Multinational Phase III Trial of Dopamine Drug Rotigotine Reports “Highly Significant” Reduction of Restless Legs Syndrome Symptoms

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Findings of a large multinational phase III trial of the drug rotigotine indicate it “has shown a clinically relevant and highly statistically significant reduction of RLS [Restless Legs Syndrome] symptoms versus placebo in both primary variables.” The six-month trial, which also indicated that rotigotine was “well tolerated” by study participants, is proceeding to a second phase III trial in patients with moderate to severe RLS, according to its maker – the German firm Schwarz Pharma – in a report on October 9, 2006. The results of this second phase III trial are due in first quarter 2007.

Rotigotine is a nonopioid drug designed to mimic the action of dopamine (called a dopamine “agonist”) – which the body produces naturally to support transmission of messages, or “nerve signaling,” in the central nervous system, and thus proper motor functioning. Administered via once-daily application of a transdermal patch (i.e., absorbed through the skin), rotigotine is designed to support a steady level of medication in the system. It is proposed that this may be one benefit of the drug versus other dopamine-agonist therapies for RLS which are delivered via the digestive tract in pill or capsule form.

RLS, also known as Ekbom’s syndrome, is believed to be a metabolic disorder of the nervous system linked to dopamine abnormalities, according to WebMD’s eMedicine Clinical Knowledge Base (http://www.emedicine.com/neuro/topic509.htm). It involves unpleasant crawling or tingling sensations, creating an “irresistible” urge to move the legs. Diagnosed in many patients with FM and CFS, the syndrome's symptoms are felt particularly in the evening and at night when the patient is inactive – and therefore interfere with rest and refreshing sleep, with resulting daytime fatigue.

The “variables” that the trial tested were improvements in symptom severity measured subjectively at the start of the trial or “baseline” and the end of the trial, using:

n The patient’s own assessment of the severity of multiple symptoms on the International Restless Legs Syndrome Study Group Rating Scale (IRLS).1 See a copy of this self-assessment form at http://www.mdvu.org/pdf/rls_rs.pdf)

n And the clinician-assessed score for Item 1 (severity of illness) on the Clinical Global Impression Scale. The CGI scale is commonly used to assess treatment response in drug effectiveness trials.

The trial included 458 patients with moderate to severe RLS, treated in a double-blind, placebo-controlled phase III study. All patients began the three-week titration period at a daily dose of 2.25 mg rotigotine transdermal patch or placebo (fake dose). During the six-month period of treatment, the patients received rotigotine transdermal patch (either 2.25, 4.5, or 6.75 mg per day) or a placebo patch on a daily basis. The most common side effects were application site reactions, nausea, headache, and fatigue.

Rotigotine has already undergone a series of trials for treatment of Parkinson’s disease, another dopamine-related condition. Parkinson’s is caused by an inability to produce quantities of dopamine sufficient to support normal motor function. Rotigotine is now approved for treatment of Parkinson’s patients in Europe, and is under FDA review for approval as a treatment for that condition in the United States.

Other dopamine-related nonopioid drugs employed for treatment of RLS are ropinirole, approved by the FDA for Parkinson’s in 1997 and for RLS in 2005; and pramipexole (Mirapex,R Sifrol,R MirapexenR in the EU), recommended for approval in the EU in February 2006 and with FDA approval possible by year-end 2006.2,3,4 These are delivered via the digestive system rather than via transdermal patch.

In many cases, RLS apparently runs in families. It is a chronic disease that progresses slowly, and occurs in up to 10 percent of the population – about as frequently as migraine and diabetes.

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1. Abstract: “Validation of the International Restless Legs Syndrome Study Group Rating Scale for Restless Legs Syndrome,” by AS Walters, et al., Sleep Medicine, 2003 Mar; 4(2):121-32; PMID: 14592342

2. Abstract: “A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with Fibromyalgia receiving concomitant medications,” http://www.immunesupport.com/library/showarticle.cfm/id/6608

3. “Pramipexole Delivered Sustained Efficacy in Clinical Trial of Patients with Restless Legs Syndrome,” http://www.immunesupport.com/library/showarticle.cfm/id/6892

4. “Symptom Improvements with Parkinson's Drug Mirapex Found in Fibromyalgia Trial,” http://www.immunesupport.com/library/showarticle.cfm/id/6783

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