A Research Protocol for a Phase II Single-Arm Clinical Trial Assessing the Feasibility and Efficacy of Neoadjuvant Anastrozole in Patients With Luminal Breast Cancer and Low Proliferative Index: The ANNE Trial.

INTRODUCTION: Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors in this context. However, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Identifying non-responsive patients early and extending treatment for responsive ones would be ideal, yet optimal strategies are awaited. AIMS: This non-randomized phase 2 clinical trial aims to assess NET feasibility and efficacy in postmenopausal stage II and III luminal BC patients, identifying predictive therapeutic response biomarkers. Efficacy will be gauged by patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) scores 0 post-surgery. Study feasibility will be determined by participation acceptance rate (recruitment rate ≥50%) and inclusion rate (>2 patients/month). METHODS: Postmenopausal women with luminal, HER2-tumors in stages II and III undergo neoadjuvant anastrozole treatment, evaluating continuing NET or receiving chemotherapy through early Ki67 analysis after 2 to 4 weeks. The study assesses NET extension for up to 10 months, using serial follow-ups with standardized breast ultrasound and clinical criteria-based NET suspension. Clinical and pathological responses will be measured overall and in the luminal tumor A subgroup. Toxicity, health-related quality of life, and circulating biomarkers predicting early NET response will also be evaluated.

Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.

We recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680). The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.

Home-based self-management for sedentary individuals with mild walking disability after stroke: protocol for a randomised pilot study.

BACKGROUND: A Phase I study showed that it is feasible to implement a home-based self-management program aimed at increasing physical activity in individuals after stroke with mild walking disability in Brazil. The next step is to test this program against a control group in order to provide a power analysis for a fully-powered Phase III clinical trial. METHODS: A Phase II pilot randomised clinical trial with concealed allocation, blinded measurement, and intention-to-treat analyses will be carried out. The inclusion criteria will be individuals diagnosed with stroke, in the acute or subacute phase, with mild walking disability, sedentary, and no significant language impairment. The participants will be randomly allocated to the experimental or control group. The experimental group will receive six sessions of a home-based self-management program based on behaviour change techniques through the Social-Cognitive Theory and Control Theory over 11 weeks. The control group will receive one session of education about stroke (regarding the importance of practising physical activity after a stroke) and usual care. A total of 24 participants will be recruited. The primary outcome will be physical activity, measured through steps taken per day by an activity monitor (Actigraph wGT3X-BT, Pensacola, FL, USA). The mean of daily steps will be analysed to compare groups after intervention. Secondary outcomes will be cardiovascular risk (body mass index, waist circumference, and blood pressure), depressive symptoms (Geriatric Depression Scale), walking ability (6-Minute Walk Test and 10-Meter Walk Test), exercise self-efficacy (Self-Efficacy for Exercise scale), social participation (Stroke Impact Scale) and quality of life (EuroQual-5D). Two-way analyses of variance will be implemented for all parametric outcomes, and the Kruskal-Wallis test for non-parametric outcomes will be used to determine the statistical significance of the between-group differences and reported as mean differences between groups (95% CI). All analyses will be conducted intention-to-treat. All outcomes will be measured at baseline (Week 0), post-intervention (Week 12), and follow-up (Week 24). This pilot clinical trial was registered online at Clinical Trials under number NCT05461976 on 4th April 2022. DISCUSSION: If beneficial, this Phase II pilot randomised trial will provide data to plan a fully powered future Phase III clinical trial aimed at verifying the efficacy of this program to promote physical activity after stroke. TRIAL REGISTRATION: Clinical Trials NCT05461976 on 4th April 2022.

Safety and efficacy of P2Et extract from Caesalpinia spinosa in breast cancer patients: study protocol for a randomized double blind phase II clinical trial (CS003-BC).

BACKGROUND: Chemotherapy in breast cancer is effective but can generate significant toxicity and lead to tumor resistance. Joint treatment with standardized plant extracts can be an alternative to improve the response and allow an effective activation of the antitumor immune response that favors recovery in the short and long term. The P2Et extract of Caesalpinia spinosa presents antitumor activity in cells and animal models of breast cancer, improves the tumor microenvironment, and induces activation of the specific immune response against the tumor and is synergistic when used together with anthracyclines, which makes it a good candidate for evaluation in patients. METHODS: Conducted at a single center, this phase II study is a randomized, double-blind, placebo-controlled trial aimed at assessing the safety and efficacy of P2Et extract in patients diagnosed with stage II and III breast cancer, who are eligible for neoadjuvant treatment. The study aims to determine the safety profile at the previously established optimal biological dose from phase I trial while investigating various efficacy outcomes. These outcomes include improvements in quality of life, immunomodulation, metabolic profile, microbiome, as well as clinical indicators such as tumor reduction, disease-free survival, and pathological response, assessed at different stages of the treatment regimen. DISCUSSION: Treatment with the P2Et extract in breast cancer patients is hypothesized to enhance overall well-being, positively influencing their quality of life, while also triggering an antitumor immune response and enhancing immune infiltration. These combined effects have the potential to contribute to improved long-term survival outcomes for patients receiving the phytomedicine alongside neoadjuvant chemotherapy treatment. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT05007444. First Registered August 16th, 2021. Last Updated: August 9th, 2022.

Exploring the safety and efficacy of phytomedicine Petiveria alliacea extract (Esperanza) in patients with metastatic gastrointestinal tumors and acute leukemias: study protocol for a phase Ib/randomized double blind phase II trial (PA001).

BACKGROUND: The energy metabolism of drug-resistant tumor cells can provide a survival advantage during therapy, and treatment itself may influence metabolic reprogramming. Petiveria alliacea (Traditional name: Anamu) could inhibit glycolysis and OXPHOX modulating tumor metabolism, making it a potential treatment for tumors with altered metabolism. This clinical study aims to evaluate the safety and efficacy of a standardized Anamu phytomedicine called Esperanza in treating gastric tumors and acute leukemias. METHODS: This is a prospective, open label, phase I/ randomized, double-blind single-center phase II study designed to evaluate the safety and efficacy of Esperanza extract in patients with metastatic gastrointestinal tumors and acute leukemias. In stage 1, the study will determine the MTD and assess safety. In stage 2, safety at the MTD will be evaluated, and the efficacy of Esperanza extract will be explored in both metastatic gastric tumors and acute leukemias. Quality of life improvement will be the primary outcome in the gastric tumor group, while different efficacy outcomes will be assessed in the acute leukemia group. A placebo group will be used for comparison in the gastric tumor group, and a historical control group will be used in the acute leukemia arm. DISCUSSION: This clinical trial aims to evaluate the safety profile of the Esperanza extract in patients with metastatic gastrointestinal tumors and acute leukemias, while exploring its potential efficacy in conjunction with standard treatment for these pathologies. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT05587088. Registered October 19th, 2022.

INTRAPERITONEAL CHEMOTHERAPY FOR GASTRIC CANCER WITH PERITONEAL CARCINOMATOSIS: STUDY PROTOCOL OF A PHASE II TRIAL.

BACKGROUND: Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases. AIMS: The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis. METHODS: This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18-75 years; Peritoneal carcinomatosis with peritoneal cancer index<12; Eastern Cooperative Oncology Group 0/1; good clinical status; and lab exams within normal limits. The study protocol consists of four cycles of intraperitoneal chemotherapy with paclitaxel associated with systemic chemotherapy. After treatment, patients with peritoneal response assessed by staging laparoscopy undergo conversion gastrectomy. RESULTS: The primary outcome is the rate of complete peritoneal response. Progression-free and overall survivals are other outcomes evaluated. The study started in July 2022, and patients will be screened for inclusion until 30 are enrolled. CONCLUSIONS: Therapies for advanced gastric cancer patients have been evaluated in clinical trials but without success in patients with peritoneal metastasis. The treatment proposed in this trial can be promising, with easy catheter implantation and ambulatory intraperitoneal chemotherapy regime. Verifying the efficacy and safety of paclitaxel with systemic chemotherapy is an important progress that this study intends to investigate.

Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine U100 for type 2 diabetes: a systematic review and meta-analysis of phase 2 randomized controlled trials.

Objective: Insulin Icodec is a novel basal insulin analogue designed for once-weekly administration, therefore might propitiate reduction in the frequency of injections and facilitate treatment adherence. This study aimed to determine the glycemic control and safety profile of Insulin Icodec, compared with Glargine U100 in patients with diabetes mellitus type 2. Materials and methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCT) data comparing OnceWeekly Insulin Icodec and Once-Daily Insulin Glargine U100 in patients with type 2 diabetes mellitus. PubMed, Embase, and Cochrane databases were searched for trials published up to May 14, 2022. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. Results: Three studies were included comprising 453 patients, 230 (50.77%) using Once-Weekly Insulin Icodec and 223 (49.22%) using Once-Daily Insulin Glargine U100. In the pooled data, Glycated Hemoglobin (MD -0.20% CI -0.33 to -0.07%; P=0.002) change from baseline demonstrated a significantly higher reduction in the Icodec group. Time with Glucose in Range (MD 6.60% CI 3.63 to 9.57%; P < 0.0001) and Insulin Dose Difference (MD 0.97UI CI 0.76 to 1.18UI; P < 0.0001) were higher in the Icodec group. There was no significant difference in fasting plasma glucose, body weight change, hypoglycemia or any adverse event evaluated. Conclusion: OnceWeekly Insulin Icodec was associated with a small reduction in Glycated Hemoglobin, as well as higher Time with Glucose in Range, with similar hypoglycemic adverse events, when compared with Once-Daily Insulin Glargine U100.

Effect of statins on inflammation and cardiac function in patients with chronic Chagas disease: A protocol for pathophysiological studies in a multicenter, placebo-controlled, proof-of-concept phase II trial.

BACKGROUND: Cardiac complications, including heart failure and arrhythmias, are the leading causes of disability and death in Chagas disease (CD). CD, caused by the Trypanosoma cruzi parasite, afflicts 7 million people in Latin America, and its incidence is increasing in non-endemic countries due to migration. The cardiac involvement is explained by parasite-dependent, immune-mediated myocardial injury, microvascular abnormalities, and ischemia. Current treatment of early CD includes the administration of nifurtimox and benznidazole. However, their efficacy is low in the chronic phase and may induce severe adverse events, forcing therapy to halt. Therefore, finding innovative approaches to treat this life-threatening tropical disease is of utmost importance. Thus, improving the efficacy of the current antichagasic drugs by modifying the inflammatory response would render the current treatment more effective. It has been reported that, in mice, simvastatin decreases cardiac inflammation and endothelial activation, and improves cardiac function, effects that require clinical confirmation. OBJECTIVE: The study aims to analyze whether two doses of Atorvastatin, administered after CD treatment is completed, are safe and more efficacious than the antiparasitic drugs alone in reducing general inflammation and improving endothelial and cardiac functions in a proof-of-concept, placebo-controlled phase II trial. METHODS: 300 subjects will be recruited from four Chilean hospitals with an active Program for the Control of Chagas Disease. 40 or 80 mg/day of atorvastatin or placebo will be administered after completion of the antichagasic therapy. The patients will be followed up for 12 months. Efficacy will be determined by measuring changes in plasma levels of anti-inflammatory and pro-inflammatory cytokines, soluble cell adhesion molecules, BNP, and cTnT. Also, the resting 12-lead ECG and a 2D-echocardiogram will be obtained to evaluate cardiac function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04984616.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

A triple-masked, two-center, randomized parallel clinical trial to assess the superiority of eight weeks of grape seed flour supplementation against placebo for weight loss attenuation during perioperative period in patients with cachexia associated with colorectal cancer: a study protocol.

Background: Progressive, involuntary weight and lean mass loss in cancer are linked to cachexia, a prevalent syndrome in gastrointestinal malignancies that impacts quality of life, survival and postoperative complications. Its pathophysiology is complex and believed to involve proinflammatory cytokine-mediated systemic inflammation resulting from tumor-host interaction, oxidative stress, abnormal metabolism and neuroendocrine changes. Therapeutic options for cachexia remain extremely limited, highlighting the need for clinical research targeting new interventions. Thus, this study primarily assesses the effects of grape-seed flour (GSF), rich in polyphenols and fibers, for attenuating perioperative weight loss in colorectal cancer. Methods: This is a dual-center, triple-masked, placebo-controlled, parallel-group, phase II, randomized clinical trial designed to investigate GSF supplementation in subjects with pre- or cachexia associated with colorectal cancer during the perioperative period. Eighty-two participants will receive 8g of GSF or cornstarch (control) for 8 weeks. Assessments are scheduled around surgery: pre-intervention (4 weeks prior), day before, first week after, and post-intervention (4 weeks later). The primary endpoint is the difference in body weight mean change from baseline to week 8. The secondary endpoints describe the harms from 8-week supplementation and assess its superiority to improve body composition, post-surgical complications, quality of life, anorexia, fatigue, gastrointestinal symptoms, and handgrip strength. The study will also explore its effects on gut bacteria activity and composition, systemic inflammation, and muscle metabolism. Discussion: The current trial addresses a gap within the field of cancer cachexia, specifically focusing on the potential role of a nutritional intervention during the acute treatment phase. GSF is expected to modulate inflammation and oxidative stress, both involved in muscle and intestinal dysfunction. The research findings hold substantial implications for enhancing the understanding about cachexia pathophysiology and may offer a new clinical approach to managing cachexia at a critical point in treatment, directly impacting clinical outcomes. Trial registration: The Brazilian Registry of Clinical Trials (ReBEC), RBR-5p6nv8b; UTN: U1111-1285-9594. Prospectively registered on February 07, 2023.

A systematic review and meta-analysis assessing antiretroviral therapy for treatment-experienced HIV adult patients using an optimized background therapy approach: is there evidence enough for a standardized third-line strategy?

BACKGROUND: The World Health Organization (WHO) has identified the need for evidence on third-line antiretroviral therapy (ART) for adults living with HIV/AIDS, given that some controversy remains as to the best combinations of ART for experienced HIV-1-infected patients. Therefore, we conducted a systematic review and meta-analysis to (i) assess the efficacy of third-line therapy for adults with HIV/AIDS based on randomized controlled trials (RCT) that adopted the "new antiretroviral (ARV) + optimized background therapy (OBT)" approach and (ii) address the key issues identified in WHO's guidelines on the use of third-line therapy. METHODS: MEDLINE, EMBASE, LILACS, ISI Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials were searched for RCTs assessing third-line ARV therapy that used an OBT approach between 1966 and 2015. Data was extracted using an Excel-structured datasheet based on the Consolidated Standards of Reporting Trials (CONSORT) recommendations. The primary outcome of this meta-analysis was the proportion of patients reaching undetectable HIV RNA levels (< 50 copies/mL) at 48 weeks of follow-up. Included studies were evaluated using the Cochrane's Risk of Bias assessment tool. Summarized evidence was rated according to the GRADE approach. RESULTS: Eighteen trials assessing 9 new ARV + OBT combinations defined as third-line HIV therapy provided the efficacy data: 7 phase IIb trials and 11 phase III trials. Four of the 18 trials provided extension data, thus resulting in 14 trials providing 48-week efficacy data. In the meta-analysis, considering the outcome regarding the proportion of patients with a viral load below 50 copies/ml at 48 weeks, 9 out of 14 trials demonstrated the superiority of the new combination being studied (risk difference = 0.18, 95% CI 0.13-0.23). The same analysis stratified by the number of fully active ARVs demonstrated a risk difference of 0.29 (95% CI 0.12-0.46), 0.28 (95% CI 0.17-0.38) and 0.17 (95% CI 0.10-0.24) respectively from zero, one, and two or more active drugs strata. Nine of the 18 trials were considered to have a high risk of bias. CONCLUSIONS: Efficacy results demonstrated that the groups of HIV-experienced patients receiving the new ARV + OBT were more likely to achieve viral suppression when compared to the control groups. However, most of these trials may be at a high risk of bias. Thus, there is still not enough evidence to stipulate which combinations are the most effective for therapeutic regimens that are to be used sequentially due to documented multi-resistance.

Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan. / Antivirais para pacientes adultos hospitalizados com infecção por SARS-CoV-2: Um estudo de Fase II/III, randomizado, multicêntrico, controlado por placebo, adaptativo, com múltiplos braços e estágios. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocolo e plano de análise estatística.

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.

Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov: NCT04468087.

Plasmodium vivax vaccine: What is the best way to go?

Malaria is one of the most devastating human infectious diseases caused by Plasmodium spp. parasites. A search for an effective and safe vaccine is the main challenge for its eradication. Plasmodium vivax is the second most prevalent Plasmodium species and the most geographically distributed parasite and has been neglected for decades. This has a massive gap in knowledge and consequently in the development of vaccines. The most significant difficulties in obtaining a vaccine against P. vivax are the high genetic diversity and the extremely complex life cycle. Due to its complexity, studies have evaluated P. vivax antigens from different stages as potential targets for an effective vaccine. Therefore, the main vaccine candidates are grouped into preerythrocytic stage vaccines, blood-stage vaccines, and transmission-blocking vaccines. This review aims to support future investigations by presenting the main findings of vivax malaria vaccines to date. There are only a few P. vivax vaccines in clinical trials, and thus far, the best protective efficacy was a vaccine formulated with synthetic peptide from a circumsporozoite protein and Montanide ISA-51 as an adjuvant with 54.5% efficacy in a phase IIa study. In addition, the majority of P. vivax antigen candidates are polymorphic, induce strain-specific and heterogeneous immunity and provide only partial protection. Nevertheless, immunization with recombinant proteins and multiantigen vaccines have shown promising results and have emerged as excellent strategies. However, more studies are necessary to assess the ideal vaccine combination and test it in clinical trials. Developing a safe and effective vaccine against vivax malaria is essential for controlling and eliminating the disease. Therefore, it is necessary to determine what is already known to propose and identify new candidates.

Nebulized enriched heparin to treat no critical patients with Sars-Cov-2: Triple-blind clinical trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that spreads rapidly, reaching pandemic status, causing the collapse of numerous health systems, and a strong economic and social impact. The treatment so far has not been well established and there are several clinical trials testing known drugs that have antiviral activity, due to the urgency that the global situation imposes. Drugs with specific mechanisms of action can take years to be discovered, while vaccines may also take a long time to be widely distributed while new virus variants emerge. Thus, drug repositioning has been shown to be a good strategy for defining new therapeutic approaches. Studies of the effect of enriched heparin in the replication of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) in vitro assays justify the advance for clinical tests. METHODS AND ANALYSIS: A phase I/II triple-blind parallel clinical trial will be conducted. Fifty participants with radiological diagnosis of grade IIA pneumonia will be selected, which will be allocated in 2 arms. Participants allocated in Group 1 (placebo) will receive nebulized 0.9% saline. Participants allocated in Group 2 (intervention) will receive nebulized enriched heparin (2.5 mg/mL 0.9% saline). Both groups will receive the respective solutions on a 4/4 hour basis, for 7 days. The main outcomes of interest will be safety (absence of serious adverse events) and efficacy (measured by the viral load).Protocols will be filled on a daily basis, ranging from day 0 (diagnosis) until day 8.

Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial.

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of severe SARS-CoV-2 infection in hospitalized patients with COVID-19: A structured summary of a study protocol for a randomized, parallel-group, open-label, multi-center pilot trial (PROTECT-COVID-19).

OBJECTIVES: Conestat alfa, a recombinant human C1 esterase inhibitor, is a multi-target inhibitor of inflammatory cascades including the complement, the kinin-kallikrein and the contact activation system. The study objective is to investigate the efficacy and safety of conestat alfa in improving disease severity and short-term outcome in COVID-19 patients with pulmonary disease. TRIAL DESIGN: This study is an investigator-initiated, randomized (2:1 ratio), open-label, parallel-group, controlled, multi-center, phase 2a clinical trial. PARTICIPANTS: This trial is conducted in 3 hospitals in Switzerland, 1 hospital in Brazil and 1 hospital in Mexico (academic and non-academic). All patients with confirmed SARS-CoV-2 infection requiring hospitalization for at least 3 calendar days for severe COVID-19 will be screened for study eligibility. INCLUSION CRITERIA: - Signed informed consent - Age 18-85 years - Evidence of pulmonary involvement on CT scan or X-ray of the chest - Duration of symptoms associated with COVID-19 ≤ 10 days - At least one of the following risk factors for progression to mechanical ventilation on the day of enrolment: 1) Arterial hypertension 2) ≥ 50 years 3) Obesity (BMI ≥ 30 kg/m2) 4) History of cardiovascular disease 5) Chronic pulmonary disease 6) Chronic renal disease 7) C-reactive protein > 35mg/L 8) Oxygen saturation at rest of ≤ 94% when breathing ambient air Exclusion criteria: - Incapacity or inability to provide informed consent - Contraindications to the class of drugs under investigation (C1 esterase inhibitor) - Treatment with tocilizumab or another IL-6R or IL-6 inhibitor before enrolment - History or suspicion of allergy to rabbits - Pregnancy or breast feeding - Active or anticipated treatment with any other complement inhibitor - Liver cirrhosis (any Child-Pugh score) - Admission to an ICU on the day or anticipated within the next 24 hours of enrolment - Invasive or non-invasive ventilation - Participation in another study with any investigational drug within the 30 days prior to enrolment - Enrolment of the study investigators, their family members, employees and other closely related or dependent persons INTERVENTION AND COMPARATOR: Patients randomized to the experimental arm will receive conestat alfa in addition to standard of care (SOC). Conestat alfa (8400 U followed by 4200 U every 8 hours) will be administered as a slow intravenous injection (5-10 minutes) over a 72-hour period (i.e. 9 administrations in total). The first conestat alfa treatment will be administered on the day of enrolment. The control group will receive SOC only. SOC treatment will be administered according to local institutional guidelines, including supplemental oxygen, antibiotics, corticosteroids, remdesivir, and anticoagulation. MAIN OUTCOMES: The primary endpoint of this trial is disease severity on day 7 after enrolment assessed by an adapted WHO Ordinal Scale for Clinical Improvement (score 0 will be omitted and score 6 and 7 will be combined) from 1 (no limitation of activities) to 7 (death). Secondary outcomes include (i) the time to clinical improvement (time from randomization to an improvement of two points on the WHO ordinal scale or discharge from hospital) within 14 days after enrolment, (ii) the proportion of participants alive and not having required invasive or non-invasive ventilation at 14 days after enrolment and (iii) the proportion of subjects without an acute lung injury (defined by PaO2/FiO2 ratio of ≤300mmHg) within 14 days after enrolment. Exploratory outcomes include virological clearance, C1 esterase inhibitor pharmacokinetics and changes in routine laboratory parameters and inflammatory proteins. RANDOMISATION: Subjects will be randomised in a 2:1 ratio to treatment with conestat alfa in addition to SOC or SOC only. Randomization is performed via an interactive web response system (SecuTrial®). BLINDING (MASKING): In this open-label trial, participants, caregivers and outcome assessors are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We will randomise approximately 120 individuals (80 in the active treatment arm, 40 in the SOC group). Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels αp = 0.0221. The results of the interim analysis will allow adjustment of the sample size (Lehmacher, Wassmer, 1999). TRIAL STATUS: PROTECT-COVID-19 protocol version 3.0 (July 07 2020). Participant recruitment started on July 30 2020 in one center (Basel, Switzerland, first participant included on August 06 2020). In four of five study centers patients are actively recruited. Participation of the fifth study center (Mexico) is anticipated by mid December 2020. Completion of trial recruitment depends on the development of the SARS-CoV-2 pandemic. TRIAL REGISTRATION: Clinicaltrials.gov, number: NCT04414631 , registered on 4 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Profile of entrectinib in the treatment of ROS1-positive non-small cell lung cancer: Evidence to date.

ROS proto-oncogene 1 (ROS1) encodes a type I integral membrane protein with tyrosine kinase activity and whose activating alterations are involved in the aggressiveness of several tumor types. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against NTRK1, NTRK2, NTRK3, ALK, and ROS1 with the ability to cross the blood-brain barrier. Results of Phase I and II trials have led the Food and Drug Administration to grant approval to entrectinib for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC). In this review, we will describe the biology of ROS1, as well as results of the efficacy and safety of different clinical trials evaluating entrectinib in ROS1-positive NSCLC.

An evaluation of ticagrelor for the treatment of sickle cell anemia.

INTRODUCTION: Ticagrelor is an antiplatelet agent approved for the treatment of patients with an acute coronary syndrome or a history of myocardial infarction. Considering the evidence demonstrating that ticagrelor-mediated inhibition of platelet activation and aggregation have beneficial effects in the treatment of thrombotic conditions, clinical studies have been conducted to evaluate the use of this drug for the treatment of sickle cell disease (SCD), demonstrating satisfactory tolerability and safety. AREAS COVERED: Clinical investigation has characterized the pharmacokinetic and pharmacodynamical profile, as well as the efficacy and safety of ticagrelor to prevent painful vaso-occlusive crisis (painful episodes and acute chest syndrome) in SCD patients. EXPERT OPINION: While phase 1 and 2 clinical trials demonstrated satisfactory tolerability and safety, the conclusion of phase 3 clinical trials is crucial to prove the efficacy of ticagrelor as a therapeutic option for the treatment of SCD. Thus, it is expected that ticagrelor, especially in combination with other drugs, will improve the clinical profile and quality of life of patients with SCD.

Phase II trial evaluating the clinical efficacy of cefixime for treatment of active syphilis in non-pregnant women in Brazil (CeBra).

BACKGROUND: Syphilis is a sexually and vertically transmitted infection caused by the bacteria Treponema pallidum for which there are few proven alternatives to penicillin for treatment. For pregnant women infected with syphilis, penicillin is the only WHO-recommended treatment that will treat the mother and cross the placenta to treat the unborn infant and prevent congenital syphilis. Recent shortages, national level stockouts as well as other barriers to penicillin use call for the urgent identification of alternative therapies to treat pregnant women infected with syphilis. METHODS: This prospective, randomized, non-comparative trial will enroll non-pregnant women aged 18 years and older with active syphilis, defined as a positive rapid treponemal and a positive non-treponemal RPR test with titer ≥1:16. Women will be a, domized in a 2:1 ratio to receive the oral third generation cephalosporin cefixime at a dose of 400 mg two times per day for 10 days (n = 140) or benzathine penicillin G 2.4 million units intramuscularly based on the stage of syphilis infection (n = 70). RPR titers will be collected at enrolment, and at three, six, and nine months following treatment. Participants experiencing a 4-fold (2 titer) decline by 6 months will be considered as having an adequate or curative treatment response. DISCUSSION: Demonstration of efficacy of cefixime in the treatment of active syphilis in this Phase 2 trial among non-pregnant women will inform a proposed randomized controlled trial to evaluate cefixime as an alternative treatment for pregnant women with active syphilis to evaluate prevention of congenital syphilis. TRIAL REGISTRATION: Trial identifier: www.Clinicaltrials.gov, NCT03752112. Registration Date: November 22, 2018.