Clinical trial NCT02308449: Iron Status and Human Metabolism
Official title: Effects of Endogenous Iron Status and Intravenous Iron on Human Skeletal Muscle Metabolism at Rest and During Exercise
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Iron Deficiency
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
name: National Institute for Health Research, United Kingdom
First posted: 2014-12-04
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Iron deficiency is common in cardiorespiratory diseases and appears to contribute to a worse outcome. This human physiology study will examine the extent to which human skeletal muscle metabolism and exercise physiology are impaired by iron deficiency.

Detailed description: This is a prospective double-blind randomised controlled study of the effect of endogenous iron status on skeletal muscle metabolism and exercise physiology. 32 healthy volunteers will take part, half of whom will be iron-deficient. The study involves a screening visit and two half-day visits during which assessments are performed. 50% of each group will be randomised to receive iron-repletion with ferric carboxymaltose at the end of the first experimental visit before returning to repeat identical assessments around one week later. This approach will make it possible to explore whether baseline differences in skeletal muscle metabolism are explained by differences in iron status per se, whilst controlling for any learning effect during participation in the study.

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
* For iron-deficient volunteers: ferritin ≤ 15 microg/L and transferrin saturation \< 16%
* For iron-replete volunteers: ferritin ≥ 20 microg/L and transferrin saturation ≥ 20%

Exclusion Criteria:

* Haemoglobin \< 8.0 g/dL
* Haemoglobinopathy
* Iron overload, defined as ferritin \> 300 microg/L
* Hypoxaemia (SpO2 \< 94%) or significant co-morbidity that may affect haematinics, metabolic or ventilatory responses
* Iron supplementation or blood transfusion within the previous 6 weeks
* Pregnancy or breast feeding
* Inability to exercise isolated calf muscle using a pedal or on a bicycle ergometer
* Contraindication to magnetic resonance spectroscopy exposure such as metallic implant
* Contraindication to receiving intravenous ferric carboxymaltose

Primary outcomes:
measure: Phosphocreatine depletion during small muscle mass exercise
timeFrame: 36 minute long graded exercise test; performed at baseline and follow-up visits (approximately a week apart)
Secondary outcomes:
measure: Cardiopulmonary exercise test performance
timeFrame: Hour long graded exercise test; performed at baseline and follow-up visits (approximately a week apart)
measure: Muscle biopsy findings
timeFrame: Immediately before and immediately after hour long cardiopulmonary exercise test, performed at baseline and follow-up visits (approximately a week apart)
measure: Participant reported symptoms
timeFrame: At study screening visit compared to four weeks following infusion of iron or placebo
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: University of Oxford OCMR & CCRF, John Radcliffe Hospital
state: Oxfordshire
Study officials:
affiliation: University of Oxford
name: Peter A Robbins, DPhil
role: STUDY_DIRECTOR
affiliation: University of Oxford
name: Matthew C Frise, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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.
citation: Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, Maxwell PH, McMullin MF, McNamara CJ, Percy MJ, Pugh CW, Ratcliffe PJ, Talbot NP, Treacy M, Robbins PA. Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology. PLoS Med. 2006 Jul;3(7):e290. doi: 10.1371/journal.pmed.0030290.
citation: Finch CA, Gollnick PD, Hlastala MP, Miller LR, Dillmann E, Mackler B. Lactic acidosis as a result of iron deficiency. J Clin Invest. 1979 Jul;64(1):129-37. doi: 10.1172/JCI109431.
citation: Frise MC, Holdsworth DA, Johnson AW, Chung YJ, Curtis MK, Cox PJ, Clarke K, Tyler DJ, Roberts DJ, Ratcliffe PJ, Dorrington KL, Robbins PA. Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation. Sci Rep. 2022 Jan 19;12(1):998. doi: 10.1038/s41598-021-03968-4.