Symptoms and General Pathology

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Telangiectasis

Arteriovenous Malformations

Telangiectasia, Hereditary Hemorrhagic

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Gastrointestinal Diseases

Vascular Malformations

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Neoplasms, Vascular Tissue

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Hereditary Hemorrhagic Telangiectasia

Anti-Infective Agents

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All Drugs and Chemicals

Thalidomide

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Angiogenesis Inhibitors

Growth Inhibitors

Atul Kumar, MD

James Gossage, MD

The purpose of this study is to determine whether Thalidomide is effective in the treatment of arteriovenous malformations in the gastrointestinal tract.

Arteriovenous malformations (AVM's) are the commonest vascular abnormalities of the gut. AVM's or Angiodysplasia may be acquired or inherited as in a hereditary hemorrhagic telangiectasia (HHT). Repeated episodes of gastrointestinal bleeding (GIB), especially in the elderly have been attributed to angiodysplasia. Clinically significant GIB may be also seen in up to 40% of HHT patients, usually in the fourth and fifth decades of life. GIB may manifest both as acute major hemorrhage, slow intermittent blood loss or a combination of these findings and patients may be symptomless, present with acute bleeding or iron deficiency anemia. Recurrent hemorrhage and persistent iron-deficiency anemia is common despite supplemental iron therapy and patients require repeated transfusions. Amongst patients with preexisting co-morbidities, repeated bleeding may lead to significant morbidity and mortality. Furthermore, re-bleeding among these patients consumes a disproportionate share of healthcare resources devoted to multiple admissions, repeated endoscopies and blood transfusions. There are no effective treatment options available currently. The purpose of this study is to determine whether Thalidomide is effective in the treatment of arteriovenous malformations in the gastrointestinal tract.

Thalidomide Reduces Arteriovenous Malformation Related Gastrointestinal Bleeding

Augusta University

University of Massachusetts, Worcester

Northport Veterans Affairs Medical Center

Atul Kumar

Respiratory Tract (Lung and Bronchial) Diseases

Dyspnea

Respiratory Aspiration

Fistula

Arteriovenous Fistula

Vascular Fistula

Pathological Conditions, Anatomical

Pulmonary Arteriovenous Malformation

A group of up to 30 healthy controls will be recruited to have a cardiopulmonary exercise test and a blood test.

A group of up to 30 pulmonary AVM patients will be recruited to have a cardiopulmonary exercise test, and a blood test.

Most patients with pulmonary AVMs have underlying hereditary hemorrhagic telangiectasia (HHT). If there is a difference between pulmonary AVM and control groups that does not correct following embolization of pulmonary AVMs, a group of up to 30 people with HHT but no evidence of pulmonary AVMs will be selected to have a cardiopulmonary exercise test and a blood test.

On Day 1, subjects will have the test in the Exercise Suite of Hammersmith Hospital, London, UK. They will have painless skin probes placed on their fingers, chest, and legs to monitor heart rate, ECG, blood oxygen levels, and oxygen delivery during the test. Subjects will also be shown how to breathe through a mouthpiece with a nose clip on, and how to indicate on a sliding device whether they feel breathless. They will then start cycling against a very low resistance at a steady speed. As long as they feel comfortable, there will be a gradual increase in work load until they feel they cannot keep going at the same speed. They can also stop sooner for any reason. Afterwards, while they are "cooling down" (within the hour on Day 1), they will fill in a short questionnaire describing how they feel.

Cardiopulmonary exercise test

On same day (Day 1), the subject will have 20-30mls of blood (that is, 4-6 teaspoonful) taken for analysis.

Blood test

Claire L Shovlin

Pulmonary arteriovenous malformations (PAVMs) are a rare vascular condition affecting the lungs. PAVMs lead to low blood oxygen levels, yet are very well tolerated by patients. This study will examine the exercise capacity of PAVM patients using formal cardiopulmonary exercise tests performed on a stationary bicycle.

It is well known that the lung is the site at which oxygen enters the blood stream, diffusing from the alveolar air sacs into the pulmonary capillaries. This newly oxygenated blood is carried to the heart in the pulmonary veins, then passes into the systemic circulation to provide oxygen to the tissues.

Patients with pulmonary arteriovenous malformations (PAVMs) have abnormal vascular connections between pulmonary arteries and pulmonary veins in the lung. Blood flowing through PAVMs therefore bypasses the oxygenation sites in the pulmonary capillaries. Low blood oxygen levels (hypoxemia) is frequent in PAVM patients but breathlessness (dyspnea) is not. The investigators have shown that dyspnea was not a common presenting complaint in a large UK series, and that there is little correlation between severity of dyspnea in PAVM patients, and blood oxygen levels.

In this study the investigators will address the question "Why are hypoxemic PAVM patients not more dyspneic?"

The investigators will address this by first performing standardised cardiopulmonary exercise testing, as used in the clinic, on age and sex matched patients with PAVMs and healthy controls. Physiological parameters will be compared, to test the null hypothesis that the impact of exercise on PAVM patients' cardiopulmonary systems does not differ to normal controls.

If the expected differences are confirmed, the investigators will examine if there is any difference to normals by re-examining the exercise tolerance of the PAVM cohort after they have had their PAVMs treated by embolization.

Most patients with PAVMs have an underlying hereditary vascular disorder, hereditary haemorrhagic telangiectasia. Assuming the expected differences between PAVM patients and controls are confirmed, the investigators will therefore also examine which pattern HHT patients without PAVMs display. Finally, cellular and molecular methods will be used to dissect mechanistic pathways.

Cardiopulmonary Exercise Testing to Evaluate Pulmonary AVMs

Hypoxemia, Dyspnea, and Exercise Tolerance in Patients With Pulmonary Arteriovenous Malformations

Of the many measurements and derived indices that can be measured during cardiopulmonary exercise testing, the peak consumption of oxygen (VO2 max) is perhaps the best indicator of integrated cardiorespiratory capacity. The principle research question will therefore test the null hypothesis that "The VO2 max does not differ between PAVM patients and age matched healthy controls."

We will also test in univariate and multiple regression analyses whether breathing reserve differs between PAVM patients and controls.

We will also test in univariate and multiple regression analyses whether ventilatory efficiency differs between PAVM patients and controls.

Imperial College London

Ear, Nose, and Throat Diseases

Nervous System Diseases

Epistaxis

Intracranial Arteriovenous Malformations

Nose Diseases

Respiratory Tract Diseases

Otorhinolaryngologic Diseases

Signs and Symptoms, Respiratory

Cerebrovascular Disorders

Brain Diseases

Central Nervous System Diseases

Central Nervous System Vascular Malformations

Nervous System Malformations

Intracranial Arterial Diseases

Intracranial Arteriovenous Malformation

Those diagnosed with HHT based on the Curacao diagnostic criteria or genetic testing

Melissa A Dickey, MSN

Nolie Krock, MSc

Sayeh Jafari

Victoria Rueda

Justin McWilliams, MD

Lucas Cusumano, MD

Lindsay Park, MS

Steven Hetts, MD

Miles Conrad, MD

Johan Allingmon

Peter Hountras, MD

Katharine Henderson

Jeffrey Pollak, MD

Melissa James, RN

Madeleine Macy, BS

Carolena Othman, MS

Josanna Rodriguez-Lopez, MD

Greg Schwichtenberg

Sue Ann Donlinger

Vivek Iyer, MD

Melissa Beasley, AA

Kristine Kempf

Murali Chakinala, MD

Kelsey Weddig, RN, BSN

Charles Murphy, MD

Karen Smith, RN

Kristi Kirkland

Raj Kasthuri, MBBS

Lori Russell, RN

Eleanor Lottsfeldt, BA

Mark Chesnutt, MD

Claire Kaufman, MD

Ala Streater, BS

Isaac Elysee, MS

Theodore Drivas, MD

Mhd Wisam Alnablsi, MD

John Battaile, MD

An Lu, MD

Cassidy Sion, RN, BSN

Kevin Whitehead, MD

The Comprehensive HHT Outcomes Registry of the United States (CHORUS) is an observational registry of patients diagnosed with Hereditary Hemorrhagic Telangiectasia (HHT). The purpose of this study is to better understand HHT, the symptoms and complications it causes, and the impact the disease has on people's lives. The investigators will collect long-term information about the participant, allowing us to understand how the disease changes over time, and what factors can influence those changes. Ultimately, this should help improve treatments for the disease.

Another important goal of the study is to provide a way to contact people to participate in future clinical trials and other research. The registry will be a centralized resource for recruitment for clinical trials. People in the registry will not be obligated to join any of these additional studies, but if interested, can agree to be contacted if they may be eligible for a study.

Participants will:

* Be asked to provide permission to collect information from their medical records, including things like demographic information, diagnosis information, family history, test results, treatment information, symptoms, complications, lifestyle and other relevant medical information.
* Be asked study-related questions by phone or at a clinic visit.
* Be asked study-related questions every year after enrollment for up to 10 years or until the study ends. A member of the study team will communicate with participants by phone or at clinic visits to collect information regarding any changes to their health over the previous year/s including new test results, treatment information, symptoms, and complications from HHT.

The Comprehensive HHT Outcomes Registry of the United States (CHORUS) is a research initiative led by the HHT Foundation International, Inc. ("Cure HHT"). The study focuses on Hereditary Hemorrhagic Telangiectasia (HHT), a rare genetic disorder characterized by the development of abnormal blood vessels in various organs of the body, including the brain, spine, lungs, liver, GI tract, skin, nasal mucosa, and oral cavity. The prevalence of HHT is estimated to be 1 in 5000, affecting children and adults. These abnormal blood vessels can lead to acute and chronic bleeding, stroke, heart failure, and death. Treatments are currently predominately limited to managing complications, while approximately 90% of adults have ongoing symptoms, despite the best surgical and medical therapies. With recent drug developments related to angiogenesis, there is hope for effective novel therapies.

A natural history registry for HHT has significant implications for improving the understanding and management of this rare genetic disorder. The purpose of this study is to better understand HHT, the symptoms and complications it causes ("outcomes"), and to understand how the disease impacts people's lives. The investigators hypothesize that a natural history registry for HHT will improve our understanding of the disease, lead to better management of patients, and ultimately, contribute to developing novel therapies to treat this disease.

The investigators will collaborate with multiple HHT Centers of Excellence across the U.S. to establish a comprehensive registry of HHT patients. The study aims to enroll approximately 10,000 HHT patients over a 10-year period. Longitudinal data will be collected both retrospectively and prospectively, with a focus on increasing the understanding of this rare disease, accelerating the development of new diagnostic and treatment options, and working collaboratively with clinicians who care for individuals with HHT to identify and address gaps in the system of care, especially those from underserved populations.

The study aims to serve as a centralized resource for future clinical trials and research in HHT. Data security and confidentiality are prioritized, and participants have the option to withdraw from the study at any time. The study is funded by the U.S. Department of Health Resources and Service Administration (HRSA) through a grant awarded to Cure HHT.

Comprehensive HHT Outcomes Registry of the United States (CHORUS)

CHORUS: Comprehensive HHT (Hereditary Hemorrhagic Telangiectasia) Outcomes Registry of the United States

Utilizing the "HHT Baseline Assessment Scale," this measure focuses on recruiting a diverse cohort of HHT patients across North America. Comprehensive baseline clinical, demographic, and lifestyle data will be collected and entered into CHORUS. The data, aggregated as mean change from baseline using the scale, will serve as a foundational resource for future clinical translational studies, addressing the urgent need for natural history data in HHT.

Utilizing the "HHT Clinical Outcomes Scale," this measure aims to prospectively and longitudinally assess the clinical outcomes of HHT patients. Determinants such as demographic factors, environmental influences, lifestyle choices, comorbidities, medications, HHT-genotype, and organ vascular malformations (VMs) will be measured. The data, aggregated as mean change from baseline using the scale, will enhance understanding and accelerate the development of new diagnostic and treatment options for HHT.

Description: Utilizing the "HHT Clinical Outcomes Scale," this measure aims to prospectively and longitudinally assess severe complications in HHT. This measure focuses on measuring rates of severe complications in HHT. Determinants of these complications will be characterized, and the data will be aggregated as mean change from baseline using the index, providing valuable insights into the disease progression.

Description: Utilizing the "Epistaxis Severity Scale," this measure aims to characterize epistaxis in adults with HHT, considering aspects such as frequency, duration, intensity, and variability. Outcome determinants related to epistaxis will be elucidated, and the data will be aggregated as mean change from baseline using the scale to inform comprehensive patient care.

Utilizing the "Organ VMs Assessment Tool," this measure involves the prospective measurement of the development and growth of organ vascular malformations (VMs) in HHT patients over time. Outcome determinants related to these VMs will be investigated, and the data will be aggregated as mean change from baseline using the tool, contributing to a better understanding of disease progression.

Utilizing the "HHT Treatment Outcomes Scale," this measure involves the prospective measurement of treatment outcomes for HHT and its clinical manifestations. Treatment outcome determinants will be characterized, and the data will be aggregated as mean change from baseline using the scale to guide effective management strategies for patients with HHT.

The Cleveland Clinic

Mayo Clinic

Massachusetts General Hospital

Columbia University

Oregon Health and Science University

University of California, Los Angeles

University of California, San Francisco

University of Colorado, Denver

University of North Carolina, Chapel Hill

University of Pennsylvania

University of Texas

University of Utah

Washington University School of Medicine

Yale University

Health Resources and Services Administration (HRSA)

Children's Hospital of Philadelphia

Cure HHT

Immune System Diseases

Asthma

30 patients with pulmonary AVMs and no airflow obstruction will undergo cardiopulmonary exercise testing

30 patients with pulmonary AVMs and airflow obstruction will undergo cardiopulmonary exercise testing

Subjects will have the test in the Exercise Suite of Hammersmith Hospital, London, UK. They will have painless skin probes placed on their fingers, chest, and legs to monitor heart rate, ECG, blood oxygen levels, and oxygen delivery during the test. Subjects will also be shown how to breathe through a mouthpiece with a nose clip on, and how to indicate on a sliding device whether they feel breathless. They will then start cycling against a very low resistance at a steady speed. As long as they feel comfortable, there will be a gradual increase in work load until they feel they cannot keep going at the same speed. They can also stop sooner for any reason. Afterwards, while they are "cooling down", they will fill in a short questionnaire describing how they feel. 20-30mls of blood will be taken for analysis.

Claire L Shovlin, PhD FRCP

Luke Howard, DPhil FRCP

Pulmonary arteriovenous malformations (PAVMs) are a rare vascular condition affecting the lungs. PAVMs lead to low blood oxygen levels, yet are very well tolerated by patients. This study will examine the exercise capacity of PAVM patients using formal cardiopulmonary exercise tests performed on a stationary bicycle, and whether this is affected by the presence of concurrent airflow obstruction, such as due to asthma.

It is well known that the lung is the site at which oxygen enters the blood stream, diffusing from the alveolar air sacs into the pulmonary capillaries. This newly oxygenated blood is carried to the heart in the pulmonary veins, then passes into the systemic circulation to provide oxygen to the tissues.

Patients with pulmonary arteriovenous malformations (PAVMs) have abnormal vascular connections between pulmonary arteries and pulmonary veins in the lung. Blood flowing through PAVMs therefore bypasses the oxygenation sites in the pulmonary capillaries. Low blood oxygen levels (hypoxemia) is frequent in PAVM patients but breathlessness (dyspnea) is not. The investigators have shown that dyspnea was not a common presenting complaint in a large UK series, and that there is little correlation between severity of dyspnea in PAVM patients, and blood oxygen levels.

In this study the investigators will address the question "Do PAVM patients have lower exercise tolerance if they have concurrent airflow obstruction?" The primary outcome measure will be the total body oxygen consumption in mls/min/kg, at peak exercise (the V\[dot\]O2 peak (also known as "VO2 max")).

The investigators will address this by first performing standardised cardiopulmonary exercise testing, as used in the clinic and our previous study (11/H0803/9), on age and sex matched patients with PAVMs. 30 will be recruited with airflow obstruction, and 30 without airflow obstruction. Physiological parameters will be compared, to test the null hypothesis that the impact of exercise on PAVM patients' cardiopulmonary systems does not differ according to the presence or absence of airflow obstruction. Cellular and molecular methods will be used to dissect mechanistic pathways.

Cardiopulmonary Exercise Testing to Evaluate Pulmonary AVMs With and Without Airflow Obstruction

Hypoxemia, Dyspnea, and Exercise Tolerance in Patients With Pulmonary Arteriovenous Malformations , With and Without Airflow Obstruction

Of the many measurements and derived indices that can be measured during cardiopulmonary exercise testing, the peak consumption of oxygen (VO2 max) is perhaps the best indicator of integrated cardiorespiratory capacity. The principle research question will therefore test the null hypothesis that "The VO2 max does not differ between PAVM patients with and without airflow obstruction."

We will also test in univariate and multiple regression analyses whether breathing reserve differs between PAVM patients with and without airflow obstruction.

We will also test in univariate and multiple regression analyses whether ventilatory efficiency differs between PAVM patients with and without airflow obstruction.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Thalidomide Reduces Arteriovenous Malformation Related Gastrointestinal Bleeding	NCT00389935	Arteriovenous M... Hereditary Hemo... Hematochezia Melena	Thalidomide	18 Years -	Northport Veterans Affairs Medical Center
Cardiopulmonary Exercise Testing to Evaluate Pulmonary AVMs	NCT02436213	Pulmonary Arter... Hereditary Hemo...	Cardiopulmonary... Blood test	18 Years -	Imperial College London
Comprehensive HHT Outcomes Registry of the United States (CHORUS)	NCT06259292	Hereditary Hemo... Arteriovenous M... Telangiectasia Epistaxis GastroIntestina... Cerebral Arteri... Vascular Malfor...		-	Cure HHT
Cardiopulmonary Exercise Testing to Evaluate Pulmonary AVMs With and Without Airflow Obstruction	NCT02458703	Pulmonary Arter... Hereditary Hemo... Asthma COPD	Cardiopulmonary...	16 Years - 80 Years	Imperial College London
Cardiopulmonary Exercise Testing to Evaluate Pulmonary AVMs	NCT02436213	Pulmonary Arter... Hereditary Hemo...	Cardiopulmonary... Blood test	18 Years -	Imperial College London
Comprehensive HHT Outcomes Registry of the United States (CHORUS)	NCT06259292	Hereditary Hemo... Arteriovenous M... Telangiectasia Epistaxis GastroIntestina... Cerebral Arteri... Vascular Malfor...		-	Cure HHT
Cardiopulmonary Exercise Testing to Evaluate Pulmonary AVMs With and Without Airflow Obstruction	NCT02458703	Pulmonary Arter... Hereditary Hemo... Asthma COPD	Cardiopulmonary...	16 Years - 80 Years	Imperial College London
Thalidomide Reduces Arteriovenous Malformation Related Gastrointestinal Bleeding	NCT00389935	Arteriovenous M... Hereditary Hemo... Hematochezia Melena	Thalidomide	18 Years -	Northport Veterans Affairs Medical Center

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