American Academy of Neurology (AAN) 63rd Annual Meeting

April 9-16, 2011; Honolulu, HI
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Benefits With Fluoxetine Therapy After Ischemic Stroke

Honolulu, HI—Data from the phase 3 FLAME (Fluoxetine in Motor Recovery of Patients with Acute Ischaemic Stroke) trial demonstrate that starting patients on a 20-mg dose of daily fluoxetine promptly after an ischemic stroke contributes to better recovery of motor function at 3 months. As a result of the improved function, François Chollet, MD, PhD, head of the neurovascular department at Toulouse University Hospital and chief of the Toulouse Institute for Neurosciences in France, said that participants taking fluoxetine were also more likely than those given placebo to be independent in activities of daily living at 90 days. Chollet, a lead investigator for the FLAME trial, presented his team’s findings at the AAN meeting.

FLAME’s primary outcome measure was mean change in the Fugl-Meyer motor scale (FMMS) score from baseline to trial conclusion at 90 days. Secondary end points included mean change in National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and  Montgomery-Åsberg Depression Rating Scale (MADRS) assessments from study outset to completion.

Patients were eligible for the double-blind, placebo-controlled trial if they had experienced a recent acute ischemic stroke resulting in hemiparesia or hemiplegia, producing moderate to severe motor deficit as indicated by a score of ≤55 on the FMMS. Persons scoring >20 on the NIHSS were excluded, as were those demonstrating residual disability from a prior stroke or with premorbid disability or cognitive deficits serious enough to hinder assessments. Patients with clinical depression or who had been treated with antidepressants, neuroleptics, or benzodiazepines in the month before randomization were also excluded.

A total of 118 stroke patients from 9 stroke centers across France were enrolled within 5 to 10 days of stroke onset and randomized to fluoxetine 20 mg per day (n = 59) or placebo (n = 59) for 90 days. Chollet said that all patients received standard care from the facility’s inpatient stroke team and physiotherapy. A physiotherapist administered motor function tests at baseline and again at 30 days and 90 days postrandomization. NIHSS, mRS, and MADRS scores were also assessed according to this timeline.

After censoring patients who died or withdrew, the 90-day statistical analysis included data for 56 patients assigned to placebo and 57 given fluoxetine. Chollet said that the analysis corrected for some differences in baseline characteristics between the groups. Patients in the fluoxetine group tended to be older than those in the placebo arm (mean age, 66.4 vs 62.9 years, respectively), and more patients randomized to fluoxetine had had a stroke previously (16.9% vs 6.8%). Another adjustment was made to account for differences in mean FMMS score at baseline, which was higher in the fluoxetine group than in the placebo group (17.1±11.7 vs 13.4±8.8, respectively).

Patients treated with fluoxetine demonstrated significant improvement in overall FMMS motor function scores at 3 months. “This is true for the [over]all score and for the upper limb and lower limb part,” Chollet said. The fluoxetine group had an adjusted mean gain of 34.0 points (95% confidence interval [CI], 29.7-38.4) in overall FMMS scores compared with 24.3 points (95% CI, 19.9-28.7) in the placebo arm (P = .003). FMMS scores reflected a mean gain of 22.9 points (95% CI, 18.6-27.1) in upper limb motor function with fluoxetine compared with 13.1 points (95% CI, 8.9-17.4) with placebo (P = .002); patients recovered slightly less lower limb motor function, with a mean increase of 12.8 points (95% CI, 11.1-14.5) in the fluoxetine group versus 9.5 points (95% CI, 7.8-11.2) in the placebo arm (P = .010).

Minimal difference in total NIHSS scores was observed between the fluoxetine and placebo groups at 90 days (5.8 vs 6.9, respectively). “However, if we look at the motor items of the NIHSS, there is a statistically significant difference in favor of fluoxetine,” Chollet said. Patients treated with fluoxetine had a mean motor score on the NIHSS of 4.7 compared with 6.3 for patients given placebo (P = .012).

Investigators found no significant difference in MADRS scores between the groups, although the adjusted mean change slightly favored fluoxetine over placebo (–0.1 vs +3.2, respectively; P = .032). Researchers identified 17 patients in the placebo group as clinically depressed compared with 4 patients in the fluoxetine group (P = .002), and Chollet said this might suggest that fluoxetine protects against depression.

Fluoxetine was also associated with improvement in mRS scores. “If we look at Rankin score 1 or 2, which means the patient is independent in daily living activities, the number of patients independent is higher—significantly higher—in the fluoxetine group than in the placebo group,” said Chollet, noting that 26.3% of patients given fluoxetine had an mRS score of 0 to 2 compared with only 8.9% of patients taking placebo (P = .015).

Rates of serious adverse events were low, and Chollet said that fluoxetine was well tolerated. Of the most common adverse events, nausea, diarrhea, and partial seizure were more prevalent among fluoxetine users; whereas, a greater proportion of patients given placebo experienced hepatic enzyme disorders, psychiatric disorders, and insomnia. Both arms reported equal rates of hyponatremia and abdominal pain.

Chollet cited FLAME’s small patient sample and the fact that patients were selectively recruited according to degree of motor deficiency rather than consecutively enrolled as limitations of the study. He also cited the lack of follow-up beyond 3 months as a concern.

Because fluoxetine has a hormonal target rather than a vascular one like intravenous thrombolysis with artery deocclusion, which Chollet said is the only treatment currently validated for the acute phase of stroke, the drug might produce benefits in areas such as mood, motivation, and attention. “One can accept that if attention is better and motivation is better, patients participate better in their rehabilitation program,” Chollet said. He concluded that the drug is now in the public domain, and FLAME’s positive findings suggest its use in stroke is probably in the public health interest, but more studies are needed.
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Poster

Investigators Update 2-Year Data on Safinamide Use in Patients With Parkinson’s Disease

Honolulu, HI—A 2-year trial of patients with Parkinson’s disease (PD) and motor fluctuations found that the addition of daily safinamide increased the amount of time each day in which patients experienced symptom relief with levodopa (ON time) and little to no dyskinesia. Safinamide is a novel agent being investigated as an adjunct therapy to dopamine agonists for patients with early PD and to levodopa for patients with mid- to late-stage PD. The oral drug has dopaminergic and nondopaminergic mechanisms of action, increasing dopamine levels through selective inhibition of monoamine oxidase (MAO)-B, dopamine reuptake, and glutamate release.

In a two-part investigation of safinamide use, consisting of a 6-month phase 3 clinical trial (Study 016) and an 18-month extension study (Study 018), investigators assessed the safety and efficacy of 50-mg and 100-mg daily doses of safinamide in patients with mid- to late-stage PD. Updated 24-month data were presented in a poster session at the AAN meeting. The poster was titled First Long-Term (2-year) Controlled Study to Evaluate Treatment with Safinamide as Add-on to Levodopa in Patients with Parkinson’s Disease and Motor Fluctuations.

Study 016 included 669 patients aged 30 to 80 years with idiopathic PD (<stage V on the Hoehn and Yahr scale) of ≥3 years in duration who were prescribed levodo-‑pa. The investigators randomized patients to 6 months of daily safinamide 50 mg (n = 223), safinamide 100 mg (n = 224), or placebo (n = 222). Patients completing all 24 weeks of treatment, who adhered to their assigned therapeutic regimen, experienced no significant adverse events, and were <stage V on the Hoehn and Yahr scale at trial completion, could choose to participate in Study 018 (n = 544). Protocol called for patients to continue receiving the same therapy assigned in Study 016, although patients unable to tolerate safinamide 100 mg could switch to the 50-mg dose. The 18-month extension study allowed for changes in dosing for levodopa and other PD medications and initiation of new PD drugs other than MAO inhibitors.

Study 018’s primary end point was degree of improvement from baseline in Dyskinesia Rating Scale (DRS) scores during ON time, and analyses included data for Study 016’s entire intent-to-treat population. Although DRS scores worsened for patients receiving placebo and improved slightly for patients given safinamide, change from baseline did not differ significantly among the cohorts. The authors hypothesized that the low number of participants with severe dyskinesia at enrollment contributed to the failure of Study 018 to meet its primary end point.

A post hoc analysis of data for patients with a DRS score of >4 at baseline showed significant improvement in ON time DRS scores at 24 weeks with safinamide 100 mg versus placebo (P = .03). Patients in this subgroup assigned to safinamide 100 mg were more likely to have their levodopa dose decreased compared with patients randomized to safinamide 50 mg or placebo (15.8% vs 19.8% vs 26.3%, respectively). The authors noted that, overall, patients in the safinamide 100-mg group demonstrated greater improvement in motor function, nonmotor symptoms such as depression and activities of daily living, and clinical status compared with patients in the other arms.

At the end of Study 016, patients taking safinamide experienced an increase in the average amount of ON time each day with no/minor dyskinesia and a decrease in the average amount of OFF time (the time the medication is not effective or is wearing off) compared with patients given placebo. The authors noted that the benefits seen with safinamide persisted at 2 years, with a mean increase in daily ON time with no/minor dyskinesia at 24 months of 0.67 hours in the 50-mg cohort and 0.83 hours in the 100-mg arm as compared with placebo. Daily OFF time decreased by a mean of 0.62 hours in the safinamide 50-mg arm and 0.75 hours in the 100-mg group as compared with placebo.

A safety analysis found similar 2-year rates of serious adverse events, deaths, and discontinuations due to adverse events across all study arms. Completion rates among all three groups were also high. The authors reported no new safety concerns during the extension study.

This study was funded by Newron and Merck Serono S.A.-Geneva.