Main Efficacy Endpoint Research Articles

ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation

ObjectiveThis study evaluated the safety and efficacy of elamipretide in dry age-related macular degeneration (AMD) with non-central geographic atrophy (GA). DesignReCLAIM-2 was a prospective, phase 2, randomized, placebo-controlled, double-masked, multicenter trial (NCT03891875). SubjectsPatients aged ≥55 years with at least one eye with dry AMD with GA were enrolled. MethodsAdministration of daily subcutaneous elamipretide 40 mg was investigated in subjects for 48 weeks followed by a 4-week follow-up period. Main Outcome MeasuresThe primary efficacy endpoints were the mean change from baseline in low-luminance best-corrected visual acuity (LL BCVA) and the change in square root converted GA area from baseline as measured by optical coherence tomography (OCT). Additional predefined endpoints included ellipsoid zone (EZ) integrity preservation assessment and categorical changes in LL BCVA. The primary safety endpoint was the incidence and severity of adverse events. ResultsOf the 176 patients randomized, there were 117 and 59 patients in the elamipretide and placebo groups, respectively. Although elamipretide did not meet statistical significance for the primary endpoints (mean change in LL BCVA and mean change in square root converted GA area), elamipretide produced a 43% reduction in the mean progression from baseline in the macular percentage of total EZ attenuation/loss (i.e., complete loss of EZ band; nominal P=0.003) and 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (i.e., EZ-RPE thickness of 20 microns or less; nominal P=0.004) versus placebo at week 48. Elamipretide treatment was also associated with significantly more patients experiencing a ≥10 letter gain in LL-BCVA versus placebo (14.6% vs 2.1%; nominal P=0.0404). Adverse events were reported in 86% of those receiving elamipretide and 71% of the placebo group with the most common events being injection site reactions (e.g., pruritus, injection site pain, bruising, erythema). ConclusionsWhile the primary endpoints were not met in this phase 2 study, elamipretide treatment was associated with a slowing of progressive EZ degradation/loss, a surrogate for photoreceptor damage. These findings have important clinical relevance since EZ attenuation/photoreceptor loss precedes and predicts the progressive pathological changes associated with vision loss and AMD. The EZ attenuation/loss endpoint will serve as the regulatory-approved primary endpoint in the elamipretide Phase 3 clinical development program.

Efficacy and safety of regorafenib combined with PD-1 inhibitors in patients with advanced hepatocellular beyond atezolizumab plus bevacizumab: A retrospective analysis of real-world evidence.

e16172 Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapy scheme is debatable and the efficacy of regorafenib combined with PD-1 inhibitors is still unclear. Methods: In this retrospective study, advanced HCC patients who received regorafenib combined with PD-1 inhibitors progressing after atezolizumab plus bevacizumab were consecutively enrolled from February 2022 to January 2024. Main efficacy endpoint was overall survival (OS), following progression free survival (PFS), evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: A total of 11 eligible patients were enrolled, with 8 in Child-Pugh A and 3 in Child-Pugh B7. All patients had hepatitis B infection by with tumor embolus. All patients were classified as Barcelona Clinic Liver Cancer stage C. The AFP level is above 400ng/ml in all patients. At data cut-off at February 2024, the median OS was 16.9 months and the median PFS was 3.7 months. The 3-month and 6-month PFS rates were 70% and 35% , respectively. The 12-month OS rate was 71.4%. Grade≥3 TRAEs occurred in 9.1% (1/11) of the patients. Conclusions: Though application of regorafenib combined with PD-1 inhibitors progressing after atezolizumab plus bevacizumab present safe and effective in our cohort, these data need to be confirmed in prospective comparative studies. [Table: see text]

Efficacy and safety in advanced hepatocellular carcinoma between patients with negative and positive APF treated with targeted and immunotherapy.

e16162 Background: Serum alpha-fetoprotein (AFP) is widely accepted as a crucial tool for clinical diagnosis and screening of HCC. However, there are cases where patients test negative for AFP but are confirmed to have Hepatocellular Carcinoma through imaging or pathological examinations. Despite these findings, there is limited research focusing on the medicine selection for AFP-negative patients. Methods: This retrospective cohort study, involving 223 untreated advanced HCC patients, and the first-line regimen consisted of targeted therapy and TKI+ICIs therapy. Patients are categorized into negative and positive AFP groups based on initial serum levels. Main efficacy endpoint was progression free survival (PFS), evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: According to the level of serum AFP, they were divided into negative group(100) and positive group(123). The two groups showed no statistically significant differences in age, gender, Child-Pugh score and other baseline clinical characteristics( P> 0.05). At data cut-off at February 2023, median OS was not matured and mPFS in negative group was higher than positive group(8.2 vs 5.3months, P< 0.0001). In the ICIs+TKI therapy cohort, mPFS in the negative AFP group(52) was significantly higher than in the positive AFP group(70) (10 vs. 5.8 months, P = 0.0021). Considering all patients in the negative AFP group as a subgroup, an analysis of survival benefits between those receiving targeted therapy and those receiving TKI+ICIs therapy revealed no significant difference in PFS( P> 0.05). Moreover, AEs were compared between the negative and positive group, with no significant differences observed in Any Grade or Grade 3/4( P> 0.05). Conclusions: Patients with negative AFP exhibited superior survival benefits compared to those with positive AFP in first-line therapy. Regarding PFS, the TKI+ICIS therapy did not demonstrate a better benefit over targeted therapy in the negative AFP subgroup.

Opicapone to Treat Early Wearing-off in Parkinson's Disease Patients: The Korean ADOPTION Trial.

Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

Efficacy and safety of intracoronary pro-urokinase combined with low-pressure balloon pre-dilatation during percutaneous coronary intervention in patients with anterior ST-segment elevation myocardial infarction

BackgroundThe efficacy and safety of low-pressure balloon pre-dilatation before intracoronary pro-urokinase (pro-UK) in preventing no-reflow during percutaneous coronary intervention (PCI) remains unknown. This study aimed to evaluate the clinical outcomes of intracoronary pro-UK combined with low-pressure balloon pre-dilatation in patients with anterior ST-segment-elevation myocardial infarction (STEMI).MethodsThis was a randomized, single-blind, investigator-initiated trial that included 179 patients diagnosed with acute anterior STEMI. All patients were eligible for PCI and were randomized into two groups: intracoronary pro-UK combined with (ICPpD group, n = 90) or without (ICP group, n = 89) low-pressure balloon pre-dilatation. The main efficacy endpoint was complete epicardial and myocardial reperfusion. The safety endpoints were major adverse cardiovascular events (MACEs), which were analyzed at 12 months follow-up.ResultsPatients in the ICPpD group presented significantly higher TIMI myocardial perfusion grade 3 (TMPG3) compared to those in the ICP group (77.78% versus 68.54%, P = 0.013), and STR ≥ 70% after PCI 30 min (34.44% versus 26.97%, P = 0.047) or after PCI 90 min (40.0% versus 31.46%, P = 0.044). MACEs occurred in 23 patients (25.56%) in the ICPpD group and in 32 patients (35.96%) in the ICP group. There was no difference in hemorrhagic complications during hospitalization between the groups.ConclusionPatients with acute anterior STEMI presented more complete epicardial and myocardial reperfusion with adjunctive low-pressure balloon pre-dilatation before intracoronary pro-UK during PCI.Trial registration2019xkj213.

Individualized homeopathic medicines in preventing the progression from pre-diabetes to diabetes: A double-blind, randomized, placebo-controlled, parallel-arm trial

ContextPre-diabetes is a significant public health problem worldwide. India has a very high rate of progression from pre-diabetes to diabetes, 75–78 per thousand persons per year. ObjectiveTo study the efficacy of individualized homeopathic medicinal products (HMPs) against placebos in preventing the progression from pre-diabetes to diabetes. DesignSix-month, double-blind, randomized (1:1), two parallel arms, placebo-controlled trial. SettingOutpatient departments of D. N. De Homoeopathic Medical College and Hospital, Kolkata, West Bengal, India. PatientsSixty participants with pre-diabetes. InterventionsVerum: HMPs plus yoga therapy (YT; n = 30); control: identical-looking placebos plus YT (n = 30). Main outcome measuresThe primary efficacy endpoint was the proportion of participants progressing from pre-diabetes to diabetes, measured after three and six months. Secondary outcomes comprised of fasting blood glucose (FBS), oral glucose tolerance test (OGTT), glycated hemoglobin percentage (HbA1c%), lipid profile, liver enzymes (alanine transaminase, aspartate transaminase), urea and creatinine, and Measure Yourself Medical Outcome Profile version 2 (MYMOP-2); all measured after 3 and 6 months. ResultsThe proportion of participants converted from pre-diabetics to diabetics (n/N; n = diabetics, N = prediabetics) was significantly less in the verum group than control: HbA1C% (month 3: verum – 2/30 versus control – 11/30, p = 0.003; month 6: 3/30 vs. 2/30, p = 0.008), OGTT (month 3: 0/30 vs. 8/30, p = 0.015; month 6: 0/30 vs. 1/30, p = 0.008), but not according to FBS (month 3: 1/30 vs. 1/30, p = 0.779; month 6: 1/30 vs. 3/30, p = 0.469). Several secondary outcomes also revealed significant improvements in the verum group than in placebo: HbA1C% (p < 0.001), OGTT (p = 0.001), serum ALT (p = 0.031), creatinine (p = 0.012), and MYMOP-2 profile scores (p < 0.001). Sulphur, Bryonia alba, and Thuja occidentalis were the most frequently indicated medicines. Thus, HMPs outperformed placebos by successfully preventing the progression of pre-diabetes to diabetes. Trial registrationClinical Trials Registry – India CTRI/2022/04/042,026; UTN: U1111–1277–0021

A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium

PurposeTo evaluate the safety and efficacy of CBT-001, a multi-target tyrosine kinase inhibitor (MKI) eyedrop, for pterygia. DesignPhase 2 clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial. ParticipantsPatients with primary or recurrent pterygia. Main Outcome MeasuresThe primary efficacy endpoint was lesion vascularity based on masked grading of photographs by an independent reading center. Other endpoints included dimensions of pterygia and safety. MethodsIn Stage 1, 24 eyes of 24 patients received one drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events and blood drug levels. In Stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed three times a day (TID) for 4 weeks with a 20-week follow up. ResultsIn Stage 1, the plasma maximum concentration (Cmax) values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/mL). The most commonly reported adverse events were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in Stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, mean change from baseline in pterygium vascularity scores was –0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle (P < 0.001; 95% confidence interval [CI]: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. Mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared to vehicle at weeks 2, 4, and 8 (P≤0.014). The most commonly reported adverse events were ocular, mild in severity, resolved after therapy, and did not result in discontinuation. ConclusionsCBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels.

Efficacy and safety of caspofungin for the treatment of invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

Ten-year analysis of the efficacy of vaccination against pneumococcal infection in patients with chronic obstructive pulmonary disease

Major problems in the course of chronic obstructive pulmonary disease (COPD) include frequent exacerbations and related deaths. The use of pneumococcal vaccines, primarily a 13-valent polysaccharide conjugate vaccine, is a generally recognized tool for reducing the number of exacerbations.The aim of the study was to analyze the prospective clinical efficacy of vaccine prophylaxis with conjugated pneumococcal vaccine Prevenar-13 (PCV13) in patients with COPD over 10 years.Methods. A total of 362 male patients who were treated or monitored at the Regional Pulmonological Center of Chelyabinsk in 2012 – 2022 were enrolled in the study. The main efficacy endpoints of observation over 10 years were: the dynamics of dyspnea (mMRC score), forced expiratory volume in 1st second, the number of exacerbations, hospitalizations, the number of pneumonias. After confirming the diagnosis of COPD, the patients were divided into two observation groups. The first group (n = 150) included patients vaccinated with PCV13. The second group (n = 212) included patients with COPD who had not received pneumococcal vaccination for various reasons.Results. Severe forms of the disease and frequent exacerbations predominated in both groups. 96 (27%) deaths were recorded in the PCV13-vaccinated group, and 171 (47%) deaths in the unvaccinated group. The difference between vaccinated and unvaccinated is statistically significant (p &lt; 0.05). In the unvaccinated patients, there was a steady progression of shortness of breath with an increase by 12% compared to baseline (p &lt; 0.05) by the 10th year. A positive trend in FEV1 was noted in patients vaccinated with PCV13. They also showed a significant decrease in BODE prognostic index.Conclusion. The use of PCV13 allows for stabilization of the main clinical and functional indicators of the respiratory system in patients with COPD in the long term (at least 10 years of follow-up). Vaccination maintains a low risk of adverse events according to the BODE index; an increase in patient survival was noted over a 10-year horizon (odds ratio – 2.35; 95% confidence interval – 1.45; 3.77), including cases with acute viral damage with COVID-19 (COronaVIrus Disease 2019).

ASCEND-Eye: Effects of Omega-3 Fatty Acids on Diabetic Retinopathy

PurposePreclinical studies support a protective role for omega-3 fatty acids (FAs) on diabetic retinopathy (DR), but these observations have not been confirmed in randomized trials. We present randomized evidence for the effects of omega-3 FAs on DR outcomes. Design and ParticipantsA sub-study of the ASCEND (A Study of Cardiovascular Events iN Diabetes) double-blind, randomized, placebo-controlled trial of 1g omega-3 fatty acids (containing 460mg eicosapentaenoic acid and 380mg docosahexaenoic acid) daily for the primary prevention of serious cardiovascular events, in 15,480 UK adults at least 40 years of age, with diabetes. MethodsLinkage to electronic NHS Diabetic Eye Screening Programme records in England and Wales, and confirmation of participant-reported eye events via medical record review. Logrank and stratified logrank methods were used for intention-to-treat analyses of time until the main outcomes of interest. Main Outcome MeasuresThe primary efficacy endpoint was time to the first post-randomization recording of referable disease, a composite of referable retinopathy (R2 or R3a/s) or referable maculopathy (M1) based on the grading criteria defined by the UK National Screening Committee. Secondary and tertiary outcomes included the referable disease outcome stratified by the severity of DR at baseline, any progression in retinopathy grade, and incident diabetic maculopathy. ResultsLinkage data were obtained for 7360 participants (48% of those who were randomized in ASCEND). During their mean follow-up of 6.5 years, 548 [14.8%] had a referable disease event in the omega-3 FAs group, compared to 513 [13.9%] in the placebo group (rate ratio 1.07; 95% confidence interval: 0.95-1.20; P = 0.29). There were no statistically significant between-group differences in the proportion of events for either of the secondary or tertiary outcomes. DiscussionRepresenting the first large-scale, prospective test of its kind, these data exclude any clinically meaningful benefits of 1g daily omega-3 FAs on DR.

Patent foramen ovale closure reduces migraine burden: a meta-analysis

Abstract Background Patent foramen ovale (PFO) closure has been shown to reduce the risk of recurrent stroke in selected patients. On the other hand, the efficacy of PFO closure in reducing migraine attacks remains a matter of debate. Purpose We performed a systematic review and meta-analysis of randomized controlled trials that compared PFO closure plus medical therapy to medical therapy alone for the management of migraine. Methods A comprehensive search was conducted in PubMed through December 10, 2022. The main efficacy endpoints were the complete cessation of migraine, the mean reduction in monthly migraine days and the mean reduction in monthly migraine attacks. The main safety outcome was the occurrence of major procedure related adverse events. Results Our search retrieved 667 results. Three randomized controlled trials including 448 patients were included in the final analysis. Of these, 231 patients (mean age 43.4±10.5 years) underwent PFO closure, while 217 (43.7±10.6) were treated conservatively with medical therapy. In the medical treatment group, 190 patients underwent a sham procedure. The follow-up period ranged from 6 to 12 months. Overall, no significant association between PFO closure and complete migraine cessation was observed [Hazard Ration 3.31, 95% confidence intervals (CI): 0.72 – 15.17 – Figure 1). On the other hand, PFO closure was associated with a significant reduction in the mean number of migraine days per month [mean difference (MD): 1.23, 95% CI: 0.44-2.10, p=0.024, Figure 2A] as well as with a significant decrease in monthly migraine attacks (MD: 0.58, 95%CI : 0.25-0.91, p=0.017, Figure 2B). In respect of efficacy endpoint, a total of 9 transient, procedure related adverse events, including access-site bleeding, hematoma and tachycardia were reported in the implantation group. Conclusions PFO closure plus medical treatment compared to medical treatment alone was related with fewer and shorter migraine attacks. These results suggest clinical benefit of PFO closure in selected patients with migraine.Figure 1.Figure 2.

Observational, multicenter registry of Impella-assisted high-risk percutaneous coronary interventions and cardiogenic shock in Poland (IMPELLA-PL): efficacy and safety outcomes

Abstract Introduction Impella (Abiomed, Danvers, MA, USA) is the smallest and the least invasive mechanical circulatory support device used in the setting of cardiogenic shock (CS) and high-risk percutaneous coronary interventions (HR-PCI). Data regarding the efficacy and safety of Impella in the real-life setting are urgently needed. Purpose The main goal of the IMPELLA-PL registry is to evaluate the efficacy and safety of Impella in patients with CS and undergoing HR-PCI, identify independent predictors of in-hospital and 12-month outcomes and compare it with other registries. Methods IMPELLA-PL is a national, multicentre, retrospective registry including consecutive patients treated with Impella for CS and high-risk PCI in 20 Polish interventional cardiological centres from January 2014 until December 2021, with 12-month follow-up until December 2022. The main efficacy and safety endpoints included (i) in-hospital mortality, (ii) 12-month mortality, (iii) 12-month rate of major adverse cardiovascular events (MACE) following hospital discharge, evaluated according to the prespecified definitions. Results A total of 308 patients were enrolled in the registry: 55 had CS (56.4%) and 253 underwent HR-PCI (43.6%). In the CS group, in-hospital mortality rate was 76.4%, 12-month mortality rate was 80.0% and post-discharge MACE rate was 9.1%. Device-related complications included access site bleeding (30.9%), limb ischaemia (12.7%) and haemolysis (10.9%). In the HR-PCI group, in-hospital mortality rate was 8.3%, 12-month mortality rate was 18.2% and MACE rate post-discharge was 22.5%. Device-related complications included access site bleeding (14.6%), limb ischaemia (2.4%) and haemolysis (1.6%). The independent predictors of 12-month mortality included atrial fibrillation (OR 3.50, 95% CI 1.38-8.95), chronic kidney disease (OR 2.77, 95% CI 1.06-7.26). Conclusions The mortality and complications rate in patients with CS remains high, despite the use of Impella, and higher than reported in other registries. The mortality and complications rate in patients undergoing HR-PCI is acceptable and consistent with other registries.

Effects of mulberry twig alkaloids(Sangzhi alkaloids) and metformin on blood glucose fluctuations in combination with premixed insulin-treated patients with type 2 diabetes.

We aimed to evaluated the effect of premixed insulin (Ins), premixed insulin combined with metformin (Ins+Met) or mulberry twig alkaloids(Ins+SZ-A) on blood glucose fluctuations in patients with type 2 diabetes (T2DM) using continuous glucose monitors (CGM). Thirty patients with T2DM and poor blood glucose control using drugs were evaluated for eligibility during the screening period. Subsequently, their original hypoglycemic drugs were discontinued during the lead-in period, and after receiving Ins intensive treatment for 2 weeks, they were randomly assigned to receive either Ins, Ins+Met, or Ins+SZ-A treatment for the following 12 weeks. The main efficacy endpoint comprised changes in their CGM indicators changes (mean blood glucose level [MBG], standard deviation of blood glucose [SDBG], mean amplitude of glycemic excursions [MAGE], postprandial glucose excursions [PPGE], the largest amplitude of glycemic excursions [LAGE], mean of daily difference [MODD], time in range between 3.9-10.0 mmol/L [TIR] and area under the curve for each meal [AUCpp]) during the screening, lead-in, and after 12-week treatment period. Changes in glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 1-h postprandial blood glucose (1h-PBG), 2-h postprandial blood glucose (2h-PBG), fasting blood lipids and postprandial blood lipids were also measured at baseline and after 12 weeks of treatment. The CGM indicators of the three groups during the lead-in period all showed significant improvements compared to the screening period (P<0.05). Compared with those in the lead-in period, all of the CGM indicators improved in the the Ins+Met and Ins+SZ-A groups after 12 weeks of treatment (P<0.05), except for MODD. After 12-week treatment, compared with the Ins group, Ins+Met and Ins+SZ-A groups showed improved MBG, SDBG, TIR, breakfast AUCpp,lunch AUCpp, HbA1c, FBG, 1h-PBG, fasting blood lipid and postprandial blood lipid indicators (P<0.05). Further, the LAGE, PPGE, MAGE, dinner AUCpp and 2h-PBG levels of the Ins+SZ-A group were significantly lower than those of the Ins+Met and Ins groups (P<0.05). Our findings highlight the efficacy of combination therapy (Ins+SZ-A or Ins+Met) in improving blood glucose fluctuations, as well as blood glucose and lipid levels. Ins+SZ-A reduces postprandial blood glucose fluctuations more than Ins+Met and Ins groups. ISRCTN20835488.

Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo-controlled, phase 1b trial

SIM0417 (SSD8432) is an orally administered coronavirus main proteinase (3CLpro) inhibitor with potential anti-SARS-CoV-2 activity. This study aimed to evaluate the efficacy and safety of SIM0417 plus ritonavir (a pharmacokinetic enhancer) in adults with COVID-19. This was a randomised, double-blind, placebo-controlled, phase 1b study in China. Adults with asymptomatic infection, mild or moderate COVID-19 were randomly assigned (3:3:2) to receive either 750mg SIM0417 plus 100mg ritonavir, 300mg SIM0417 plus 100mg ritonavir or placebo every 12h for 10 doses. The main efficacy endpoints included SARS-CoV-2 viral load, proportion of participants with positive SARS-CoV-2 nucleic acid test and time to alleviation of COVID-19 symptoms. This trial is registered with ClinicalTrials.gov, NCT05369676. Between May 12 and August 29, 2022, 32 participants were enrolled and randomised to high dose group (n=12), low dose group (n=12) or placebo (n=8). The viral load change from baseline in high dose group was statistically lower compared with placebo, with a maximum mean difference of-2.16±0.761 log10 copies/mL (p=0.0124) on Day 4. The proportion of positive SARS-CoV-2 in both active groups were lower than the placebo. The median time to sustained alleviation of COVID-19 symptoms was 2.0 days in high dose group versus 6.0 days in the placebo group (HR=3.08, 95% CI 0.968-9.818). SIM0417 plus ritonavir were well tolerated with all adverse events in grade1. SIM0417 plus ritonavir was generally well tolerated. The efficacy of SIM0417 showed a monotonic dose-response relationship, and the 750mg SIM0417 plus 100mg ritonavir was selected as the recommended clinical dose. The study was funded by Jiangsu Simcere Pharmaceutical Co., Ltd.

Efficacy and safety in unresectable hepatocellular carcinoma with VP4 tumor embolus using sinilimab plus bevacizumab: A retrospective analysis of real-world evidence.

e16156 Background: Recently, sinilimab plus bevacizumab has shown promising effects on unresectable hepatocellular carcinoma (uHCC) in ORIENT-32. However, its efficacy and safety in uHCC patients with VP4 cancer embolus remained unclear. Methods: In this retrospective study, uHCC patients with VP4 tumor embolus who received first-line sinilimab plus bevacizumab were consecutively enrolled. We also included similar patients who were treated with first-line sorafenib as comparison. Main efficacy endpoint was overall survival (OS), following progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR) to be secondary endpoints, evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: Total 43 eligible patients were enrolled, with 15 in sinilimab plus bevacizumab arm (arm 1) and the other 28 in sorafenib arm (arm 2). No statistical differences were found in etiology, liver function and performance status. At data cut-off at February 2023, median PFS in arm 1 and arm 2 were 3.7 (95%CI: 1.2-6.2) and 3.8 (95%CI:3.1-4.5) months, following ORR and DCR were 6.7% &amp; 46.7% and 7.1% &amp; 35.7%. OS in arm 1 was not matured and in arm 2 was 16.1 (11.1-21.1). Not any difference was detected among all efficacy endpoints. AEs happened among almost all patients. But nobody died of AEs. Conclusions: Efficacy and safety of sinilimab plus bevacizumab in uHCC patients with VP4 tumor embolus was similar with sorafenib, which needs to be further confirmed. [Table: see text]

Quantitative comparison of the efficacy of clinical drug treatments for primary progressive multiple sclerosis

ObjectiveThis study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS). MethodsA literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS. ResultsFifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon β-1a, and interferon β-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55–70%. ConclusionThe results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.

Sovleplenib (HMPL-523), a novel Syk inhibitor, for patients with primary immune thrombocytopenia in China: a randomised, double-blind, placebo-controlled, phase 1b/2 study

Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 109 platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. HUTCHMED.

Preventive CGRP-targeted therapies for chronic migraine with and without medication-overuse headache

Background: Calcitonin gene-related peptide (CGRP) targeted therapies are an important breakthrough in migraine prevention. Randomized clinical trials, post-hoc analyses, and phase IV studies have demonstrated their efficacy and safety in chronic migraine patients, including those with concomitant medication-overuse and medication-overuse headache. Real world evidence studies support these findings and provide realistic endpoints for estimation of effect. Methods and results We have performed a narrative review including results from double-blind placebo-controlled randomized clinical trials and real-world evidence studies regarding efficacy of the CGRP(-receptor) monoclonal antibodies and CGRP-receptor antagonists (gepants) in patients with chronic migraine with concomitant medication overuse (headache). We have included patient profiles and main efficacy endpoints (monthly migraine days, monthly headache days, monthly acute medication days and percentage responder rates). Conclusion The results of this review show that CGRP monoclonal antibodies are effective in chronic migraine patients, also in those with medication overuse (headache). At the time of this review, atogepant clinical trials in chronic migraine have not been communicated. Direct comparative studies are needed for comparison with other treatment options.

Observational Study on The Efficacy and Effects in The Quality of Life of Cluster Immunotherapy Schedule in Patients with Asthma Sensitized to House Dust Mites

Background: The conventional schedule administration of subcutaneous allergen immunotherapy (SCIT) for Acaroid®, requires eight weeks to get the maintenance dose. To reduce the duration of the build-up phase, the cluster schedules have been introduced. The objective was to analyze the one-year efficacy of Acaroid® in a cluster schedule, as well as the effect on the patient’s quality of life. Methods: A real-world observational study was designed, with one-year follow-up. Patients 5-65 years-old with allergic bronchial asthma, sensitized to house dust mites and treated with Acaroid®, in cluster schedule 2/2/2 were included. The main efficacy endpoint was the Asthma Control Test (ACT) score at month 12 compared to baseline. The patient’s quality of life was measured with the Asthma Quality of Life Questionnaire (AQLQ) and ESPRINT-15 questionnaire. Results: A total of 81 patients, 55.6% female, were included with a mean age of 29.7 years old. The ACT score from baseline-12 months significantly improved (p=0.003) 1.4 points (95%CI 0.4-2.4). The proportion of patients with a good asthma control increased significantly from baseline-6-12 months (p&lt;0.05). AQLQ (p=0.014) and ESPRINT-15 quality of life domains significantly improved at 12 months. Conclusions: The cluster schedule 2/2/2 of SCIT with Acaroid® was effective and allowed shortening the build-up phase to three weeks, instead of the conventional schedule of eight weeks. This resulted in the benefit of the patient in terms of comfort and could reduce the costs related to SCIT administration while maintaining patient efficacy and safety of the conventional schedules.

Estimating the sample size of sham-controlled randomized controlled trials using existing evidence.

Background: In randomized controlled trials (RCTs), the power is often 'reverse engineered' based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that use a sham control arm (sham-RCTs). Methods: We explore the design of sham-RCTs, the role of sequential meta-analysis and conditional planning in a systematic review of renal sympathetic denervation for patients with arterial hypertension. The main efficacy endpoint was mean change in 24-hour systolic blood pressure. We performed sequential meta-analysis to identify the time point where the null hypothesis would be rejected in a prospective scenario. Evidence-based conditional sample size calculations were performed based on fixed-effect meta-analysis. Results: In total, six sham-RCTs (981 participants) were identified. The first RCT was considerably larger (535 participants) than those subsequently published (median sample size of 80). All trial sample sizes were calculated assuming an unrealistically large intervention effect which resulted in low power when each study is considered as a stand-alone experiment. Sequential meta-analysis provided firm evidence against the null hypothesis with the synthesis of the first four trials (755 patients, cumulative mean difference -2.75 (95%CI -4.93 to -0.58) favoring the active intervention)). Conditional planning resulted in much larger sample sizes compared to those in the original trials, due to overoptimistic expected effects made by the investigators in individual trials, and potentially a time-effect association. Conclusions: Sequential meta-analysis of sham-RCTs can reach conclusive findings earlier and hence avoid exposing patients to sham-related risks. Conditional planning of new sham-RCTs poses important challenges as many surgical/minimally invasive procedures improve over time, the intervention effect is expected to increase in new studies and this violates the underlying assumptions. Unless this is accounted for, conditional planning will not improve the design of sham-RCTs.