Figures
- FIGURE 1
CONSORT flow diagram indicating the enrolment, randomisation, allocation, follow-up and analysis procedures for this double-blind, placebo-controlled, parallel trial. Initially, participants with a confirmed diagnosis or clinical suspicion of OSA responded to a research advertisement or were contacted via a research volunteer database. Participants attended an in-laboratory physiology screening PSG to determine eligibility for the trial. Eligible patients (untreated OSA (apnoea–hypopnoea index ≥5 events·h−1), overnight nadir SaO2 ≥75% and low–moderate respiratory arousal threshold (≥ −25 cmH2O) that were otherwise healthy) attended a standard in-laboratory baseline PSG. If still eligible following baseline, patients were then randomised to either the placebo or zopiclone condition. Participants received either once-nightly placebo or 7.5 mg of zopiclone just prior to bed for 1 month. Participants attended two standard in-laboratory PSGs on the first (night 1) and last night (night 30) of the treatment nights. One patient was excluded from the study after the baseline PSG as they were found not to have OSA. One patient discontinued involvement in the study prior to completing night 30 due to an unrelated personal issue. PSG: polysomnography; SaO2: arterial blood oxygen saturation; OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure.
- FIGURE 2
Polysomnographic recordings in an individual patient demonstrating how the respiratory arousal threshold measures were obtained. This example shows an ∼40-s epoch of non-rapid eye movement N2 sleep in which the 35-year-old male patient (apnoea–hypopnoea index 20 events·h−1; body mass index 32.2 kg·m−2) experienced an ∼25-s respiratory event (shaded area of the respiratory flow channel labelled “Obstructive apnoea”) that ended with a cortical arousal from sleep (shaded area of the two EEG channels labelled “Arousal”). The respiratory arousal threshold is quantified as the nadir epiglottic pressure during the respiratory effort occurring immediately prior to arousal (circled area on the epiglottic pressure channel, in this example approximately −32 cmH2O). Flow is the nasal airflow measured via a mask and pneumotachograph; mask pressure is the pressure at the nasal mask measured using a pressure transducer. EEG: electroencephalogram.
- FIGURE 3
a) Apnoea–hypopnoea index (AHI) scatter plot representing each individual's AHI during placebo (n=16) versus zopiclone (n=14) conditions for baseline and night 30. Grey lines and error bars indicate mean±sd. *: significant difference from baseline. b) Scatter plot indicating each individual's change in AHI (ΔAHI) from baseline to night 30 for both conditions. Lines and error bars indicate mean±sd.
Tables
- TABLE 1
Participant anthropometric and sleep characteristics
Placebo Zopiclone Participants 16 14 Sex Male 13 12 Female 3 2 Age years 46±13 50±8 BMI kg·m−2 29±4 28±4 Mean AHI events·h−1 21±10 23±12 AHI range events·h−1 6–38 6–53 Arousal threshold cmH2O −16±5 −16±7 Data are presented as n or mean±sd, unless otherwise stated. Group anthropometric and baseline obstructive sleep apnoea severity data acquired from the baseline and physiology (for respiratory arousal threshold data only) overnight sleep studies. BMI: body mass index; AHI: apnoea–hypopnoea index.
- TABLE 2
Adverse events reported during the 1-month trial
Placebo Zopiclone# Related to zopiclone¶ Minor Serious Minor Serious Abnormal dreams 2/16 1/15 Probably Abscess drainage 1/15 No Anxiety 1/15 Possibly Balance disorder 1/15 Probably Bradycardia 1/16 Change in sleep pattern 3/16 Constipation 1/16 Decreased appetite 2/15 Probably Diarrhoea 1/15 Probably Disturbance in memory or attention 2/15 Probably Dysgeusia 3/15 Definite Fatigue or asthenia 1/16 1/15 Probably Feeling abnormal 2/15 Probably Headache or migraine 2/15 Probably Insomnia 2/15 Possibly Joint swelling 1/15 No Loss of libido 1/15 Probably Muscle ache or injury 1/16 1/15 No Nasopharyngitis 2/16 1/15 No Oral ulcer 1/16 Rash 2/16 Stress 1/15 Possibly Weight loss 2/15 Possibly Data represent adverse events reported during the 1-month trial or during the week after completion. None of these events required withdrawal from the study. A total of seven out of 16 participants randomised to placebo and 14 out of 15 randomised to zopiclone reported adverse events during the 1-month trial. Six participants in the placebo group and eight in the zopiclone group reported more than one adverse event. #: one participant from the zopiclone group withdrew from the study prior to completing the 1-month trial due to nonmedical issues; ¶: whether each adverse event was related to zopiclone was determined by a physician according to the following criteria: not related (“No”), unlikely, possibly, probably or definitely.
- TABLE 3
Participant feedback at study conclusion
Placebo Zopiclone Did you feel like your sleep improved or worsened? Improved 9/16 11/14 Worsened 1/16 1/14 Same 6/16 2/14 If available, would you continue to use the study medication? Yes 5/16 5/14 No 10/16 9/14 Unsure 1/16 0/14 Do you feel like you were taking the sleeping pill or the placebo during the study? Placebo 11/16 3/14 Zopiclone 5/16 11/14 Data are presented as counts according to participant feedback over the 1-month trial. Data were collected on the morning of the final visit (night 30).
- TABLE 4
Placebo and zopiclone polysomnography data for the 8-h overnight sleep studies during the baseline and night 30 conditions
Placebo# Zopiclone¶ Delta change p-value Baseline Night 30 Baseline Night 30 Sleep onset latency min 10 (6–13) 6 (2–15) 9 (5–26) 16 (10–32) 6 (−11–17) 0.47 Sleep efficiency % sleep 84±7 85±10 79±13 86±6 5 (−2–13) 0.16 TST min 415±34 424±45 386±61 427±27 32 (−2–67) 0.07 Non-REM sleep N1 % TST 7±4 5±3 10±3 7±4 −1 (−3–1) 0.35 Non-REM sleep N2 % TST 49±8 49±7 46±10 49±7 4 (−3–10) 0.24 Non-REM sleep N3 % TST 25±6 26±7 24±7 24±4 −1 (−4–4) 0.80 REM sleep % TST 19±5 20±5 20±5 19±5 −2 (−6–2) 0.33 Wake after sleep onset min 71±33 65±51 87±56 53±32 −28 (−61–6) 0.10 Arousal index arousals·h−1 27±10 24±11 28±11 24±8 −1 (−8–6) 0.75 Supine % TST 48±28 52±31 49±28 46±28 −7 (−25–11) 0.43 Supine AHI events·h−1 38±28 32±21 46±24 37±23 −2 (−14–18) 0.82 Low arousal threshold AHI events·h−1+ 23±12 20±11 21±11 16±10 −1 (−10–8) 0.82 Moderate arousal threshold AHI events·h−1§ 19±7 18±10 26±14 19±5 −6 (−16–3) 0.18 Respiratory event duration s 25±3 27±5 27±5 27±5 −2 (−6–1) 0.20 Mean SaO2 during sleep % 95±2 95±1 94±2 94±2 0 (−1–1) 0.93 Nadir SaO2 during sleep % 86±5 86±6 86±6 85±5 −1 (−4–3) 0.64 Data are presented as mean±sd or median (interquartile range), unless otherwise stated; the delta change column indicates the difference from baseline to night 30 between conditions (mean (95% CI) for normally distributed data and Hodge–Lehmann estimated median (95% CI) for nonnormally distributed data). REM: rapid eye movement; TST: total sleep time; AHI: apnoea–hypopnoea index; SaO2: estimated arterial blood oxygen saturation (measured via pulse oximetry). #: n=16; ¶: n=14; +: for low arousal threshold (> −15 cmH2O) AHI, n=9 in the placebo group and n=7 in the zopiclone group; §: for moderate arousal threshold (< −15 and > −25 cmH2O) AHI, n=7 in the placebo and zopiclone groups. p-values refer to the difference from baseline to night 30 compared between placebo and zopiclone conditions.
- TABLE 5
Placebo and zopiclone sleepiness/alertness and driving simulator performance data collected during the baseline and night 30 conditions
Placebo# Zopiclone¶ Delta change p-value Baseline Night 30 Baseline Night 30 ESS+ 5 (4–12) 6 (4–11) 8 (5–12) 7 (4–9) −1 (−4–1) 0.55 FOSQ+ 101±11 101±12 101±8 103±11 3 (−2–7) 0.25 Leeds§ 5±1 5±1 4±1 5±1 0 (−1–1) 0.62 KSS 6±2 6±2 6±1 6±2 0 (−1–1) >0.99 AusEd driving simulator Deviation from median of lane cm 59±22 51±13 48±16 47±13 7 (−1–15) 0.10 Deviation from 60–80 km·h−1 km·h−1 2±2 2±1 2±1 2±1 1 (0–1) 0.11 Braking reaction time ms+ 1016±233 1017±203 1034±312 957±206 −77 (−206–50) 0.22 Data are presented as mean±sd or median (interquartile range), unless otherwise stated; the delta change column indicates the difference from baseline to night 30 between conditions (mean (95% CI) for normally distributed data and Hodge–Lehmann estimated median (95% CI) for nonnormally distributed data). Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ) data were collected in the evening 1.5 h prior to sleep; Leeds Sleep Evaluation Questionnaire (Leeds), Karolinska Sleepiness Scale (KSS) and AusEd data were collected 30 min after awakening. #: n=16; ¶: n=14; +: for ESS, FOSQ and AusEd braking reaction time n=15 in the placebo group; §: for Leeds n=13 in the placebo group and n=11 in the zopiclone group. p-values refer to the difference from baseline to night 30 compared between placebo and zopiclone conditions.
Supplementary Material
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Supplementary material ERJ-00149-2018_Supplement
