Clinical Trials In Pulmonary Hypertension Research Articles

Socioeconomic and Social Determinants of Health: Effects on Pulmonary Arterial Hypertension Care

There is increasing awareness on the significance of socioeconomic status, social determinants of health, and the role of ethnicity and race in clinical outcomes of patients with pulmonary arterial hypertension. However, to date, underrepresentation of minorities in pulmonary hypertension clinical trials and registries remains. In the present review, we summarize the current knowledge on race, ethnicity, traditional and novel socioeconomics and social determinants of health, and its association with clinical outcomes in patients with pulmonary arterial hypertension. We present case examples on the interplay of these factors for specific disease phenotypes and discuss strategies for addressing these variables at the patient care level.

Pulmonary Hypertension Clinical Trials and COVID-19: A Discussion With John Ryan and Roham Zamanian

Pulmonary Hypertension Clinical Trials and COVID-19: A Discussion With John Ryan and Roham Zamanian

Novel composite clinical endpoints and risk scores used in clinical trials in pulmonary arterial hypertension.

This manuscript on endpoints incorporates the broad experience of members of Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It reviews our current understanding of endpoints used in phase 2 and 3 trials for pulmonary hypertension and discusses in detail the value of newer approaches. These include the roles of composite endpoints and how these can be developed and validated. The newer concept of risk analysis is also discussed, including how such risk scores might be utilised as endpoints in clinical trials.

Repurposing of medications for pulmonary arterial hypertension.

This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.

Clinical trial design in phase 2 and 3 trials for pulmonary hypertension.

This article on clinical trial design incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s (PVRI) Innovative Drug Development Initiative (IDDI) as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It is increasingly clear that the design of phase 2 and 3 trials in pulmonary hypertension will have to diversify from the traditional randomised double-blind design, given the anticipated need to trial novel therapeutic approaches in the immediate future. This article reviews a wide range of differing approaches and places these into context within the field of pulmonary hypertension.

Memos

Deborah Jo Levine, MDProfessor of Medicine, Pulmonary and Critical Care, Medical Director Lung Transplantation, Director of Pulmonary Hypertension, University of Texas Health Science Center San Antonio, San Antonio, TXIt is a great pleasure to introduce this issue's Guest Editors of Advances in Pulmonary Hypertension. Drs Mark Nicolls and Marc Humbert lead an elite group of experts in a timely compilation on drug development and clinical trials in pulmonary hypertension (PH).The opening article by Drs Martin Wilkins and Marlene Rabinovitch eloquently illustrates novel exciting targets for drug development. These targets are based on the understanding of the mechanisms driving pulmonary arterial hypertension (PAH). They discuss this “mechanism-driven” focused approach to developing new therapies. The authors detail many of these targets and where they are in the pathway of development.Dr Tsukasa Shimauchi and colleagues follow with an important discussion of the challenges and limitations in the design of preclinical PH trials. They emphasize the need for the rigorous assessment of study design from each part of the development, including researchers, peer reviewers, funding agencies, and academic institutions, among others.This is followed by the expert roundtable discussion focused on the topics of drug development, clinical trials, and the importance of publishing of negative trial results. Drs Marc Humbert, Mark Nicolls, Norman Stockbridge, and Roham Zamanian examine the importance and the opportunities that a negative clinical trial provides to all of us as a community.In our “Ask the Expert” column, Drs Christine Garnett and Norman Stock-bridge, both experts on trial regulation from the US Food and Drug Administration, discuss the challenges of finding new therapies with a novel mechanism of action, of improving the efficiency of clinical trials, and of developing endpoints that reflect benefits in patient symptoms and quality of life.We conclude this issue with a poignant discussion by Lena Bolivar. Lena, a patient who was diagnosed with PAH in 2011, takes us through her experience, starting with diagnosis of PAH, initiating therapy, going through a clinical trial, and ultimately receiving a heart-lung transplant. It is because of Lena and all of our patients that we as a community continue to work together to define new targets and develop improved therapies for the present and the future.Congratulations and thank you, Drs Nichols and Humbert, for an exceptional issue.Mark Nicolls, MD and Marc Humbert, MDProfessor of Medicine, Stanford University of Medicine, Stanford, CA and Professor of Medicine, Paris-Saclay University, Paris, FranceThis issue of Advances in Pulmonary Hypertension addresses the challenges and opportunities of drug development for pulmonary arterial hypertension (PAH) patients. As combinational vasodilator regimens continue to improve the lives of PAH patients, there is growing interest in also targeting novel pathways implicated in disease pathogenesis. To this end, Drs Martin Wilkins and Marlene Rabinovitch summarize exciting new disease pathways which show promise as therapeutic targets. Enthusiasm for these emerging therapies are linked to high-impact preclinical publications. In a review that highlights the importance of experimental rigor, Dr Tsukasa Shimauchi and colleagues make a compelling call for strong study design to optimize the likelihood of subsequent successful clinical trials. However, even trials that fail to show benefit for a drug can educate the PAH community. In a wide-ranging roundtable discussion, we moderate a discussion with Drs Roham Zamanian and Norman Stockbridge to address the merits of publishing negative trials, as well as the current obstacles for developing new drug treatments. Lena Bolivar, a PAH patient, then describes what it's like to participate in a clinical trial. Finally, this compendium of articles concludes with a perspective written by two US Food and Drug Administration leaders who discuss strategies for improving trial design, primary endpoints, disease biomarkers, and pediatric care.

Soluble Guanylate Cyclase Activators Increase cGMP Expression and Improve Vascular Function and Placental Ischemia‐Induced Hypertension

Preeclampsia (PE) is a pregnancy specific disorder associated with maternal hypertension and endothelial dysfunction caused by the release of anti‐angiogenic and pro‐inflammatory factors from the ischemic placenta. In addition, nitric oxide (NO), which typically binds to soluble guanylate cyclase (sGC), and synthesizes cGMP, to facilitate vasodilation, is depleted in PE and contributes to vascular dysfunction. A novel class of drug, sGC activators, which are in clinical trials for pulmonary hypertension and heart failure, have been shown to bind to the sGC molecule and increase cGMP activity independently of NO. However, the therapeutic potential of sGC activators during PE is not known. We tested the hypothesis that sGC activators attenuate blood pressure in a placental ischemic rat model of PE by increasing cGMP production and improving vascular function. Sprague‐Dawley rats underwent Sham or RUPP (Reduced Uterine Perfusion Pressure) surgery on gestational day (GD) 14, where silver clips were placed on the abdominal aorta and branches of the ovarian artery to induce placental ischemia. Animals were then placed on placebo (P) or sGC activator (sGC‐A, 16 ppm, BAY 60‐2770) ‐supplemented diets, ad libitum, from GD14–19. On GD19, blood pressure was measured via indwelling catheter and uterine arteries were harvested to determine endothelium‐dependent vasorelaxation and cGMP expression. To determine the effect of sGC activator treatment on vascular function, uterine arteries from placebo or sGC activator‐supplemented rats were mounted on a wire myograph and pre‐constricted, followed by endothelium‐dependent vasorelaxation. A subset of uterine arteries from these rats were also prepared to determine expression of cGMP. RUPP surgery significantly increased mean arterial blood pressure (Sham+P, n=20, 105±9 mmHg; RUPP+P, n=19, 126±13 mmHg; P<0.05), and this was attenuated by treatment with the sGC activator (RUPP+sGC‐A, n=11, 107±8 mmHg; P<0.05). RUPP surgery induced endothelial dysfunction in uterine arteries (% relaxation, Sham+P, n=6, 92±2 %; RUPP+P, n=5, 34±12%, P<0.05), which was restored in the sGC activator treated group (RUPP+sGC‐A, n=5, 103±2%, P<0.05). Finally, cGMP was reduced in uterine arteries of RUPP‐operated animals (Sham+P, n=3, 0.11±0.009 pmol/mg; RUPP+P, n=3, 0.033±0.009 pmol/mg, P<0.05); however, sGC activation significantly increased cGMP production in the treated group (RUPP+sGC‐A, n=3, 0.127±0.013 pmol/mg, P<0.05). The results of this study demonstrate that activating sGC can reduce blood pressure by restoring cGMP production and improving vascular function in the RUPP rat. In conclusion, these findings suggest there could be a therapeutic potential for treating PE with sGC activators.Support or Funding InformationThis research was supported by the American Heart Association (18POST33990293) and the National Institutes of Health (P01HL051971, P20GM104357).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Editorial introductions

Editorial introductions

Abstract W MP85: Prostacyclin Receptor Activation With MRE-269 Reduces Infarct Size and Improves Long-term Neurological Recovery Following Ischemic Stroke in Both Young and Aged Rats

Activation of the prostacyclin (PGI2) IP receptor is protective in brain ischemia. However, there is very limited information of the molecular mechanisms of protection and the feasibility to target this pathway in stroke. MRE-269, a highly selective PGI2/IP receptor agonist, has been recently discovered. This IP agonist has a long half-life in vivo and is currently in phase III clinical trials for pulmonary hypertension. We hypothesized that post-ischemic treatment with MRE-269 provides neuroprotection in a rat ischemic stroke model. Young male rats (3-4-month old) were subjected to middle cerebral artery occlusion (MCAO) for 90 min and treated intravenously with either vehicle (n=14) or MRE-269 (0.1, 0.25, 0.5, and 1 mg/kg, n=10-14/group) at the start of reperfusion. At 48 h post-MCAO, rats were sacrificed to determine infarct size, blood-brain barrier (BBB) damage (IgG extravasation), hemorrhagic transformation (brain hemoglobin levels), and matrix metalloproteinase (MMP)-9 activity. In a separate experiment, aged male rats (18-20-month old) underwent 90 min of MCAO and randomly selected to receive intravenously either vehicle (n=11) or MRE-269 (0.25 mg/kg, n=11) starting at 4.5 h post-MCAO. Additional doses were given every 12 h for the first 48 h, and then one injection daily for 7 days post-MCAO. The accelerating rotarod and the adhesive removal tests were conducted before and at 3, 7, 14 and 21 days after MCAO by an investigator blinded to treatment groups. Infarct volume was quantified by MRI at 48 h and 21 days post-MCAO. In young rats, MRE-269 dose-dependently reduced cortical infarct size. MRE-269-treated rats (0.25 mg/kg) had significantly reduced BBB damage and less hemorrhagic transformation. Compared with the vehicle group, MRE-269-treated animals showed a significant reduction in brain MMP-9 activity. In aged rats, MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions following MCAO. Quantitative MRI data showed that MRE-269 significantly reduced infarct volume compared with vehicle-treated rats. Our data suggest that targeting the PGI2/IP receptor with MRE-269 is a novel strategy to reduce neurovascular injury and promote long-term neurological recovery in ischemic stroke.

The first annual Drug Discovery and Development Symposium for Pulmonary Hypertension.

The first annual Drug Discovery and Development Symposium for Pulmonary Hypertension.

Geometry of the Randomized Evidence for Treatments of Pulmonary Hypertension

We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication. We searched MEDLINE, Embase and Cochrane Library Databases for published studies. We queried clinicaltrials.gov and WHO International Clinical Trials Registry platform for non-published studies. We found 75 randomized trials (41 published [n=4136 participants] and 34 registered unpublished [planned n=3470 participants]). Of the published randomized studies, all used placebo as the comparator arm except for two nonindustry-sponsored comparisons between phosphodiestearase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERA), and one study comparing two different regimens of treprostinil. Similarly, only five unpublished/ongoing trials used an active PH treatment as comparator (PDE-5 inhibitors versus ERA (n=3), different doses of sildenafil (n=1) and two formulations of epoprostenol (n=1). Of the 75 trials, 47 were sponsored by the manufacturer of the tested active product(s), and only two trials were sponsored by two companies comparing their products. The relative merits of different treatment options are not directly known, as there are very few head-to-head comparisons. A limited number of ongoing studies are using active FDA-approved PH-treatments for comparison. This lack of information can be overcome by carefully designing comparative effectiveness trials.

Clinical Trials in Pulmonary Hypertension: Time for a Consortium

Current and past clinical trials in pulmonary hypertension, while valuable, are limited by the absence of mechanistic aims, by dissatisfaction with endpoints and the inability to share data. Clinical studies in pulmonary hypertension might be enhanced by a consortium approach that utilizes the expertise of academic medicine, the treatment initiatives of the pharmaceutical industry and study design from funding agencies interested in biological mechanisms. A meeting of interested parties, the Pulmonary Hypertension Academic Research Consortium (PHARC), was held from 30 April to 1 May 2012 in Bethesda, Maryland. Members at the conference were from the USA Federal Drug Administration (FDA); pharmaceutical industry (Pfizer, Novartis, Bayer and Gilead); USA National Institutes of Health (NHLBI); the Pulmonary Vascular Research Institute (PVRI), a non-governmental organization (NGO); and research and clinical members of pulmonary hypertension programs of international scope. A recommendation to develop a clinical trials consortium was the product of the working group on academic standards in clinical trials. The working group concluded that clinical trials hold immense promise to move the field of pulmonary hypertension forward if the trials are designed by a consortium with input from multiple groups. This would result in study design, conduct and analysis determined by consortium members with a high degree of independent function. The components of a well-balanced consortium that give it scientific effectiveness are: (1) the consortium can work with multiple companies simultaneously; (2) sponsors with special interests, such as testing biological mechanisms, can add investigations to a study at lower cost than with present granting strategies; (3) data handling including archiving, analysis and future sharing would be improved; (4) ancillary studies supported by the collection and dissemination of tissues and fluids would generate a broader approach to discovery than is now possible; and (5) development of improved endpoints in consultation with regulatory agencies, industry and academia would be possible.

Future of Clinical Trials for Pulmonary Hypertension

> “It is better to lose the battle and win the war.” > > —Sun Tzu (circa 6th century BCE Chinese General and military strategist) In 1995, the first successful randomized controlled trial (RCT) for pulmonary arterial hypertension (PAH) led to the approval of the pulmonary vasodilator epoprostenol.1 Under the assumption that PAH was a disease of inappropriate pulmonary vasoconstriction, testing a drug that had vasodilator properties seemed reasonable. The 6-minute walk test was the primary end point in the trial because it was in keeping with the Food and Drug Administration precedent that an outcome assessment in a patient with cardiopulmonary disease needs to reflect how the patient feels, functions, or survives. Article see p 2985 There are now 7 vasodilator therapies for PAH, all approved because they improved exercise capacity for 3 to 4 months.2 Whether they affect long-term survival remains a valid question.3 Recently, a sobering report from a highly respected referral center in France noted that the current 3-year survival for patients with pulmonary hypertension managed with state-of-the-art multiple drug therapy was only 58%, marginally better than in 1980s when there were no treatments at all.4 In addition, it appears that these drugs do not protect patients from developing severe pulmonary vascular disease.5,6 Our knowledge of the pathobiology of PAH today is quite different from what it was 20 years ago. Scientific studies have demonstrated that cellular proliferation, inflammation, and thrombosis are the dominant underlying pathobiological processes and that chronic pulmonary vasoconstriction appears to play a relatively minor role.7 It is therefore understandable why the RCT by Kawut et al8 in this issue of Circulation chose to study the safety and efficacy of simvastatin and/or aspirin, therapies directed at normalizing endothelial cell function and platelet activation, as a treatment for …

Clinical Trials for Pulmonary Hypertension in the Developing World: Pulmonary Vascular Disease: The Global Perspective

More clinical trials in pulmonary hypertension (PH) are being conducted in developing countries now compared with the past. This is a welcome development, considering the rarity of the disease, with its limited treatment options and poor prognosis. Conducting clinical trials in the developing world potentially decreases the time and costs of drug development and provides access to new drugs to an underserved population. However, the range of PH presentations, standards of care, and socioeconomic environments among developing countries is different from that of developed countries. Eagerness to complete clinical trials universally should not compromise accepted ethical practices. Patients from developing countries may be particularly vulnerable because of illiteracy and poverty and may not truly understand the informed consent process and clinical trials. Investigators, ethics committees, and regulators must ensure that potential participants are not exploited. Drug trials should be done only in those communities in which the drug would be made accessible if proven effective. Studies have to be designed taking safety, accessibility, and generalizability into consideration. Selecting appropriate investigators and institutions, supporting them with proper training, and providing infrastructure and facilities would promote uniform standards of clinical research across the globe. Coordination and cooperation among regulatory bodies of different countries is an urgent necessity that would facilitate the globalization of clinical research. If done appropriately, the potential benefit for the worldwide population of patients with PH would be substantial.

Issues facing the conduct of clinical trials in pulmonary hypertension on a global scale

Issues facing the conduct of clinical trials in pulmonary hypertension on a global scale

NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension

The recent development of treatment modalities for patients with idiopathic pulmonary arterial hypertension has been based on the evaluation of many different markers such as functional capacity, addressed by NYHA classification, six-minute walk test (6MWT) and hemodynamic parameters. The aim of this study was to evaluate the correlation of N-terminal fragment (NT-proBNP) with other markers in IPAH and its potential for patient stratification. We studied 42 IPAH patients consecutively evaluated through right heart catheterization in the absence of any specific treatment for pulmonary hypertension. Blood samples, clinical evaluation and 6MWF distance were collected at baseline. The levels of NT-proBNP showed a high correlation with hemodynamic parameters, such as pulmonary vascular resistance (r=0.80, P<0.001). A significant difference was found among patients with different functional classes, addressed by NYHA classification (P< 0.02 for all groups comparison). The discriminant analysis reinforced the ability of NT-proBNP to stratify patients according to NYHA functional class. Compared to the other variables studied (hemodynamics and 6MWT), NT-proBNP had the lowest level of overlap in the stratification of IPAH patients. We conclude that NT-proBNP differs among the different functional classes and correlates with other measures of disease severity, although its role in predicting survival still needs to be addressed.