concluding, Dr. St. Peter said, “I don’t want to say that these drugs are detrimental, but I can absolutely unequivocally say they don’t help… and shouldn’t be given unless there is a clear indication.”

Reference:
Arch Surg 2010;145:143-146.

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Skin manifestations of psoriatic arthritis respond best to twice weekly etanercept

2010-02-12T20:20:15+00:00

NEW YORK (Reuters Health) - In patients with psoriatic arthritis, once weekly etanercept (Enbrel) is suitable for joint symptoms but twice weekly dosing is needed to best address skin lesions, according to a report in the February 9th Online First issue of BMJ

"Inflammation in the skin seems to be more pronounced than in joints of psoriasis patients, and thus requires a higher dosing, particularly in the induction phase of treatment," lead author Dr. Wolfram Sterry, from Charite University Medicine, Berlin, told Reuters Health by email.

According to Dr. Sterry, the trial was the first to compare "two different dosing regimens of etanercept in patients with psoriasis, suffering both from moderate to severe skin involvement as well as marked arthritis."

The 98-center PRESTA study, conducted in Europe, Latin America, and the Asia Pacific region, featured 752 outpatients. During the first phase, patients were randomized to receive etanercept 50 mg once or twice weekly (by subcutaneous injection) for 12 weeks. During the second phase, all subjects received the drug once weekly for 12 more weeks.

At 12 weeks, based on physician's global assessment, lesions had cleared or almost cleared in 46% of subjects in the twice-weekly group compared to only 32% in the once-weekly group (p < 0.001).

Twice weekly etanercept patients also showed greater mean reductions in the psoriasis area and severity index at week 12 than did once weekly etanercept patients (71% vs. 62%, p < 0.001). By week 24, however, the difference was no longer statistically significant (78% vs. 74%).

In terms of patients achieving arthritis response criteria, by contrast, once weekly etanercept performed just as well as twice weekly (76% vs. 77%). Likewise, joint and tendon manifestations improved to a similar extent in both groups.

Side effects with etanercept were consistent with previous reports on the drug. The most common adverse events were upper respiratory tract infection, injection site reaction, pharyngitis, and headache. There was no significant difference in side effects between groups.

The take-home message, Dr. Sterry said, is that the "skin and joints of patients suffering from psoriasis respond excellently to etanercept treatment, with skin involvement requiring higher dosing" than joint symptoms.

"It might be interesting to see whether other treatments also show this differential effect, and what could be the mechanisms behind it," he added.

The study was sponsored by Wyeth Pharmaceuticals, which markets etanercept as Enbrel and employs five of the nine authors.

Reference:
BMJ 2010.

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Inhaled steroids only modestly useful in preventing COPD flare-ups

2010-02-09T18:40:59+00:00

NEW YORK (Reuters Health) – Although inhaled corticosteroids (ICS) can help prevent exacerbations of chronic obstructive pulmonary disease (COPD), an analysis of randomized trials suggests that the benefits have been overstated.

“Given the possible morbidity associated with the use of ICS, it is important to reevaluate the benefit of ICS, especially with its claim of reducing exacerbations,” Dr. Ritesh Agarwal and colleagues, from the Postgraduate Institute of Medical Education and Research, Chandigarh, India, note.

As reported in the February issue of Chest, the researchers conducted a systematic review and meta-regression analysis of 11 trials (with 8164 patients) that were identified through a search of PubMed, EmBase, and the Cochrane Central Database of Controlled Trials databases (1988-2008). All of the studies compared ICS to placebo for preventing COPD exacerbations.

On initial analysis, ICS reduced the risk of COPD flare-ups by 18%. Although there was no apparent publication bias, there was significant statistical heterogeneity between the studies.

On sensitivity analysis, the benefit of ICS use in preventing exacerbations was confined to patients with a baseline forced expiratory volume in one second (FEV1) of less than 50%. Even in these patients, though, the reduction in risk was only modest (RR, 0.79) and statistical heterogeneity persisted.

Finally, on meta-regression, the benefit of ICS use disappeared completely, regardless of baseline lung function.

“ICS is likely to have only modest benefits in preventing COPD exacerbations, if at all, and should be judiciously used in patients with COPD keeping in mind the risk-benefit ratio,” the authors conclude.

Still, because only 11 studies were included and because the meta-regression considers only mean FEV1 and not the standard deviation, the authors warn that the results should be interpreted with “extreme caution.”

To better define the role of ICS in preventing COPD flare-ups, they call for further meta-analyses using individual patient data.

Reference:
Chest 2010;137:318-325.

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Long-term antibiotic treatment effective for Crohn's disease

2010-02-08T20:01:56+00:00

NEW YORK (Reuters Health) - Long-term treatment with clofazimine or nitroimidazoles may help control Crohn's disease, according to the authors of a systematic review and meta-analysis.

Several bacteria have been implicated in Crohn's disease, but antibiotics are currently recommended only for certain complications, such as sepsis or perianal disease, the researchers note in the February 15th issue of Clinical Infectious Diseases.

The meta-analysis, by Dr. Martin Feller from the University of Bern, Switzerland, and colleagues, pooled data from 16 randomized, placebo-controlled trials involving a total of 865 patients, in order to assess the effectiveness of long-term antibiotic treatment for Crohn's disease. The outcomes were remission (in patients with active disease) or relapse (in patients with inactive disease).

The studies examined 13 different treatment regimens, ranging from single drugs to combinations of up to 4 drugs. The median treatment duration was 6 months. Four studies specifically excluded the use of steroids; the others either included them or allowed them to be added when indicated.

The quality of reporting of study methods was generally low, the authors report.

Three trials of nitroimidazoles (206 patients) showed a significant benefit (odds ratio, 3.54), the researchers note, as did 4 trials of clofazimine (322 patients; OR, 2.86).

The number of patients with active disease needed to treat to keep 1 additional patient in remission was 3.4 for nitroimidazoles and 4.2 for clofazimine. For inactive disease, the number needed to treat was 6.1 for nitroimidazoles and 6.9 for clofazimine.

One trial of ciprofloxacin, involving 47 patients, showed a benefit (OR, 11.3), but with a wide confidence interval.

Three trials involving 107 patients showed no benefit from treatment with classic anti-tuberculosis drugs.

The 4 studies of clarithromycin alone or in combination with other antibiotics (287 patients) were highly heterogeneous and could not be combined in the meta-analysis, according to the report.

"We believe that further research is justified to better define the role of antibacterial agents and combination regimens in Crohn's disease," the investigators say. "Future studies should focus on clofazimine, alone or in combination with a macrolide and a rifamycin, as well as in combination with a nitroimidazole, and perhaps ciprofloxacin."

Reference:
Clin Infect Dis 2010;50:473-480.

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Only two testing visits needed to confirm asthma in most patients

2010-02-01T19:40:22+00:00

NEW YORK (Reuters Health) - Only two visits to the pulmonary function lab -- one for pre- and post-bronchodilatory spirometry and one for a methacholine challenge test -- are necessary to confirm an asthma diagnosis in over 90% of patients, according to a report in the January 14th online issue of the European Respiratory Journal.

In a study reported in 2008, Dr. Shawn D. Aaron and colleagues had used a stepwise algorithm to show that in 30% of adults with physician-diagnosed asthma, objective assessment led to reversal of the diagnosis. Features of the algorithm included serial spirometry, bronchial challenge testing, and tapering of asthma medications.

But that 2008 algorithm often required four visits to the pulmonary function lab.

Thinking back to the findings reported in 2008, the authors questioned whether all of the steps in the confirmatory algorithm were truly necessary and whether it might be possible to save patients a trip or two to the pulmonary function lab.

Therefore, Dr. Aaron and colleagues, from the University of Ottawa, Canada, re-analyzed their data. They had recruited 540 subjects with physician-diagnosed asthma who were randomly selected from across Canada. Ultimately, 499 patients completed all of the study assessments and were evaluable for asthma.

Using the full algorithm, 346 of 499 (69%) had their asthma diagnosis confirmed. However, 329 of the 346 (95%) had their diagnosis confirmed within just 2 visits to the pulmonary function laboratory. The key measures were pre- and post-bronchodilator spirometry and methacholine challenge test results.

Just 49 of 499 subjects (9%) required tapering of asthma medications and repeat bronchial challenge tests to confirm or exclude asthma.

"Our study has shown that more than 90% of subjects who report physician-diagnosed asthma, even those who are taking regular asthma controlling medications, can have their diagnosis of asthma confirmed with only 2 testing visits to the pulmonary function laboratory," the authors conclude.

Reference:
Eur Respir J 2010.

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Biomarker-guided treatment of infection reduces antibiotic exposure in ICUs

2010-01-28T16:43:58+00:00

NEW YORK (Reuters Health) - The biomarker procalcitonin can help guide treatment of severe bacterial infections in the intensive care unit (ICU), French investigators report online in The Lancet on January 23.

They suggest that procalcitonin-guided therapy can cut treatment duration and perhaps reduce the emergence of antibiotic-resistant strains.

Serum levels of procalcitonin have been used to diagnose bacterial sepsis, the authors explain, and its use has been shown to reduce antibiotic exposure in patients with acute respiratory tract infections. However, the few ICU trials were small and “underpowered for safety, which in this setting is of the utmost importance.”

In the prospective, open-label PRORATA trial, Dr. Michel Wolff at Hopital Bichat-Claude-Bernard in Paris and colleagues compared procalcitonin-guided treatment with standard care in 8 ICUs. In patients randomized to the procalcitonin group, levels were measured each day, and 0.5 mcg/L was the threshold for starting antibiotics. Physicians were urged to stop treatment when procalcitonin dropped below 80% of the peak concentration or when the absolute concentration was < 0.5 mcg/L.

In both groups, all treatment decisions were left in the hands of the treating physicians.

According to the report, the patients had a wide range of infections; 40% had septic shock, and close to 70% were on mechanical ventilation.

Mortality did not differ significantly between the 307 patients in the procalcitonin group and the 314 controls at day 28 (21.2% vs 20.4%, respectively) or at day 60 (30% vs 26.1%, respectively), the investigators report, demonstrating non-inferiority of the procalcitonin algorithm. None of the deaths was related to infection relapse.

During the first 4 weeks, antibiotic treatment lasted an average of 10.3 days in the procalcitonin group and 13.3 days in the control group, for a 23% relative reduction in days of antibiotic exposure (p < 0.0001). Days of antibiotic exposure per 1000 inpatient days totaled 653 and 812, respectively (p < 0.0001).

Rates of physician adherence to the treatment algorithm were 47% in the procalcitonin group and 55% in the control group. However, findings were similar for patients strictly managed according to study algorithms.

After the 28th day, 39% of patients in each group had not been discharged, but only 17% of the procalcitonin group and 14% of the control group were still in the ICU.

The authors found no differences between the groups in most secondary outcomes, including rates of relapse or superinfection, number of days without mechanical ventilation, ICU or hospital length of stay, and percentage of emerging multidrug-resistant bacteria.

They note that their findings cannot be extrapolated to surgical patients, who represented about 10% of the study cohort, or to those needing long-term antibiotics or who are neutropenic or infected with high-risk pathogens.

Still, the researchers believe their conclusions are likely to be generalizable to most other non-surgical ICU patients, including those who are immunocompromised.

Furthermore, they add, “A procalcitonin-guided strategy could reduce antibiotic selective pressure with potential benefits in the era of multiresistance.”

Reference:
Lancet 2010.

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New oral agents effective against relapsing multiple sclerosis

2010-01-28T16:18:48+00:00

NEW YORK (Reuters Health) – Cladribine and fingolimod, the first oral agents for multiple sclerosis (MS), significantly reduce relapse rates, risks of disability progression, and disease activity, according to three papers in the January 19th online issue of The New England Journal of Medicine.

“The long-awaited arrival of oral formulations for the treatment of relapsing-remitting MS is welcome news for the estimated 2.5 million people worldwide who have this chronic disabling problem,” Dr. William M. Carroll, from Sir Charles Gairdner Hospital, Perth, Australia, comments in an editorial. He adds that the findings “provide a new horizon for patients with relapsing-remitting MS and a welcome increase in the range of treatment options.”

Cladribine is being developed by Merck and fingolimod by Novartis. Neither drug has yet been approved as anti-MS agents in the United States.

In the CLARITY trial, Dr. Gavin Giovannoni, from Queen Mary University London, and colleagues compared cladribine, at either 3.5 or 5.25 mg/kg, to placebo in 1326 patients. Overall, 1184 patients (89.3%) completed the 96-week study. Adverse events led to withdrawal in 3.5%, 7.9%, and 2.1% of patients in the low-dose, high-dose, and placebo groups, respectively.

The assigned agent was given in two or four short courses for 48 weeks and then in two short courses starting at week 48 and week 52. The main endpoint was the relapse rate at 96 weeks.

The annualized relapse rate in both cladribine groups was roughly 0.15, significantly lower than the 0.33 rate seen in the placebo group (p < 0.001). The relapse-free rate was about 79% in each cladribine group compared with 60.9% in the placebo group (p < 0.001).

Patients in the 3.5 and 5.25 mg/kg groups were 33% and 31% less likely to show disability progression over 3 months than were control subjects.

Lastly, patients given cladribine had fewer brain lesions on MRI than did those given placebo (p < 0.001).

In terms of side effects, lymphocytopenia was more common in the cladribine groups (21.6% with 3.5-mg/kg dose, 31.5% with 5.25 mg/kg-dose, and 1.8% for placebo) as was herpes zoster (8 patients, 12 patients, no patients, respectively).

In the second and third papers, Dr. Ludwig Kappos, from University Hospital, Basel, Switzerland, and colleagues report on studies of fingolimod versus placebo and fingolimod versus intramuscular interferon.

In the FREEDOMS study, 1272 patients were randomized to receive oral fingolimod (0.5 mg or 1.25 mg per day) or placebo for 24 months. A total of 1033 subjects (81.2%) completed the study. Thirty-five patients in the treatment groups and 18 in the placebo group discontinued the study due to adverse events.

The annualized relapse rate in both fingolimod groups was roughly 0.17, significantly lower than the 0.40 rate seen in the placebo group (p < 0.001). The relapse-free rates were 75% and 70% in the high- and low-dose fingolimod groups and 46% in the placebo group (p < 0.001 for each).

Patients in the lower and higher dose fingolimod groups were 30% and 32% less likely to show disability progression over 24 months than were control subjects.

Here again, patients in the treatment groups had fewer new or enlarged brain lesions on MRI than did those given placebo (p < 0.001).

Side effects seen with fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, liver enzyme elevations, and mild hypertension, the report indicates.

In the 12-month TRANSFORMS study, Dr. Kappos and his colleagues randomized 1292 patients to receive fingolimod, at the doses used in FREEDOMS, or intramuscular interferon beta-1a at a weekly dose of 30 micrograms. A total of 1153 patients (89%) completed the study. Forty-eight patients in the fingolimod groups and 12 patients in the interferon group withdrew because of adverse events.

The annualized relapse rates with the lower and higher doses of fingolimod were 0.16 and 0.20, respectively, versus 0.33 with interferon. The MRI results were consistent with these findings. Fingolimod and interferon were similar in terms of the impact on progression of disability.

Two fatal infections -- disseminated varicella zoster (in a patient exposed to a child with chicken pox during a course of steroids for a relapse) and herpes simplex encephalitis -- occurred in the 1.25-mg fingolimod group. Other side effects seen with fingolimod were similar to those seen in FREEDOMS.

Reference:
N Engl J Med 2010.

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