Hawthorne Effect with Transient Behavioral and Biochemical Changes in a Randomized Controlled Sleep Extension Trial of Chronically Short-Sleeping Obese Adults: Implications for the Design and Interpretation of Clinical Studies

<div><p>Objective</p><p>To evaluate the effects of study participation <i>per se</i> at the beginning of a sleep extension trial between screening, randomization, and the run-in visit.</p><p>Design</p><p>Subjects were screened, returned for randomization (Comparison <i>vs.</i> Intervention) after 81 days (median), and attended run-in visit 121 days later.</p><p>Setting</p><p>Outpatient.</p><p>Patients</p><p>Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6±19.7 kg, <6.5 h sleep/night.</p><p>Intervention</p><p>Non-pharmacological sleep extension.</p><p>Measurements</p><p>Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids.</p><p>Results</p><p>Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 ±51.2 <i>vs.</i> 388.1±48.6 min/night; mean±SD; P<0.001 screening vs. randomization; actigraphy: 344.3 ±41.9 <i>vs.</i> 358.6±48.2 min/night; P<0.001) sleep quality improved (9.1±3.2 <i>vs.</i> 8.2±3.0 PSQI score; P<0.001), sleepiness tended to improve (8.9±4.6 <i>vs.</i> 8.3±4.5 ESS score; P = 0.06), insulin resistance decreased (0.327±0.038 <i>vs.</i> 0.351±0.045; Quicki index; P<0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% <i>vs.</i> 11%; P = 0.007), and metabolic syndrome (42% <i>vs.</i> 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit.</p><p>Limitations</p><p>Relatively small sample size.</p><p>Conclusions</p><p>Improvements in biochemical and behavioral parameters between screening and randomization changed the “true” study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the “Hawthorne effect”, according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/show/NCT00261898" target="_blank">NCT00261898</a>.</p></div

Characteristics at screening (Visit 1) of participants who completed randomization.

<p>(Visit 2) and run-in (Visit 3).</p><p>Data is reported as mean±SD or count (frequency).</p><p><b>*: P<0.05</b>.</p>1<p>Daytime sleepiness (ESS score): a score of 10 or more is considered sleepy.</p>2<p>Subjective sleep quality (PSQI score): a score of 5 or more is considered abnormal.</p

Study flow diagram.

<p>Study flow diagram.</p

Characteristics of Participants at Screening (Visit 1) and Randomization (Visit 2).

<p>Data is reported as mean±SD or count (frequency).</p><p><b>**: P<0.05</b>.</p>1<p>Daytime sleepiness (ESS score): a score of 10 or more is considered sleepy.</p>2<p>Subjective sleep quality (PSQI score): a score of 5 or more is considered abnormal.</p

Glucowse characteristics for study subjects during fasting conditions and the oral glucose tolerance test.

<p>Unless otherwise stated, values in each cell are reported as mean ± SD or as percentage.</p>1<p>Values are reported as median with interquartile range due to skewed distribution.</p

Endocrine and metabolic parameters of study participants.

<p>Values are means ± SD or ^#median and interquartile range for skewed variables.</p>$<p>Measured in fasting morning plasma samples. <i>P</i>-values for <i>t</i>-tests are depicted.</p

Stress hormones and heart rate <i>vs.</i> chronotype score.

<p>Chronotype scores on the horizontal axis are regressed against plasma ACTH (<i>n</i> = 118; A), 24 h urinary epinephrine (<i>n</i> = 110; B) and norepinephrine (<i>n</i> = 114; C), and resting heart rate (<i>n</i> = 113; D). R² for the gender-corrected model is reported, and slope and <i>p</i>-value for the prediction of chronotype score on variables in the model are given. Closed circles represent women, open diamonds represent men.</p

Sleep characteristics per chronotype.

<p>Horizontal bars represent sleep time as measured by actigraphy. Bedtime (mean±SD) and risetime (mean±SD) on all days combined and separately on non-working days and on work days in Morning (grey bars) and Evening types (black bars). The mid-sleep times (MSTs) (mean±SD) are depicted by open diamonds and compared between chronotypes by <i>t</i>-tests.</p

Sleep characteristics of study participants.

<p>Values are means ± SD,</p>#<p>median and interquartile range for skewed variables, or %. Skewed variables were log-transformed prior to analysis. <i>P</i>-values for <i>t</i>-tests or *Fisher exact test are depicted and significant <i>p</i>-values (<0.05) are bolded.</p>*<p>Fisher exact test including all races;</p>**<p>Fisher exact test excluding “Other races”.</p>1<p>Sleep duration differed on working <i>vs.</i> non-working days in Morning (diary and actigraphy: <i>p</i><0.001) and in Evening chronotypes (diary: <i>p</i> = 0.053; actigraphy: <i>p</i> = 0.005).</p

Demographic and anthropometric characteristics of study participants.

<p>Values are means ± SD,</p>#<p>median and interquartile range for skewed variables, or %. Skewed variables were log-transformed prior to analysis. <i>P</i>-values for <i>t</i>-tests or *Fisher exact test are depicted and significant <i>p</i>-values (<0.05) are bolded.</p>*<p>Fisher exact test including all races;</p>**<p>Fisher exact test excluding “Other races”.</p