Placebo Exposure Research Articles

0753 Cataplexy-Free Days in a Phase 3, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of JZP-258 in Adults With Narcolepsy With Cataplexy

Abstract Introduction Sodium oxybate (SXB) is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate with 92% less sodium. This analysis evaluated cataplexy-free days/week, as a measure of treatment impact, in a placebo-controlled randomized withdrawal study of JZP-258 treatment in patients with narcolepsy. Methods Treatment for cataplexy at study entry included 1) SXB (SXB-only); 2) SXB plus other anticataplectics (SXB+other); 3) anticataplectics other than SXB (other anticataplectics); or 4) cataplexy treatment-naive (anticataplectic-naive). Participants (aged 18-70 years with narcolepsy with cataplexy) began JZP-258 treatment during a 12-week, open-label, optimized treatment and titration period (OLOTTP), followed by a 2-week stable-dose period (SDP). Participants were randomized to receive placebo or continue JZP-258 treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). Results Of 201 enrolled participants, 134 comprised the efficacy population (placebo, n=65; JZP-258, n=69). Median (Q1, Q3) cataplexy-free days/week at first week of OLOTTP (while initiating JZP-258) by prior treatment were SXB-only, 5.8 (2.0, 7.0); SXB+other, 6.4 (5.0, 7.0); other anticataplectics, 4.0 (1.8, 6.0); anticataplectic-naive, 3.5 (0, 5.8). At end of SDP (on stable dose of JZP-258), median (Q1, Q3) cataplexy-free days/week were 6.0 (3.5, 7.0), 6.1 (1.4, 7.0), 6.0 (2.6, 7.0), and 6.2 (4.0, 7.0), respectively. Prior to randomization, there was no difference in median cataplexy-free days/week between participants to be randomized to placebo (6.0 [3.5, 7.0]) or JZP-258 treatment (6.0 [3.0, 7.0]); during DBRWP, median cataplexy-free days/week decreased in participants randomized to placebo (3.5 [0, 5.83]) but remained similar in participants randomized to continue JZP-258 treatment (5.6 [2.8, 7.0]). The overall safety profile of JZP-258 was similar to SXB. Conclusion Number of cataplexy-free days/week increased with JZP-258 treatment in participants previously naive to oxybate. Number of cataplexy-free days/week decreased during placebo exposure in participants randomized to placebo. Support Jazz Pharmaceuticals

The Impact of SGLT‐2 Inhibition on Obesity and the Metabolic Profile in a PCOS Rat Model

Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in young women, is characterized by hyperandrogenemia, and is associated with obesity and insulin resistance. It is suggested that hyperandrogenemia is the cause of these metabolic complications. Current treatment for obesity in PCOS is lackluster, which is why new therapies are being investigated. Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors such as Empagliflozin (EMPA) have been shown in diabetics to reduce body fat and insulin resistance. We have previously reported that exposure of female rats to dihydrotestosterone (DHT) before puberty resembles many characteristics found in PCOS: increase in food intake (FI), body weight (BW), fat/lean mass, blood pressure, and renal injury. We want to test the hypothesis that EMPA improves obesity and metabolic complications in a PCOS‐like rat model.MethodsForty four‐week old female SD rats were randomized to either placebo (PBO) or DHT exposure (7.5mg/90 days). Body weight was measured weekly. Body composition was analyzed monthly by EchoMRI. Fasting plasma was analyzed monthly for glucose and insulin. A 24‐hour urine was collected in metabolic cages monthly to assess the concentration of urinary glucose. After 10 wks of DHT, rats were randomized to receive drinking water alone or with EMPA (10mg/kg/day) for another 3 wks. FI was measured daily. At the end of the treatment, body composition, fasting plasma, and glucosuria were assessed. Morning plasma was collected for leptin and adiponectin after 3 wks of EMPA treatment.ResultsIn PCOS rats, EMPA decreased fat mass (21.1 ± 2.7 g vs 12.2 ± 0.8 g, p=0.0019), leptin (0.86 ± 0.16 ng/mL vs 0.45 ± 0.05 ng/mL, p<0.05), and adiponectin (19.2 ± 1.3 mg/mL vs 14.4 ± 1.0 mg/mL, p<0.05) and increased glucosuria (89 ± 8 mg/dL vs 4065± 400 mg/dL, p < 0.0001). In PCOS rats, EMPA did not affect BW (309.0 ± 11.0 g vs 293.7 ± 6.1 g, p=0.6288), cumulative FI (251.8 ± 8.5 g vs 261.1 ± 6.5 g, p=0.8123), or lean mass. In PCOS rats, EMPA did not affect fasting glycemia, fasting insulin (17.6 ± 1.3 mU/mL, p= vs 18.0 ± 1.7 mU/mL, p=0.9922), or insulin sensitivity through the quantitative insulin‐sensitivity check index (0.302 ± 0.003 vs 0.299 ± 0.003, p=0.8615). While causing increased glucosuria in PBO rats, EMPA did not affect fat mass, BW, cumulative food intake, lean mass, fasting glycemia, or insulin sensitivity.In summary, SGLT‐2 inhibition had beneficial effects on fat mass and leptin in PCOS‐like rats. This occurred in the absence of changes in food intake, fasting glycemia, and insulin sensitivity. This suggests that SGLT‐2 inhibition is exerting a positive impact on the cardiometabolic profile in female hyperandrogenemia via more than excessive loss of glucose in the urine alone. Therefore, EMPA could be a novel therapeutic approach to treat obesity in PCOS women to ameliorate the adverse cardiometabolic profile associated with this pathology.Support or Funding InformationAHA 0830239N and 12SDG8980032, EFFERG, and NIH R21 DK‐113500 and P20 GM‐121334

Novel study design to assess the efficacy and tolerability of antiseizure medications for focal-onset seizures in infants and young children: A consensus document from the regulatory task force and the pediatric commission of the International League against Epilepsy (ILAE), in collaboration with the Pediatric Epilepsy Research Consortium (PERC).

High‐quality placebo‐controlled drug trials for focal‐onset seizures in infants and children younger than 4 years have become increasingly difficult to perform because of eligibility constraints and onerous study designs. Traditional designs used in these populations require a high baseline seizure frequency, two hospitalizations for video‐electroencephalography (video‐EEG) monitoring, and willingness to accept potential exposure to placebo when the drugs to be tested are usually already available for off‐label prescription. To address these constraints, the International League Against Epilepsy (ILAE) regulatory taskforce and the ILAE pediatric commission, in collaboration with the Pediatric Epilepsy Research Consortium (PERC), propose a novel trial design which involves seizure counting by caregivers based on previous video‐EEG/video validation of specific seizure semiologies. We present a novel randomized placebo‐controlled trial design intended to be used for studying new antiseizure medications (ASMs) for focal‐onset seizures (FOS) in children aged one month to four years. This design uses “time to Nth seizure” as the primary outcome and incorporates a new element of variable baseline duration. This approach permits enrollment of infants with lower seizure burden, who might not have video‐EEG‐recorded seizures within 2‐3 days of monitoring. Repeated hospitalizations for video‐EEG recordings are avoided, and duration of baseline and exposure to placebo or ineffective treatment(s) are minimized. By broadening eligibility criteria, reducing risks from prolonged placebo exposure, and relying on validated recording of seizure counting by caregivers, clinical trials will be likely to be completed more efficiently than in the recent past.

Development of a new diaper dermatitis-like reconstructed skin equivalent for testing children atopic dermatitis relieving cosmetics.

Diaper dermatitis (DD) is the most common acute inflammatory skin disease. It has a serious effect on children's and families' quality of life. We aimed to screen and evaluate the efficacy of different formulas for relieving the diaper dermatitis symptoms by developing a kind of diaper dermatitis-like reconstructed human skin equivalent in vitro. We developed the human skin equivalent for diaper dermatitis with 0.2% Sodium lauryl sulfate (SLS). The diaper dermatitis-like human skin equivalent was characterized by high level of inflammation, such as overexpression of interleukin-1α (IL-1α), and impaired skin barrier. Four formulas with potential of anti-inflammation and promotion of skin barrier function were topically applied on the diaper dermatitis-like human skin equivalent surface. The afterward protection efficacy was evaluated by endpoints of IL-1α, tissue viability, and skin barrier function. The chemical irritant induced high release of IL-1α, impaired tissue viability, and skin barrier function. The cream prepared with potential of anti-inflammation and skin protection could effectively decrease and relive the impact of irritant with decreased level of IL-1α and the higher tissue viability than the placebo exposure. The results showed that diaper dermatitis-like human skin equivalent induced by SLS can mimic the skin irritation response of the diaper rash.

Cumulative mild partial sleep deprivation negatively impacts working memory capacity but not sustained attention, response inhibition, or decision making: a randomized controlled trial

BackgroundTwenty-eight per cent (28%) of adults sleep at least 1 hour less than they consider optimal, yet the effects of such cumulative mild partial sleep deprivation on cognitive functions are unknown. The objective of this study was to examine how cumulative mild partial sleep deprivation over 6 nights can impact working memory, sustained attention, response inhibition, and decision making. MethodsA double-blind placebo-controlled randomized study was conducted to determine the impact of sleep restriction (elimination of 1 hour of sleep relative to the baseline habitual sleep duration) vs placebo (exposure to a lamp with no known therapeutic effect) on cognitive performance. The primary outcomes were performance on tasks that measure working memory, sustained attention, response inhibition, and decision making. The participants consisted of 93 adults (mean age 24.3 years, SD 4.7; 46 men, 47 women) with no reported sleep problem, behavioral issue, or medical issue. ResultsPerformance on the working memory capacity task improved between the baseline and experimental sessions for the placebo group but not the sleep-restriction group. Performance on tasks measuring sustained attention, response inhibition, and decision making did not change under either experimental condition. ConclusionCumulative partial sleep deprivation negatively affects performance on a test of working memory capacity but does not affect performance on tests of sustained attention, response inhibition, or decision making.

The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose

Disturbances of the circadian system are common in depression. Though they typically subside when depression is treated with antidepressants, the mechanism by which this occurs is unknown. Despite being the most commonly prescribed class of antidepressants, the effect of selective serotonin reuptake inhibitors (SSRIs) on the human circadian clock is not well understood. To examine the effect of the SSRI citalopram (30mg) on the sensitivity of the human circadian system to light. This study used a double-blind, placebo-controlled, within-subjects, crossover design. Participants completed two melatonin suppression assessments in room level light (~ 100lx), taking either a single dose of citalopram 30mg or a placebo at the beginning of each light exposure. Melatonin suppression was calculated by comparing placebo and citalopram light exposure conditions to a dim light baseline. A 47% increase in melatonin suppression was observed after administration of an acute dose of citalopram, with all participants showing more suppression after citalopram administration (large effect, d= 1.54). Further, melatonin onset occurred later under normal room light with citalopram compared to placebo. Increased sensitivity of the circadian system to light could assist in explaining some of the inter-individual variability in antidepressant treatment responses, as it is likely to assist in recovery in some patients, while causing further disruption for others.

The Common Food Additive Carrageenan Increases Intestinal Permeability without Affecting Whole-Body Insulin Sensitivity in Humans—Results from a Randomized, Double-Blind Crossover Study

It is not known whether food additives associated with western lifestyle, such as the widely used carrageenan, also play a role in the pathogenesis of diabetes. Animal data suggest that increased carrageenan consumption causes insulin resistance and diabetes, mainly by interfering with hepatic insulin signaling. This is the first trial in humans that tested whether carrageenan added to the diet affects key metabolic traits. We conducted a randomized, double-blind, placebo-controlled, cross-over trial (registered as NCT02629705). Healthy males (N=20) were randomly allocated to 14 days of carrageenan (250 mg twice daily) or matching placebo. After a washout-period of 30±7 days, they received the other compound. At the end of each treatment phase, participants underwent an oral glucose tolerance test (OGTT), a hyperinsulinemic-euglycemic clamp with labeled glucose, whole-body MR-tomography and 1H-MR-spectroscopy, blood immune cell phenotyping and a lactulose-mannitol test for investigating intestinal permeability. Participants had a mean (±SD) age of 27.6±4.8 years and a BMI of 24.4±2.6 kg/m2. Intestinal permeability significantly increased after carrageenan vs. placebo exposure (lactulose-mannitol-ratio 0.0196 vs. 0.015, p=0.03). Whole-body insulin sensitivity index (ISI) did not differ between placebo and carrageenan exposure (p=0.5 for both ISIclamp and ISIOGTT). No changes of hepatic fat content, body fat mass, distribution, liver transaminases and inflammatory cytokines were observed (all p>0.4). In young healthy males, short-term carrageenan intake resulted in increased gut permeability. This was not accompanied by changes of whole-body insulin sensitivity, body fat mass, distribution and liver fat content. Further investigations of hepatic and brain insulin sensitivity, immune phenotyping will reveal whether carrageenan intake affected these variables. Disclosure R. Wagner: None. J. Büttner: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc.. L. Fritsche: None. S. Kullmann: None. M. Wagmüller: None. A. Peter: None. H. Preissl: None. J. Machann: None. U. Pape: None. G. van Hall: None. P. Plomgaard: None. R. Klein: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. H. Haering: None. N. Stefan: Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd..

Bayesian informed evidence against modulation of androstadienone-effects by genotypic receptor variants and participant sex: A study assessing Stroop interference control, mood and olfaction

The androgen derivative androstadienone (AND) is present in human sweat and may act as human chemosignal. Though effects of AND have been reported with respect to emotional and cognitive processes, results have been highly inconsistent. For this reason, it is likely that AND-action is dependent on modulatory factors. Here we wanted to specifically investigate the impact of genotypic variations of the AND-receptor OR7D4, as well as the influence of participant sex and concomitant hormonal fluctuations on AND-action during emotional interference processing, olfactory performance and mood assessments.To this end 80 healthy individuals (women taking oral contraceptives; naturally cycling women measured during the luteal phase and men) were tested twice on two consecutive days (AND vs. placebo exposure) with an emotional Stroop task. Also, olfactory performance and mood was assessed. Participants provided saliva samples to measure testosterone, progesterone and estradiol and a blood sample to assess genotypic variations of the AND-receptor OR7D4.We found a small task-dependent reduction of overall error rates under AND but no modulation of effects by genetic variation or group (female OC, female NC, male) with respect to olfactory performance and mood. Additional analyses with help of Bayesian statistics gave strong evidence in favor of specific null hypotheses suggesting that the action of AND was not modulated by either genotypic variations or sex of participants with respect to interference control (bias indices), olfactory self-reports and mood parameters.Additional effects of AND in connection with hormonal fluctuations are reported.

Technical specifications of the Global Allergy and Asthma European Network (GA2LEN) chamber: a novel mobile allergen exposure chamber

Field trials are the traditional approach for clinical trials in allergy but are under criticism for lack of standardization as they are affected by uncontrollable parameters such as environmental conditions, pollen counts, or lifestyle. Stationary allergen exposure chambers with a defined concentration of allergens under stable and standardized environmental conditions have been used to overcome these restrictions but have not allowed multicenter studies. We here describe the technical specifications and validation of a novel mobile pollen chamber specifically designed for multicenter studies—the GA2LEN chamber. Two inter-connectable standard-sized container frames were used as a structural basis for the newly developed allergen exposure chamber. One container accommodates an observation room, also used as an office, and a changing room. The other container houses the test chamber itself and the technical installations. A customized air condition system was integrated and several environmental sensors were installed in the test chamber. Environmental tests have been performed at various outside conditions. The airflow in the test chamber was designed to prevent unspecific symptoms. To allow for an individual particle exposure at each seat, a new particle disperse and distribution system was developed, patented and validated. Technical and clinical validation tests have been successfully performed with Phleum pratense, Betula pendula, and mixtures of Dermatophagoides farinae, and Dermatophagoides pteronyssinus. The newly developed particle disperse system enable individual verum and placebo exposure, an even particle distribution at every seating position. The built-in air-conditioner is able to generate a tightly controlled, standardized and comfortable environment and the airflow did not provoke clinically significant irritation to lower respiratory tract, nose, or eyes. The chamber transportation has proven to be flexible and cost-effective. The GA2LEN chamber provides a novel mobile exposure chamber technology for research and clinical trials allowing a fast, affordable, and standardized multicenter approach.

Acute exposure to blue wavelength light during memory consolidation improves verbal memory performance.

Acute exposure to light within the blue wavelengths has been shown to enhance alertness and vigilance, and lead to improved speed on reaction time tasks, possibly due to activation of the noradrenergic system. It remains unclear, however, whether the effects of blue light extend beyond simple alertness processes to also enhance other aspects of cognition, such as memory performance. The aim of this study was to investigate the effects of a thirty minute pulse of blue light versus placebo (amber light) exposure in healthy normally rested individuals in the morning during verbal memory consolidation (i.e., 1.5 hours after memory acquisition) using an abbreviated version of the California Verbal Learning Test (CVLT-II). At delayed recall, individuals who received blue light (n = 12) during the consolidation period showed significantly better long-delay verbal recall than individuals who received amber light exposure (n = 18), while controlling for the effects of general intelligence, depressive symptoms and habitual wake time. These findings extend previous work demonstrating the effect of blue light on brain activation and alertness to further demonstrate its effectiveness at facilitating better memory consolidation and subsequent retention of verbal material. Although preliminary, these findings point to a potential application of blue wavelength light to optimize memory performance in healthy populations. It remains to be determined whether blue light exposure may also enhance performance in clinical populations with memory deficits.

Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy.

The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.

The human body odor compound androstadienone leads to anger-dependent effects in an emotional Stroop but not dot-probe task using human faces.

The androgen derivative androstadienone is a substance found in human sweat and thus is a putative human chemosignal. Androstadienone has been studied with respect to effects on mood states, attractiveness ratings, physiological and neural activation. With the current experiment, we aimed to explore in which way androstadienone affects attention to social cues (human faces). Moreover, we wanted to test whether effects depend on specific emotions, the participants' sex and individual sensitivity to smell androstadienone. To do so, we investigated 56 healthy individuals (thereof 29 females taking oral contraceptives) with two attention tasks on two consecutive days (once under androstadienone, once under placebo exposure in pseudorandomized order). With an emotional dot-probe task we measured visuo-spatial cueing while an emotional Stroop task allowed us to investigate interference control. Our results suggest that androstadienone acts in a sex, task and emotion-specific manner as a reduction in interference processes in the emotional Stroop task was only apparent for angry faces in men under androstadienone exposure. More specifically, men showed a smaller difference in reaction times for congruent compared to incongruent trials. At the same time also women were slightly affected by smelling androstadienone as they classified angry faces more often correctly under androstadienone. For the emotional dot-probe task no modulation by androstadienone was observed. Furthermore, in both attention paradigms individual sensitivity to androstadienone was neither correlated with reaction times nor error rates in men and women. To conclude, exposure to androstadienone seems to potentiate the relevance of angry faces in both men and women in connection with interference control, while processes of visuo-spatial cueing remain unaffected.

Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial

Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease. We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile. Galapagos.

Temporary deafferentation evoked by cutaneous anesthesia: behavioral and electrophysiological findings in healthy subjects.

Motor function and motor excitability can be modulated by changes of somatosensory input. Here, we performed a randomized single-blind trial to investigate behavioral and neurophysiological changes during temporary deafferentation of left upper arm and forearm in 31 right-handed healthy adults. Lidocaine cream was used to anesthetize the skin from wrist to shoulder, sparing the hand. As control condition, on a different day, a neutral cream was applied to the same skin area. The sequence (first Lidocaine, then placebo or vice versa) was randomized. Behavioral measures included the Grating Orientation Task, the Von Frey hair testing and the Nine-hole-peg-test. Transcranial magnetic stimulation was used to investigate short-interval intracortical inhibition, stimulus response curves, motor evoked potential amplitudes during pre-innervation and the cortical silent period (CSP). Recordings were obtained from left first dorsal interosseous muscle and from left flexor carpi radialis muscle. During deafferentation, the threshold of touch measured at the forearm was significantly worse. Other behavioral treatment-related changes were not found. The CSP showed a significant interaction between treatment and time in first dorsal interosseous muscle. CSP duration was longer during Lidocaine application and shorter during placebo exposure. We conclude that, in healthy subjects, temporary cutaneous deafferentation of upper and lower arm may have minor effects on motor inhibition, but not on sensory or motor function for the adjacent non-anesthetized hand.

A Preliminary Study to Investigate Relaxation and Sleep-Inducing Effects of Cedrol

Background: Cedrol exhibits relaxation effects, and its scent may reduce stress, thereby contributing to various stressful life situation. However, cedrol has also been reported to induce sleep, which is dangerous by case. Therefore, studies are needed in order to determine whether the relaxation or sleep-inducing effects of cedrol are induced under stressful situation and also how to only attain the former. Method: A cross-over open study was conducted. Subjects were randomly divided into two groups (n = 3 per group). After one course of the Kraepelin test and additional dumbbell lifting before and after the test was performed, subjects entered the placebo or cedrol exposure room, and rested in a sitting position for 20 minutes. Electrocardiographic, electroencephalographic, and blood pressure measurements as well as VAS assessments were conducted. Result: In the present study, no stress response was clearly detected. However, the results of analyses with respect to individuals suggested that cedrol exhibited relaxation effects, and that it did not induce sleep under the conditions adopted in this study.

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis

BackgroundIn a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti–interleukin-17A monoclonal antibody, in such patients.MethodsIn this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains.ResultsACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group.ConclusionsSecukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326.)

Application of low8intensity laser for adrenal stimulation in males with chronic obstructive pulmonary disease and hormonal disorders

The aim of this study was to investigate a role of adrenal function stimulation in patients with stage 3 chronic obstructive pulmonary disease (COPD). Methods . Blood levels of cortisol, aldosterone and testosterone were measured in 82 males with severe COPD and in 25 healthy subjects. The study involved three patient groups: 41 patients with stage 3 COPD who received lowintensity infrared laser radiation with a frequency of 80 Hz applied on the adrenal gland area additionally to the standard therapy; 26 patients with stage 3 COPD who received standard therapy only and 15 patients with COPD who received standard therapy and a placebo exposure using a switched off laser device. Results . A significant reduction in blood cortisol, aldosterone and testosterone levels in patients with stage 3 COPD was found. A role of adrenal function stimulation was confirmed in patients with stage 3 COPD. Conclusion. Severity of adrenal hormonal disorders correlates directly to severity of COPD. Treatment of male patients with stage 3 COPD should include adrenal hormone correction using both medication and nonmedication on individual basis. The lowintensity laser radiation of adrenal area could significantly increase blood cortisol level and improve quality of life of the patients.

Randomized, crossover, double-blind, placebo-controlled trial to assess the lipid lowering effect of co-formulated TDF/FTC.

IntroductionPrevious studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1–3] It is unknown, however, if TDF has an intrinsic lipid-lowering effect or such findings are due to the addition or removal of other offending agents or other reasons.Materials and MethodsThis was a randomized, crossover, double-blind, placebo-controlled clinical trial (NCT 01458977). Subjects with HIV-1 RNA <50 copies/mL during at least 6 months on stable DRV/r (800/100 mg QD) or LPV/r (400/100 mg BID) monotherapy, with confirmed fasting total cholesterol ≥200 or LDL-cholesterol ≥130 mg/dL and not taking lipid-lowering drugs were randomized to (A) adding TDF/FTCduring 12 weeks followed by 24 weeks without TDF/FTC, or (B) continuing without TDF/FTC for 12 weeks, adding TDF/FTC for 12 weeks and then withdrawing TDF/FTC for 12 additional weeks. Randomization was stratified by DRV/r or LPV/r use at study entry. All subjects received a specific dietary counselling. Primary endpoints were changes in median fasting total, LDL and HDL-cholesterol 12 weeks after TDF/FTC addition. Analyses were performed by ITT.Results46 subjects with a median age of 43 (40–48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL-cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL-cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL-cholesterol (p<0.001) and HDL-cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total-cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL-cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure.ConclusionCoformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF.

231P - &Agr;-Fetoprotein (Afp) Response By Gc33 Correlates to Progression Free Survival (Pfs) in Patients with Advanced Hepatocellular Carcinoma (Hcc)

ABSTRACT Aim: GC33 is a first-in-class recombinant, humanized mAb that binds to glypican-3 which is highly expressed in HCC. The aims of the analysis were to investigate AFP response after administration of GC33 in patients with advanced HCC and to assess the relationship between AFP response and PFS. Methods: Placebo and GC33 1600 mg biweekly with two loading doses were administered to previously treated patients with advanced HCC in a double-blind manner with 1:2 randomization. Seventy-one patients (placebo: GC33 = 24:47) who had AFP measurements at baseline (AFPB) and 6 weeks post treatment (AFP6W) were evaluated. Patients with steady state GC33 trough concentration higher than230 µg/ml (the median of the projected trough concentration on cycle 3 day1) were included in GC33 high exposure group. AFP response was defined as a 20% decrease in AFP at 6 weeks post treatment. Results: Twenty seven out of 47 patients treated with GC33 had trough concentration higher than 230 µg/ml. AFP change (%) from baseline at 6 weeks post treatment (calculated as (AFP6W-AFPB)/AFPB) in high exposure group was significantly lower than that in placebo and GC33 low exposure group combined (p = 0.029). In addition, 2 out of 24 (8.3%), 2 out of 20 (10%), and 8 out of 27 patients (30%) were AFP responder in placebo, GC33 low exposure group, and GC33 high exposure group, respectively. In landmark analysis (n = 71), AFP response was a prognostic factor of PFS (HR = 0.63, 80%CI: 0.41-0.97) regardless of treatment. Within GC33 treatment group, hazard ratio of PFS comparing AFP non-responder (n = 37) vs. AFP responder (n = 10) was 0.56 (80% CI: 0.34-0.91). Conclusions: GC33 high exposure group had better AFP response than placebo and low exposure group. Early assessment of AFP response may potentially be a valuable biomarker for predicting antitumor response in patients with advanced HCC. Disclosure: Yuyan Jin, Jun Shi, Alex Phipps and Ruey-min Lee have declared: is an employee of Hoffmann-La Roche; Mikiko Nakamura and Toshihiko Ohtomo have declared: is an employee of Chugai Pharmaceutical Co. Ltd.Ya-Chi Chen is an employee of Hoffmann-La Roche and also holds stocks of Hoffmann-La Roche.

135. Comparison of multiplex immunoassays and ELISAs for the determination of circulating levels of inflammatory cytokines

To determine whether multiplex immunoassays yield results that are comparable to those obtained with traditional enzyme-linked immunosorbent assays (ELISAs), cytokine concentrations were determined in 53 EDTA plasma samples from 7 college-age healthy individuals (3 female) undergoing experimental placebo ( n = 4) or endotoxin ( n = 3) exposure; 6–8 blood samples per subject were collected over a 7-h observation period. Plasma was assayed according to the manufacturer’s protocols for IL1-β, IL6, and TNF-α by high sensitivity ELISAs (Quantikine, R& D Systems), and as part of an 11-plex Performance High Sensitivity Human Cytokine multiplex bead-based (Luminex) assay (R& D Systems). When all samples in the placebo and endotoxin conditions were examined together, strong correlations were seen between ELISA and multiplex concentrations of IL1-β ( r = 0.91), IL6 ( r = 0.99), and TNF-α ( r = 0.94; all p values r = 0.89) and IL6 ( r = 0.98; both p values r = −0.28). This difference for TNF was not a function of assay sensitivity, as the calculated TNF concentrations for all placebo samples were within the range of the standard curve on both ELISA and multiplex assays. For IL-1 and IL-6, ELISAs and multiplex immunoassays yield similar results for samples in the physiological circulating range.