Secondary Clinical Endpoints Research Articles

Preprocedural Ticagrelor Treatment was Associated with Improved Early Reperfusion and Reduced Short-term Heart Failure in East-Asian ST-segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention.

PurposeThe purpose of this monocentric retrospective observational study is to investigate whether a loading dose of ticagrelor treatment before percutaneous coronary intervention (PCI) procedure improves the early reperfusion and short-term heart function in East-Asian ST segment elevation myocardial infarction (STEMI) patients.Patients and MethodsThe study included 326 STEMI patients undergoing primary PCI in Jiading Central Hospital. One hundred and forty patients received a loading dose of ticagrelor before entering the catheter laboratory. One hundred and eighty-six patients received a loading dose of ticagrelor in the catheter laboratory before the initiation of PCI. Reperfusion endpoints included the presence of self-patency in the culprit artery, the ST-segment elevation resolution over 50% within 24 h after PCI, and the presence of no-reflow in the culprit artery. Clinical endpoints included all-cause mortality, new-onset heart failure, reinfarction and stent thrombosis within 28 days after PCI. Secondary clinical endpoints included mechanical complications and bleeding events.ResultsIn comparison with the in-lab treatment group, the preprocedural treatment group had a significant higher proportion of self-patency in the culprit artery (25.71% vs 16.67%, P=0.045) and early ST-segment elevation resolution (48.57% vs 27.96%, P<0.001). Preprocedural ticagrelor treatment was associated with a significant reduction of new-onset heart failure (9.29% vs 18.82%, p=0.016). Stent thrombosis risks were numerically reduced in the preprocedural treatment group (0.71% vs 1.61%, P=0.466). The rates of major cardiovascular adverse events, reinfarctions and mortality did not differ between the two groups. Bleeding events in the preprocedural treatment group was notn significantly higher than the in-lab treatment group (4.39% vs 1.39%, P=0.142).ConclusionPreprocedural administration of a loading dose of ticagrelor was associated with improved early reperfusion and reduced short-term heart failure in East-Asian STEMI patients undergoing primary PCI, but care should be taken for excess bleeding events.

Moderate Dose of Tranexamic Acid and Complications after Valvular Heart Surgery.

In valvular open-heart surgery, data regarding the effect of a moderate dose of tranexamic acid (TXA) on clinical outcomes are limited. Out of a cohort of 13,293 patients, we performed a propensity-score-matched analysis in 6,106 patients and assessed the risk of convulsive seizures (CS, primary endpoint), stroke, renal replacement therapy, and mortality (secondary endpoints). In the entire study cohort of 13,293 patients, we also assessed the multivariable-adjusted association of CS with postoperative outcomes. The risk of CS was significantly higher in the TXA group (2.4%; n = 72) than in the non-TXA group (1.0%; n = 32), with a relative risk ratio (RR) of 2.28 (95% confidence interval [CI]: 1.50-3.47; p < 0.001). The risk of CS was also higher in patients receiving TXA doses ≥25 mg/kg body weight (3.7%; n = 40) than in patients receiving <25 mg/kg body weight (1.6%; n = 32; p < 0.001). Perioperative secondary clinical endpoints and 1-year mortality did not differ significantly between study groups (p-value > 0.05). Compared with non-CS patients (n = 13,000), patients with nonhemorrhagic, nonembolic CS (n = 253) revealed higher multivariable-adjusted in-hospital risks of stroke (RR: 3.82 [95% CI: 2.44-5.60; p < 0.001]) and mortality (RR: 2.07 [95% CI: 1.23-3.48; p = 0.006]), and a higher 1-year mortality risk (RR: 1.85 [95% CI: 1.42-2.41; p < 0.001]). A moderate TXA dose was associated with a significantly higher risk of seizure, but not with other clinical complications such as stroke, renal replacement therapy, and mortality. However, in the small group of patients experiencing a seizure, the risks of stroke and short- and mid-term mortality were substantially higher than in patients not experiencing a seizure, indicating that the use of a low-dose TXA protocol (<25 mg/kg body weight) should be considered.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

Comparison of the Efficacy and Safety of Sacubitril/Valsartan versus Ramipril in Patients With ST-Segment Elevation Myocardial Infarction

The role of sacubitril and/or valsartan in patient with heart failure (HF) is established. Whether sacubitril and/or valsartan plays a role in improving outcomes in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. The current study aims to comparing the efficacy and safety of sacubitril and/or valsartan versus ramipril in post-STEMI patients. Patients presenting with STEMI were randomized to receive either sacubitril and/or valsartan or ramipril after primary percutaneous coronary intervention. The main efficacy endpoint was major adverse cardiac events (MACE) at 30 days and 6 months, defined as a composite of cardiac death, myocardial infarction, and HF hospitalizations. Multiple secondary clinical safety and efficacy endpoints were examined. A total of 200 patients were randomized from January 2018 to March 2019, mean age 54.5±10.4, 87% men, 75% presented with anterior wall STEMI. Baseline clinical and echocardiographic characteristics were comparable between groups. The primary endpoint of MACE was similar with sacubitril/valsartan versus ramipril at 30 days (p = 0.18); however, at 6 months, sacubitril/valsartan was associated with significant reduction of MACE (p = 0.005), mainly driven by reduction in HF hospitalizations (18% vs 36%, OR 0.40, 95% 0.22 to 0.75; p = 0.004). At 6 months, LV ejection fraction was higher with sacubitril/valsartan (46.8±12.5% vs 42.09±13.8%; p = 0.012), with improved LV remodelling (LV end diastolic dimension 50.6±3.9 mm vs 53.2±2.7 mm, p = 0.047; and LV end systolic dimension 36.1±3.4 mm versus 39.9±6.3 mm, p = 0.001) compared with ramipril. No difference in other efficacy or safety clinical endpoints was observed. In conclusion, early initiation of sacubitril/valsartan may offer clinical benefit and improvement in myocardial remodelling in post-STEMI patients.

Evaluation of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 Patients: Results from the NOR-Solidarity Randomised Trial

Background: There is an urgent need for new treatment modalities in COVID-19 patients. Recently, the WHO Solidarity trial showed no effects of remdesivir or hydroxychloroquine (HCQ) on mortality. However, the antiviral effects of these drugs and the possible relation to clinical characteristics at admission is not known.Methods: NOR-Solidarity is an independent add-on study to the WHO Solidarity trial, including biobanking, and a clinical three-month follow-up. Eligible patients were adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection. Patients were randomly assigned to receive remdesivir, HCQ or standard of care (SoC). In-hospital mortality, admission to intensive care unit and initiation of mechanical ventilation were primary and secondary clinical endpoints shared with WHO Solidarity. Secondary endpoints were impact of remdesivir or HCQ on SARS-CoV-2 clearance in the oropharynx, as well as their effects on systemic inflammation and the degree of respiratory failure (ClinicalTrials.gov: NCT04321616).Findings: Between March 28 and October 4, 185 patients from 23 hospitals in Norway were randomized and 181 included in the full analysis set: remdesivir (n=42), HCQ (n=52) and SoC (n=87). No significant differences in mortality during hospitalisation, ICU admission or occurrence of mechanical ventilation between the treatment groups and SoC were observed. There was a marked decrease in SARS-CoV-2 load in oropharynx during the first week with similar decrease and 10-day levels between remdesivir, HCQ and their respective SoC. Remdesivir and HCQ did not exert any effect on the degree of respiratory failure or on inflammatory parameters in peripheral blood. Notably, the lack of anti-viral effect was not associated with symptom duration, level of viral load or presence of antibodies against SARS-CoV-2 at hospital admittance.Interpretation: We found no effect on viral clearance by either remdesivir or HCQ in hospitalised COVID-19 patients.Trial Registration: (ClinicalTrials.gov: NCT04321616)Funding: National Clinical Therapy Research in the Specialist Health Services, Norway.Declaration of Interests: All authors declare no competing interest.Ethics Approval Statement: The trial protocol was approved by the Regional Ethic Committee (118684) and by the Norwegian Medicines Agency (20/04950-23) and was overseen by an independent data and safety monitoring board.

Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial

ObjectivesTo evaluate efficacy and safety of abatacept in adults with active primary Sjögren’s syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.MethodsEligible patients (moderate-to-severe pSS [2016 ACR/European League Against...

Impact of first medical contact to revascularisation time on long-term clinical outcomes in ST-segment elevation myocardial infarction patients.

Increased age impacts the first medical contact to revascularisation delay in patients with STEMI. Patients with shorter treatment delays (&lt;90 minutes after first medical contact) have significantly lower major adverse cardiac events rates at 3 years.

Percutaneous Coronary Intervention for Vulnerable Coronary Atherosclerotic Plaque

BackgroundAcute coronary syndromes most commonly arise from thrombosis of lipid-rich coronary atheromas that have large plaque burden despite angiographically appearing mild. ObjectivesThis study sought to examine the outcomes of percutaneous coronary intervention (PCI) of non–flow-limiting vulnerable plaques. MethodsThree-vessel imaging was performed with a combination intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) catheter after successful PCI of all flow-limiting coronary lesions in 898 patients presenting with myocardial infarction (MI). Patients with an angiographically nonobstructive stenosis not intended for PCI but with IVUS plaque burden of ≥65% were randomized to treatment of the lesion with a bioresorbable vascular scaffold (BVS) plus guideline-directed medical therapy (GDMT) versus GDMT alone. The primary powered effectiveness endpoint was the IVUS-derived minimum lumen area (MLA) at protocol-driven 25-month follow-up. The primary (nonpowered) safety endpoint was randomized target lesion failure (cardiac death, target vessel–related MI, or clinically driven target lesion revascularization) at 24 months. The secondary (nonpowered) clinical effectiveness endpoint was randomized lesion–related major adverse cardiac events (cardiac death, MI, unstable angina, or progressive angina) at latest follow-up. ResultsA total of 182 patients were randomized (93 BVS, 89 GDMT alone) at 15 centers. The median angiographic diameter stenosis of the randomized lesions was 41.6%; by near-infrared spectroscopy–IVUS, the median plaque burden was 73.7%, the median MLA was 2.9 mm2, and the median maximum lipid plaque content was 33.4%. Angiographic follow-up at 25 months was completed in 167 patients (91.8%), and the median clinical follow-up was 4.1 years. The follow-up MLA in BVS-treated lesions was 6.9 ± 2.6 mm2 compared with 3.0 ± 1.0 mm2 in GDMT alone–treated lesions (least square means difference: 3.9 mm2; 95% confidence interval: 3.3 to 4.5; p < 0.0001). Target lesion failure at 24 months occurred in similar rates of BVS-treated and GDMT alone–treated patients (4.3% vs. 4.5%; p = 0.96). Randomized lesion–related major adverse cardiac events occurred in 4.3% of BVS-treated patients versus 10.7% of GDMT alone–treated patients (odds ratio: 0.38; 95% confidence interval: 0.11 to 1.28; p = 0.12). ConclusionsPCI of angiographically mild lesions with large plaque burden was safe, substantially enlarged the follow-up MLA, and was associated with favorable long-term clinical outcomes, warranting the performance of an adequately powered randomized trial. (PROSPECT ABSORB [Providing Regional Observations to Study Predictors of Events in the Coronary Tree II Combined with a Randomized, Controlled, Intervention Trial]; NCT02171065)

Long-Term Clinical Outcome in Elderly Patients Undergoing Mitral Valve Repair.

Long-term data on patients over 75 years undergoing mitral valve (MV) repair are scarce. At our high-volume institution, we, therefore, aimed to evaluate mortality, stroke risk, and reoperation rates in these patients. We investigated clinical outcomes in 372 patients undergoing MV repair with (n = 115) or without (n = 257) tricuspid valve repair. The primary endpoint was the probability of survival up to a maximum follow-up of 9 years. Secondary clinical endpoints were stroke and reoperation of the MV during follow-up. Univariate and multivariable Cox regression analysis was performed to assess independent predictors of mortality. Mortality was also compared with the age- and sex-adjusted general population. During a median follow-up period of 37 months (range: 0.1-108 months), 90 patients died. The following parameters were independently associated with mortality: double valve repair (hazard ratio, confidence interval [HR, 95% CI]: 2.15, 1.37-3.36), advanced age (HR: 1.07, CI: 1.01-1.14 per year), diabetes (HR: 1.97, CI: 1.13-3.43), preoperative New York Heart Association (NYHA) functional class (HR: 1.41, CI: 1.01-1.97 per class), and operative creatininemax levels (HR: 1.32, CI: 1.13-1.55 per mg/dL). The risk of stroke in the isolated MV and double valve repair groups at postoperative year 5 was 5.0 and 4.1%, respectively (p = 0.65). The corresponding values for the risk of reoperation were 4.0 and 7.0%, respectively (p = 0.36). Nine-year survival was comparable with the general population (53.2 vs. 53.1%). Various independent risk factors for mortality in elderly MV repair patients could be identified, but overall survival rates were similar to those of the general population. Consequently, our data indicates that repairing the MV in elderly patients represents a suitable and safe surgical approach.

An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19.

BackgroundEpidemic outbreaks caused by SARS-CoV-2 are worsening around the world, and there are no target drugs to treat COVID-19. IFN-κ inhibits the replication of SARS-CoV-2; and TFF2 is a small secreted polypeptide that promotes the repair of mucosal injury and reduces the inflammatory responses. We used the synergistic effect of both proteins to treat COVID-19.MethodsWe conducted an open-label, randomized, clinical trial involving patients with moderate COVID-19. Patients were assigned in a 1:1 ratio to receive either aerosol inhalation treatment with IFN-κ and TFF2 every 24 h for six consecutive dosages in addition to standard care (experimental group) or standard care alone (control group). The primary endpoint was the time until a viral RNA negative conversion for SARS-CoV-2 in all clinical samples. The secondary clinical endpoint was the time of CT imaging improvement. Data analysis was performed per protocol. This study was registered with chictr.org.cn, ChiCTR2000030262.FindingsBetween March 23 and May 23 of 2020, 86 COVID-19 patients with symptoms of moderate illness were recruited, and 6 patients were excluded due to not matching the inclusion criteria (patients with pneumonia through chest radiography). Among the remaining 80 patients, 40 patients were assigned to experimental group, and the others were assigned to control group to only receive standard care. Efficacy and safety were evaluated for both groups. The time of viral RNA negative conversion in experimental group (Mean, 3·80 days, 95% CI 2·07–5·53), was significantly shorter than that in control group (7·40 days, 95% CI 4·57 to 10·23) (p = 0.031), and difference between means was 3·60 days. The percentage of patients in experimental group with reversion to negative viral RNA was significantly increased compared with control group on all sampling days (every day during the 12-day observation period) (p = 0·037). For the secondary endpoint, the experimental group had a significantly shorter time until improvement was seen by CT (Mean 6·21 days, N = 38/40, 95% CI 5·11–7·31) than that in control group (8·76 days, N = 34/40, 95% CI 7·57–9·96) (p = 0.002), and difference between means was 2·55 days. No discomfort or complications during aerosol inhalation were reported to the nurses by any experimental patients.InterpretationIn conclusion, we found that aerosol inhalation of IFN-κ plus TFF2 in combination with standard care is safe and superior to standard care alone in shortening the time up to viral RNA negative conversion in all clinical samples. In addition, the patients in experimental group had a significantly shortened CT imaging improvement time than those in control group. This study suggested that this combination treatment is able to facilitate clinical improvement (negative for virus, improvement by CT, reduced hospitalization stay) and thereby result in an early release from the hospital. These data support the need for exploration with a large-scale trial of IFN-κ plus TFF2 to treat COVID-19.FundingFunding was provided by the National Natural Science Foundation of China, National Major Project for Control and Prevention of Infectious Disease in China, Shanghai Science and Technology Commission, Shanghai Municipal Health Commission.

Abstract IA09: A phase II trial to promote recovery from COVID-19 with endocrine therapy

Abstract Background: Death from COVID-19 disproportionately affects men, with up to 80% of deaths in severe COVID-19 cases being in men. There are a number of potential differences that might contribute to these sex differences. TMPRSS2 is a serine protease that primes the spike protein of SARS-CoV-2, a critical step in viral entry. TMPRSS2 is most highly expressed in the prostate where it is under androgen control, upregulated by testosterone and downregulated by antiandrogens. ACE2, the receptor used for entry into the host cell, is located on the X chromosome and may also have levels that are altered by hormones, with estradiol downregulating its expression. Previous research on acute lung injury demonstrated that estradiol seems to have beneficial effects on repair of lung injury. Therefore, our central hypothesis is that hormones may partially contribute to the gender disparity seen in COVID-19 patients, with high levels of testosterone being harmful and high levels of estrogen being helpful. Bicalutamide is a nonsteroidal antiandrogen that inhibits the action of androgens and, via feedback on the hypothalamic-pituitary axis, upregulates estradiol. We are conducting a phase II clinical trial to determine if bicalutamide improves the percentage of COVID+ patients with clinical improvement by 7 days. Methods: We will enroll 40 patients who are hospitalized for COVID-19 with minimal respiratory symptoms (respiratory rate &amp;lt;30 and &amp;lt; 6L oxygen by nasal canula). Patients with more severe symptoms or oxygen requirements, who have taken hormones within the past month, or have pre-existing liver or cardiac disease will be excluded. Patients will be randomized 1:1 (20 in each arm) to bicalutamide or standard of care and will be stratified by gender. The primary outcome is comparing the percentage of patients with clinical improvement at day 7, compared to historical controls based on the World Health Organization categorical scale of clinical improvement. Key secondary clinical endpoints include all-cause mortality at 28 and 60 days, need for mechanical ventilation or ICU care, and safety of bicalutamide in this population. We will also determine the impact of bicalutamide therapy on viral infectivity by studying the reduction in viral load, hormone modulation and engagement of the endocrine axis, and immune response modulation promoting pro-repair immune function in patients with COVID-19. Clinical trial registration number: NCT04374279. Citation Format: Catherine H. Marshall, Srinivasan Yegnasubramanian, Hao Wang, Jennifer Durham, Ting Wang, Rachel Damico, Franco R. D'Alessio, Venkataramana K. Sidhaye, Andrew Pekosz, Joseph L. Mankowski, Sabra L. Klein, Sumati Murli, Elizabeth M. Jaffee, Samuel R. Denmeade. A phase II trial to promote recovery from COVID-19 with endocrine therapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr IA09.

Drug-Coated balloons vs drug-eluting stents for the treatment of small coronary artery disease: A meta-analysis of randomized trials.

There is conflicting evidence about the effects of drug-coated balloons (DCB) compared with drug-eluting stents (DES) in patients with native small vessel coronary artery disease (CAD). The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases and main international conference proceedings were searched for randomized controlled trials (RCT) comparing DCB versus DES in patients with native small vessel CAD. Data were pooled by meta-analysis using a random-effects model. The primary endpoint was target vessel revascularization (TVR). Secondary clinical endpoints were: myocardial infarction (MI), target lesion revascularization (TLR), all-cause death, cardiac death, and stent thrombosis or target vessel thrombosis. Secondary angiographic outcomes were: in-segment restenosis, in-segment percentage-diameter stenosis, in-segment late lumen loss, in-segment net luminal gain, and in-segment minimal lumen diameter. Five trials enrolling 1,459 patients were included. Mean clinical follow-up was 10.2months. The use of DCB, compared with DES, was associated with similar risk of TVR (odds ratio [OR]: 0.97; 95% confidence interval [CI] 0.56 to 1.68; p=.92), TLR (OR: 1.74; 95% CI: 0.57 to 5.28; p=.33), all-cause death (OR: 1.03; 95% CI: 0.14 to 7.48; p=.98), with a trend toward a lower risk of MI (OR: 0.49; 95% CI: 0.23 to 1.03; p=.06), and with significant lower risk of vessel thrombosis (OR: 0.12; 95% CI: 0.01 to 0.94; p=.04). DCB use was associated with similar risk of angiographic restenosis (OR: 1.12; 95% CI 0.69 to 1.84; p=.64), comparable late luminal loss (standardized mean difference (SMD): -0.18; 95% CI: -0.39 to 0.03; p=.09), while leading to significant higher percentage diameter stenosis (SMD: 0.27; 95% CI 0.12 to 0.41; p < .01) and smaller minimal luminal diameter (SMD: -0.52; 95% CI: -0.86 to -0.18; p=.003). Compared with DES, the use of DCB for the treatment of native small vessel CAD is associated with similar TVR and restenosis and reduces the risk of vessel thrombosis, although DES implantation yields slightly better angiographic surrogate endpoints.

A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS)

BackgroundMetastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa.MethodsPatients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response.DiscussionThe RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/− radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm.Trial registrationsClinicaltrials.gov. Identifier: NCT04037358. Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

A phase II study of anti-PD1 monoclonal antibody (Nivolumab) administered in combination with anti-LAG3 monoclonal antibody (Relatlimab) in patients with metastatic melanoma naive to prior immunotherapy in the metastatic setting.

TPS10085 Background: Novel checkpoint inhibitors are a promising treatment for advanced melanoma, as only a fraction of patients have durable responses to current FDA-approved immunotherapy. Lymphocyte activation gene 3 (LAG3) is an inhibitory checkpoint receptor on CD4+ and CD8+ T cells, where engagement results in suppression of T cell activation and proliferation. LAG3 and PD1 are co-expressed on T cells during T cell receptor signaling and are down-regulated after antigen clearance. Persistent stimulation leads to prolonged LAG3 and PD1 expression and to T cell exhaustion, a possible mechanism of resistance to immunotherapy. Both LAG3 and PD1 are expressed on tumor-infiltrating T cells in melanoma. Murine tumors treated with both anti-LAG3 and anti-PD1 have demonstrated increased tumor regression than tumors in mice treated with either single agent. Further, a phase I trial has demonstrated safety of combined anti-LAG3 monoclonal antibody, relatlimab and anti-PD1 monoclonal antibody, nivolumab. Methods: This phase II, single-center clinical trial is designed to enroll treatment naive patients with unresectable or metastatic melanoma to ultimately receive combined relatlimab and nivolumab after a lead-in arm where patients are randomized to receive relatlimab, nivolumab, or the combination for the first 4 week cycle. For the lead-in phase, patients will have baseline and post-treatment blood and tumor sampling. Disease assessment by imaging will occur after the lead-in phase at 4 weeks. After completion of the lead-in phase, all patients proceed to combination therapy with disease assessment at 12-week intervals. The primary endpoint for the lead-in phase is to evaluate changes in immune cell populations in peripheral blood and tumor with the single agents and combination treatment. The primary endpoint for the combination phase is best overall anti-tumor response. Secondary clinical endpoints include progression-free survival, overall survival, duration of response and toxicity. Exploratory endpoints are to determine the mechanistic effects of anti-LAG3 and anti-PD1 on the blood and tumor microenvironment, cytokine signatures, and correlation of these with clinical response. The study is currently accruing with enrollment of 9 out of 42 patients. Clinical trial information: NCT03743766.

A phase II randomized trial of RAdium-223 dichloride and SABR versus SABR for oligomEtastatic prostate caNcerS (RAVENS).

TPS5586 Background: Metastasis directed therapy (MDT) is able to prolong progression free survival (PFS) and forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be effective in HSOPCa, a large percentage of men will have disease recurrence. Patterns of failure demonstrate patients tend to recur in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of Stereotactic ablative radiation (SABR) + radium-223 dichloride in prolonging PFS in men with HSOPCa. Methods: Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis (by conventional imaging) will be randomized 1:1 to SABR alone vs. SABR + radium-223 dichloride. Eligibility criteria include PSA doubling time of &lt; 15 months and ECOG performance status of &lt; 2. Patients cannot be on ADT and must have normal testosterone levels at the time of randomization. Patients randomized to the combination arm will receive six doses of Radium-223 dichloride at four week intervals. A sample size using a 1:1 randomization scheme of 30 patients per arm will provide 80% power to detect an increase of median PFS from 10 months to 20 months with type I error = 0.1, using a one-sided log-rank test. To account for 5% early drop out, we will randomize a total of 64 patients (32 per arm). The primary end point is PFS with a primary hypothesis that SABR + radium-223 dichloride will increase median PFS from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. Progression is a composite endpoint including PSA progression per Prostate Cancer Working Group 2 (PCWG2), symptomatic progression, radiologic progression per RECIST 1.1 criteria, initiation of ADT, or death due to any cause. Secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. Biological correlates will be evaluated including changes in circulating tumor cells following therapy, deep sequencing of circulating tumor DNA, and T-cell repertoire profiling before and after therapy. Clinical trial information: NCT04037358 .

An intergroup collaboration for advanced stage classical Hodgkin lymphoma (cHL) in adolescents and young adults (AYA): SWOG S1826.

TPS8067 Background: Treatment for pediatric cHL varies considerably from that in adult cHL. Hence there are gaps in risk prediction and optimal therapy for de-novo advanced stage disease across the adolescent and young adult (AYA) age spectrum. Early access to novel agents for AYA could be facilitated via collaboration with adult research groups through the U.S. National Cancer Institute’s National Clinical Trials Network (NCTN). The PD-1 inhibitor Nivolumab (Nivo) has safety and efficacy in relapsed and refractory disease in children and adults, but has not been evaluated in de-novo disease to date. Methods: North American cooperative group lymphoma chairs, Cancer Therapy Evaluation Program (CTEP) representatives and patient advocates met to establish consensus on the comparison arms and study design, based on recent historical approaches across adult and pediatric groups. Study champions were identified across North American cooperative groups and include expertise in imaging, radiation oncology, biology and patient-reported outcomes. A therapeutic study was designed with the primary aim being to compare progression-free survival with novel targeted agents in advanced stage cHL. S1826 (NCT03907488), led by SWOG Cancer Research Network, opened to accrual in July 2019. Eligibility criteria include age &gt; 12 years, and Stage III or IV cHL. Patients are randomized (1:1) to 6 cycles of either Nivo-Adriamycin, Vinblastine, Dacarbazine (AVD) or Brentuximab vedotin (Bv)-AVD. Enrollment is stratified by age, baseline International Prognostic Score, and provider intent to use involved site radiation therapy (ISRT). Protocol-prescribed ISRT is response-adapted, based on end of therapy imaging. The primary endpoint is a comparison of progression-free survival between arms. Secondary clinical endpoints include comparison of: overall survival, metabolic response at the end of therapy, physician-reported adverse events, patient-reported adverse events, and health-related quality of life (overall, and specific to fatigue and neuropathy). This unique intergroup collaboration demonstrates the process and the feasibility of consensus study designs toward early adoption of targeted therapies and harmonization of treatment approaches for AYA populations. Clinical trial information: NCT03907488 .

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect.Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619

Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-Concept Trial Protocol.

BackgroundAll current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade.AimsThis investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin.Materials and EquipmentForty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses.Outcome MeasuresThe primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response.Anticipated ResultsClinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored.PerspectivesSub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a “serotonergic subtype” of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry.Clinical Trial RegistrationClinicalTrials, identifier NCT03994965.

COMPARison of pre-hospital CRUSHed vs. uncrushed Prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary interventions: Rationale and design of the COMPARE CRUSH trial

Dual antiplatelet therapy constitutes the cornerstone of medical treatment in patients with ST elevation myocardial infarction (STEMI). However, oral antiplatelet agents, such as prasugrel or ticagrelor, are characterized by slow gastrointestinal drug absorption in the acute phase of STEMI, leading to decreased bioavailability and therefore delayed onset of platelet inhibition. Evidence suggests that administration of crushed tablets of the P2Y12 inhibitor prasugrel improves drug absorption and achieves earlier antiplatelet effects in STEMI patients undergoing primary percutaneous coronary intervention (PCI). However, the clinical implications of these pharmacokinetic and pharmacodynamic findings are unknown. The present study is designed to test the hypothesis that patients presenting with STEMI planned for primary PCI will have improved markers of optimal reperfusion and clinical outcomes by prehospital administration of crushed tablets of prasugrel loading dose. COMPARE CRUSH (NCT03296540) is a randomized trial in a regionally organized ambulance care setting evaluating the efficacy and safety of pre-hospital loading dose with prasugrel crushed tablets versus integral tablets in approximately 674 patients presenting with STEMI planned for primary PCI. The independent primary endpoints are percentage of patients reaching thrombolysis in myocardial infarction (TIMI) flow grade 3 in the infarct-related artery at initial angiography, or achieving ≥70% ST-segment elevation resolution at 1 hour post-PCI. Secondary clinical endpoints are death, myocardial infarction, revascularization, and stent thrombosis followed up to 1 year. Moreover, the primary safety endpoint is bleeding events assessed at 48 hours. The COMPARE CRUSH trial will assess whether prehospital administration of loading dose prasugrel in form of crushed tablets - which is expected to provide faster platelet inhibition compared to standard treatment with integral tablets - results in improved reperfusion and clinical outcomes. RCT# NCT03296540.

Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Long-term follow up of secondary endpoints.

125 Background: RA, a bone targeting alpha radiopharmaceutical, and EZ, are approved for mCRPC. Per phase 3 SWOG0421 trial, men with mCRPC and a significant decline in serum bone metabolism markers (BMM) had improved survival with atrasentan, a bone targeting agent (PMID 24565955). We hypothesized that RA+EZ is safe, and decrease bone metabolism markers compared to EZ alone. Here we report the long-term follow up of the secondary clinical endpoints. Methods: In this phase 2 trial (NCT02199197), men with progressive mCRPC were treated with EZ (160 mg daily) ± RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives: 1) changes in N-telopeptide compared from baseline to end of treatment; 2) safety. Secondary objectives: changes in 4 other markers of bone resorption or formation, and PSA progression free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). Results: After a safety lead in phase (n=8), 39 men were randomized (2:1) to RA+EZ vs EZ. Median follow up is 19.3 months (range 3 – 24 months). Combining RA+EZ was safe (2018 ASCO annual meeting abstract: 5057) and met the primary endpoint (2018 ESMO annual meeting: Annals of Oncology). There was a consistent trend regarding PSA-PFS, rPFS and OS favoring RA+EZ over EZ. . . (Table). Notably, no bone fractures have occurred in either group with extended follow up. Conclusions: The use of RA+EZ was safe with a longer follow up with no increase in skeletal related events including fractures. All secondary endpoints, numerically favored RA+EZ vs EZ. Clinical trial information: NCT02614859.