NAtional cohort study of Idiopathic AnD heritable pulmonary arterial hypertension
| ISRCTN | ISRCTN91688209 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN91688209 |
| ClinicalTrials.gov number | NCT01907295 |
| Secondary identifying numbers | A092860 |
- Submission date
- 03/07/2013
- Registration date
- 14/08/2013
- Last edited
- 09/07/2020
- Recruitment status
- Suspended
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Current plain English summary as of 04/10/2018:
Background and study aims
High blood pressure in the lungs is a rare condition that can shorten life. Although the cause of this disease is usually unknown, in about 70% of heritable and 15-20% of cases with unknown cause there is a change in a gene (a mutation) that controls how blood vessels grow and function. The gene is called BMPR2. Although mutations in BMPR2 are a risk factor for high blood pressure in the lungs, not everyone with a mutation gets the disease. Additional genetic and environmental factors are likely to contribute. We suspect that mutations in other genes are responsible for some cases. In this study we aim to recruit patients and follow them up for several years. We hope to discover new mutations for this disease and to find out what factors lead to poor outcome, and to understand what triggers disease in patients with mutations.
Who can participate?
Adults with high blood pressure in the lungs, their relatives and controls
What does the study involve?
Subjects are enrolled into a national study. Patients will be seen at their routine follow-up and have additional blood samples taken. Relatives will be seen every year and have tests and blood samples taken.
What are the possible benefits and risks of participating?
It is not known whether you will gain any personal benefit from this research. However, information from this study could improve our understanding of the disease and help doctors to treat patients better in the future.
Where is the study run from?
All pulmonary hypertension centres in the UK
When is the study starting and how long is it expected to run for?
The study is expected to start in September 2013 and will run for at least 5 years.
Who is funding the study?
The British Heart Foundation (UK) and Medical Research Council (MRC), UK.
Who is the main contact?
Professor Nicholas Morrell
Tel: 01223 331666
nwm23@cam.ac.uk
Previous plain English summary:
Background and study aims
High blood pressure in the lungs is a rare condition that can shorten life. Although the cause of this disease is usually unknown, in about 70% of heritable and 15-20% of cases with unknown cause there is a change in a gene (a mutation) that controls how blood vessels grow and function. The gene is called BMPR2. Although mutations in BMPR2 are a risk factor for high blood pressure in the lungs, not everyone with a mutation gets the disease. Additional genetic and environmental factors are likely to contribute. We suspect that mutations in other genes are responsible for some cases. In this study we aim to recruit patients and follow them up for several years. We hope to discover new mutations for this disease and to find out what factors lead to poor outcome, and to understand what triggers disease in patients with mutations.
Who can participate?
Adults with high blood pressure in the lungs and their relatives can participate in this study.
What does the study involve?
Subjects are enrolled into a national study. Patients will be seen at their routine follow-up and have additional blood and urine samples. Relatives will be seen every 6 months and have tests, blood and urine samples.
What are the possible benefits and risks of participating?
It is not known whether you will gain any personal benefit from this research. However, information from this study could improve our understanding of the disease and help doctors to treat patients better in the future.
Where is the study run from?
The study will be run from all pulmonary hypertension centres in the UK and Dublin, Ireland.
When is the study starting and how long is it expected to run for?
The study is expected to start in September 2013 and will run for at least 5 years.
Who is funding the study?
The British Heart Foundation (UK) and Medical Research Council (MRC), UK.
Who is the main contact?
Professor Nicholas Morrell
Tel: 01223 331666
nwm23@cam.ac.uk
Contact information
Scientific
University of Cambridge
Department of Medicine
Box 157 Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 331666 |
|---|---|
| nwm23@cam.ac.uk |
Study information
| Study design | Multicentre observational cohort study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cohort study |
| Study setting(s) | Not specified |
| Study type | Screening |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient, control or relative patient information sheet. Study co-ordinators, tel: 01223 763094 cohortcoordination@medschl.cam.ac.uk |
| Scientific title | NAtional cohort study of Idiopathic AnD heritable pulmonary arterial hypertension |
| Study acronym | NAIAD |
| Study objectives | Current study hypothesis as of 18/10/2019: Idiopathic and heritable forms of pulmonary arterial hypertension (PAH) are devastating conditions associated with high morbidity and mortality. The disease is usually diagnosed late by finding a markedly increase mean pulmonary arterial pressure, the result of progressive narrowing and remodeling of the pulmonary vasculature, and leading to the failure of the right ventricle. This disease tends to present in the middle decades of life, with a female predominance (f:m 2.3:1). Untreated, it carries a 3 year mortality of 60%. A major breakthrough in our understanding of the pathobiology of PAH was the identification of heterozygous disease causing mutations in the gene coding the bone morphogenetic protein type 2 receptor (BMPR2) in families with PAH. Although research over the last 10 years has provided important clues, the precise cellular and molecular mechanisms leading to the disease manifestation remain incompletely understood. In addition, the penetrance of this mutation in families is low, on average approximately 20%. The existence of discordant monozygotic twins points to the presence of important environmental factors. A further 15-26% of apparently sporadic cases of idiopathic PAH harbour mutations in BMPR2. Data is now emerging that patients with mutations present earlier and die of their disease at an earlier age than patients without BMPR2 mutations. The exact aetiology remains unknown and patients appear to progress at different rates, and respond differently to existing treatments. This study will provide a more complete understanding of the aetiology and natural history of idiopathic and heritable PAH from a detailed analysis of their genetic influences and the contribution of potential environmental factors, linked to deep phenotyping of a national cohort. Identification of the critical environmental and additional genetic factors leading to the disease manifestation in PAH will lead to strategies for disease prevention and may identify pathways for the development of novel therapies, and provide a basis for mechanistic studies in vitro and in vivo. Funding has been awarded from the British Heart Foundation and the Medical Research Council to establish and maintain a UK & Ireland cohort study of heritable and idiopathic pulmonary arterial hypertension (March 2013-2018). The purpose of this study is to set up a national cohort study of patients with idiopathic PAH, and PAH due to mutations in BMPR2. Family members with and without BMPR2 mutations will also be studied. The identification and follow up of patients with and without BMPR2 mutations, and possibly other mutations, will provide important information on the clinical course of genetic causes of PAH. It will also provide a platform for the identification of novel genetic variation in the BMPR2 negative patients. The longitudinal follow up and sampling of unaffected BMPR2 mutation carriers, and mutation negative family members, will provide information on penetrance, and whether different mutations confer specific risks. In addition, the cohort will provide samples for hypothesis driven studies to ascertain genetic or environmental triggers for this disease. The cohort will further provide a basis for future research and prevention studies or experimental medicine interventions targeting the BMPR2 pathway. Patients and relatives will be followed up longitudinally for sampling and clinical assessment and data will be collected and semi-anonymised. Previous study hypothesis: Idiopathic and heritable forms of pulmonary arterial hypertension (PAH) are devastating conditions associated with high morbidity and mortality. The disease is usually diagnosed late by finding a markedly increase mean pulmonary arterial pressure, the result of progressive narrowing and remodeling of the pulmonary vasculature, and leading to the failure of the right ventricle. This disease tends to present in the middle decades of life, with a female predominance (f:m 2.3:1). Untreated, it carries a 3 year mortality of 60%. A major breakthrough in our understanding of the pathobiology of PAH was the identification of heterozygous disease causing mutations in the gene coding the bone morphogenetic protein type 2 receptor (BMPR2) in families with PAH. Although research over the last 10 years has provided important clues, the precise cellular and molecular mechanisms leading to the disease manifestation remain incompletely understood. In addition, the penetrance of this mutation in families is low, on average approximately 20%. The existence of discordant monozygotic twins points to the presence of important environmental factors. A further 15-26% of apparently sporadic cases of idiopathic PAH harbour mutations in BMPR2. Data is now emerging that patients with mutations present earlier and die of their disease at an earlier age than patients without BMPR2 mutations. The exact aetiology remains unknown and patients appear to progress at different rates, and respond differently to existing treatments. This study will provide a more complete understanding of the aetiology and natural history of idiopathic and heritable PAH from a detailed analysis of their genetic influences and the contribution of potential environmental factors, linked to deep phenotyping of a national cohort. Identification of the critical environmental and additional genetic factors leading to the disease manifestation in PAH will lead to strategies for disease prevention and may identify pathways for the development of novel therapies, and provide a basis for mechanistic studies in vitro and in vivo. Funding has been awarded from the British Heart Foundation and the Medical Research Council to establish and maintain a UK & Ireland cohort study of heritable and idiopathic pulmonary arterial hypertension (March 2013-2018). The purpose of this study is to set up a national cohort study of patients with idiopathic PAH, and PAH due to mutations in BMPR2. Family members with and without BMPR2 mutations will also be studied. The identification and follow up of patients with and without BMPR2 mutations, and possibly other mutations, will provide important information on the clinical course of genetic causes of PAH. It will also provide a platform for the identification of novel genetic variation in the BMPR2 negative patients. The longitudinal follow up and sampling of unaffected BMPR2 mutation carriers, and mutation negative family members, will provide information on penetrance, and whether different mutations confer specific risks. In addition, the cohort will provide samples for hypothesis driven studies to ascertain genetic or environmental triggers for this disease. The cohort will further provide a basis for future research and prevention studies or experimental medicine interventions targeting the BMPR2 pathway. Patients and relatives will be screened for the BMPR2 mutation before recruitment into to the study. They will be followed up every 6 months with for sampling and clinical assessment and data will be collected and semi-anonymised. |
| Ethics approval(s) | NRES Committee East of England-Hatfield, 01/08/2018, REC reference: 13/EE/0203 |
| Health condition(s) or problem(s) studied | Idiopathic, heritable and anorexigenic pulmonary arterial hypertension |
| Intervention | Current interventions as of 04/10/2018: PAH patients will be seen at their local centre by their service team but they will have additional blood samples taken. Relatives of PAH patients will be seen every year at their nearest PAH centre. Subjects will be followed up long term for the length of the study. Tests will include: 1. Epidemiology Questionnaire to assess factors affecting health 2. An echocardiogram (ECHO) to assess the size, shape, pumping action and the extent of any damage to the heart 3. Lung function tests, which include blowing measurements to assess gas volumes within the lungs, as well as assessment of how the lungs exchange gases 4. Optional right heart catheterisation (RHC) to determine how much blood the heart is pumping during rest and exercise 5. Optional cardiac magnetic tesonance tests to measure heart function (to be done only once) 6. Six minute walk test to measure exercise capacity 7. Cardiopulmonary exercise test (bicycle exercise test), which will indicate how much blood the heart pumps during rest and different levels of exercise 8. Electrocardiogram (ECG) to measure the electrical activity of the heart 9. Blood tests Previous interventions: PAH patients will be seen at their local centre by their service team but they will have additional bloods and urine samples taken. Relatives of PAH patients will be seen every 6 months at their nearest PAH centre. Subjects will be seen for up to 5 years depending on when they are recruited in to the study. Tests will include: 1. CAMPHOR questionnaire to assess your quality of life 2. Epidemiology Questionnaire to assess factors affecting health 3. An echocardiogram (ECHO) to assess the size, shape, pumping action and the extent of any damage to the heart. 4. Lung function tests which include blowing measurements to assess gas volumes within the lungs as well as assessment of how the lungs exchange gases. 5. Optional right heart catheterisation (RHC) to determine how much blood your heart is pumping while you are resting and on exercise. Optional Cardiac Magnetic Resonance tests. To measure heart function. ( to be done only once) 6. Six minute walk test. To measure exercise capacity 7. Cardiopulmonary exercise test. A bicycle exercise test, which will indicate how much blood your heart pumps while resting and with different levels of exercise. 8. Electrocardiogram (ECG), a test that measures the electrical activity of the heart 9. Blood tests 10. Urine |
| Intervention type | Other |
| Primary outcome measure | Recruitment of significant numbers of cases of heritable and idiopathic PAH to the cohort. Measured at 5 years |
| Secondary outcome measures | 1. Recruitment of significant numbers of relatives of patients with HPAH for follow up. 2. Identification of novel causal genetic variation underlying heritable and idiopathic PAH. 3. Identification of novel biomarkers of disease progression or response to therapy from patient samples 4. Identification of potential environmental triggers of disease from epidemiological studies Outcomes measured at 5 years |
| Overall study start date | 01/09/2013 |
| Completion date | 30/06/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 3600 |
| Key inclusion criteria | Patient 1. Participant is willing and able to give informed consent for participation in the study. 2. Male or Female, aged 16-80 years 3. Diagnosed with idiopathic, anorexigen-induced or heritable PAH. Relative: 1. Participant is willing and able to give informed consent for participation in the study. 2. Male or Female, aged 16-80 years 3. Has a family member diagnosed with idiopathic, anorexigen-induced, or heritable PAH |
| Key exclusion criteria | Patient The participant may not enter the study if ANY of the following apply: 1. Patient is unable to give informed consent. 2. Not suffering from idiopathic, anorexigen-induced, or heritable PAH Relative The participant may not enter the study if ANY of the following apply: 1. Patient is unable to give informed consent |
| Date of first enrolment | 01/09/2013 |
| Date of final enrolment | 31/12/2022 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
CB2 0QQ
United Kingdom
Sponsor information
Hospital/treatment centre
c/o Mr Stephen Keller
Research and Development Department
Box 277 Addenbrookes Hospital
Hills Road
Cambridge
CB2 OQQ
United Kingdom
| Website | http://www.cuh.org.uk/cms/ |
|---|---|
"ROR" |
https://ror.org/04v54gj93 |
Funders
Funder type
Charity
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- the_bhf, The British Heart Foundation, BHF
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
09/07/2020: The trial contact details have been made publicly visible.
04/05/2020: Due to current public health guidance, recruitment for this study has been paused.
18/10/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/09/2019 to 31/12/2022.
2. The overall end date was changed from 30/09/2020 to 30/06/2023.
3. The intention to publish date was added.
4. The study hypothesis was changed.
05/10/2018: The following changes have been made to the trial record:
1. The ethics approval date was added
2. The overall trial end date was changed from 31/08/2018 to 30/09/2020
3. The recruitment end date was changed from 31/08/2018 to 30/09/2019
04/10/2018: The following changes have been made to the trial record:
1. The clinicaltrials.gov number has been added
2. The interventions have been updated
3. The trial website has been added
4. The participant information sheet has been changed from "Not available in web format, please use the contact details below to request a patient or relative patient information sheet. Professor Nick Morrell, Tel: 01223 331666, nwm23@cam.ac.uk" to "Not available in web format, please use the contact details below to request a patient, control or relative patient information sheet. Study co-ordinators, tel: 01223 763094 cohortcoordination@medschl.cam.ac.uk"
5. The plain English summary has been updated
