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Iron Status and Hypoxic Pulmonary Vascular Responses

Primary Purpose

Lung Hypoxia, Pulmonary Arterial Hypertension, Iron Deficiency

Status
Completed
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Intravenous administration of ferric carboxymaltose
Subacute hypoxic exposures
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Lung Hypoxia focused on measuring Hypoxia, Pulmonary hypertension, Iron deficiency, Hypoxic pulmonary vasoconstriction

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Willing and able to give informed consent for participation in the study
  • Men and women aged 18 years or older and generally in good health
  • Detectable tricuspid regurgitation on echocardiography during both normoxia and hypoxia enabling measurement of pulmonary arterial pressure
  • For iron-deficient volunteers: ferritin ≤15microg/L and transferrin saturation <16%
  • For iron-replete volunteers: ferritin ≥20microg/L and transferrin saturation ≥20%

Exclusion Criteria:

  • Haemoglobin <8.0g/dl
  • Haemoglobinopathy
  • Iron overload defined as ferritin >300microg/L
  • Hypoxia at rest or on walking (SaO2 <94%) or significant comorbidity that may affect haematinics, pulmonary vascular or ventilatory responses, e.g. current infection, a chronic inflammatory condition, known cardiovalvular lesion or pulmonary hypertension, uncontrolled asthma or chronic obstructive pulmonary disease
  • Exposure to high altitude (>2,500m) within the previous six weeks or air travel >4 hours within the previous week
  • Iron supplementation or blood transfusion within the previous 6 weeks
  • Pregnancy or breast feeding

Sites / Locations

  • University of Oxford Department of Physiology, Anatomy and Genetics

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Iron-deficient

Iron-replete

Arm Description

Healthy volunteers meeting iron-deficient entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures

Healthy volunteers meeting iron-replete entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures

Outcomes

Primary Outcome Measures

∆PASP in iron-replete compared to iron-deficient volunteers
Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers

Secondary Outcome Measures

∆PASP, with versus without prior iron infusion, in iron-replete compared to iron-deficient volunteers
Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers, with versus without a prior iron infusion
Blood parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers
Ventilation parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers

Full Information

First Posted
May 1, 2013
Last Updated
May 5, 2016
Sponsor
University of Oxford
Collaborators
National Institute for Health Research, United Kingdom, British Heart Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT01847352
Brief Title
Iron Status and Hypoxic Pulmonary Vascular Responses
Official Title
Effect of Endogenous Iron Status on Hypoxic Pulmonary Vascular Responses and Their Attenuation by Intravenous Iron
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
February 2013 (undefined)
Primary Completion Date
April 2014 (Actual)
Study Completion Date
April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
National Institute for Health Research, United Kingdom, British Heart Foundation

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
On exposure to hypoxia (low oxygen) the normal response is for pulmonary arterial systolic blood pressure (PASP, blood pressure through the lungs) to increase. We have previously shown that raising iron by giving an infusion of iron into a vein reduces this pressure rise and that lowering iron by giving a drug that binds iron, magnifies this response. This is potentially a clinically important observation since iron-deficient people may be at increased risk of pulmonary hypertension if exposed transiently or permanently to hypoxia due to lung disease or residence at high altitude; furthermore if this were true then intravenous iron could be an important treatment in this patient group in the event of hypoxic exposure. The observed effects of iron on PASP are likely to be because iron levels affect oxygen sensing. Low iron levels make the body behave as if exposed to low oxygen by inhibiting the breakdown of the family of oxygen-sensing transcription factors, 'hypoxia inducible factor' or HIF. This includes one of the body's normal responses to low oxygen levels - raising blood pressure through the lungs. This study will answer the question (1) do iron-deficient volunteers have a greater rise in PASP with hypoxia than those who are iron-replete, and (2) does giving intravenous iron cause a greater reduction in the rise in PASP in those who are iron-deficient than iron-replete? The purpose of this study is not to test the safety or clinical efficacy of iron which is already known.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lung Hypoxia, Pulmonary Arterial Hypertension, Iron Deficiency
Keywords
Hypoxia, Pulmonary hypertension, Iron deficiency, Hypoxic pulmonary vasoconstriction

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Non-Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Iron-deficient
Arm Type
Other
Arm Description
Healthy volunteers meeting iron-deficient entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures
Arm Title
Iron-replete
Arm Type
Other
Arm Description
Healthy volunteers meeting iron-replete entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures
Intervention Type
Drug
Intervention Name(s)
Intravenous administration of ferric carboxymaltose
Other Intervention Name(s)
Ferinject
Intervention Description
Intravenous administration of ferric carboxymaltose 15mg/kg up to a maximum dose of 1000mg
Intervention Type
Other
Intervention Name(s)
Subacute hypoxic exposures
Other Intervention Name(s)
Hypoxia, Hypoxic challenge
Intervention Description
Exposure to six hours of isocapnic hypoxia with end-tidal partial pressure of oxygen clamped at 55 Torr, with and without prior iron infusion
Primary Outcome Measure Information:
Title
∆PASP in iron-replete compared to iron-deficient volunteers
Description
Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers
Time Frame
During six hours of hypoxia without prior iron infusion
Secondary Outcome Measure Information:
Title
∆PASP, with versus without prior iron infusion, in iron-replete compared to iron-deficient volunteers
Description
Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers, with versus without a prior iron infusion
Time Frame
During two six-hour periods of hypoxia; assessments separated by at least a week
Title
Blood parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers
Time Frame
After six hours of hypoxia, at both study assessments
Title
Ventilation parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers
Time Frame
During six hours of hypoxia, at both study assessments
Other Pre-specified Outcome Measures:
Title
Fatigue scores in iron-replete versus iron-deficient volunteers
Time Frame
Assessed at baseline visit

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Willing and able to give informed consent for participation in the study Men and women aged 18 years or older and generally in good health Detectable tricuspid regurgitation on echocardiography during both normoxia and hypoxia enabling measurement of pulmonary arterial pressure For iron-deficient volunteers: ferritin ≤15microg/L and transferrin saturation <16% For iron-replete volunteers: ferritin ≥20microg/L and transferrin saturation ≥20% Exclusion Criteria: Haemoglobin <8.0g/dl Haemoglobinopathy Iron overload defined as ferritin >300microg/L Hypoxia at rest or on walking (SaO2 <94%) or significant comorbidity that may affect haematinics, pulmonary vascular or ventilatory responses, e.g. current infection, a chronic inflammatory condition, known cardiovalvular lesion or pulmonary hypertension, uncontrolled asthma or chronic obstructive pulmonary disease Exposure to high altitude (>2,500m) within the previous six weeks or air travel >4 hours within the previous week Iron supplementation or blood transfusion within the previous 6 weeks Pregnancy or breast feeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annabel H Nickol, MBBS PhD
Organizational Affiliation
University of Oxford
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Oxford Department of Physiology, Anatomy and Genetics
City
Oxford
State/Province
Oxfordshire
ZIP/Postal Code
OX1 3PT
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
18955380
Citation
Smith TG, Balanos GM, Croft QP, Talbot NP, Dorrington KL, Ratcliffe PJ, Robbins PA. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol. 2008 Dec 15;586(24):5999-6005. doi: 10.1113/jphysiol.2008.160960. Epub 2008 Oct 27.
Results Reference
background
PubMed Identifier
19809026
Citation
Smith TG, Talbot NP, Privat C, Rivera-Ch M, Nickol AH, Ratcliffe PJ, Dorrington KL, Leon-Velarde F, Robbins PA. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA. 2009 Oct 7;302(13):1444-50. doi: 10.1001/jama.2009.1404.
Results Reference
background
PubMed Identifier
21962070
Citation
Talbot NP, Smith TG, Privat C, Nickol AH, Rivera-Ch M, Leon-Velarde F, Dorrington KL, Robbins PA. Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial. High Alt Med Biol. 2011 Fall;12(3):265-9. doi: 10.1089/ham.2011.1005.
Results Reference
background
PubMed Identifier
12015365
Citation
Balanos GM, Dorrington KL, Robbins PA. Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. J Appl Physiol (1985). 2002 Jun;92(6):2501-7. doi: 10.1152/japplphysiol.00965.2001.
Results Reference
background
PubMed Identifier
27140401
Citation
Frise MC, Cheng HY, Nickol AH, Curtis MK, Pollard KA, Roberts DJ, Ratcliffe PJ, Dorrington KL, Robbins PA. Clinical iron deficiency disturbs normal human responses to hypoxia. J Clin Invest. 2016 Jun 1;126(6):2139-50. doi: 10.1172/JCI85715. Epub 2016 May 3.
Results Reference
result
Links:
URL
http://www.dpag.ox.ac.uk/team/peter-robbins
Description
Research Group Website
URL
https://www.bhf.org.uk/research-projects/effects-of-iron-deficiency-and-intravenous-iron-on-human-cardiorespiratory-physiology
Description
Funding Body Website

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Iron Status and Hypoxic Pulmonary Vascular Responses

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