Research

Title: Features and outcomes of viral infections in sarcoidosis and other Interstitial Lung diseases (ILDs): A prospective study during a pandemic.

• PI: Ogugua Ndili Obi, MD, MPH, MSc (Epid)
• Sponsor: University of Pennsylvania, Investigator Initiated
• IRB Number: UMCIRB: 20-001705

Status: Data collection ongoing (2020 to 2023)

Study Description: Ongoing prospective multi-national project between East Carolina University (ECU), other national and international sites and University of Pennsylvania as lead site to define the outcomes of viral infections in patients with sarcoidosis or and other ILDs.

Study Background: Viral infections are associated with worse outcomes in patients with underlying cardiac or pulmonary disease. They are also worse in immunosuppressed or immunocompromised patients. In addition, even normal patients can have sustained reduction in lung function following viral infection, a sequela that may be worse in patients with underlying parenchymal lung disease.

Study description: The study is designed to gather information about the course of infection in patients with sarcoidosis and ILD, and to determine whether disease subtypes or medication regimens are a risk for severe infections and poor outcomes.

Study purpose: The purpose of the study is to assess key clinical and treatment features which are biologically likely to have an impact on both the risk for infection and risk for poor outcome among patients with sarcoidosis or other ILDs. The identification of modifiable risk factors would revolutionize the care of patients, across place and time; the modification of risk factors would be of especially high impact during times of severe viral agents.

The primary objective is to determine if patients with sarcoidosis or other ILDs are at higher-than-average risk for poor outcome during pandemic COVID-19 infection, or from other respiratory or opportunistic infections.

The secondary objective is to determine which clinical and treatment features may predispose patients to viral infections, and, if they become infected, to degree of severity and outcomes from COVID-19.

Status: The study involves review of medical records and is ongoing.

Title: Sarcoidosis Around the World: A multi-national study conducted to provide details regarding the clinical presentation and therapy of sarcoidosis around the world

• PI: Ogugua Ndili Obi, MD, MPH, MSc (Epid)
• Sponsor: University of Cincinnati, Investigator Initiated
• IRB Number: UMCIRB: 20-000339

Status: Data collection completed. Data analysis and manuscript preparation ongoing

Study description: Multi-national project between East Carolina University, other national and international sites and University of Cincinnati OH as lead site to provide details regarding the clinical presentation and therapy of sarcoidosis around the world.

The purpose of this study is to provide details regarding the clinical presentation and therapy of sarcoidosis in various parts of the world. This will be an update of the information provided by a similar symposium led by Dr. Izumi at an international meeting in 1992. ¹ While Dr. Izumi’s report has been useful over the years, it used an outdated version of organ involvement. It also did not include information about therapy. We will be using the revised criteria for organ involvement in sarcoidosis.

Each site will recruit 100 patients with sarcoidosis from the clinic. For each patient, information on age, race, sex, organ involvement, and current and past therapy will be recorded into a central database on REDCap, a secure National Institutes of Health developed database. No identifying information on the patients will be recorded.

Each country will be allotted a five-minute time period to discuss their findings at a symposium of the World Association of Sarcoidosis and Other Granulomatous disease (WASOG) meeting in Miami. Data analysis including comparisons between sites will be presented.

Reference List: Izumi T. Symposium: Population differences in clinical features and prognosis of sarcoidosis throughout the world. Sarcoidosis 1992;9:S105–S118.

Title: East Carolina University Sarcoidosis Registry (ECUSaR): An ongoing longitudinal registry and database of all patients seen in the East Carolina University (ECU) pulmonary clinic with pulmonary and extra pulmonary sarcoidosis.

• Registry Design and maintenance: Ogugua Ndili Obi, MD, MPH, MSc (Epid)
• Sponsor: East Carolina University, Investigator initiated
• IRB Number: UMCIRB 06-0312

Status: Actively enrolling

Purpose of Registry: This is an ongoing longitudinal registry of patients with sarcoidosis seen in the ECU pulmonary and sarcoidosis clinic. The purpose of the registry is to gather demographic, clinical, radiographic and other information that will allow us to learn more about sarcoidosis, available therapies and their effect on quality of life. Data collected will be evaluated for common familial and environmental factors that may be linked to the disease, so that better therapies may be developed for treating or even curing the disease. The patient database will enable us to collect information on each patient who presents with a diagnosis of sarcoidosis at the ECU pulmonary clinic. The database will also serve to identify and recruit sarcoidosis patients for future clinical studies and patient focus groups.

Impact of registry: The ECU Sarcoidosis registry will enable us to learn more about sarcoidosis in Eastern North Carolina. North Carolina has one of highest numbers of patients with sarcoidosis in the nation and ranks fourth in the nation with respect to mortality from sarcoidosis¹. Eastern North Carolina has perhaps the highest prevalence of sarcoidosis in the state; and a focus on this disease serves the community well.

References:

1. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999-2016. Respir Med. Mar 2019;149:30-35. doi:10.1016/j.rmed.2018.11.010

Title: Registry for Advanced Sarcoidosis (ReAS)

• PI: Ogugua Obi, MD, MPH, MSc (Epid)
• Sub I: Veeranna Maddipati, MD
• Funded by: University of Cincinnati and Mallinckrodt Pharmaceuticals

Status: Closed for enrollment

Background and significance
The clinical outcome of sarcoidosis is variable. While over half of patients have resolution of their disease within two years of diagnosis, at least a quarter of patients will have chronic disease requiring therapy for more than five years. 2;3 Certain manifestations of sarcoidosis are associated with chronic disease. These include pulmonary fibrosis, neurologic and cardiac disease, lupus pernio, and those requiring treatment. 4;5 Recent genetic markers have been associated with advanced sarcoidosis. 6;7 Most of these studies are based on evaluating patients at single time points. In addition, they lack control sarcoidosis patients who have been matched for race, age, and gender. The use of potent agents such as infliximab have proved useful in treating advanced sarcoidosis. 8;9 This treatment regimen is associated with significant cost and requires careful monitoring. 10 Other potent agents have also been used for advanced sarcoidosis, including adalimumab, rituximab, cyclophosphamide, and Acthar. 11-13 This registry will determine the risk factors for chronic disease and natural course of these manifestations.

Title: Registry of Sarcoidosis Associated Pulmonary Hypertension (ReSAPH)

• PI: Veeranna Maddipati, MD
• Sub I: Ogugua Obi, MD, MPH, MSc (Epid)
• Funded by: University of Cincinnati – Investigator Initiated

Status: Closed for enrollment

In sarcoidosis, respiratory failure is the major cause of death. Reduced lung volume is a predictor for the at risk patient. Among patients with low vital capacity, the presence of pulmonary hypertension and elevated right atrial pressure are the best predictors of early mortality.

There have been several single case reports of pulmonary hypertension, including therapy for pulmonary sarcoidosis. There have been a limited number of prospective studies of any group of sarcoidosis patients, because of the need for catheterization to confirm the diagnosis.

On the other hand, pulmonary hypertension may be relatively common in sarcoidosis patients. In a prospective study of pulmonary sarcoidosis, over 70% had significant changes in their right ventricle ejection fraction with exercise, suggesting pulmonary hypertension. The cause of pulmonary hypertension in sarcoidosis is multi-factorial, including diastolic dysfunction, vessel compression by adenopathy, lung destruction by fibrosis, and granulomatous vasculitis.

With the advent of new vasodilator drugs effective for pulmonary hypertension, interest has risen in treating pulmonary hypertension due to secondary causes, including sarcoidosis. To date, studies have usually been limited to one or two centers with minimal long term follow up for patients begun on therapy.

We have joined a multi-center registry of sarcoidosis associated pulmonary hypertension (SAPH). With this registry, we will characterize the demographics, clinical course, hemodynamics, pulmonary physiology, and disease management of sarcoidosis associated pulmonary hypertension on the United States. We will also compare these features to non-US sites.

Title: A Longitudinal Prospective Observational Study of the Characteristics, Treatment Patterns and Health Outcomes of Individuals with Severe Asthma in the United States (CHRONICLE)

• PI: Bryan Dunn, MD
• Funded by: AstraZeneca.

Status: Open for enrollment

Asthma is a syndrome characterized by airway inflammation, reversible airflow obstruction,and airway hyper-responsiveness. The majority of asthma patients have mild to moderate disease that can be controlled by low- to medium-dose inhaled corticosteroids (ICS), with or without additional controllers including long-acting bronchodilators, leukotriene modifiers or have severe asthma characterized by a requirement for high-dose ICS plus a second controller (most commonly long-acting beta agonists [LABA]) to prevent it from becoming ‘uncontrolled’ or that remains ‘uncontrolled’ despite this therapy. For those whose severe asthma remains uncontrolled, treatment options currently include maintenance use of systemic corticosteroids, treatment with monoclonal antibody therapies that block Type 2 immune responses, or treatment with bronchial thermoplasty. To continue to drive improvements in the understanding and management of severe asthma, there is a need for longitudinal data describing the real-world clinical profile of this patient cohort, their current treatment patterns and associated health outcomes. Real-world data from an unselected population may also enable a better understanding of severe asthma phenotypes and provide insights into more personalized approaches to the clinical management of severe asthma.

The current non-interventional study will collect information on patient demographics, asthma history, relevant comorbidities, asthma treatment patterns, and health outcomes over multiple years from a large, geographically diverse cohort of US patients with severe asthma. The study will include patients with severe asthma who have either experienced frequent exacerbations despite high-dose ICS therapy and additional controllers, require chronic systemic corticosteroids to control asthma symptoms, or are receiving monoclonal antibody treatment for severe asthma.

The primary objective of this study is to describe patient characteristics, treatment patterns, and health outcomes among US adults with severe asthma who are not controlled on high dose ICS with additional controllers and/or require systemic corticosteroid or monoclonal antibody therapy.

Title: Randomized, Double-blind, Placebo-controlled Phase 2 Study with Open-label Extension to Assess the Efficacy and Safety of Namilumab in Subjects with Chronic Pulmonary Sarcoidosis.

• PI:  Ogugua Ndili Obi, MD, MPH, MSc (Epid)
• Sub I: Anagha Malur PhD, Binita Vadhar, MD
  
• Sponsor Kinevant Sciences GmbH

Status: Closed for enrollment

Sarcoidosis is a multi-organ autoimmune disease characterized by non-necrotizing granulomas believed to be formed from an exaggerated immune response to unidentified antigens. Granulomas are tight clusters of monocytes/macrophages and multinucleated giant cells (MGCs) interspersed with CD4+ T cells. Nearly all (~90%) subjects exhibit pulmonary involvement.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a proinflammatory cytokine and myeloid cell growth factor, is thought to play a key role in the granulomatous response by stimulating the fusion of macrophages into MGCs, activating the mobilization of macrophage precursors into tissues, and supporting the crosstalk between CD4+ T cells and myeloid cells.

Successful late-phase clinical trials of anti-GM-CSFmonoclonal antibodies in rheumatoid arthritis, giant cell arteritis, and severe coronavirus disease 2019 (COVID-19) have provided strong evidence for the pathogenic role of GM-CSF in aberrant immune responses. Over the past 30 years, a multitude of human tissue and mouse model studies have shown that GM-CSF plays a key role in the formation of granulomas, including sarcoid granulomas. Namilumab, a monoclonal antibody that neutralizes GM-CSF, has the potential to improve outcomes in CPS by downregulating the granulomatous response that drives the disease.

Title: Randomized, Double-blind, Placebo-controlled Parallel-Group Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of SAR440340/REGN3500/Itepekimab (Anti-IL-33 Mab) in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease (COPD)

• PI:  Bryan Dunn, MD
• Sub I: Hassan Al-Khalisy, MD
• Sponsor SANOFI

Status: Closed for enrollment

EFC16750 is a multinational, randomized, double-blind, placebo-controlled, parallel-group (3 groups), 52-week, Phase 3 study to assess the efficacy, safety, and tolerability of 2 dosing regimens of itepekimab in patients with moderate-to-severe COPD who are former smokers and are on an established double (ICS + LABA or LAMA + LABA) or triple controller therapy (LAMA + LABA + ICS). Study treatments are itepekimab 300 mg every 2 weeks (Q2W), itepekimab 300 mg every 4 weeks (Q4W), or matching placebo administered subcutaneously (SC) during the 52-week treatment period.

Title: A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy, safety, and tolerability of dexpramipexole administered orally for 52 weeks in participants with severe eosinophilic asthma (EXHALE-2)  

PI:  Bryan Dunn MD
Sub I:  Zia Rehman MD, Anagha Malur PhD
Sponsor: Areteia Therapeutics
IRB: 24-000662

Status: Open for enrollment

Study Objectives: To demonstrate the efficacy of dexpramipexole in reducing severe asthma exacerbations.

Title: A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy, safety, and tolerability of dexpramipexole administered orally for 24 weeks in participants with eosinophilic asthma (EXHALE-4)

PI:  Bryan Dunn MD
Sub I:  Zia Rehman MD, Anagha Malur PhD
Sponsor: Areteia Therapeutics
IRB: 24-000663

Status: Open for enrollment

Study Objectives: To demonstrate the efficacy of dexpramipexole on pulmonary function.

Title: A double-blinded extension study to evaluate the long-term safety and tolerability of itepekimab in patients with chronic obstructive pulmonary disease (COPD) who participated in either EFC16750 or EFC16819 clinical studies: LTS18133

PI:  Bryan Dunn MD
Sub I:  Hassan Al-Khalisy MD
Sponsor: Sanofi
IRB: 24-000659

Status: Open – Rollover of subjects from AERIFY 1

Study Objectives:  Evaluate the long-term safety and tolerability of itepekimab in participants with moderate-to-severe COPD who participated in previous itepekimab COPD clinical studies (EFC16750, EFC16819)

Title: A Phase III, Multcentre, Randomised, Double-blind,Chronic-dosing,Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Tozorakimab in Participants with Symptomatic Chronic Obstructive Pulmonary Disease(COPD) with a History of COPD Exacerbations(MIRANDA)

PI:  Kush Gupta MD
Sub I:  Bryan Dunn MD, Anagha Malur PhD
Sponsor: AstraZeneca
IRB: 24-000666

Status: Open for enrollment

Study Objectives:  The purpose of this Phase III study is to evaluate the efficacy and safety of tozorakimab 300 mg administered subcutaneously (SC) every 2 weeks (Q2W) in adult participants with symptomatic Chronic Obstructive Pulmonary Disease (COPD) with a history of ≥ 2 moderateor ≥ 1 severe exacerbations of COPD in the 12 months prior to enrolment.

Title: A randomized, Double-blind, Parallel Group, Mulit-center, Phase III Study to Assess the Efficacy of Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhaler Relative to Glycopyrronium and Formoterol Fumarate MDI on Cardiopulmonary Outcomes in Chronic Obstructive Pulmonary Disease (THARROS)

PI:  Kush Gupta MD
Sub I:  Bryan Dunn MD, Anagha Malur PhD
Sponsor: AstraZeneca
IRB: 24-000669

Status: Open for enrollment

Study Objectives:  This study seeks to confirm previous findings and aims to demonstrate that triple ICS/LAMA/LABA therapy with BGF MDI 320/14.4/9.6 μg (Breztri/Trixeo) will improve cardiopulmonary outcomes relative to LAMA/LABA therapy with GFF MDI 14.4/9.6 μg(Bevespi) in a population with COPD and high cardiopulmonary risk.

Title: A Randomized, Double-blind, Placebo-controlled, Multinational, Phase 3 Study of the Efficacy and Safety of Inhaled Treprostinil in Subjects with Progressive Pulmonary Fibrosis (TETON-PPF)

PI: Shehabaldin Alqalyoobi MD
Sub I: Veeranna Maddipati MD, Anagha Malur PhD
Sponsor: United Therapeutics Corp.
IRB: 23-002450

Status: Open for enrollment

Study: To evaluate the superiority of inhaled treprostinil against placebo for the change in absolute FVC from baseline to Week 52 in subjects with PPF.

Title: Chart Review Data Collection for Post Market Clinical Follow-up for Pleural and Pneumothorax Sets

PI: Jennifer Stahl MD
Sub I: Anagha Malur PhD
Sponsor: Premier INC
IRB: 24-000072

Status: Data entry

Study: The Pleural and Pneumothorax Sets of Cook Medical have received approval by the Food and Drug Administration (FDA) in the United States and have been widely used in clinical practice. It is important to understand the safety and effectiveness outcomes of these devices in real clinical setting. Premier is conducting a retrospective multi-center chart-review study in collaboration with Cook Medical to better understand the important safety and performance outcomes associated with the use of these devices. The findings will also be used to support European market approval.

Current Grant Funding

Research Curriculum – Fellowship Program

Components

The research curriculum has several components:

1. Research Projects
2. Research Rotations
3. Presentations
4. Journal Clubs
5. Lecture Series
6. Publications
7. National Meetings

Overview

In addition to clinical training, fellows will participate in the division research program and complete a minimum of 6 blocks of research time. There are a wide variety of potential projects ranging from basic science in the Lung Cell Biology Laboratory to clinical studies to epidemiological studies. During the first year the fellow will choose a mentor and begin working on a research program. In addition to longitudinal big picture projects there are a number of different smaller projects that can be accomplished during the time the fellow is on the clinical services.

As a minimum, each fellow is expected to present their work in progress at the monthly research meeting and to prepare and present at least one abstract at a national meeting as well as yearly presentations at the Internal Medicine Research Day. The fellow will be expected to make a presentation at the end of each research block.