2007 OPEN FORUM Abstracts
THE EFFECTS OF RAMELTEON ON BREATHING DURING SLEEP IN SUBJECTS WITH MODERATE TO SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
M. Kryger1, T. Roth2, S. Wang-Weigand3, J. Zhang3
Background: Traditional sleep agents can negatively affect respiration during sleep in subjects with chronic obstructive pulmonary disease (COPD). This study evaluated potential respiratory depressant effects of ramelteon, an MT1/MT2 melatonin receptor agonist indicated for insomnia treatment.
Methods: Using a double-blind, crossover design, 25 subjects (â¥40 yrs) with moderate to severe COPD (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC]<70% and FEV1 between 50 and 80% of predicted value [moderate], or FEV1/FVC<70% and FEV1<50% predicted value [severe]) were enrolled. On Day 1, subjects were randomized to receive ramelteon 8mg or placebo 30 min before overnight monitoring of oxygen saturation (SaO2) by pulse oximetry and sleep by polysomnography. Following a 5- to 10-day washout, subjects crossed over to the alternate treatment and repeated the procedure. The primary endpoint was mean SaO2 for the entire night. Least-squares means were calculated for comparison analyses.
Results: No statistically significant difference in SaO2 for the entire night was observed with ramelteon vs placebo (92.2 vs 92.4%, P=0.576); the lower limit of the 95% confidence interval (-1.09 to 0.62) of the treatment effect did not reach a clinically meaningful difference of -1.5%. Mean SaO2 was similar between ramelteon and placebo for each of the 8 hrs of the night and for each sleep stage (awake, REM, NREM). Compared with placebo, there was no statistically significant difference in the number of minutes in the night that SaO2 was <80% and <90% (P=0.927 and P=0.653, respectively). The mean apnea-hypopnea index was similar between ramelteon and placebo (P=0.804). A significant increase in total sleep time (389.0 vs 348.4 min, P=0.019) and sleep efficiency (81.0 vs 72.6%, P=0.019) was observed with ramelteon vs placebo. Latency to persistent sleep was shorter with ramelteon vs placebo (23.1 vs 56.9 min) (P=0.051). Wake time after sleep onset and number of awakenings did not significantly differ between ramelteon and placebo. Eight subjects (4 in each group) reported an adverse event (AE). All AEs were mild to moderate; none led to study discontinuation.
Conclusion: In subjects with moderate to severe COPD, ramelteon did not produce respiratory depressant effects as measured by oxygenation or abnormal breathing events. Ramelteon was also well tolerated and demonstrated improvements on objective sleep parameters compared to placebo in this population.