Pretoia, South Africa

Perioperative Analgesia with Erector Spinae Plane Block in Liver Transplant Recipients

Investigation of Impact of Indocyanine Green on Volume of Lymphadenectomy in Resectable Gastric Cancer

1. Introduction and rationale Radical gastrectomy with D2 lymph node dissection remains the main treatment for resectable gastric adenocarcinoma. Lymph node status is a significant prognostic factor for the survival of patients with gastric cancer, as high-quality lymph node dissection improves patient prognosis. However, lymph node dissection in gastric cancer surgery is sometimes not performed in full and is routinely performed without the use of additional imaging methods. As a result, a complete lymphadenectomy is technically difficult, which leads to smaller lymphadenectomies and, in turn, to tumor recurrence and poorer overall survival rates for this group of patients. The use of intraoperative navigation technology to assist in systemic lymph node dissection is essential for radical gastrectomy. The sentinel lymph node (SLN) is defined as the first lymph node on the path of lymphatic drainage from the primary tumor. Currently, the method of labeling the SLN is widely used in the treatment of tumors of various localizations. Gastric cancer has also been identified as an object for signal node navigation surgery. The results of studies indicate that sentinel lymph node navigation surgery can become the basis for minimally invasive surgery with personalized lymphadenectomy and improve the treatment outcomes and quality of life of patients with various types of malignancies, including gastric cancer. Dyes, radioisotopes, or a combination of both are used to label SLNs in gastric cancer. However, they all have certain limitations that make it impossible to use them routinely. Indocyanine green (ICG) is a well-known diagnostic reagent that is approved for clinical use in the study of liver function and cardiac output. It absorbs light in the near-infrared with a maximum at 800 nm and emits maximum fluorescence at 840 nm when bound to plasma proteins. Based on the fluorescence characteristics of IR, an intraoperative imaging system was developed to assess blood flow during surgical interventions, such as coronary artery bypass grafting, neurovascular surgery, and organ transplantation. In addition, the use of fluorescence imaging has been widely used for labeling of SLAs in cancer. 2. The purpose of the study The study aims to evaluate the safety and benefits of using indocyanine green in lymph node dissection for gastric cancer surgery. The primary endpoint is the average number of lymph nodes removed. Secondary study points are the average number of ICG-positive lymph nodes; the average number of metastatic ICG-positive lymph nodes; the number of postoperative complications and complications associated with the administration of ICG. 3. Design. This study is a prospective, open-label, single-center clinical trial with one study group to investigate the number of lymph nodes removed using ICG. Patients who meet the inclusion criteria for this study will be enrolled in the study after reviewing and signing an informed consent form. All patients will be included in one group and will receive surgical treatment in the amount of total or subtotal gastrectomy with lymphadenectomy D1, D1+, D2 or D2+. ICG is injected by the patient by endoscopic submucosal injection into 4 points around the tumor 24-12 hours before the start of the surgical intervention. Assessment of the number of fluorescent lymph nodes will be performed intraoperatively with their subsequent removal and mapping. The incidence of postoperative complications will be assessed by Clavien-Dindo. 4. Study population 4.1 General data The study population consists of patients with newly diagnosed gastric cancer of stages Ib, II, III. Patients are treated according to national standards for the treatment of gastric cancer. 4.2 Inclusion criteria: A. Tumor spread: cT2-4a cN0-3, cM0; B. Age: 18 - 80; C. Gender: men and women; D. ECOG: 0 - 1; E. Histologic type of tumor: Adenocarcinoma of any subtype; F. Degree of differentiation: G1 - G4; G. Tumor localization: cardiac region, stomach floor, stomach body, antrum, pylorus, and pyloric region of the stomach; H. Tumor spread: absence of tumor invasion into adjacent structures; I. No history of cancer in the last 5 years. J. No previous chemotherapy, surgery or radiation treatment for another cancer (except for neoadjuvant chemotherapy for gastric cancer); K. Absence of decompensated concomitant pathology. 4.3. Exclusion criteria : A. M1 (distant metastases); B. ECOG 2 - 4; C. Age over 80 and under 18; D. Presence of decompensated comorbidities, ASA> 3; E. Patient refusal to participate in the study. 5. Statistics 5.1 Sample calculation According to the literature, the average number of lymph nodes removed is 48.9 (+- 14.6). An increase in the average number of lymph nodes by 4 will be sufficient to reject the null hypothesis with 80% power and a one-sided significance criterion of 0.05. This will require the recruitment of 105 patients. Patient recruitment is planned over a three-year period, with each patient followed for 90 days after surgical treatment. About 30 patients are planned to be included each year. 5.2 Analysis. The primary endpoint analysis is planned in accordance with the intention-to-treat provision, which provides for the analysis of all patients who will be included in the study, regardless of the treatment and its effect. The difference in the mean number of lymph nodes will be analyzed using the t-test. For the analysis of other treatment-related complications, multivariate analysis will be used for each clinical factor and its association with the development of the main types of complications. Continuous data will be analyzed using the unpaired Student's t-test. Multivariate analysis to determine the correlation between clinical variables and complications will be performed using a logistic regression model. 6. Quality control 6.1 Quality criteria for surgical intervention The criterion for the quality of indocyanine green injection will be intraoperative visual assessment of lymph node fluorescence, visual assessment of adjacent tissue fluorescence. The quality of lymph node dissection will be assessed by the number of lymph nodes removed and the number of lymph node groups removed for each patient and the R-status of the lymph nodes (R0/R1/R2). The quality of gastric tumor removal will be assessed by evaluating the resection margins (R0/R1/R2). 6.2 Protocol for recording complications associated with indocyanine administration and postoperative complications The frequency and nature of complications associated with the administration of indocyanine green will be assessed according to the Common Terminology Criteria for Adverse Events 5.0. The frequency and nature of surgical complications will be assessed according to the Clavien-Dindo classification. 7. Algorithm of patient registration and inclusion in the study After signing the informed consent, a unique number will be assigned to the patient, which will be entered into the paper CRF form and duplicated in the electronic . The paper form and the electronic database completely duplicate each other. The electronic form and the paper form are filled in by the researcher as soon as the patient signs the informed consent to participate in the study. The electronic form is based on the Redcap database. 8.1 Principles of administration of green indocyanine Before endoscopic injection of indocyanine green and surgical treatment, the tests listed in Appendix 6 are required. Endoscopic injection of indocyanine green is performed under general anesthesia. Indocyanine green is injected into the submucosal layer of the stomach at 4 points around the tumor. The dosage for one administration is up to 5 mg. The total dosage for one patient for 4 doses is 20 mg. Monitoring of indocyanine green side effects occurs before the start of general anesthesia during radical surgery. 8.2 Principles of clinical and laboratory monitoring Clinical and laboratory monitoring of patients is performed before the administration of indocyanine green and the start of surgery. If side effects occur between the administration of indocyanine green and the beginning of general anesthesia for carrying out curative surgery, it is possible to conduct additional clinical and laboratory examinations at the discretion of the investigator. 8.3 List of tests for the administration indocyanine green and radical surgical treatment See Annex 6. 8.4 Principles of surgical treatment Surgical treatment of gastric cancer is performed in accordance with national guidelines for the treatment of gastric cancer. The main goal of surgery is: radical removal of the tumor; achievement of R0 status of the resection margins; lymph node dissection in the volume corresponding to the volume of the primary tumor removal (D1/D1+/D2/D2+). Criteria for gastric cancer unresectability: ● invasion of the following vessels: aorta, vena cava, abdominal trunk, common hepatic artery, hepatic artery proper, left hepatic artery, right hepatic artery, portal vein, liver parenchyma. 9. Postoperative patient management. In 16-20 hours after the end of the surgery, the patient starts drinking water (50 ml per dose). The patient is prescribed antiemetics, pain relief, anticoagulant therapy, infusion therapy, gastric and intestinal motility stimulants. The patient starts drinking medical formula 24 hours after the end of surgical treatment. Postoperative physical activity - from 9.00 to 22.00 - walking for 10 minutes for every hour. The urinary catheter is removed 24 hours after the end of the surgical procedure.

L-Annamycin for Injection in Combination With Cytarabine Injection as Second Line Therapy for Remission Induction in Adult Subjects With Refractory/Relapsed AML

This pivotal phase 2/3, multi-center, adaptive design study of L-Annamycin for Injection in combination with Cytarabine Injection as second line therapy for remission induction in adult subjects with refractory/relapsed AML is divided into two parts, Part A and Part B. Part A (Determination of Optimal Dosage Regimen) Part A of this study is a randomized, double-blind, placebo-controlled (RDBPC), efficacy, safety, tolerability, and pharmacokinetics study comparing two dose levels of L Annamycin for Injection (190 versus 230 mg/m2/day) in combination with Cytarabine Injection (2.0 g/m2/day) versus placebo in combination with Cytarabine Injection to identify the optimal dosage regimen as second line therapy for remission induction in adult subjects with refractory/relapsed AML. Seventy-five to ninety subjects with a pathologically confirmed diagnosis of AML who have refractory/relapsed AML after having received one prior induction therapy and who have received only one prior induction therapy for the treatment of AML will be enrolled in Part A. Remission induction followed by consolidation therapy or consolidation therapy and maintenance therapy will count as one prior line of therapy. Subjects who meet all eligibility criteria after the completion of both screening and baseline assessments will be enrolled. Initially, 45 subjects will be randomized 1:1:1 to one of the three treatment arms listed below (i.e., 15 per treatment arm). Randomization will be stratified by continent. Depending on the outcome of the first interim analysis (see further below), either 45 additional subjects will be randomized 1:1:1 to one of the three treatment arms listed below (for a total of 30 per treatment arm in Part A) or 30 additional subjects will be randomized 1:1 to either placebo in combination with Cytarabine Injection (Treatment Arm 1) or the L-Annamycin for Injection in combination with Cytarabine Injection arm that was selected to continue after the first interim analysis (i.e., Treatment Arm 2 or 3) (for a total of 30 per treatment arm in Part A, except for the arm that is dropped after the first interim analysis, which will have a total ≥15 and ≤30, depending on how many subjects were enrolled at the point the decision to drop the arm occurs). - Treatment Arm 1: placebo (0.9% Sodium Chloride Injection, i.e., the diluent for L-Annamycin for Injection) for three consecutive days in combination with 2.0 g/m2/day Cytarabine Injection for five consecutive days. - Treatment Arm 2: 190 mg/m2/day L-Annamycin for Injection for three consecutive days in combination with 2.0 g/m2/day Cytarabine Injection for five consecutive days. - Treatment Arm 3: 230 mg/m2/day L-Annamycin for Injection for three consecutive days in combination with 2.0 g/m2/day Cytarabine Injection for five consecutive days. L-Annamycin for Injection will be administered as an intravenous (IV) infusion over 2 hours. The placebo will be administered the same (i.e., IV infusion over 2 hours). Cytarabine Injection will be administered as an IV infusion over 4 hours. The first day of Cytarabine Injection treatment will start on the first day of L-Annamycin for Injection or placebo treatment (Day 1). On the days where both Cytarabine Injection and L-Annamycin for Injection or placebo are administered, the Cytarabine Injection infusion will be initiated after the L-Annamycin for Injection or placebo infusion is completed.Part A of this study will include two interim analyses as follows: First Interim Analysis: After the first 45 subjects enrolled in Part A of this study have completed their first treatment cycle response assessment at Day 35 ± 14 days, the data for those subjects will be verified/cleaned and locked, and the data will be unblinded and analyzed (n = 15 per treatment arm). Enrollment in the study will not be halted while the first interim analysis is performed. Comparisons will be made between the three treatment arms to determine if continuation of the study should be halted due to a lack of efficacy difference between the placebo in combination with Cytarabine Injection arm (Treatment Arm 1) and the L-Annamycin for Injection in combination with Cytarabine Injection arms (Treatment Arms 2 and 3; i.e., futility analysis) or too excessive of a risk of serious adverse events (SAEs) with Treatment Arms 2 and/or 3 relative to Treatment Arm 1. An unblinded independent data monitoring committee (iDMC) will review the available efficacy, safety, and pharmacokinetic (PK) data and make recommendations to the Sponsor on how to proceed with the remainder of Part A of the study. The primary options will be to recommend that the study be halted for futility reasons, for safety reasons, or that the study continue. If the iDMC recommends that the study continues, they will recommend if one or both L-Annamycin for Injection dosage regimens (i.e., 190 mg/m2/day or 230 mg/m2/day) continue for Part A. Second Interim Analysis: After all subjects enrolled in Part A of this study (total of 75 to 90 subjects; see above for explanation of variable total subject number) have completed their first treatment cycle response assessment at Day 35 ± 14 days, enrollment in the study will be temporarily halted, the data will be verified/cleaned and locked, the data for the second group of subjects (i.e., who were not part of the first interim analysis) will be unblinded, and the pooled Part A data will be analyzed. If all three arms were continued after the first interim analysis, three treatment arms will be compared (n = 30 per treatment arm) to determine which of the L Annamycin for Injection dosage regimens (190 mg/m2/day versus 230 mg/m2/day) is the optimal dosage regimen for continuing with for the remainder of the study (Part B) and which dosage regimen will be dropped from further enrollment. If one of the two L Annamycin for Injection in combination with Cytarabine Injection dosage regimens (Treatment Arm 2 or 3) was dropped after the first interim analysis, the remaining arm will be compared against placebo in combination with Cytarabine Injection (Treatment Arm 1) (n = 30 per treatment arm) to confirm that the study should continue with that regimen to Part B.Part B (Expansion at Optimal Dosage Regimen) Part B of this study is a RDBPC, efficacy, safety, tolerability, and pharmacokinetics study of the optimal dosage regimen of L-Annamycin for Injection in combination with Cytarabine Injection (as determined in Part A) versus placebo in combination with Cytarabine Injection as second line therapy for remission induction in adult subjects with refractory/relapsed AML. Once the optimal dosage regimen is determined (see Part A above), enrollment will resume under Part B of the study. Approximately 244 additional subjects with a pathologically confirmed diagnosis of AML who have refractory/relapsed AML after having received one prior induction therapy and who have received only one prior induction therapy for the treatment of AML (i.e., the same patient population as for Part A) will be enrolled in Part B. Subjects who meet all eligibility criteria after the completion of both screening and baseline assessments will be enrolled and randomized 1:1 to one of the two treatment arms listed below (i.e., 122 per treatment arm). Randomization will be stratified by continent. - Treatment Arm 1: placebo (0.9% Sodium Chloride Injection) for three consecutive days in combination with 2.0 g/m2/day Cytarabine Injection for five consecutive days (i.e., the same as Treatment Arm 1 of Part A). - Treatment Arm X: optimal dosage regimen (as determined in Part A) of L Annamycin for Injection (190 mg/m2/day or 230 mg/m2/day) for three consecutive days in combination with 2.0 g/m2/day Cytarabine Injection for five consecutive days (i.e., the same as Treatment Arm 2 or 3, respectively, of Part A).

A Phase III Renal Outcomes and Cardiovascular Mortality Study to Investigate the Efficacy and Safety of Baxdrostat in Combination With Dapagliflozin in Participants With Chronic Kidney Disease and High Blood Pressure

The purpose of this study is to investigate the efficacy, safety, and tolerability of baxdrostat in combination with dapagliflozin, compared with placebo and dapagliflozin, in reducing the risk of the composite of > 50% decline in eGFR, kidney failure, or CV death, in individuals with CKD and HTN. This study consists of a 4-week dapagliflozin Run-in Period for participants untreated with SGLT2i at screening, and a double-blinded period where participants will receive either baxdrostat/dapagliflozin or placebo/dapagliflozin. Site visits will take place at 2-, 4-, 8-, 16-, 34, and 52-weeks following randomisation. Thereafter visits will occur approximately every 4 months. The study closure procedures will be initiated when the predetermined number of primary endpoint events is predicted to have occurred ie, the PACD. All randomised participants including any participants who have prematurely discontinued study intervention will be scheduled for a SCV within a few weeks of the PACD. This period can be extended by the Sponsor. In case of premature discontinuation of blinded study intervention, participants will continue in the study and receive dapagliflozin 10 mg, unless the participant meets dapagliflozin specific discontinuation criteria. If study intervention is temporarily or permanently discontinued, the participant should remain in the study, and it is important that the scheduled study visits (including the PTDV for participants with permanent discontinuation of study intervention) and data collection continue according to the study protocol until the SCV.

A Study to Evaluate Zilovertamab Vedotin (MK-2140) Combination With Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Previously Untreated DLBCL (MK-2140-010)

Preventing Mental Disorders Among Women Internally Displaced by War in Ukraine: The SHAWL Trial

The war in Ukraine has provoked the world's current largest humanitarian displacement: since February 2022, one-third of Ukrainians have been forced to leave their homes, resulting in upwards of 7 million internally displaced persons. Estimates suggest that 60% of Ukraine's displaced persons are women, who face stressors including difficulty accessing necessary primary health and psychological care, restricted access to food and stable housing, and increased strain from separation from their social networks and additional family care responsibilities. Early reports from Ukraine consistently describe the psychological distress that displaced women are presently experiencing. It is anticipated that nearly one in five people exposed to conflict will develop mental disorders, notably depressive and anxiety disorders. Thus, improving access to mental health prevention programs that mitigate development of mental disorders for women in Ukraine is critical. This study will adapt a community-based Acceptance and Commitment Therapy (ACT) intervention to prevent the development symptoms of depression and anxiety among women displaced by war in Ukraine. ACT is an evidence-based approach that uses acceptance, mindfulness and behavioral change processes to improve psychological flexibility. Recently displaced women who screen positive for symptoms of depression and anxiety will be recruited. The investigators plan to adapt and evaluate a single-session ACT group intervention to limit effects of mental health distress among these displaced women. The central hypothesis of this research is that an ACT-based intervention delivered in a humanitarian context will help displaced women in Ukraine learn skills to improve psychological flexibility, thereby decreasing symptoms of depression and anxiety and ultimately mitigating onset of mental disorders.

An Extension Study to Assess Impact of Multiple Sclerosis (MS) on Physical Function and Provide Continued Ocrelizumab Treatment

Phase III Study Investigating Heart Failure and Cardiovascular Death With Baxdrostat in Combination With Dapagliflozin

A Study to Evaluate the Efficacy and Safety of Tulisokibart (MK-7240) in Participants With Moderate to Severe Crohn's Disease (MK-7240-008)

The protocol consists of 2 studies. Study 1 includes induction and maintenance treatment, and Study 2 includes only induction treatment. Each study has its own hypotheses and outcome measures that will be assessed independently.

Safety and Efficacy of KLS-1 Monotherapy in Malignant Neoplasms

This is a Phase I/II, open-label, non-randomized, multicenter study of KLS-1 administered via intravenous (IV) infusions in 21-day treatment cycles to adult participants with different types of solid tumors and CLL. Phase I (a dose-escalation part) will explore multiple-dose levels, PK and select a single dose level to explore in Phase II of the study. A conventional 3+3 design will be utilized. Once a dose level is selected, the additional cohort of 3-6 patients will be enrolled to assess more effectively the safety during 2 treatment cycles and confirm Phase II dose (P2D). Phase II (a dose expansion part) will evaluate the evidence of anti-tumor activity of the selected dose in four dose expansion cohorts of patients with different types of solid locally advanced and/or metastatic tumors or CLL. The study is designed to identify and characterize the safety, tolerability, efficacy, and PK profile of KLS-1 in oncological patients.