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A Phase I/Ib, Study to Evaluate Safety and Efficacy of RP4010, in Patients with Relapsed or Refractory Lymphomas

The primary objectives of this study are to determine the efficacy, safety, and tolerability of treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) fixed-dose combination (FDC) for 12 weeks in participants with chronic hepatitis C virus (HCV) infection with or without cirrhosis, who did not achieve sustained viral response (SVR) after receiving prior treatment in a Gilead-sponsored HCV treatment study of direct-acting antiviral (DAA)-containing regimens.

The overarching objective of this study is to use novel precision medicine strategies based on inherited and acquired leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy). Primary Therapeutic Objectives: * To improve the event-free survival of provisional standard- or high-risk patients with genetically or immunologically targetable lesions or minimal residual disease (MRD) = 5% at Day 15 or Day 22 or =1% at the end of Remission Induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T cell / blinatumomab for refractory B-acute lymphoblastic leukemia (B-ALL) or B-lymphoblastic lymphoma (B-LLy), and the proteasome inhibitor bortezomib for those lacking targetable lesions. * To improve overall treatment outcome of T acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LLy) by optimizing pegaspargase and cyclophosphamide treatment and by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD =0.01% at the end of induction. * To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in standard/high-risk patients with the CEP72 CC or CT genotype. Secondary Therapeutic Objectives: * To estimate the event-free survival and overall survival of children with ALL and to assess the non-inferiority of TOTXVII compared to the historical control given by TOTXVI. * To estimate the event-free survival and overall survival of children with LLy when ALL diagnostic and treatment approaches are used. * To evaluate the efficacy of blinatumomab in B-ALL patients with end of induction MRD =0.01% to \<1% and those (regardless of MRD level or TOTXVII risk category) with the genetic subtypes of BCR-ABL1, ABL-class fusion, JAK-STAT activating mutation, hypodiploid, iAMP21, ETV6-RUNX1-like, MEF2D, TCF3-HLF, or BCL2/MYC or with Down syndrome, by comparing event-free survival to historical control from TOTXVI. * To determine the tolerability of combination therapy with ruxolitinib and Early Intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD =5%, Day 42 MRD =1%, or LLy patients without complete response at the End of Induction and all patients with early T cell precursor leukemia. Biological Objectives: * To use data from clinical genomic sequencing of diagnosis, germline/remission and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance. * To evaluate and implement deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid. * To assess clonal diversity and evolution of pre-leukemic and leukemic populations using DNA variant detection and single-cell genomic analyses in a non-clinical, research setting. * To identify germline or somatic genomic variants associated with drug resistance of ALL cells to conventional and newer targeted anti-leukemic agents in a non-clinical, research setting. * To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis. Supportive Care Objectives * To conduct serial neurocognitive monitoring of patients to investigate the neurocognitive trajectory, mechanisms, and risk factors. * To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover. There are several Exploratory Objectives.

The aim of this study is to determine if treatment monitoring schedule for chronic HCV patients treated with glecaprevir (300mg)/pibrentasvir (120mg) can be simplified. Data has shown that direct acting antiviral (DAA) regimen of glecaprevir (300mg)/pibrentasvir (120mg), a protease inhibitor and NS5A inhibitor respectively , provides key features for HCV treatment simplification. Eligible participants (naïve pre-cirrhosis chronic HCV patients) will be randomized (1:2) to the standard or simplified monitoring arm and will receive treatment for 8 weeks. One post treatment visit will be conducted 12 weeks after the final dose of study medication to evaluate the proportion of patients with undetectable HCV RNA at this timepoint (SVR12).

To date there are no available data on the utility of the endoscopic mucosal resection (EMR) defect in stratifying the risk of immediate or delayed adverse outcomes, particularly clinically significant post EMR bleeding (CSPEB). The investigators aimed to analyse the data to determine if any of these EMR defect features allow us to estimate the risk of CSPEB. This will help endoscopists to identify defects with a high risk of adverse outcomes and may translate into improved patient outcomes.

This randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The primary efficacy assessment will be performed at 105 weeks. The participants who do not enter open-label extension will enter for a long term follow-up period for up to 52 weeks after the last crenezumab dose (Week 153).

The TAME Cardiac Arrest trial will study the ability of higher arterial carbon dioxide (PaCO2) levels to reduce brain damage, comparing giving patients 'normal' to 'slightly higher than normal' blood PaCO2 levels and assessing their ability to return to normal life-tasks. It will be the largest trial ever conducted in heart attack patients in the intensive care unit. This therapy is cost free and, if shown to be effective, will improve thousands of lives, transform clinical practice, and yield major savings.

This is a single centre open label phase II trial to determine the antitumor efficacy of the oral immunomodulatory agent pomalidomide in persistent human papillomavirus (HPV) -associated high grade squamous intra-epithelial lesions (HSIL) in patients with and without human immunodeficiency virus (HIV) infection.

Sensorineural type of hearing loss is the most common sensory deficit among older adults. Some of the psychosocial consequences of this condition include difficulty in understanding speech, depression and social isolation. Studies have shown that older adults with hearing loss show some age-related cognitive decline. There is no clinically proven method to predict the onset of this condition, as its occurrence is slow and progressive, affecting both ears equally. Although hearing aid use and auditory training have been proven as successful interventions to alleviate sensorineural hearing loss, no research has been designed to look at the effect of both hearing aid use coupled with auditory training on cognitive performance in older adults. This study will investigate whether wearing hearing aids will improve the impact of auditory training on cognition, mood and social interaction for older adults with sensorineural hearing loss. This is a crossover trial targeting older adults between 50 and 90 years with either mild or moderate symmetric sensorineural hearing loss. Consented, willing participants will undergo a six month intensive auditory training program (active control), as a rigorous means of examining the impact hearing aid use has on a person's cognition, mood and social interaction. Participants will be assigned in random order to receive hearing aid (intervention) for either the first three or last three months of the six month auditory training program. Each participant will be tested at baseline, three and six months on a battery of computer based cognitive assessments, together with mood, and social engagement measures. Effectiveness of hearing aids and auditory training will be evaluated using an online speech perception test (SPT) and the Abbreviated Profile of Hearing Aid Benefit (APHAB) Inventory. This study will investigate whether using a hearing aid coupled with auditory training can improve a person's cognition and learning abilities, relationships with family and friends, and quality of life. Results from the study will inform strategies for aural rehabilitation, hearing aid delivery and future hearing loss intervention trials.

The purpose of this study is to assess the efficacy of ruxolitinib against best available therapy in participants with steroid-refractory chronic graft-versus-host disease (SR cGvHD).