Treatment of auditory hallucinations with bilateral theta burst stimulation (cTBS): protocol of a randomized, double-blind, placebo-controlled, multicenter trial.
Eur Arch Psychiatry Clin Neurosci. 2017 Dec 09;:
Authors: Plewnia C, Brendel B, Schwippel T, Martus P, Cordes J, Hasan A, Fallgatter AJ
Auditory verbal hallucinations (AH) are core symptoms of schizophrenia. They are often severely distressing and refractory to therapy. Their perception is associated with increased activity in temporoparietal areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) can reduce focal brain hyperactivity and has been shown to ameliorate AH. However, controlled multicenter clinical trials are still missing, effect sizes are moderate, and the treatment with rTMS is time consuming. Continuous theta burst stimulation (cTBS) is a quicker and potentially more effective technique to reduce cortical hyperactivity. First case and pilot studies indicate effectiveness in the treatment of AH. In this randomized, sham-controlled, double-blind multicenter clinical trial, 86 patients with schizophrenia spectrum disorder will be randomized to either cTBS or sham to the left and right temporoparietal cortex during three consecutive weeks (15 sessions totally). In each session, both hemispheres will be stimulated sequentially. The order in the first session (left-right or right-left, respectively) will be determined by randomization and alternated in all following sessions. Primary outcome is the reduction of mean PSYRATS-AH score after cTBS as compared to sham treatment. Follow-up measurements will be performed 1, 3 and 6 months after the end of the treatment. Statistical analysis will be based on the intention-to-treat population including all randomized patients using an analysis of covariance. This multicenter-controlled clinical trial will be able to provide decisive evidence for the efficacy of cTBS in the treatment of AH. The results will be suitable to clarify the role of this innovative, pathophysiology-based therapeutic approach in treatment guidelines for AH.
TRIAL REGISTRY: ClinicalTrials.gov identifier: NCT02670291.
PMID: 29224040 [PubMed - as supplied by publisher]
Design considerations for handling dropouts in anti-depressant drug trials.
Contemp Clin Trials. 2017 Dec 06;:
Authors: Zhong J, Khin NA, Yang P
BACKGROUND: In clinical trials, statistical analysis often requires certain assumptions about missing data for a valid statistical inference. If the dropout rate is high, a wrong assumption about the missing data may compromise the validity of statistical inferences.
PURPOSE: To mitigate the high dropout rates commonly observed in psychiatry clinical trials, we consider two design approaches for short-term controlled trials submitted in support of marketing applications for drug products for the major depressive disorder (MDD) indication: (1) shortening the trial duration and (2) treating time to treatment discontinuation as an alternative primary efficacy endpoint.
METHODS: Subject-level efficacy data from 45 trials for drugs approved for an MDD indication between 1997 and 2014 were collected. We analyzed change from baseline in Hamilton Depression Rating Scale (HAMD-17) total score using the mixed model repeated measures approach. We compared the least squares means and the 95% confidence intervals of the treatment effect among three different trial durations, 4, 6, and 8weeks. We considered two definitions of discontinuation: (i) all-cause discontinuation, (ii) discontinuation due to lack of efficacy. We compared the two-sided log-rank p-values with the p-values from the protocol-specified primary analysis.
CONCLUSIONS: Our findings suggest that MDD trials in the acute setting may be shortened to 6weeks provided that the treatment difference between drug and placebo on HAMD-17 total score reaches approximately 2units at Week 6. However, our exploratory analyses of available data do not support the use of time to treatment discontinuation as an alternative primary efficacy endpoint.
PMID: 29223579 [PubMed - as supplied by publisher]
Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-Treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial.
Clin Ther. 2017 Dec 06;:
Authors: Kim CH, Han KA, Yu J, Lee SH, Jeon HK, Kim SH, Kim SY, Han KH, Won K, Kim DB, Lee KJ, Min K, Byun DW, Lim SW, Ahn CW, Kim S, Hong YJ, Sung J, Hur SH, Hong SJ, Lim HS, Park IB, Kim IJ, Lee H, Kim HS
PURPOSE: The purpose of this study was to examine the efficacy and safety of adding ω-3 fatty acids to rosuvastatin in patients with residual hypertriglyceridemia despite statin treatment.
METHODS: This study was a multicenter, randomized, double-blind, placebo-controlled study. After a 4-week run-in period of rosuvastatin treatment, the patients who had residual hypertriglyceridemia were randomized to receive rosuvastatin 20 mg/d plus ω-3 fatty acids 4 g/d (ROSUMEGA group) or rosuvastatin 20 mg/d (rosuvastatin group) with a 1:1 ratio and were prescribed each medication for 8 weeks.
FINDINGS: A total of 201 patients were analyzed (mean [SD] age, 58.1 [10.7] years; 62.7% male). After 8 weeks of treatment, the percentage change from baseline in triglycerides (TGs) and non-HDL-C was significantly greater in the ROSUMEGA group than in the rosuvastatin group (TGs: -26.3% vs -11.4%, P < 0.001; non-HDL-C: -10.7% vs -2.2%, P = 0.001). In the linear regression analysis, the lipid-lowering effect of ω-3 fatty acids was greater when baseline TG or non-HDL-C levels were high and body mass index was low. The incidence of adverse events was not significantly different between the 2 groups.
IMPLICATIONS: In patients with residual hypertriglyceridemia despite statin treatment, a combination of ω-3 fatty acids and rosuvastatin produced a greater reduction of TGs and non-HDL-C than rosuvastatin alone. Further study is needed to determine whether the advantages of this lipid profile of ω-3 fatty acids actually leads to the prevention of cardiovascular event. ClinicalTrials.gov identifier: NCT03026933.
PMID: 29223557 [PubMed - as supplied by publisher]
REVEAL risk scores applied to riociguat-treated patients in PATENT-2: Impact of changes in risk score on survival.
J Heart Lung Transplant. 2017 Nov 11;:
Authors: Benza RL, Farber HW, Frost A, Ghofrani HA, Gómez-Sánchez MA, Langleben D, Rosenkranz S, Busse D, Meier C, Nikkho S, Hoeper MM
BACKGROUND: The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score (RRS) calculator was developed using data derived from the REVEAL registry, and predicts survival in patients with pulmonary arterial hypertension (PAH) based on multiple patient characteristics. Herein we applied the RRS to a pivotal PAH trial database, the 12-week PATENT-1 and open-label PATENT-2 extension studies of riociguat. We examined the effect of riociguat vs placebo on RRS in PATENT-1, and investigated the prognostic implications of change in RRS during PATENT-1 on long-term outcomes in PATENT-2.
METHODS: RRS was calculated post hoc for baseline and Week 12 of PATENT-1, and Week 12 of PATENT-2. Patients were grouped into risk strata by RRS. Kaplan-Meier estimates were made for survival and clinical worsening-free survival in PATENT-2 to evaluate the relationship between RRS in PATENT-1 and long-term outcomes in PATENT-2.
RESULTS: A total of 396 patients completed PATENT-1 and participated in PATENT-2. In PATENT-1, riociguat significantly improved RRS (p = 0.031) and risk stratum (p = 0.018) between baseline and Week 12 compared with placebo. RRS at baseline, and at PATENT-1 Week 12, and change in RRS during PATENT-1 were significantly associated with survival (hazard ratios for a 1-point reduction in RRS: 0.675, 0.705 and 0.804, respectively) and clinical worsening-free survival (hazard ratios of 0.736, 0.716 and 0.753, respectively) over 2 years in PATENT-2.
CONCLUSIONS: RRS at baseline and Week 12, and change in RRS, were significant predictors of both survival and clinical worsening-free survival. These data support the long-term predictive value of the RRS in a controlled study population.
PMID: 29223470 [PubMed - as supplied by publisher]
Supplementation of gamma-aminobutyric acid (GABA) affects temporal, but not spatial visual attention.
Brain Cogn. 2017 Dec 06;120:8-16
Authors: Leonte A, Colzato LS, Steenbergen L, Hommel B, Akyürek EG
In a randomized, double-blind, and placebo-controlled experiment, the acute effects of gamma-aminobutyric acid (GABA) supplementation on temporal and spatial attention in young healthy adults were investigated. A hybrid two-target rapid serial visual presentation task was used to measure temporal attention and integration. Additionally, a visual search task was used to measure the speed and accuracy of spatial attention. While temporal attention depends primarily on the distribution of limited attentional resources across time, spatial attention represents the engagement and disengagement by relevant and irrelevant stimuli across the visual field. Although spatial attention was unaffected by GABA supplementation altogether, we found evidence supporting improved performance in the temporal attention task. The attentional blink was numerically, albeit not significantly, attenuated at Lag 3, and significantly fewer order errors were committed at Lag 1, compared to the placebo condition. No effect was found on temporal integration rates. Although there is controversy about whether oral GABA can cross the blood-brain barrier, our results offer preliminary evidence that GABA intake might help to distribute limited attentional resources more efficiently, and can specifically improve the identification and ordering of visual events that occur in close temporal succession.
PMID: 29222993 [PubMed - as supplied by publisher]
Effects of preoperative oral carbohydrate therapy on perioperative glucose metabolism during oral- maxillofacial surgery: randomised clinical trial.
Asia Pac J Clin Nutr. 2018;27(1):137-143
Authors: Esaki K, Tsukamoto M, Sakamoto E, Yokoyama T
BACKGROUND AND OBJECTIVES: Preoperative oral carbohydrate therapy has been suggested to attenuate postoperative insulin resistance. The purpose of this study was to investigate the effect of a carbohydrate-rich beverage given preoperatively on intraoperative glucose metabolism.
METHODS AND STUDY DESIGN: This study was a randomised, open-label, placebo-controlled trial. Patients undergoing oral-maxillofacial surgery were divided into two groups. In the glucose group, patients took glucose (50 g/278 mL, p.o.) 2 h before anaesthesia induction after overnight fasting; control-group patients took mineral water. Primary outcome was blood concentrations of ketone bodies (KBs); secondary outcomes were blood concentrations of free fatty acids, insulin and glucose. Concentrations were measured 2 h before anaesthesia (T0), induction of anaesthesia (T1), and 1 h (T2), 3 h (T3), and 5h after anaesthesia start (T4).
RESULTS: In the control group (n=11), KBs increased continuously from anaesthesia induction. In the glucose group (n=12), KBs were maintained at low concentrations for 3h after beverage consumption but increased remarkably at T3. At T1 and T2, concentrations of KBs in the glucose group were significantly lower than those in the control group (T1, p=0.010; T2, p=0.028). In the glucose group, glucose concentrations decreased significantly at T2 temporarily, but in the control group, glucose concentrations were stable during this study (T2, p<0.001: glucose vs control).
CONCLUSIONS: Preoperative intake of glucose (50 g, p.o.) can alleviate ketogenesis for 3 h after consumption but can cause temporary hypoglycaemia after anaesthesia induction.
PMID: 29222891 [PubMed - in process]
Effect of Losartan on RV Dysfunction: Results from the Double-Blind, Randomized REDEFINE Trial in Adults with Repaired Tetralogy of Fallot.
Circulation. 2017 Dec 08;:
Authors: Bokma JP, Winter MM, van Dijk AP, Vliegen HW, van Melle JP, Meijboom F, Post MC, Berbee JK, Boekholdt SM, Groenink M, Zwinderman AH, Mulder BJM, Bouma BJ
Background -The effect of angiotensin II receptor blockers (ARBs) on right ventricular (RV) function is still unknown. ARBs are beneficial in patients with acquired left ventricular (LV) dysfunction and recent findings suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an ARB, on subpulmonary RV dysfunction in adults after repair of tetralogy of Fallot (rTOF). Methods -REDEFINE is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with rTOF and RV dysfunction (RV ejection fraction (EF) <50%) but without severe valvular dysfunction were eligible. Patients were randomized between losartan (150mg daily) and placebo with target treatment duration between 18-24 months. The primary outcome was RV EF change, determined by cardiovascular magnetic resonance imaging in intention-to-treat analysis. Results -Of 95 included patients, 47 patients received 150mg losartan daily (age: 38.0±12.4 years, 74% male), and 48 patients received placebo (age: 40.6±11.4, 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF compared to placebo (+0.51%, 95% CI:-1.0, +2.0, p=0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro brain natriuretic peptide (p>0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with: symptoms, restrictive RV, RV EF<40%, PVR, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with non-restrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%, 95 CI:+0.1,+5.4, p=0.045). Conclusions -Losartan had no significant effect on RV dysfunction or secondary outcome parameters in rTOF. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. Clinical Trial Registration -URL: https://clinicaltrials.gov Unique Identifier: NCT02010905.
PMID: 29222139 [PubMed - as supplied by publisher]
Benefits of probiotics in preterm neonates in low-income and medium-income countries: a systematic review of randomised controlled trials.
BMJ Open. 2017 Dec 07;7(12):e017638
Authors: Deshpande G, Jape G, Rao S, Patole S
OBJECTIVE: Although there is an overall reduction in underfive mortality rate, the progress in reducing neonatal mortality rate has been very slow. Over the last 20 years, preterm births have steadily increased in low-income and medium-income countries (LMICs) particularly in sub-Saharan Africa and South Asia. Preterm birth is associated with increased mortality and morbidity, particularly in LMICs. Based on systematic reviews of randomised controlled trials (RCTs), many neonatal units in high-income countries have adopted probiotics as standard of care for preterm neonates. We aimed to systematically review the safety and efficacy of probiotics in reducing mortality and morbidity in preterm neonates in LMICs.
DESIGN: Systematic review and meta-analysis of RCTs.
DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and E-abstracts from Pediatric Academic Society meetings and other paediatric and neonatal conference proceedings were searched in January 2017.
ELIGIBILITY CRITERIA: RCTs comparing probiotics versus placebo/no probiotic in preterm neonates (gestation<37 weeks) conducted in LMICs.
RESULTS: Total 23 (n=4783) RCTs from 4 continents and 10 LMICs were eligible for inclusion in the meta-analysis using fixed effect model. The risk of necrotising enterocolitis (NEC greater than or equal to stage II) (risk ratio (RR) 0.46 (95% CI 0.34 to 0.61), P<0.00001, numbers needed to treat (NNT) 25 (95% CI 20 to 50)), late-onset sepsis (LOS) (RR 0.80 (95% CI 0.71 to 0.91), P=0.0009, NNT 25 (95% CI 17 to 100)) and all-cause mortality (RR 0.73 (95% CI 0.59 to 0.90), P=0.003, NNT 50 (95% CI 25 to 100)) were significantly lower in probiotic supplemented neonates. The results were significant on random effects model analysis and after excluding studies with high risk of bias. No significant adverse effects were reported.
CONCLUSION: Probiotics have significant potential to reduce mortality and morbidity (eg, NEC, LOS) in preterm neonates in LMICs.
PMID: 29222137 [PubMed - in process]
Are Bisphosphonates Efficacious in Knee Osteoarthritis? A Meta-Analysis of Randomized Controlled Trials.
Osteoarthritis Cartilage. 2017 Dec 05;:
Authors: Vaysbrot EE, Osani MC, Musetti MC, McAlindon TE, Bannuru RR
OBJECTIVE: To clarify the effects of bisphosphonates in knee osteoarthritis (OA) using an up-to-date meta-analysis of randomized controlled trials (RCTs).
DESIGN: The protocol is registered in PROSPERO (CRD42017073449). We searched MEDLINE, EMBASE, Google Scholar, Web of Science, and Cochrane Database from inception until August 2017. We included only RCTs comparing any bisphosphonates vs. placebo in knee OA patients and reporting validated pain and function scales, radiographic progression, and adverse events outcomes. We excluded studies using active comparators or concomitant medications besides NSAIDs and acetaminophen. We calculated standardized mean differences (SMD) to account for variation in outcome scales. Random effects meta-analyses were performed.
RESULTS: We included seven RCTs (3,013 patients, 69% female); most patients (N=2,767) received oral risedronate. No pain or function outcomes, regardless of dose, route, time point or measuring instrument, revealed statistically significant results (end of trial pain SMD -0.16 [95% CI-0.34, 0.02]). Similarly, we found no statistically significant effect on radiographic progression (Risk Ratio 0.98 [0.77, 1.26]). One small RCT in patients with bone marrow lesions (BML) suggested a reduction in BML size at 6 months. Bisphosphonates displayed good tolerability, with no statistically significant differences in adverse event outcomes vs. placebo.
CONCLUSIONS: Contrary to prior reviews, our analysis showed that bisphosphonates neither provide symptomatic relief nor defer radiographic progression in knee OA. However, these agents may still be beneficial in certain subsets of patients who display high rates of subchondral bone turnover. Future studies should be directed at defining such OA subsets and investigating the effects of bisphosphonates in those patients.
PMID: 29222056 [PubMed - as supplied by publisher]
Evaluation of the effect of mesotherapy in the management of back pain in police working dog.
Vet Anaesth Analg. 2017 Aug 19;:
Authors: Alves JC, Dos Santos AM, Fernandes ÂD
OBJECTIVE: To evaluate the feasibility and effectiveness of mesotherapy in dogs compared with a positive control group.
STUDY DESIGN: Experimental, randomized, blinded study.
ANIMALS: Fifteen working police dogs with chronic back pain.
METHODS: Animals were divided randomly into control (CG; n = 5) and treatment groups (TG; n = 10). A combination of 140 mg lidocaine, 15 mg dexamethasone and 20 mg thiocolchicoside was administered to group TG along with a 70-day course of a placebo, administered as if it was carprofen. Carprofen was administered to Group CG for 70 days, at a dose adjusted to their weight. On day 0, an intradermal injection of Ringer's lactate was also administered. Both groups were rested for 3 days and resumed normal activity over a 5-day period. Response to treatment, measured by the Canine Brief Pain Inventory (CBPI) and the Hudson Visual Analogue Scale (HVAS), was evaluated before treatment (T0), after 15 days (T1) and 1 (T2), 2 (T3), 3 (T4), 4 (T5) and 5 (T6) months. Results were compared using a Mann-Whitney test or a paired samples t test.
RESULTS: When comparing CBPI results, no differences were found between groups TG and CG at T0 through T3 and in T6 and T7. Differences were observed in CBPI sections after the discontinuation of carprofen: at T4 [p = 0.02 for Pain Interference Score (PIS) and p = 0.03 for Pain Severity Score (PSS)] and T5 (p = 0.16 for PIS and p = 0.03 for PSS), with group TG having overall better results. Individual treatment results were considered successful in one dog of group CG (20%), whereas in group TG, success was higher (ranging from 78% at T1 to 22% at T7). No significant differences were registered with the HVAS.
CONCLUSIONS AND CLINICAL RELEVANCE: Mesotherapy may be a promising treatment option for canine musculoskeletal-related pain. Further studies are required.
PMID: 29222031 [PubMed - as supplied by publisher]
The relationship of physical performance and osteoporosis prevention with vitamin D in older African Americans (PODA).
Contemp Clin Trials. 2017 Dec 05;:
Authors: Dhaliwal R, Mikhail M, Usera G, Stolberg A, Islam S, Ragolia L, Aloia JF
RATIONALE: Vitamin D deficiency is associated with bone loss, poor muscle strength, falls and fracture. This information in older African Americans (AAs) is sparse.
OBJECTIVE: The study of the relationship of Physical performance, Osteoporosis prevention with vitamin D in older African Americans (PODA) is a randomized, double-blind, placebo-controlled 3-year trial examining the effect of vitamin D on bone loss and physical performance in older AA women.
METHODS: 260 healthy AA women aged >60years were assigned to receive placebo or vitamin D3. Initial vitamin D3 dose was determined by the baseline serum 25OHD level, and adjusted further to maintain serum 25OHD between 30 and 69ng/ml. Subjects with baseline 25OHD levels ≤8ng/ml or ≥26ng/ml were excluded. Objective measures of neuromuscular strength [Short Physical Performance Battery (SPPB), grip strength and 6-minute walking distance (6MWD)] and bone mineral density (BMD) were obtained.
RESULTS: SPPB gait speed, grip strength and 6MWD showed a significant positive correlation with free 25OHD. 1pg/ml increase in free 25OHD predicted a 32% increase in the odds of having higher gait speed and a 1.42lb. increase in grip strength. No significant differences in BMI, BMD, muscle mass, grip strength, serum total 25OHD and free 25OHD were observed between groups. None of the measures of physical performance showed an association with baseline serum 25OHD.
CONCLUSIONS: This is the first study to show an association between free 25OHD and physical performance. These findings indicate a positive relationship of free 25OHD with gait speed and grip strength in older AA women. Further studies are needed to understand the role of free 25OHD.
PMID: 29221945 [PubMed - as supplied by publisher]
Gabapentin as an adjuvant therapy for prevention of acute phantom-limb pain in pediatric patients undergoing amputation for malignant bone tumors: a prospective double-blind randomized controlled trial.
J Pain Symptom Manage. 2017 Dec 05;:
Authors: Wang X, Yi Y, Tang D, Chen Y, Jiang Y, Peng J, Xiao J
CONTEXT: Gabapentin is reported to have an analgesic effect of reducing phantom-limb pain(PLP) in adult patients. There's no study on preoperative use of gabapentin in pediatric population in term of PLP prevention.
OBJECTIVE: To determine whether gabapentin could be used as an adjuvant agent of opioid-based pain control to lower the rate of phantom-limb pain in pediatric patients undergoing amputation for malignant bone tumors in observation period of 60 days post-operatively.
METHODS: Pediatric patients who were diagnosed with osteosarcoma or Ewing's sarcoma around the knee and underwent amputation from May 2013 to March 2016 were registered to this prospective double-blind randomized controlled trial. Four days before amputation, the patients were randomized to a study group receiving oral gabapentin, and a control group receiving oral placebo, both for 30 days. Pain intensity was recorded using the visual analog scale (VAS) at different time points in all patients. Phantom-limb pain was assessed daily during their postoperative hospital stay and at the last follow-up visit 60 days after operation.
RESULTS: Of the 45 patients included in our study, 23 patients were randomized to gabapentin group and 22 to placebo group. There was no significant difference in preoperative baseline pain intensity between the two groups (p=0.12). The overall postoperative pain intensity in gabapentin group was significantly lower than that in placebo group (p<0.05). The rate of phantom-limb pain in gabapentin group was significantly lower than that in placebo group (43.48% vs. 77.27%, p=0.033) at the last follow-up visit.
CONCLUSIONS: In pediatric patients, gabapentin shows the effect of preventing PLP and reducing postoperative pain intensity in acute period after amputation. Initiation gabapentin therapy as an adjuvant to opioids before amputation is beneficial and with no severe adverse effect.
PMID: 29221844 [PubMed - as supplied by publisher]
Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy.
Sleep Med. 2017 Dec;40:53-57
Authors: Dauvilliers Y, Roth T, Guinta D, Alvarez-Horine S, Dynin E, Black J
OBJECTIVE: To assess the effects of three narcolepsy treatment modalities on sleep stage shifts associated with disrupted nighttime sleep (DNS) using data from a clinical trial.
METHODS: Polysomnograms were reviewed from 155 patients (who had these data available at baseline and 8 weeks) of the 278 patients who were randomized to placebo, 9-g sodium oxybate (SXB)/nightly, 200-600 mg/d modafinil, or SXB + modafinil. Major outcomes of these post hoc analyses, analyzed using analysis of covariance, were change from baseline in number of shifts from Stages N2/3/rapid eye movement (REM) to Stage N1/Wake, and from Stage N1/Wake to REM. Sleep quality was evaluated using the sleep-quality question from the Pittsburgh Sleep Quality Index.
RESULTS: SXB alone or in combination with modafinil significantly decreased the number of shifts from Stage N2/3/REM to Stage N1/Wake (p < 0.01); least-squares mean change in number of shifts from baseline was -0.6, -16.5, 1.8, and -13.7 in the placebo, SXB, modafinil and SXB + modafinil groups, respectively. A similar pattern was observed for changes in shifts from REM to Stage N1/Wake and from Stage N1/Wake to REM. Relative to placebo, sleep quality significantly improved with SXB and SXB + modafinil (p ≤ 0.05) but not with modafinil alone.
CONCLUSION: These results show that SXB with and without modafinil significantly consolidated sleep and improved patient-reported sleep quality relative to placebo. In contrast, no such effects were observed with modafinil alone, suggesting a specific effect of SXB on DNS in addition to its effect on daytime sleepiness. CLINICALTRIALS.
GOV IDENTIFIER: NCT00066170.
PMID: 29221779 [PubMed - in process]
Effect of Grass Sublingual Tablet Immunotherapy is Similar in Children and Adults: A Bayesian Approach To Design Pediatric Sublingual Immunotherapy Trials.
J Allergy Clin Immunol. 2017 Dec 05;:
Authors: Kaur A, Skoner D, Ibrahim J, Li Q, Lockey RF, Blaiss M, Bufe A, Andersen JS, Canonica GW, Nolte H
BACKGROUND: Large sample sizes are needed for sublingual immunotherapy (SLIT) trials due to inherent data variability secondary to inconsistent allergen exposure. Obtaining large sample sizes for pediatric SLIT trials is challenging, but a Bayesian approach using prior adult data can reduce the necessary sample size.
OBJECTIVE: To describe how a Bayesian framework utilizing prior information from adult trials can be used to improve pediatric SLIT clinical development.
METHODS: Data were compiled using a frequentist approach (conventional clinical trial approach independent of prior data) from trials conducted during the clinical development of timothy grass SLIT-tablet.
RESULTS: The treatment effect of timothy grass SLIT-tablet was considered similar between pediatric (N=795) and adult (N=2299) data pools, with relative total combined symptom plus medication score improvement (95% CI) vs placebo of 21% (11.0, 30.4) and 20% (14.6, 24.4), respectively. Phleum pratense-specific IgG4 and IgE blocking factor increased from baseline in both children and adults treated with timothy grass SLIT-tablet. Given the reasonable assumption in similarity of treatment response between adults and children, a Bayesian approach is described to demonstrate rigorous efficacy criterion for pediatric trials incorporating information from prior adult trials, and thereby reduce the sample size.
CONCLUSIONS: Data support the similarity of efficacy and immunologic changes between children and adults treated with SLIT for allergic rhinoconjunctivitis. Therefore, it is appropriate to utilize data from adult trials to design feasible trials in children, which may reduce unsafe off-label use by promoting more quickly proper labeling of approved products.
PMID: 29221713 [PubMed - as supplied by publisher]
Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis.
Lancet Diabetes Endocrinol. 2017 Dec 05;:
Authors: Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, Pagidipati NJ, Chan JC, Gustavson SM, Iqbal N, Maggioni AP, Öhman P, Poulter NR, Ramachandran A, Zinman B, Hernandez AF, Holman RR, EXSCEL Study Group
BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs. Findings from cardiovascular outcome trials showed cardiovascular safety of GLP-1 receptor agonists, but results for cardiovascular efficacy were varied. We aimed to examine overall cardiovascular efficacy for lixisenatide, liraglutide, semaglutide, and extended-release exenatide.
METHODS: In this systematic review and meta-analysis, we analysed data from eligible trials that assessed the safety and efficacy of GLP-1 receptor agonists compared with placebo in adult patients (aged 18 years or older) with type 2 diabetes and had a primary outcome including, but not limited to, cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. We searched PubMed and MEDLINE without language restrictions up to Sept 18, 2017, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) for cardiovascular efficacy outcomes and odds ratios for key safety outcomes.
FINDINGS: Of 12 articles identified in our search and screened for eligibility, four trials of cardiovascular outcomes of GLP-1 receptor agonists were identified: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide). Compared with placebo, GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke; HR 0·90, 95% CI 0·82-0·99; p=0·033), a 13% RRR in cardiovascular mortality (0·87, 0·79-0·96; p=0·007), and a 12% relative risk reduction in all-cause mortality (0·88, 0·81-0·95; p=0·002), with low-to-moderate between-trial statistical heterogeneity. No significant effect of GLP-1 receptor agonists was identified on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. Overall, no significant differences were seen in severe hypoglycaemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer reported between GLP-1 receptor agonist treatment and placebo.
INTERPRETATION: Our findings show cardiovascular safety across all GLP-1 receptor agonist cardiovascular outcome trials and suggest that drugs in this class can reduce three-point major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk, albeit to varying degrees for individual drugs, without significant safety concerns. GLP-1 receptor agonists have a favourable risk-benefit balance overall, which should allow the choice of drug to be individualised to each patient's needs.
FUNDING: Amylin Pharmaceuticals (AstraZeneca).
PMID: 29221659 [PubMed - as supplied by publisher]
Effect of Evolocumab on Lipoprotein Particles.
Am J Cardiol. 2017 Nov 08;:
Authors: Toth PP, Sattar N, Blom DJ, Martin SS, Jones SR, Monsalvo ML, Elliott M, Davis M, Somaratne R, Preiss D
The level of low-density lipoprotein cholesterol (LDL-C) reflects the cholesterol carried mainly by low-density lipoprotein particles (LDL-P). LDL-C, however, does not always correlate with LDL-P because of the variable amounts of cholesterol per particle. Consideration of LDL-P concentrations in addition to LDL-C may help guide therapeutic decisions in a select number of patients. Evolocumab is a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9 that lowers both LDL-C and cardiovascular events. To evaluate the effect of evolocumab on serum levels and size of lipoprotein particles, we conducted a post hoc subanalysis of 619 patients from the Durable Effect of PCSK9 Antibody Compared with Placebo Study or DESCARTES trial, a 52-week, randomized, double-blind, placebo-controlled, global study of patients with hyperlipidemia. At baseline, mean LDL-P concentration was 1077 nmol/L for the placebo group and 1100 nmol/L for the evolocumab group. In patients receiving evolocumab, week 52 total LDL-P concentration decreased to 610 nmol/L, a treatment difference of 50% versus placebo. Evolocumab also reduced concentrations of medium very low-density lipoprotein particles (VLDL-P), small VLDL-P, and intermediate-density lipoprotein particle: median (Q1, Q3) changes were -15.2% (-48, 48), -29% (-54, 18), and -36% (-70, 22), respectively. Mean (95% confidence interval) % changes in total LDL particle size in the evolocumab group was -1.7 (-2.0, -1.4); % changes in HDL and VLDL particle sizes were 1.1 (0.7, 1.5) and 8.7 (7.0, 10.5), respectively. Changes in total LDL, HDL, and VLDL particle sizes (vs placebo) were all significant (p <0.001). In conclusion, evolocumab significantly lowers atherogenic lipoprotein particles including low-density and remnant lipoproteins.
PMID: 29221604 [PubMed - as supplied by publisher]
A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.
Alzheimers Res Ther. 2017 Dec 08;9(1):95
Authors: Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, Ashford E, Retout S, Hofmann C, Delmar P, Klein G, Andjelkovic M, Dubois B, Boada M, Blennow K, Santarelli L, Fontoura P, SCarlet RoAD Investigators
BACKGROUND: Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD).
METHODS: In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose.
RESULTS: Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints.
CONCLUSIONS: The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.
PMID: 29221491 [PubMed - in process]