Allen R, et al. Randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome.
The objective of this study was to evaluate the efficacy and safety of various pregabalin doses in patients with moderate-to-severe idiopathic restless leg syndrome. A prior study showed that gabapentin improved both sensory and motor symptoms in RLS patients; therefore, a study with pregabalin was thought to also be beneficial in these patients. This was a randomized, double-blind, placebo-controlled, parallel six-arm, phase 2b study. Eligible patients were randomized to receive either pregabalin 50, 100, 150, 300, 450 mg by mouth every day or placebo for a duration of seven weeks, with the final week being tapered. A total of 137 patients were randomized. Inclusion criteria included an age of 18 – 65 years and a diagnosis of idiopathic RLS based on the international restless legs study scale (IRLS) criteria. Further inclusion criteria included experiencing RLS symptoms on 15 or more nights (mainly at 5pm-7am), and an IRLS score of 15 or greater at the start of the run-in period with a placebo and at baseline. Exclusion criteria included having history of another sleeping disorder, any secondary RLS, failure to respond to gabapentin and/or having severe daytime symptoms. Most patients enrolled were white, and about 60% were female. The average age was about 50 years of age, with an average IRLS baseline score of about 25 and an average RLS duration of about 7 years.
The primary endpoint was the change from baseline in IRLS total score at the sixth week for each dose using an exponential decay equation. Doses were estimated using the equation that would produce 50% and 90% of the maximal effect. Secondary endpoints measured at week six included the dose response in accordance to the clinical global impression-improvement (CGI-I) response, improvements in quality of life, subjective sleep questionnaire score (SSQ), medical outcomes study sleep scale score (MOS-SS), discontinuations due to adverse effects and actigraphy. For these secondary endpoints, a linear mixed-model was utilized. The estimated doses for the primary endpoint were calculated to be 37.3 mg/day and 123.9 mg/day respectively. There was a higher percentage of CGI-I responders at week six on doses of pregabalin 300 or 400 mg/day, than there was with those on placebo or lower doses. Adverse events were reported throughout the study. Incidence of dizziness, dry mouth, fatigue and somnolence was higher in the treatment groups than in the placebo group. Additionally, somnolence and dizziness had a dose-related relationship. Of the 231 adverse effects reported, 65.4% were of mild severity and 28.6% were of moderate severity. Eight percent were considered severe adverse effects and included feeling abnormal, having nightmares, urinary tract infections, and stress. Ten patients in the pregabalin group and one patient in the placebo group discontinued the study due to adverse events.
Reddy P, et al. The GREAT (Grapefruit Effect on Atorvastatin Therapy)
The objective of this study was to assess the lipid-lowering efficacy of atorvastatin when typical quantities of grapefruit juice are consumed, along with serum atorvastatin concentrations and adverse effects. Prior studies indicated an increase in the area under the concentration curve (AUC) of atorvastatin serum levels when ingesting grapefruit juice. This was a prospective, open label, single center, randomized trial. Patients chronically on atorvastatin 10, 20 or 40 mg per day at a Florida clinic received 300 ml of 100% grapefruit juice for a 90-day duration. The study was two-armed with one arm (A) continuing their current atorvastatin dose and the other arm (B) cutting their dose by fifty percent. There were 130 patients enrolled in this study. Patients of at least 21 years of age had to be receiving doses of 10, 20 or 20mg for greater than 90 days prior to the study. Informed consent prior to the enrolment was mandatory for inclusion. The patients in both arms did not have any significant baseline characteristic differences and were about 64 years of age. Exclusion criteria included having any: evidence of myositis, a CPK level or liver function tests (ALT/AST) greater than three times the upper limit of normal, medications with potential interactions with grapefruit, grapefruit allergic intolerance or women of childbearing potential not on contraception. Patients were also restricted from consuming greater than 4 ounces of alcohol per day.
At baseline and at 30, 60, and 90 days, vital signs and serum samples were attained during a study visit. Lipid profiles, liver function, serum atorvastatin, and creatine phosphokinase (CPK) were then measured. Quality of life and functional status were also measured using a Quality of Life SF-36 Survey. Muscles soreness without myositis was assessed using a myalgia scale and memory loss was assessed using a memory scale. In arm A, average serum atorvastatin levels increased from baseline (19% to 26%). In arm B, serum atorvastatin levels decreased from baseline (12% to 25%); therefore, dosage while consuming grapefruit juice should not be reduced. On days 30 and 90, the differences in average serum concentration were significant when compared to baseline. Triglycerides, LDL and the LDL:HDL ratio all increased slightly in both arms, but significantly only in arm B; HDL decreased slightly in both arms. Total cholesterol increased in arm B, due to the decrease in dose of atorvastatin. The other endpoints assessed all changed minimally with most not achieving statistical significance. There were no adverse effects on liver function tests or CPK.