Proof of concept Phase I or Phase II clinic trial

BACKGROUND: It is known that various chronic pain conditions lead to maladaptive changes in the central nervous system. Endometriosis is frequently associated with chronic pelvic pain (CPP). Its sufficient treatment remains a clinical challenge. Transcranial direct current stimulation (tDCS) has been shown to be a powerful method to reduce chronic pain. Therefore, this study aimed to investigate pain reduction via anodal tDCS in patients with endometriosis and CPP. METHODS: This clinical phase-II, placebo-controlled, randomized, parallel designed study included 36 patients with endometriosis and CPP...

Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness...

BACKGROUND: This phase II proof-of-concept study assessed the efficacy and safety of BI 425809, a novel selective glycine transporter-1 inhibitor, for the treatment of cognitive impairment associated with probable Alzheimer's disease dementia. METHODS: This 12-week, multicenter, double-blind, placebo-controlled, parallel-group study randomized (1:1:1:1:1) patients with mild-to-moderate probable Alzheimer's disease dementia to BI 425809 2, 5, 10, and 25 mg or placebo once daily...

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...

OBJECTIVE: Exosome therapy has been theorized to be safer, more effective, and less cumbersome in replacing stem cell therapies for tissue repair and regeneration. There remains considerable uncertainty on whether exosome therapy is efficacious and safe for recovery from brain injury due to cerebral infarction. There is growing consensus that systematic reviews of data, from preclinical studies which yielded conflicting and confusing results, can provide valuable directions for novel therapeutic options for several clinical conditions...

The nonapeptide oxytocin (OT) is a master regulator of the social brain in early infancy, adolescence, and adult life. Here, we review the postnatal dynamic development of OT-system as well as early-life OT functions that are essential for shaping social behaviors. We specifically address the role of OT in neonates, focusing on its role in modulating/adapting sensory input and feeding behavior; both processes are involved in the establishing mother-infant bond, a crucial event for structuring all future social interactions...

AIMS: Late gadolinium enhancement cardiac magnetic resonance (CMR) permits characterization of left ventricular ischaemic scars. We aimed to evaluate if scar core mass, border zone (BZ) mass, and BZ channels are risk markers for subsequent ventricular arrhythmia (VA) in ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: A sub-study of the DANish Acute Myocardial Infarction-3 multi-centre trial and Danegaptide phase II proof-of-concept clinical trial in which a total of 843 STEMI patients had a 3-month follow-up CMR...

UNLABELLED: Background / Objective: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. PATIENTS AND METHODS: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 days in hospitalised patients with moderate to severe COVID-19 are reported...

BACKGROUND & AIMS: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH...

BACKGROUND: Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis...

The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof-of-concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen- and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride...

Unblinded sample size re-estimation (SSR) is often planned in a clinical trial when there is large uncertainty about the true treatment effect. For Proof-of Concept (PoC) in a Phase II dose finding study, contrast test can be adopted to leverage information from all treatment groups. In this article, we propose two-stage SSR designs using frequentist conditional power (CP) and Bayesian predictive power (PP) for both single and multiple contrast tests. The Bayesian SSR can be implemented under a wide range of prior settings to incorporate different prior knowledge...

GPR40 is a class A G-protein coupled receptor (GPCR) mainly expressed in pancreas, intestine, and brain. Its endogenous ligand is long-chain fatty acids, which activate GPR40 after meal ingestion to induce secretion of incretins in the gut, including GLP-1, GIP, and PYY, the latter control appetite and glucose metabolism. For its involvement in satiety regulation and metabolic homeostasis, partial and AgoPAM (Positive Allosteric Modulation agonist) GPR40 agonists had been developed for type 2 diabetes (T2D) by many pharmaceutical companies...

Background & Aims: The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response. Methods: Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 μg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84...

CONTEXT: The risk of disease relapse in patients allografted for acute myeloid leukemia (AML) is high and remains the main cause of transplant failure. A potent graft-versus-leukemia (GvL) effect is exerted post-stem cell transplantation (SCT); strategies that may augment a GvL effect have the potential to reduce relapse risk post SCT. Siremadlin/HDM201 is a novel investigational MDM2 inhibitor with single-agent (SA) anti-AML activity. MDM2 inhibitors possess potent immunomodulatory effects (IME) in murine solid tumor and AML models...

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma...

No abstract text is available yet for this article.

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance...

OBJECTIVES: A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment. METHODS: We randomly assigned 100 patients in a 1:1 ratio to receive either 1...

AIM: Darigabat is an α2/3/5 subunit-selective positive allosteric modulator of GABAA receptors that has demonstrated broad-spectrum activity in several preclinical models of epilepsy as well as in a clinical photoepilepsy trial. The objective here was to assess the acute antiseizure effect of darigabat in the mesial temporal lobe epilepsy (MTLE) mouse model of drug-resistant focal seizures. METHODS: The MTLE model is generated by single unilateral intrahippocampal injection of low dose (1 nmole) kainic acid in adult mice, and subsequent epileptiform activity is recorded following implantation of a bipolar electrode under general anesthesia...