Active-controlled Study Research Articles

Effectiveness and Tolerability of Ectoin® Mouth and Throat Spray Althaea Honey (ERS09) for Sore Throat due to Acute Pharyngitis and Dry Cough: A Multicentre, Actively Controlled, Open Label Study in Germany.

Acute pharyngitis can cause sore throat. This multicentre, active-controlled, randomised, open-label, and parallel-group study, conducted according to the German Medical Devices Act, compared the effectiveness and tolerability of ERS09 mouth and throat spray with a well-established device for the treatment of sore throat caused by acute pharyngitis and dry cough. Patients were randomised 1:1 into ERS09/comparator groups (EMSER® Sore Throat Spray) for 7 ± 2 days. Patients and investigators reported effectiveness (change in total symptom score [TSS]) and safety endpoints (incidence of adverse events [AEs]; adverse device effects [ADEs]). A total of 186 patients were included (ERS09: n = 92; comparator: n = 94). The baseline-adjusted mean TSS over 7 days was -90.14 and -74.91 in the ERS09 and comparator groups, respectively (p < 0.05). The majority of patients reached a 50% reduction in symptoms by day 6 (ERS09 = 78.85; comparator = 75.8%). Most patients reported a soothing effect within five minutes (ERS09 = 82%; comparator = 71%). Improvements in individual symptoms were similar with no significant differences between groups; more patients in the ERS09 group reported an improvement in pharyngeal redness/swelling. Three AEs unrelated to medication, one ADE following ERS09, and no serious AE/ADE were reported. ERS09 was as well tolerated and effective as the established device, showing greater improvement in the management of some symptoms and greater patient preference.

Size-dependent parametrisation of active vibration control for periodic piezoelectric microplate coupled systems: A couple stress-based isogeometric approach

We propose a couple stress based isogeometric analysis (IGA) model for the study of active vibration control in periodic piezoelectric microplate coupled systems. The model integrates the modified couple stress elasticity, which accounts for microstructure effects but necessitates the implementation of at least C1 continuous finite elements, and the IGA finite element, which fulfils the element continuity criterion. This complementary combination enables size-dependent parametrisation of the feedback vibration controller for piezoelectric microplate coupled systems. Therefore, we examined a two-parameter control relationship that modulates the voltage gain within the sensor-to-actuator circuit in relation to mass and stiffness with the account for varying problem sizes. To assess the vibration properties of the microplate system, we performed bandgap analysis and compared the results to transient responses. Additionally, we investigated the impact of couple stress on bandgaps and devised a computational methodology for determining optimal control parameters concerning the desired vibration bandgaps. Our computational procedure serves as valuable tool for assisting in the parametrisation of feedback vibration controllers in microplates with tunable vibration bandgaps.

Tofacitinib Versus Oral Prednisolone for Induction of Remission in Moderately Active Ulcerative Colitis [ORCHID]: A Prospective, Open-Label, Randomized, Pilot Study.

Oral corticosteroids are first-line agents to induce remission in moderately active ulcerative colitis [UC], but are associated with adverse effects. We compared the efficacy and safety of tofacitinib and prednisolone for induction of remission in moderately active UC. This was a single-centre, prospective, open-label, randomized, active-controlled pilot study. Eligible patients [aged ≥18 years] had moderately active UC. Participants were randomly assigned to receive either prednisolone [40 mg daily, tapered by 5 mg every week] or tofacitinib [10 mg twice daily] for 8 weeks. The primary endpoint was composite remission [defined as total Mayo clinic score ≤2, with endoscopic sub-score of 0 and faecal calprotectin <100 µg/g] at 8 weeks. Seventy-eight patients were randomly assigned to either of the treatment groups. At week 8, the proportion of patients achieving composite remission in the tofacitinib [7/43, 16.28%] and prednisolone groups [3/35, 8.57%] were not significantly different (odds ratio [OR] 2.07, 95% confidence interval [CI] 0.49-8.70; p = 0.31). The time to achieve symptomatic remission [normal stool frequency with absence of rectal bleeding] was similar (10 days, interquartile range [IQR 7-18.75] and 10 days [IQR 5-12.5] for tofacitinib and prednisolone, respectively; p = 0.25) in the two groups. One patient each in the tofacitinib and prednisolone group discontinued treatment due to development of pulmonary tuberculosis and pustular acne, respectively. One patient receiving tofacitinib developed herpes zoster, but did not require cessation of therapy. No serious adverse events or major adverse cardiovascular events were observed. In patients with moderately active UC, there was no difference in the efficacy and safety of tofacitinib and oral prednisolone for induction of remission at 8 weeks. Clinical Trials Registry of India [CTRI/2021/10/037641].

The active control study of a damped two-level smart spring system

The vibration reduction performance of a damped two-level smart spring system is studied. The governing equations of the smart spring system are reduced to a first-order ordinary differential equation of matrix form. An active control algorithm employing the relative velocity relationships between the primary and auxiliary systems to prevent the movement of the controlled object is applied in the simulation. Different excitation types are considered to fully examine the validity of the control law. Responses of the controlled object under the control law are obtained and compared to the case of constant friction and the case of no control. The study indicates that the active control algorithm shows a good vibration reduction efficiency and a wide vibration reduction bandwidth.

A Clinical Study to Assess the Efficacy and Safety of MP-AzeFlu Nasal Spray in Comparison to Commercially Available Azelastine Hydrochloride and Fluticasone Propionate Nasal Sprays in Chinese Volunteers with Allergic Rhinitis.

The objective of the present study was to evaluate the efficacy and safety of MP-AzeFlu nasal spray in comparison to commercially available azelastine hydrochloride and fluticasone propionate sprays in Chinese patients with moderate-to-severe allergic rhinitis (AR). We conducted a 14-day multicenter, randomized, double-blind, active controlled prospective clinical study in adult and adolescent patients with AR, who had moderate-to-severe symptoms. The primary efficacy endpoint was the change from baseline in combined 12-h reflective total nasal symptom score (rTNSS) (morning [AM] + afternoon [PM]). The safety profile of the study medications was assessed through the recording, reporting, and analysis of baseline medical conditions, adverse events (AEs), vital signs, and focused nasal examination. Three hundred patients per treatment group were randomized, which led to a total sample size estimation of 900 patients. MP-AzeFlu group showed significantly higher symptom reduction for the entire 2-week treatment period in rTNSS when compared with the AZE group (LS mean difference: -1.96; 95% CI: - 2.53, - 1.39; p < 0.0001), or the FLU group (LS mean difference: -0.98; 95% CI: - 1.55, - 0.41; p = 0.0007). The results of adult RQLQ showed improvement in QoL in all treatment groups. Except for dysgeusia (bitter taste) that was reported by more patients (13 [4.3%]) in the MP-AzeFlu group, the incidence of all other TEAEs in the MP-AzeFlu group was comparable or even lower than in other treatment groups. MP-AzeFlu, when administered as one spray per nostril twice daily for 14days, alleviated AR symptoms in Chinese patients with moderate-to-severe AR. Clinicaltrials.gov; NCT03599791, Registered June 29, 2018, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03599791 .

A hyaluronic acid-based micro-filler improves superficial wrinkles and skin quality: a randomized prospective controlled multicenter study

BackgroundNCTF®135HA is a bio-revitalizing solution containing hyaluronic acid designed to compensate for skin dehydration, fatigue, and fine wrinkles associated with endogenous and environmental aging.MethodsWe conducted a randomized, active-controlled study to evaluate the efficacy and tolerability of NCTF®135HA injections on the face (crow’s feet), neck, and décolleté regions. Subjects were randomly assigned (3:1) to receive three NCTF®135HA treatment sessions plus twice-daily anti-aging moisturizer cream or cream alone (control). The primary outcome was the reduction in superficial wrinkles between baseline and Day (D)75 in the three areas, assessed by profilometric measures, clinical scoring, subjective changes, and tolerability.Results146 subjects were randomized to NCTF®135HA (n = 107) or control (n = 38). At D75 and D120, NCTF®135HA significantly reduced wrinkles in all three areas and improved facial radiance scores compared with the control. Skin hydration significantly increased 7 d after the last NCTF®135HA injection. Self-esteem scales showed statistically significant improvements at D75 and D120 in subjects treated with NCTF®135HA versus baseline. Most adverse events were mild, resolved within 48 h, and were related to the injection procedure.ConclusionNCTF®135HA is an effective and well-tolerated treatment to reduce the skin signs of aging. The results are significantly superior to a routine anti-aging cream alone.(Funded by Laboratories FILLMED; ID-RCB number: 2018-A03167-48; clinicaltrials.gov number: NCT05609617)

Comparative effects of nebivolol and carvedilol on left ventricular diastolic function in older patients with heart failure and preserved ejection fraction

BackgroundAlthough many studies have compared carvedilol and nebivolol in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF), such comparative studies for the elderly have not been reported yet. Nebivolol is known to be effective for improving diastolic function of elderly patients with HF. Thus, this study aimed to determine whether nebivolol could improve LV diastolic function to a greater extent than carvedilol in older patients aged over 70 years. MethodsThis trial was a prospective, randomized, open-label, single-center, active-controlled study that enrolled 62 patients with class II or III HF over 70 years of age with an LVEF ≥40%. Patients were randomized into a carvedilol group or a nebivolol group. Transthoracic echocardiography was performed at baseline and 12 months by the same investigator who was blinded to clinical data. The primary endpoint was E/e′ measured by echocardiographic evaluation 12 months after treatment. ResultsThe median duration of follow-up was 24 months. Baseline clinical characteristics and echocardiographic parameters, such as LV diastolic function indices, did not differ significantly between carvedilol and nebivolol groups. Twelve-month follow-up echocardiography data showed no significant difference in E/e′ or other LV diastolic function indices between the two groups. There were no significant changes in echocardiographic parameters over 12 months in either group. ConclusionsThere was no difference between carvedilol and nebivolol for improving diastolic function of elderly HF patients with LVEF ≥40%. This study showed no superiority of nebivolol over carvedilol in elderly patients with HF.

Outcomes of additional local antibiotic to local analgesic and vasodilator in acute anal fissure - A randomized controlled study

Acute anal fissure is a common and painful condition of ano-rectal region characterized by tear in the anoderm causing pain during defecation. Mainstay of its treatment is pharmacotherapy with lifestyle modification. Current study was undertaken to evaluate the role of add-on local antimicrobial in recovery and relief of symptoms of acute anal fissure in comparison to local anesthetic and vasodilator without any antimicrobial. It was a randomized, assessor-blinded, active-controlled clinical study in which data of 68 eligible participants were analyzed. Participants of both group received local lignocaine and nifedipine and the test group (Group B) received metronidazole ointment in addition. Healing was assessed by clinical examination and pain by Numeric Pain Rating Scale. Sample size was calculated based upon result of older pilot study and the proportion of recovery were assessed by Chi-square test. After 6 weeks of treatment, 61 out of 68 (i.e., 89.7%) patients receiving add-on antimicrobial recovered completely compared to 75% of the comparator group. Reduction of pain and cessation of bleeding were also significantly better in patients receiving additional antibacterial. Healing and symptom relief in acute anal fissure is better with addition of local antibacterial along with local vasodilator and anesthetic.

Heat stable carbetocin or oxytocin for prevention of postpartum hemorrhage among women at risk: A secondary analysis of the CHAMPION trial.

To examine whether the observed non-inferiority of heat-stable carbetocin (HSC), compared with oxytocin, was influenced by biologic (macrosomia, parity 3 or more, or history of postpartum hemorrhage [PPH]) and/or pharmacologic (induction or augmentation) risk factors for PPH. The present study is a secondary analysis of the CHAMPION non-inferiority randomized trial-a two-arm, double-blind, active-controlled study conducted at 23 hospitals in 10 countries, between July 2015 and January 2018. Women with singleton pregnancies, expected to deliver vaginally with cervical dilatation up to 6 cm were eligible. Randomization was stratified by country, with 1:1 assignment. Women in the intervention and control groups received a single intramuscular injection of 100 μg of HSC or 10 IU of oxytocin, respectively. The drugs were administered immediately after birth, and the third stage of labor was managed according to the WHO guidelines. Blood was collected using a plastic drape. For this analysis, we defined a woman as being at risk if she had any one or more of the biologic or pharmacologic risk factor(s). The HSC and oxytocin arms contained 14 770 and 14 768 women, respectively. The risk ratios (RR) for PPH were 1.29 (95% confidence interval [CI] 1.08-1.53) or 1.73 (95% CI 1.51-1.98) for those with only biologic (macrosomia, parity 3 or more, and PPH in the previous pregnancy) or only pharmacologic (induced or augmented) risk factors, respectively, compared with those with neither risk factors. Findings reinforce previous evidence that macrosomia, high parity, history of PPH, and induction/augmentation are risk factors for PPH. We did not find a difference in effects between HSC and oxytocin for PPH among women who were neither induced nor augmented or among those who were induced or augmented.

Small-amplitude bogie hunting identification method for high-speed trains based on machine learning

Hunting stability is a critical aspect of the dynamic performance of high-speed trains. However, the current evaluation criteria only address heavy hunting motion, and they require supplementation and improvement to meet the increasing requirements of dynamic performance. Therefore, a study was conducted to develop an identification method for small-amplitude bogie hunting (SABH) motion. A total of 39,816 samples were obtained from field-measured bogie lateral acceleration and manually labelled as normal and SABH. The distribution comparison, Pierce coefficient, and importance ranking showed that harmonic character-related features (the autocorrelation coefficient, approximate entropy and etc.) should be considered more for SABH identification than amplitude-related features (maximum and RMS). The most critical features for SABH identification were the autocorrelation coefficient and spectral frequency spread. The classifier performance comparison showed that the decision tree was the best-performing classifier, followed by the support vector machine, while the linear discriminant, K-nearest neighbour, and naive Bayes classifiers were less effective. Sensitivity analysis indicated that the proposed method worked well with a sampling frequency of 50–200 Hz and a window length of 5–10 s. This research provides theoretical support for hunting instability monitoring and real-time active control studies for high-speed trains.

79-LB: An Open-Label, Active-Controlled Phase 2 Evaluation of Novel GLP-1 Analog Ecnoglutide in Adults with Obesity

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a multi-center, open-label, active-controlled Phase 2b study in adults with a body mass index (BMI) ≥30 to ≤40 kg/m2. The trial was conducted at nine sites in Australia and New Zealand, with 206 participants enrolled. Participants were randomized to receive target doses of ecnoglutide at 1.2, 1.8, or 2.4 mg as once weekly SC injections or liraglutide (Saxenda®) at 3.0 mg as once daily injections for 26 weeks. Doses were increased by titration for up to 14 weeks before reaching the target dose. Safety and tolerability were assessed, along with efficacy parameters including change in body weight. At baseline, participants had a mean body weight of 100.67 ± 13.54 kg and BMI of 35.29 ± 2.76 kg/m2. After 26 weeks of dosing, participants receiving 1.2, 1.8, or 2.4 mg ecnoglutide weekly achieved a least square mean (LSM) body weight reduction from baseline of -11.5%, -11.2%, and -14.7%, respectively, compared to -8.8% for those receiving 3.0 mg liraglutide daily injections. Participants receiving 2.4 mg ecnoglutide showed significantly more pronounced body weight reduction compared to liraglutide (LSM difference -5.9, 95% confidence interval -10.4, -1.5; p&amp;lt;0.001). Overall, treatment with ecnoglutide was safe and well tolerated. Treatment emergent AEs were reported in 93.5% of participants in the ecnoglutide groups and 98.0% in the liraglutide group. Gastrointestinal disorders were reported in 81.9% of ecnoglutide-treated participants and 80.4% of those receiving liraglutide, most of which were mild to moderate and most occurred during the dose escalation period. Two SAEs related to the study drug were reported. Both were cases of acute cholecystitis, one in a participant receiving 1.2 mg ecnoglutide and one in the liraglutide group. Disclosure Z. Zhu: Employee; Sciwind Biosciences. M. K. Junaidi: None. Y. Li: Employee; Sciwind Biosciences. Q. Zheng: Employee; Sciwind Biosciences. E. Adegbite: Employee; Sciwind Biosciences. S. Ross: None. L. Telusca: None. C. L. Jones: Employee; Sciwind Biosciences. M. Fenaux: Employee; Sciwind Biosciences, Stock/Shareholder; Terns Pharmaceuticals. S. Xu: Employee; Sciwind. Funding Sciwind Biosciences Co., Ltd.

Susceptibility‐guided sequential strategy versus empirical therapy for Helicobacter pylori infection: study protocol for a randomised controlled trial

BackgroundNew treatment strategies are required against infections caused by Helicobacter pylori, which grows increasingly resistant to antibiotics. Polymerase chain reaction-based methods for antibiotic susceptibility testing are available for detecting H. pylori-specific mutations that confer resistance to clarithromycin and levofloxacin. Several meta-analyses have compared eradication rates for susceptibility-guided versus empirical therapy for H. pylori treatment; however, all have significant limitations and high heterogeneity, and the results are contradictory. The main objective of this trial is to assess whether a sequential strategy based on molecular susceptibility testing-guided therapy for H. pylori has a better eradication rate than empirical therapy.MethodsThis trial is designed as a prospective, randomised, open-label, active-controlled and single-centre study. Men and women who are H. pylori-positive, naïve to treatment, and aged 18–65 years will be recruited. A total of 500 participants will be randomised to receive either empirical therapy or a susceptibility-guided sequential strategy. Bismuth quadruple therapy will be the empirical first-line therapy, and in case of failure, high-dose dual (proton-pump inhibitor + amoxicillin) treatment will be the rescue therapy. For the susceptibility-guided sequential strategy, regimen selection will be based on H. pylori susceptibility to clarithromycin (first-line) and levofloxacin (rescue). A first-line treatment of clarithromycin triple therapy will be selected for clarithromycin-sensitive strains. For clarithromycin resistance, a high-dose dual therapy will be selected. During the rescue treatment, a levofloxacin quadruple regimen will be selected for levofloxacin-sensitive strains, and a furazolidone quadruple regimen will be selected for others. The primary outcome is the first-line eradication rate in both groups, and the overall (including first and rescue therapies) H. pylori eradication rate in both groups is one of the secondary outcomes. The eradication rates of H. pylori will be analysed by intention-to-treat analysis, modified intention-to-treat analysis, and per-protocol analysis.DiscussionThis randomised controlled trial will provide objective and valid evidence about the value of polymerase chain reaction-based molecular methods for antibiotic susceptibility testing in guiding H. pylori eradication.Trial registrationClinicaltrials.gov NCT05549115. Released on 18 September 2022. First posted on 22 September 2022. Enrolment of the first participant on 20 September 2022. The study is retrospectively registered.

#4057 SUPERIOR PROTEINURIA REDUCTION WITH SPARSENTAN IN IMMUNOGLOBULIN A NEPHROPATHY (IGAN): A PROTECT STUDY INTERIM ANALYSIS

Abstract Background and Aims IgAN is the most common glomerular disease worldwide. Despite optimized standard of care, most patients with IgAN progress to kidney failure within 10-15 years, consequently seriously affecting their quality of life and mortality. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed for IgAN. Sparsentan is a novel, oral, non-immunosuppressive, single molecule that is a dual endothelin and angiotensin receptor antagonist being investigated for IgAN and focal segmental glomerulosclerosis. The Phase 3 PROTECT study is examining the long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan, in adults with IgAN. Reported here are the PROTECT pre-specified interim primary efficacy endpoint and safety outcomes. Method PROTECT is an ongoing, global, Phase 3, multicenter, randomized, double-blind, active controlled study designed to evaluate the efficacy and safety of sparsentan versus the active control irbesartan in adults with IgAN with overt proteinuria despite receiving maximized treatment with an angiotensin converting enzyme inhibitor (ACEi) and/or ARB. The study duration is 270 weeks; the double-blind period is 114 weeks (110 treatment and 4 follow-up) with an open-label extension period up to 156 weeks. Adult patients with biopsy-proven IgAN (excluding IgAN secondary to another condition or IgA vasculitis), urine protein excretion value ≥1.0 g/day, eGFR ≥30 mL/min/1.73m2, systolic/diastolic blood pressure ≤150/≤100 mmHg, and on a stable dose of ACEi and/or ARB therapy for at least 12 weeks prior to screening that is both the patient's maximum tolerated dose and at least one-half of the maximum labeled dose were eligible for inclusion. Patients took their last ACEi and/or ARB dose the day before randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 400 and 300 mg/day, respectively), stratified by screening eGFR and urine protein excretion values. The pre-specified interim primary efficacy endpoint of change from baseline in urine protein/creatinine ratio (UP/C, based on a 24-hour urine sample) at Week 36 was analyzed using a mixed model repeated measures analysis. The safety evaluation included assessment of treatment emergent adverse events. Results A total of 671 patients were screened; 406 patients from clinical sites in 18 countries, including sites in North America, Europe, and Asia Pacific, met eligibility criteria and were enrolled and randomized into PROTECT. Two randomized patients withdrew from the study prior to initiating study treatment. The 404 randomized patients who received study drug were included in the primary analysis population. The mean reduction in UP/C from baseline at 36 weeks was significantly greater in the patients who received sparsentan (-49.8%) versus irbesartan (-15.1%, P&amp;lt;0.0001). Proteinuria reduction consistency across baseline demographic and clinical characteristics and rates of complete and partial remission are reported, as well as sustained proteinuria reduction over time. Safety outcomes related to edema and liver function tests are reported. Overall, sparsentan was generally well-tolerated and comparable to irbesartan. Conclusion The interim results of the PROTECT study show that in adult patients with IgAN and persistent proteinuria above 1 g/day despite being treated with ACEis and/or ARBs, once-daily treatment with sparsentan compared head-to-head with maximum labelled or tolerated irbesartan produced a robust and clinically meaningful reduction in proteinuria. The safety of sparsentan was consistent with previous studies in FSGS and comparable to irbesartan.

A Phase 1 Two-Arm, Randomized, Double-Blind, Active-Controlled Study of Live, Oral Plasmid-Derived Adenovirus Type 4 and Type 7 Vaccines in Seronegative Adults.

PXVX0047 is an investigational vaccine developed for active immunization to prevent febrile acute respiratory disease (ARD) caused by adenovirus serotypes 4 (Ad4) and 7 (Ad7). PXVX0047 consists of a modernized, plasmid-derived vaccine that was generated using a virus isolated from Wyeth Ad4 and Ad7 vaccine tablets. A phase 1 two-arm, randomized, double-blind, active-controlled study was conducted to evaluate the safety profile and immunogenicity of the investigational adenovirus vaccines. The two components of PXVX0047 were administered orally together in a single dose to 11 subjects. For comparison, three additional subjects received the Ad4/Ad7 vaccine that is currently in use by the US military. The results of this study show that the tolerability and immunogenicity of the PXVX0047 Ad7 component are comparable with that of the control Ad4/Ad7 vaccine; however, the immunogenicity of the PXVX0047 Ad4 component was lower than expected. Clinical trial number NCT03160339.

A phase III, multicenter, double-blinded, randomized, active-controlled study on the efficacy and safety of QL1706 with chemotherapy (CT) as first-line therapy for PD-L1–negative advanced or metastatic non–small-cell lung cancer (NSCLC).

TPS9139 Background: PD-(L)1 immunotherapy plus platinum-doublet chemotherapy has been the standard 1L treatment for EGFR/ALK wild-type advanced NSCLC pts. However, pts with PD-L1 negative achieve minimal benefit from the PD-(L)1 immunotherapy plus CT. PD-(L)1 plus CTLA-4 blockade with CT in 1L treatment of PD-L1 negative NSCLC derived an improved median overall survival (OS) versus CT alone in CheckMate-9LA study ( Luis Paz-Ares et al., Lancet Oncol 2021) and POSEIDON study ( M L. Johnson et al., JCO 2022). QL1706 is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies produced in a fixed ratio (2:1) from the same single cell and manufactured together as one product (MabPair). QL1706 monotherapy or plus CT showed impressive safety and efficacy in advanced NSCLC both in phase I and phase II studies (data have been submitted for publication). Of note, QL1706+CT exhibited promising antitumor activity in advanced PD-L1 negative NSCLC. The phase III study aims to compare the efficacy of QL1706+CT versus anti-PD-1 (tislelizumab) + CT (approved in China for 1L treatment of mNSCLC) as 1L treatment in advanced PD-L1 negative NSCLC. Methods: The phase III, multicenter, double-blinded, randomized, active-controlled study is enrolling pts aged 18-75 years with ECOG PS of 0-1, previously untreated, PD-L1 negative (TPS &lt; 1%), EGFR/ALK wild-type, and pathologically identified stage IIIB-IV NSCLC. Eligible pts will be randomized (1:1) to receive 4-cycle treatment of QL1706 (5 mg/kg, Q3W) plus CT or tislelizumab (200 mg, Q3W) plus CT followed with maintenance treatment of QL1706 or tislelizumab monotherapy (squamous), or in combination with pemetrexed (non-squamous), until disease progression, intolerable toxicity, or for up to 2 years of immunotherapy. Stratification factors include histology (squamous vs non-squamous), brain metastasis (yes vs no), and sex (male vs female). Co-primary endpoints are progression-free survival (PFS) and OS. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) assessed by investigator per RECIST v1.1, 6 mo- and 12 mo-PFS, 6 mo- and 12 mo-OS, and safety. Exploratory endpoints include PK characteristics, immunogenicity, PFS2 (defined as time from randomization to progression after first subsequent therapy or any-cause death), and efficacy (iPFS, iORR, iDCR, iDOR) by investigator per iRECIST, biomarker analysis of tumor mutation burden. The study planned to enroll 650 pts to obtain approximately 493 PFS events (HR = 0.69; Power = 94%) and 445 OS events (HR = 0.75; Power = 83%) across the QL1706+CT and tislelizumab+CT arms for the final analyses of PFS and OS, respectively. The alpha was split between PFS (α = 0.005) and OS (α = 0.02). Enrollment began from Feb 2023. Clinical trial information: NCT05690945 .

P.054 Older subjects with insomnia disorder and comorbid pain at baseline: response to Lemborexant

Background: There is a well-established reciprocal relationship between pain and poor sleep. Therefore, we evaluated whether an approved sleep-promoting drug, lemborexant (LEM), could improve sleep in older adults who reported both insomnia and pain. Methods: Study E2006-G000-304 (NCT02783729) was a 1-month, placebo (PBO)- and active-controlled study in subjects (age ≥55y) with insomnia disorder. Those reporting some/severe pain on the pain/discomfort dimension of the EQ-5D-3L at baseline were included. Subjects were randomized to placebo (PBO), LEM 5mg (LEM5), 10mg (LEM10) or zolpidem (not reported here). Changes from baseline (CFB) in objective sleep parameters latency-to-persistent sleep (LPS) and total-sleep-time (TST) were analyzed in paired polysomnograms. Results: 183/743 (24.6%) subjects in the PBO (n=55/208[26.4%]), LEM5 (n=78/266[29.3%]) and LEM10 (n=50/269[18.6%]) treatment groups reported some/extreme pain at baseline, with median LPS (minutes): 31.0, 29.4, 42.1, respectively. Respective median CFB for LPS at the beginning (Nights[NT]1/2: +2.5, –8.4, –15.8; P&lt;0.005) was significantly larger/decreased for LEM5/LEM10 versus PBO and LEM5 at treatment end (NT29/30: –7.1, –9.9, –9.0; P=0.031). Mean baseline TST (minutes) was 335.3 (PBO), 336.3 (LEM5), 324.3 (LEM10), and mean CFB was significantly larger/increased (P&lt;0.001) for LEM5/LEM10 versus PBO at NT1/2 and NT29/30. Conclusions: Results suggest LEM may effectively treat insomnia in older adults with comorbid pain.Support: Eisai Inc.

P.053 Efficacy of lemborexant in adults with insomnia is supported by improvements in both objective and subjective measures

Background: Improvements in sleep-onset, maintenance, and daytime functioning, are all important outcomes for the treatment of insomnia. These improvements are usually assessed by objective or patient-reported (subjective) measures or both. Some sleep-promoting drugs do not report consistently aligned subjective and objective outcomes. Therefore, we examined concordance in change from baseline (CFB) in sleep parameters (objective/subjective measures) and daytime functioning (subjective measures) in the clinical program of lemborexant (LEM), a dual-orexin receptor antagonist. Methods: Study E2006-G000-304 (NCT02783729), a 1-month, placebo (PBO)- and active-controlled (zolpidem; not discussed here) study, and Study E2006-G000-303 (NCT02952820), a 12-month, randomized, PBO-controlled study (first 6-months), evaluated the efficacy/safety of LEM 5mg (LEM5) and LEM 10mg (LEM10) in subjects with insomnia disorder. The primary/secondary endpoints in both studies included multiple objective/subjective sleep parameters and patient-reported measures, which were assessed for concordance. Results: In both studies, statistically significant improvements with LEM5/LEM10 were reported in multiple objective and patient-reported measures versus PBO, showing a concordance of results, with observed improvements continuing through 12 months. LEM was well tolerated; most treatment-emergent adverse events were mild/moderate. Conclusions: When deciding which sleep agent to prescribe, it is important that improvement can be demonstrated in both objective and patient-reported measures. LEM treatment showed concordance among observed measures.

Mechanism-based peripheral blood biomarkers to evaluate anticancer effects of the plinabulin/docetaxel combination (plin/doc) vs. doc alone in second/third line EGFR wild-type (WT) NSCLC.

e21017 Background: Pretreatment neutrophil to lymphocyte (L) (NLR), platelet to L (PLR), and L to monocyte (LMR) levels are established prognostic biomarkers for advanced NSCLC. Plinabulin (Plin) is a well-tolerated, differentiated tubulin-binding agent being developed for neutropenia prevention as a monotherapy and in combination, and for improving the efficacy of anticancer agents. DUBLIN-3 (NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR WT NSCLC with a measurable lung lesion (RECIST 1.1). Pts (N = 559) were randomized 1:1 to Plin/Doc or Doc (21-day (D) cycle (C)). Doc (75 mg/m2) on D1 and Plin (30 mg/m2) on D1/D8 were given by IV infusion with steroid premedication (8 mg PO BID x 3D). Differential WBCs and platelet counts were collected at baseline (pre-steroid), D1, and D8. We analyzed the posttreatment effects of Plin on NLR, PLR, and LMR. Methods: All evaluable Plin/Doc vs Doc pts were included. NLR/PLR/LMR ratios and their respective change from baseline (cNLR/cPLR/cLMR) were obtained from blood draws taken at predose, C1D8, and/or C2D8. For intra/inter-arm overall survival (OS) stratification, baseline median NLR (3.2), PLR (177), and LMR (3.5) values were selected as thresholds. By examining responders &amp; long-term survivors in both arms, posttreatment NLR/LMR and cNLR/cLMR thresholds were established for C1D8 and C2D8. Finally, PFS/OS benefits were stratified to determine the statistical significances of Plin/Doc vs Doc. Results: In agreement with literature, baseline threshold levels for NLR = 3.2, PLR = 177, LMR = 3.5 were statistically significantly predictive of OS in both the Plin/Doc and Doc arms (p values ranging from 0.05 to 0.0001). Plin prevents Doc-induced neutropenia, and post-Doc neutrophil counts were higher on D8 with Plin/Doc vs Plin (p &lt; 0.001). Despite Doc-induced myelosuppression, Plin/Doc responding pts maintained similar NLR/LMR values as baseline at C1D8 and C2D8. After a single Plin dose at C1D8, lower NLR (cutoff = 3.0; 1.2x median value of all pts) and higher LMR (cutoff = 4.5; median value of all pts) thresholds independently predicted PFS/OS benefits of Plin/Doc vs Doc. Further, a higher cNLR threshold (cutoff = 0.25) at C2D8, best predicted Plin/Doc vs Doc in PFS and OS (p &lt; 0.0001 and p = 0.0035 respectively). Conclusions: Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone. Clinical trial information: NCT02504489 .

Simulation study of active vibration control of planetary gear: Theoretical and numerical analysis using pole placement

This paper presents analytical and numerical studies on the active assignment of poles to a planetary gear system for vibration control in order to avoid resonance. This involves feeding back the displacement and velocity to add active stiffness and damping, respectively. A rotating frame of reference has been adopted in order to describe the dynamics over a broad range of rotational speed. As an illustration, the closed loop poles were assigned to the translational directions of the sun gear first and thereafter the carrier. This can be achieved by placing the actuators on the outer race of their bearings mounted onto their shafts. The controller was designed such that the closed loop poles can be assigned considering the rotational speed. In this way, it is possible to apply a robust pole-placement that is insensitive to the rotational speed. Numerical examples, where sensors and actuators were collocated, are presented to demonstrate the feasibility of the method when applied to a physical system. The results shows that the active control force and power required for the system, when rotating, can be determined using a rotating frame of reference and transformed for practical implementation. In addition, the same conjugate poles were assigned to the carrier and sun gear and the optimal place to apply control forces was discovered. This depends upon the control power required to shift the poles from one location to another. The results show that more control power will be required to shift the poles of the system when poles were assigned to the sun gear, where higher active bearing stiffness was required. Therefore, the optimal place to assign poles in this case is the carrier due to lower control power required to shift the system poles.

Efficacy and safety of fixed-dose combination of Bilastine-Montelukast in adult patients with allergic rhinitis: a phase III, randomized, multi-center, double-blind, active controlled clinical study

Background Histamine and cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators in allergic rhinitis (AR). Studies involving other combinations of antihistaminics (Levocetirizine) and highly selective leukotriene receptor antagonist (LTA) (Montelukast) combination have shown additive benefits and are widely prescribed for AR. Objective Evaluate the efficacy and safety of Bilastine 20 mg and Montelukast 10 mg fixed-dose combination (FDC) therapy in patients with AR. Methods A randomized, double-blind, comparative, parallel, phase III study was conducted to evaluate efficacy and safety of Bilastine 20 mg and Montelukast 10 mg FDC at 16 tertiary care otolaryngology centres in India. Adult patients with AR for one year with IgE antibody positive and 12-h NSS score >36 in 3 days were randomized to receive either Bilastine 20 mg and Montelukast 10 mg or Montelukast 10 mg & Levocetirizine 5 mg tablets for 4 weeks. The change in total symptom score (nasal symptom scores (NSS) & non-nasal symptom scores (NNSS)) from baseline to week 4 was assessed as primary endpoint. Secondary endpoints included changes in TSS, NSS, NNSS, individual symptom scores (ISS), Rhinoconjunctivitis Quality of Life (RQLQ), discomfort due to rhinitis (VAS), and clinical global impression (CGI) scores. Results The change in mean TSS from baseline to week 4 in Test group (16.6 units) was comparable to reference group (17 units) (p= 0.8876). The difference in change in mean NSS, NNSS and ISS from baseline to day 7, 14, 28 were comparable. RQLQ improved from baseline to Day 28. Significant improvements were observed in discomfort due to AR measured by VAS and CGI scores from baseline to day 14 and 28. The safety and tolerability of patients were comparable between the groups. All adverse events (AEs) were mild to moderate in severity. No patient discontinued due to AEs. Conclusions The FDC of Bilastine 20 mg and Montelukast 10 mg was efficacious and well tolerated in Indian patients with AR.