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

Plasma concentrations of sucralose in children and adults

<p>We aimed to measure concentrations of the commonly used artificial sweetener sucralose, following ingestion of doses reflecting a range of consumption and to compare concentrations in children and adults. Eleven adults consumed 355 mL water containing 0 mg (control), 68, 170, or 250 mg sucralose (equivalent to 1–4 diet sodas). A second group of adults (<i>n</i> = 11) consumed 355 mL Diet Rite Cola™ (68 mg sucralose and 41 mg acesulfame-potassium (ace-K)) or 68 mg sucralose and 41 mg ace-K in seltzer. Beverages were provided at separate visits in randomized order, prior to an oral glucose tolerance test. Eleven children consumed 0 or 68 mg sucralose in 240 mL water, in an identical study design. Blood was collected before beverage ingestion and serially for 120 min. Sucralose doses (corrected for weight) resulted in similar plasma concentrations in children and adults. Concentrations were comparable whether sucralose was administered in water, combined with ace-K, or in diet soda. Due to their lower body weight and blood volume, children have markedly higher plasma sucralose concentrations after the consumption of a typical diet soda, emphasizing the need to determine the clinical implications of sucralose use in children.</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

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

Anthropometrics and HDL-C <i>vs.</i> chronotype score.

<p>Plot of Chronotype scores versus BMI (A), neck circumference (B), and HDL-C (C) with a trend line, respectively. N = 119 for all. R² slope, and <i>p</i>-value for the prediction of chronotype score on variables in each plot are calculated from gender-corrected models. Closed circles represent women, open diamonds represent men.</p

Food intake parameters of study participants divided by chronotype on working <i>vs.</i> non-working days.

<p>Values are means ± SD. Intake parameters of chronotypes were compared with <i>t</i>-tests on working and non-working days separately. Significant <i>p</i>-values (<0.05) are bolded.</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