Dose-related Improvement Research Articles

Effects of home-based exercise alone or combined with cognitive training on cognition in community-dwelling older adults: A randomized clinical trial

BackgroundStructured and supervised physical exercise and cognitive training are two efficient ways to enhance cognition in older adults. Performing both within a combined intervention could maximize their effect on cognition due to their potential synergy on brain functions. During the COVID-19 pandemic, these interventions were particularly relevant due to the collateral impact of social restrictions regarding physical activity and the level of cognitive stimulation. However, the benefits of remotely monitored intervention combining physical exercise and cognitive training for older adult cognition remain to be demonstrated. Methods127 older adults (age: 65.20 ± 7.95) were randomized in two arms, encouraging self-engagement in six months of home-based physical exercise alone or combined with cognitive training, monitored by phone once a week. Neuropsychological assessment was performed under videoconference supervision at baseline and after three and six months. Composite Z-scores were calculated for processing speed, executive functioning, working, and episodic memory to assess changes after three and six months of training. The weekly metabolic expenditure of self-reported activities was estimated using the compendium of physical activity to distinguish participants performing higher and lower doses of exercise (median split). Results106 participants (83.46 %) completed the 6-month training. Results showed a greater Z-score change in executive functioning for participants in the combined arm than those who only exercised (F = 4.127, p = 0.046, ηp2 = 0.050). Group x Exercise dose interaction was observed for episodic memory Z-score change (F = 6.736, p = 0.011, ηp2 = 0.070), with a greater improvement for participants performing higher doses of exercise compared to those who performed a lower dose, only in exercise alone arm. Performing a higher dose of exercise increased the working memory Z-score change in both intervention arms compared to a lower dose (F = 7.391, p = 0.008, η p2 = 0.076). ConclusionRemote combined training may lead to larger improvement in executive functioning than exercise alone. Physical exercise showed a dose-related improvement in working and episodic memory performances. The combination of cognitive interventions mitigated the effects of exercise on episodic memory. These results suggest that home-based exercise and cognitive training may help improve older adults' cognition. Trial registrationCOVEPIC was retrospectively registered on December 03, 2020. Clinical trials Identifier: NCT04635462 - https://clinicaltrials.gov/ct2/show/record/NCT04635462?term=NCT04635462&draw=2&rank=1

Efficacy and safety of atogepant, a small molecule CGRP receptor antagonist, for the preventive treatment of migraine: a systematic review and meta-analysis

BackgroundMigraine is one of the most common diseases worldwide while current treatment options are not ideal. New therapeutic classes of migraine, the calcitonin gene-related peptide (CGRP) antagonists, have been developed and shown considerable effectiveness and safety. The present study aimed to systematically evaluate the efficacy and safety of atogepant, a CGRP antagonist, for migraine prophylaxis from the results of randomized controlled trials (RCTs).MethodsThe Cochrane Library, Embase, PubMed and https://www.clinicaltrials.gov/ were searched for RCTs that compared atogepant with placebo for migraine prophylaxis from inception of the databases to Feb 1, 2024. Outcome data involving efficacy and safety were combined and analyzed using Review Manager Software version 5.3 (RevMan 5.3). For each outcome, risk ratios (RRs) or standardized mean difference (SMD) were calculated.Results4 RCTs with a total of 2813 subjects met our inclusion criteria. The overall effect estimate showed that atogepant was significantly superior to placebo in terms of the reduction of monthly migraine (SMD − 0.40, 95% CI -0.46 to -0.34) or headache (SMD − 0.39, 95% CI -0.46 to -0.33) days, the reduction of acute medication use days (SMD − 0.45, 95% CI -0.51 to -0.39) and 50% responder rate (RR 1.66, 95% CI 1.46 to 1.89), while no dose-related improvements were found between different dosage groups. For the safety, significant number of patients experienced treatment-emergent adverse events (TEAEs) with atogepant than with placebo (RR 1.10, 95% CI 1.02–1.21) while there was no obvious difference between the five dosage groups. Most TEAEs involved constipation (RR 2.55, 95% CI 1.91–3.41), nausea (RR 2.19, 95% CI 1.67–2.87) and urinary tract infection (RR 1.49, 95% CI 1.05–2.11). In addition, a high dosage of atogepant may also increase the risk of treatment-related TEAEs (RR 1.64, 95% CI 1.02–2.63) and fatigue (RR 3.07, 95% CI 1.13–8.35).ConclusionsThis meta-analysis suggests that atogepant is effective and tolerable for migraine prophylaxis including episodic or chronic migraine compared with placebo. It is critical to weigh the benefits of different doses against the risk of adverse events in clinical application of atogepant. Longer and multi-dose trials with larger sample sizes are required to verify the current findings.

Histological study on the protective effect of Moringa oleifera leaf extract on indomethacin-induced degenerated testes and uterus in albino rat

Abstract Background: Indomethacin has analgesic and antipyretic properties. It is a common treatment for pain and rheumatoid diseases, but it has many side effects. We speculate that the natural antioxidants of Moringa oleifera could be a remedy for the long list of side effects. This study aimed to determine the possible protective effect of Moringa oleifera leaf extract on the indomethacin-induced degenerated testes and uterus in albino rat. Methods: Forty-eight white albino rats were assigned randomly into six groups consisting of eight rats. Group, I was the Normal control. Group II was animals induced with indomethacin but not treated. Group III was dosed with 500 mg/kg Moringa oleifera leaf extract while Groups IV-VI were induced with indomethacin and treated with 100, 250, and 500 mg/kg Moringa oleifera leaf extract respectively for 28 days. Animals were euthanized after the treatment period. The uterus and testes were excised and processed using the paraffin wax method and stained with haematoxylin and eosin. Results: Animals exposed to indomethacin became drowsy and lethargic with deep red teary eyes. The first mortality was recorded among animals administered with indomethacin without treatment. Histopathology of the testes showed that indomethacin caused degeneration of the seminiferous tubules and diminished the spermatozoa. The histology of the uterus was distorted, the endometrium and myometrium layers of the uterus were disintegrated. However, animals treated with Moringa oleifera showed dose-related improvements in the histology of the testes and uterus compared to the control group. Conclusion: Moringa oleifera leaf extract improved the histology of indomethacin-induced toxicity of the testes and uterine in white albino rats.

Ameliorative Efficacy of Combined Betel and Tea Tree Essential Oil-Incorporated Cream on DNCB-Induced Atopic Dermatitis-like Symptoms in BALB/c Mice

Aims: This study aimed to investigate the ameliorative efficacy of combined betel and tea tree essential oil-incorporated cream on DNCB-induced atopic dermatitis-like symptoms in BALB/c mice.
 Methodology: cream formulation containing blended betel essential oil (1%) and tea tree essential oil (0.5%) was topically applied onto the dorsal skin of 2,4-dinitrochlorobenzene-sensitized BALB/c mice once a day during four weeks of assay. Phosphate-Buffered Saline (PBS) and protopic (tacrolimus 0.1%) were used as negative and positive control, respectively. All mice were subjected to the assessment of AD-like symptoms including the severity of skin lesions, frequency of scratching behavior and histological features.
 Results: The blended essential oil-incorporated cream has significant effect against DNCB-induced eczematous skin lesions in BALB/c mice with the dermatitis score of 2.17 ± 0.75 (n = 6, p < 0.05) and the number of scratching behavior of 6.09 ± 1.28 (n = 6, p < 0.05) compared to negative control (7.00 ± 0.63 and 18.55 ± 1.23, n = 6, p < 0.05, respectively). Animals treated showed dose-related improvements in the histology of the skin.
 Conclusion: These findings confirmed the ameliorative efficacy of betel and tea tree essential oil-incorporated cream on DNCB-induced atopic dermatitis like symptoms in BALB/c mice. However, further studies are necessary to elucidate the possible synergistic effect of blended essential oils from betel and tea tree as well as the interplaying roles of major molecules present in essential oils.

Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity.

Although doxorubicin (DOX) is an effective anti-neoplastic drug for many types of cancer, particularly dose-related cardiotoxicity limits the use of the drug. In this study, it was aimed to investigate the protective effect of lercanidipine (LRD) against DOX-induced cardiotoxicity. In our study, 40 Wistar albino female rats were randomly divided into 5 groups as control, DOX, LRD 0.5 (DOX + 0.5mg/kg LRD), LRD 1 (DOX + 1mg/kg LRD), and LRD 2 (DOX + 2mg/kg LRD). At the end of the experiment, the rats were sacrificed, and their blood, heart, and endothelial tissues were examined biochemically, histopathologically, immunohistochemically, and genetically. According to our findings, necrosis, tumor necrosis factor alpha activity, vascular endothelial growth factor activity, and oxidative stress were increased in the heart tissues of the DOX group. In addition, DOX treatment caused the deteriorations in biochemical parameters, and levels of autophagy-related proteins, Atg5, Beclin1, and LC3-I/II were detected. Significant dose-related improvements in these findings were observed with LRD treatment. Besides, Atg5, LC3-I/II, and Beclin1 levels evaluated by western blot revealed that LRD exerts a tissue protective effect by regulating autophagy in endothelial tissue. LRD treatment, which is a new-generation calcium channel blocker, showed antioxidant, anti-inflammatory, and anti-apoptotic properties in heart and endothelial tissue in a dose-dependent manner and also showed protective activity by regulating autophagy in endothelial tissue. With studies evaluating these mechanisms in more detail, the protective effects of LRD will be revealed more clearly.

The Effects of Safinamide Adjunct Therapy on Depression and Apathy in Patients With Parkinson's Disease: Post-hoc Analysis of a Japanese Phase 2/3 Study.

Background and PurposeNeuropsychiatric symptoms in Parkinson's disease (PD) have been shown to significantly affect quality of life (QOL). We investigated the impact of safinamide on depression and apathy when administered as an adjunct to levodopa in Japanese patients with PD.MethodsThis was a post-hoc analysis of data from a phase 2/3 clinical study of safinamide in Japanese patients with PD experiencing wearing-off (JapicCTI-153056; https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-153056). Patients received placebo, safinamide 50 mg, or safinamide 100 mg as an adjunct therapy. The endpoints for this analysis were changes from baseline to Week 24 in the Unified Parkinson's Disease Rating Scale (UPDRS) Part I item 3 (depression) and item 4 (apathy) scores and the Parkinson's Disease Questionnaire (PDQ-39) “emotional well-being” domain score. Subgroup analyses investigated the relationship between neuropsychologic symptoms and improvements in motor fluctuation and assessed which patient populations might be expected to obtain neuropsychologic benefit from safinamide.ResultsCompared with placebo, safinamide (both doses) significantly improved UPDRS Part I item 3 scores in the overall analysis population, and the 100-mg dose improved UPDRS Part I item 4 scores in the population with apathy at baseline. Changes in the PDQ-39 “emotional well-being” score showed numerical, but not significant, dose-related improvements. Notable reductions in depression were associated with a change in daily ON-time ≥1 h, pain during OFF-time at baseline, and female sex.ConclusionsThe results from this post-hoc analysis of the Japanese phase 2/3 study suggest that safinamide could bring benefits to patients with PD who have mild depression, pain during the OFF phase. In addition, safinamide might provide particular benefits for patients with PD who have mild apathy and female.

Pyrroloquinoline quinone regulates the redox status in vitro and in vivo of weaned pigs via the Nrf2/HO-1 pathway

BackgroundOxidative stress is a main cause of piglet gut damage and diarrhea. Pyrroloquinoline quinone (PQQ), is a novel redox cofactor with antioxidant properties. However, the effect and mechanism that PQQ supplementation decreases oxidative injury in weaned pigs is not understood. Therefore, the aim of this study is to confirm the effect of PQQ on regulating redox status in weaned pigs and the mechanism for antioxidant function by porcine intestinal epithelial cell line (IPEC-J2) challenged with H2O2.ResultsExperiment 1, 144 Duroc × Landrace × Yorkshire pigs (weaned at 28 d) were allocated to four groups: received a basal diet (control) and diets supplemented with 0.15%, 0.30% and 0.45% PQQ, respectively. On d 28, growth performance, diarrhea incidence and redox factors were measured. Experiment 2, IPEC-J2 were treated with or without PQQ in the presence or absence of H2O2 for indicated time points. Experiment 3, IPEC-J2 were transfected with or without Nrf2 siRNA, then treated according to Experiment 2. The cell viability, redox factors, protein of tight junctions and Nrf2 pathway were determined.In vivo, PQQ supplementation demonstrated dose-related improvements in average daily gain, and gain to feed ratio (Linear P < 0.05). During d 0–28, compared to controls, 0.45% PQQ supplementation for pigs decreased diarrhea incidence and MDA content in liver and jejunum, and increased concentration of SOD in liver; 0.3% PQQ supplementation decreased ileal and liver MDA concentration; and 0.15% PQQ supplementation decreased ileal MDA concentration (P < 0.05). In vitro, compared to cells cultured with H2O2, pre-treatment with PQQ increased cell viability, tight junction proteins expression including ZO-1, ZO-2, Occludin and Claudin-1; and decreased ROS concentration and level of Caspase-3 (P < 0.05); as well as upregulated the ratio of Bcl-2 to Bax and protein expression of nuclear Nrf2, HO-1. Notably, Nrf2 knockdown by transfection with Nrf2 siRNA largely abrogated the positive effects of PQQ pretreatment on H2O2-induced intracellular changes.ConclusionsPQQ administration attenuated oxidative stress in weaned pigs which is associated with activation of Nrf2/HO-1 pathway.

Efficacy of Dulaglutide Expanded Doses by Baseline A1C Categories: Post Hoc Analysis of AWARD-11

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide (DU) once weekly doses of 3 mg and 4.5 mg compared to DU 1.5 mg in patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. This exploratory post hoc analysis of AWARD-11 assessed the effect of dulaglutide on A1C reduction by clinically-relevant baseline A1C subgroups (<8%; 8%-<9%; 9%-<10%; ≥10%) and the proportion of patients achieving A1C <7% in these subgroups through 36 and 52 weeks. Patients were randomized to once weekly DU 1.5 mg (n=612), 3 mg (n=616), or 4.5 mg (n=614). All patients initiated once weekly DU 0.75 mg for 4 weeks, followed by stepwise dose escalation every 4 weeks to the randomized dose. A mixed effects model for repeated measures was used within the A1C subgroups to assess the change in A1C from baseline at 36 and 52 weeks. A longitudinal logistic regression model was used within subgroups to analyze the proportion of patients achieving A1C <7% at 36 and 52 weeks. Efficacy analyses used data collected up to initiation of rescue medication or premature treatment discontinuation, if either occurred. DU 1.5 mg reduced A1C across all baseline A1C categories at 36 weeks (range, -1.0 to -2.2%) and effects were sustained through 52 weeks (range, -1.0 to -2.1%). A1C reductions were greater in patients randomized to DU 3 mg or 4.5 mg versus 1.5 mg in each A1C subgroup, with greater dose-related improvements in patients with higher baseline A1C through 36 weeks (A1C subgroup, least-squares mean change in A1C [%] with 1.5 mg, 3 mg, and 4.5 mg, respectively: A1C<8%, -1.0, -1.2, -1.2; A1C 8-<9%, -1.4, -1.6, -1.8; A1C 9-<10%, -2.1, -2.2, -2.3; A1C ≥10%, -2.2, -2.5, -3.2; interaction p<0.001). More patients randomized to 3 mg or 4.5 mg achieved A1C <7% versus those on 1.5 mg at 36 weeks regardless of baseline A1C, but the difference across dose groups was greater at higher baseline A1Cs. Over half of patients randomized to DU 4.5 mg achieved A1C <7% in every baseline A1C category (A1C<8%, 75%, 87%, 83%; A1C 8-<9%, 61%, 64%, 73%; A1C 9-<10%, 46%, 51%, 64%; A1C ≥10%, 19%, 33%, 55% for DU 1.5 mg, 3 mg, and 4.5 mg, respectively; interaction p=0.096). Similar patterns of dose-related improvement in A1C and proportions of patients achieving A1C <7% across baseline A1C categories were observed at 52 weeks. Gastrointestinal adverse events were similar between A1C subgroups. Glycemic control as measured by A1C and proportion of patients achieving A1C <7% was improved with DU dose escalation from 1.5 mg to 3 mg or 4.5 mg across a spectrum of clinically relevant baseline A1C categories without increasing incidence of GI adverse events. Patients at higher baseline A1Cs (9%-<10% and ≥10%) had larger dose-related improvements in glycemic control than those at lower baseline A1Cs (<8% and 8%-<9%). The majority of patients randomized to DU 4.5 mg achieved glycemic target across all categories of baseline A1C.

Treatment with Imetelstat Improves Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in Patients with Relapsed or Refractory Higher-Risk Myelofibrosis

Treatment with Imetelstat Improves Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in Patients with Relapsed or Refractory Higher-Risk Myelofibrosis

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial

Summary Background Despite inhaled corticosteroid plus long-acting β2-agonist (ICS/LABA) therapy, 30–50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. Methods In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV1 of ≥12% and ≥200 mL in the 20–60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 μg or 200/25 μg) or FF/UMEC/VI (100/31·25/25 μg, 100/62·5/25 μg, 200/31·25/25 μg, or 200/62·5/25 μg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21–24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov , NCT02924688 , and is now complete. Findings Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 μg n=407; 200/25 μg n=406) or FF/UMEC/VI (100/31·25/25 μg n=405; 100/62·5/25 μg n=406; 200/31·25/25 μg n=404; 200/62·5/25 μg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV1 change from baseline for FF/UMEC/VI 100/62·5/25 μg versus FF/VI 100/25 μg was 110 mL (95% CI 66–153; p Interpretation In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk–benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. Funding GSK.

Anxiolytic effects of acute and maintenance ketamine, as assessed by the Fear Questionnaire subscales and the Spielberger State Anxiety Rating Scale.

Ketamine has rapid anxiolytic effects in treatment-resistant obsessive compulsive, post-traumatic stress, generalised anxiety and social anxiety disorders. This study aimed to assess changes following acute and maintenance ketamine therapy on the Fear Questionnaire (FQ) subscales and the Spielberger State Anxiety Inventory (SSAI). This secondary analysis used data from a mixed open-label and double-blinded placebo-controlled study. A total of 24 patients received short-term ascending subcutaneous doses of ketamine and were then eligible to enter a 3-month maintenance phase of 1 mg/kg ketamine dosed once or twice weekly. FQ and SSAI data were analysed using mixed models to identify between-dose differences and to describe trends during maintenance. Acute ketamine dosing showed a rapid dose-related reduction in all three FQ subscales (agoraphobia, social phobia and blood-injury phobia) and in the SSAI. A progressive decrease in pre-dose rating-scale scores was evident during the 3 months of maintenance therapy. Ketamine demonstrated dose-related improvements in all FQ subscales and in the SSAI. Both scales appear to be suitable tools to assess the anxiolytic effects of ketamine in patients with treatment-resistant anxiety. Furthermore, ketamine appears to have broad, dose-related anti-phobic effects. These findings raise the possibility that ketamine may have therapeutic potential in the treatment of other phobic states, such as specific phobia.

357-OR: Efficacy and Safety of Dulaglutide 3mg and 4.5mg vs. Dulaglutide 1.5mg: 52-Week Results from AWARD-11

Dulaglutide (DU) is approved at 2 doses (0.75 and 1.5 mg) for treatment of T2D. In this phase 3 study, once weekly DU 3 mg and 4.5 mg were compared to DU 1.5 mg for efficacy and safety through 52 weeks (wks) (primary endpoint at 36 wks) in patients with inadequately controlled T2D on metformin therapy. Patients were randomized (1:1:1) to once weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All patients were initiated on once weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Efficacy measures were analyzed based on data on-treatment without initiation of rescue medication. Mean age was 57.1 yrs, mean baseline (BL) A1C was 8.6%, and mean BL body weight (BW) was 95.7 kg. DU 1.5 mg, 3 mg and 4.5 mg showed significance (p&amp;lt;0.001) compared to BL for A1C, BW and fasting serum glucose (Table). DU 3 mg and 4.5 mg were both superior to DU 1.5 mg at the 36 wk primary endpoint, and remained significantly greater at 52 wks, for improvements in measures of glycemic control and body weight (Table). As expected for the GLP-1 receptor agonist class, commonly reported adverse events were nausea, diarrhea, and vomiting (Table). There were no new safety findings with the higher DU doses. In conclusion, escalation from DU 1.5 mg to DU 3 mg or 4.5 mg provided clinically relevant, dose-related improvements in glycemic control and body weight with an acceptable safety profile. Disclosure J.P. Frias: Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., LifeScan, Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Allergan plc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi. Speaker’s Bureau; Self; Merck &amp; Co., Inc., Sanofi. E. Bonora: Advisory Panel; Self; Lilly Diabetes, Novartis AG, Sanofi. Speaker’s Bureau; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S, Sanofi. L.A. Nevarez Ruiz: None. G. Li: Employee; Self; Eli Lilly and Company. Z. Yu: None. Z. Milicevic: Employee; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Bethel: Employee; Self; Eli Lilly and Company. D. Cox: Employee; Self; Eli Lilly and Company.

OR26-08 Efficacy and Safety of Higher Dulaglutide Doses (3.0 MG and 4.5 MG) When Added to Metformin in Patients With Type 2 Diabetes: A Phase 3, Randomized, Double-Blind, Parallel ARM Study (Award-11)

Dulaglutide (DU) approved at doses of 0.75 and 1.5 mg once-weekly is an effective glucose lowering agent for treatment of type 2 diabetes (T2D). We hypothesized that higher investigational DU doses may provide further improvements in glucose control and body weight (BW) with an acceptable safety profile. The primary objective was to demonstrate superiority of once-weekly DU 3 mg and/or 4.5 mg to DU 1.5 mg for A1C change from baseline (BL) at 36 weeks (wks) in patients (pts) with inadequately controlled T2D on metformin therapy. Secondary objectives (controlled for multiplicity) included change in BW and % of pts achieving A1C <7% at 36 wks. Patients were randomized (1:1:1) to once-weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All pts initiated once-weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Two estimands were defined for efficacy analyses: an efficacy estimand (data on-treatment without rescue medication) and a treatment-regimen estimand (all data regardless of adherence or initiation of rescue). At BL, patients had a mean of: age 57.1 yrs, T2D duration 7.6 yrs, and A1C 8.6%, BW 95.7 kg, and BMI 34.2 kg/m2. Using the efficacy estimand, the DU 3 mg and 4.5 mg doses were superior to the DU 1.5 mg dose for A1C change from BL (1.5 mg, 1.53%; 3 mg, 1.71% [p=0.003]; 4.5 mg, 1.87% [p<0.001]), % of patients achieving HbA1c <7% (1.5 mg, 57%; 3.0 mg, 65% [p=0.006]; 4.5 mg, 71% [p<0.001]) and BW change from BL (1.5 mg, 3.1 kg; 3 mg, 4.0 kg [p=0.001]; 4.5 mg, 4.7 kg [p<0.001]). Using the treatment-regimen estimand, DU 4.5 mg was superior to DU 1.5 mg for A1C change, while the DU 3 mg dose did not achieve statistical significance (1.5 mg, 1.54%; 3.0 mg, 1.64% [p=0.096]; 4.5 mg, 1.77% [p<0.001]). Using the treatment-regimen estimand, more patients achieved A1C <7% with higher DU doses (1.5 mg, 50%; 3 mg, 56%; 4.5 mg, 62%) and results for BW change were similar to the efficacy estimand (1.5 mg, 3.0 kg; 3 mg, 3.8 kg; 4.5 mg, 4.6 kg), but the approach for type I error control did not permit formal statistical comparisons of these secondary objectives using this estimand. The safety profile for the higher DU doses was consistent with that known for 1.5 mg. The most commonly reported adverse events were nausea (DU 1.5 mg, 13.4%; DU 3 mg, 15.6%; DU 4.5 mg, 16.4%), vomiting (DU 1.5 mg, 5.6%; DU 3 mg, 8.3%; DU 4.5 mg, 9.3%), and diarrhea (DU 1.5 mg, 7.0%; DU 3 mg, 11.4%; DU 4.5 mg, 10.7%). Treatment discontinuation due to adverse events through 36 wks was low and similar across dose groups (DU 1.5 mg, 4.2%; DU 3 mg, 5.5%; DU 4.5 mg, 5.0%). In pts with T2D and inadequate glycemic control on metformin, escalation from DU 1.5 mg to DU 3 mg or DU 4.5 mg once-weekly provided clinically relevant, dose-related improvements in glycemic control and BW with an acceptable safety profile.

Clinical Role of Epigenetics and Network Analysis in Eye Diseases: A Translational Science Review.

Network medicine is a molecular-bioinformatic approach analyzing gene-gene interactions that can perturb the human interactome. This review focuses on epigenetic changes involved in several ocular diseases, such as DNA methylation, histone and nonhistone post-translational modifications, and noncoding RNA regulators. Although changes in aberrant DNA methylation play a major role in the pathogenesis of most ocular diseases, histone modifications are seldom investigated. Hypermethylation in TGM-2 and hypomethylation in MMP-2/CD24 promoter genes may play a crucial role in pterygium development; hypermethylation in regulatory regions of GSTP1 and OGG1 genes appear to be diagnostic biomarkers of cataract; hypomethylation of TGF-β1 promoter may trigger glaucoma onset; hypermethylation of the LOXL1 gene might be associated with pseudoexfoliation syndrome. A large panel of upregulated micro-RNAs (miRNAs), including hsa-hsa-miR-494, hsa-let-7e, hsa-miR-513-1, hsa-miR-513-2, hsa-miR-518c, hsa-miR-129-1, hsa-miR-129-2, hsa-miR-198, hsa-miR-492, hsa-miR-498, hsa-miR-320, hsa-miR-503, and hsa-miR-373,∗ may have a putative role in the development of retinoblastoma. Hypermethylation of H3K4 and hypomethylation of H3K27 at the TGFBIp locus are putative pathogenic mechanisms involved in corneal dystrophies. Determining how, where, and when specific epigenetic changes trigger ocular diseases may provide useful clinical biomarkers for their prevention, diagnosis, and management, as well as innovative drug targets. PF-04523655, a 19-nucleotide methylated double-stranded siRNA targeting the RTP80 gene, showed a dose-related improvement in best-corrected visual acuity (BCVA) in patients affected by diabetic macular edema. The observed results support a clinical network-based research program aimed to clarify the role of epigenetic regulators in the development of ocular diseases and personalized therapy.

P.338Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

P.338Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Effects of Genistein on Differentiation and Viability of Human Visceral Adipocytes.

Obesity can lead to pathological growth of adipocytes by inducing inflammation and oxidative stress. Genistein could be a potential candidate for the treatment of obesity due to its antioxidant properties. Specific kits were used to examine the effects of genistein vs adiponectin on human visceral pre-adipocytes differentiation, cell viability, mitochondrial membrane potential, and oxidative stress in pre-adipocytes and in white/brown adipocytes. Western Blot was performed to examine changes in protein activation/expression. Genistein increased human visceral pre-adipocytes differentiation and browning, and caused a dose-related improvement of cell viability and mitochondrial membrane potential. Similar effects were observed in brown adipocytes and in white adipocytes, although in white cells the increase of cell viability was inversely related to the dose. Moreover, genistein potentiated AMP-activated protein kinase (AMPK)/mitofusin2 activation/expression in pre-adipocytes and white/brown adipocytes and protected them from the effects of hydrogen peroxide. The effects caused by genistein were similar to those of adiponectin. The results obtained showed that genistein increases human visceral pre-adipocytes differentiation and browning, protected against oxidative stress in pre-adipocytes and white/brown adipocytes through mechanisms related to AMPK-signalling and the keeping of mitochondrial function.

Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies

BackgroundAntagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks.MethodsA Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100–1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS).Results579 participants were randomized in the Phase 2 trial (mean age 41.6–43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5–40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (−0.15 [95% CI −0.29, −0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (−0.02 [95% CI −0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile.ConclusionsThe Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies.Trial registration NCT01241214 and NCT01484119

Dual Orexin Receptor Antagonist, Almorexant, in Elderly Patients With Primary Insomnia: A Randomized, Controlled Study.

Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with primary chronic insomnia. Patients aged ≥65 years with primary insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, -39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, -12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [-15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Two-night oral administration of almorexant was effective and well tolerated in treating primary insomnia in elderly patients.

Safety, efficacy, and dose response of fluticasone propionate delivered via the novel MDPI in patients with severe asthma: A randomized, controlled, dose-ranging study

ABSTRACTObjective: Evaluate fluticasone propionate (Fp) using a novel, inhalation-driven, multidose dry powder inhaler (MDPI) in patients with severe persistent asthma, versus placebo MDPI and Fp dry powder inhaler (DPI). Methods: Patients with persistent asthma despite use of high-dose inhaled corticosteroids were randomized to Fp MDPI 50, 100, 200, or 400 mcg; Fp DPI 250 mcg; or placebo MDPI twice daily for 12 weeks. The primary outcome measure was change from baseline in trough forced expiratory volume in 1 second (FEV1) over the 12-week period, compared with placebo; secondary measures included change from baseline in peak expiratory flow (PEF), rescue inhaler use, and time to withdrawal due to meeting stopping criteria. Safety included adverse events and laboratory evaluations. Results: Six hundred forty patients were randomized; 459 (72%) completed the study. Numerical dose-related improvements in FEV1 were observed in all Fp MDPI groups over 12 weeks but were not significantly greater versus placebo. Increases in morning PEF (baseline to week 12) were substantially greater than placebo in all Fp MDPI groups. The Fp MDPI and Fp DPI groups had substantial reductions in rescue inhaler use from baseline to end point versus placebo (p ≤ 0.05). Efficacy was comparable between Fp MDPI and Fp DPI. No new safety signals were detected; the safety profile of Fp MDPI was similar to that of Fp DPI. Conclusions: Clinical benefit observed with Fp MDPI in patients with persistent asthma was comparable to Fp DPI. Safety was reassuring with no unexpected findings. These results support further evaluation of Fp MDPI in asthma. (ClinicalTrials.gov identifier NCT01576718; EudraCT number 2010-023601-35).

PC3 - 154 Phase I/II Study of VAL-083 in Patients with Recurrent Glioblastoma

Glioblastoma (GBM) is the most common brain cancer. Resistance to front-line systemic therapy with temozolomide (TMZ) is correlated with O6-methylguanine-DNA-methyltransferase (MGMT) expression. Second-line treatment with bevacizumab has not improved overall survival. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that has MGMT-independent cell-kill activity against GBM cell-lines and cancer stem cells in vitro. VAL-083 crosses the blood-brain barrier and showed promise against CNS tumors in prior NCI-sponsored clinical trials. The goal of this clinical trial is to determine appropriate VAL-083 dosing for advancement to Phase III trials as a new treatment for recurrent GBM. METHODS: Patients must have recurrent GBM following surgery, radiation, TMZ and bevacizumab. Phase I: Open-label, single-arm, dose-escalation study. Patients received VAL-083 on days 1,2,3 of a 21-day cycle, until reaching MTD. Phase II: Additional patients enrolled at MTD to further assess safety and outcomes. RESULTS: Phase I: 29 patients were enrolled across 9 dose cohorts (1.5-50 mg/m2/d). 40mg/m2/d was confirmed as MTD. Myelosuppression was mild; no drug-related serious adverse events were reported at doses up to 40mg/m2/d. Dose limiting G4 thrombocytopenia was observed at higher doses. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. A dose-related survival improvement was observed. Pharmacokinetic analyses show 1-2h plasma terminal half-life; average Cmax 781ng/mL at 40mg/m2/d. Phase II: 14 patients were enrolled at 40mg/m2/d. To date, safety observations in Phase II are consistent with Phase I. CONCLUSIONS: VAL-083 at 40mg/m2/d exhibits a favorable safety profile and dose-related trend toward clinically meaningful improved survival in refractory GBM patient