Clinical trial NCT03050424: Iron and Chronic Obstructive Pulmonary Disease (COPD) Exercise Trial
Official title: Iron and Chronic Obstructive Pulmonary Disease (COPD) Exercise Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Iron
Exercise Capacity
Non-anaemic iron deficiency
Lead sponsor: Royal Brompton & Harefield NHS Foundation Trust
Sponsor class: OTHER
First posted: 2017-02-10
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II single centre, double blind, placebo-controlled, randomised trial aims to test the hypothesis that intravenous iron improves exercise performance in Chronic Obstructive Pulmonary Disease (COPD) as measured by constant rate cycle ergometry.

Detailed description: Iron deficiency (ID) is one of the most common nutritional deficiencies affecting humans. Chronic diseases, including COPD, are commonly complicated by iron deficiency anaemia (IDA). It has been well documented that there is an association between both ID and anaemia and reduced exercise capacity. It has been postulated that addressing this ID may be a novel approach to improve exercise capacity and quality of life.

The ECLIPSE cohort found that the prevalence of anaemia in patients with COPD is 19% and is associated with functional limitation and poor outcomes; similarly Nickol et al (2015) found ID to be prevalent in 17.7% of patients with COPD.

Barberan-Garcia et al (2015) evaluated the relationship between Non-anaemic iron deficiency (NAID) and aerobic capacity in seventy COPD patients before and after an 8 week high intensity endurance exercise training programme. Endurance time was assessed as endurance time during constant work rate exercise testing at 80% of oxygen consumption (VO2) peak. At baseline it was noted that the NAID group in comparison to the normal iron status group had a lower exercise tolerance of approximately 90 seconds, which is close to normally reported minimal clinical important difference (MCID's) for this test, P=0.007. After adjusting for confounding variables with a multiple regression analysis it was shown that training induced increase in aerobic exercise capacity was only found in the normal iron status group, with the effect of training on exercise tolerance being lower in the NAID (P=0.041).

Exercise capacity in COPD is strongly linked to outcome measures and mortality. The benefit of correcting NAID in COPD subjects would be to achieve an increase in exercise endurance and thus an improvement in Quality of Life (QoL). Currently there is no standard treatment for NAID in COPD, so this pilot, randomised, double-blind, placebo-controlled trial will attempt to answer this question.

Eligibility criteria: Inclusion Criteria:

1. Clinically stable patients (\>18 years old), Global Initiative for Chronic Obstructive Lung Disease (GOLD) II-IV COPD Forced Expiratory Volume in 1 second (FEV1):Forced Vital capacity (FVC) \< 0.70
2. Non-anaemic: males haemoglobin (Hb) ≥ 130g/L, and females ≥ 120g/L
3. Iron deficiency, defined as:

   1. Serum Ferritin \< 100 µg/ml
   2. Serum Ferritin 100-299 µg/ml with Transferrin saturation (TSAT) \< 16%
   3. Soluble transferring receptor \> 28.1nmol/L
4. No history of lower respiratory tract infection or exacerbation of COPD in the last 6 weeks
5. No participation in Pulmonary Rehabilitation (PR) for at least 3 months prior to initial assessment.

Exclusion Criteria:

1. Polycythemia defined as Hb \> 170g/L and haematocrit \> 0.6 in males and Hb \> 150g/L and haematocrit \> 0.56 in females.
2. Significant co-morbidity contributing to reduced exercise tolerance
3. Congestive cardiac failure defined as Left Ventricular Ejection Fraction (LVEF) \< 45% or plasma B-type natriuretic peptide (BNP) \> 100pg/ml.
4. Oral iron therapy at doses \> 100mg/day in the previous week prior to randomisation.
5. Chronic liver disease (including active hepatitis) and/or screening alanine transaminase or aspartate transaminase above 3 times the upper limit of normal range.
6. Anaemia (WHO \[31\]) defined as Hb \< 130g/L in males \> 15 yrs old and Hb \< 120g/L in non-pregnant females.
7. Current malignancy or haematological disorders.
8. Currently receiving systemic chemotherapy and/or radiotherapy.
9. Renal dialysis (previous, current or planned).
10. Unstable angina.
11. Subject is of child-bearing potential or is pregnant or breast feeding.
12. Contraindication to Ferrous Carboxymaltose (Ferinject):

    1. Hypersensitivity to active substance
    2. Known serious hypersensitivity to other parental iron substance
    3. Anaemia not attributed to iron deficiency (e.g. other microcytic anaemia)
    4. Evidence of iron overload or disturbance in utilisation of iron.

Primary outcomes:
measure: Constant Rate Cycle Ergometry (75% Max Load)
timeFrame: 8 weeks
Secondary outcomes:
measure: Quality of Life
timeFrame: Week 0; Week 8; Week 10; Week 14
measure: Quality of Life
timeFrame: Week 0; Week 8; Week 10; Week 14
measure: Quality of Life
timeFrame: Week 0; Week 8; Week 10; Week 14
measure: Quality of Life
timeFrame: Week 0; Week 8; Week 10; Week 14
measure: Quality of Life
timeFrame: Week 0; Week 8; Week 10; Week 14
measure: Muscle Oxygen Delivery
timeFrame: Week 0; Week 8; Week 14
measure: Endurance Shuttle Walk Test (ESWT)
timeFrame: Week 0; Week 4; Week 10; Week 14
measure: Adverse Effects of Iron Administration
timeFrame: Week 0; Week 4; Week 8; Week 10; Week 14
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Royal Brompton & Harefield NHS Foundation Trust
Study officials:
affiliation: Royal Bromtpon and Harefield NHS Foundation Trust
name: Michael Polkey, MRCP, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Demeyer H, Louvaris Z, Frei A, Rabinovich RA, de Jong C, Gimeno-Santos E, Loeckx M, Buttery SC, Rubio N, Van der Molen T, Hopkinson NS, Vogiatzis I, Puhan MA, Garcia-Aymerich J, Polkey MI, Troosters T; Mr Papp PROactive study group and the PROactive consortium. Physical activity is increased by a 12-week semiautomated telecoaching programme in patients with COPD: a multicentre randomised controlled trial. Thorax. 2017 May;72(5):415-423. doi: 10.1136/thoraxjnl-2016-209026. Epub 2017 Jan 30.
citation: Zoumot Z, Davey C, Jordan S, McNulty WH, Carr DH, Hind MD, Polkey MI, Shah PL, Hopkinson NS. Endobronchial valves for patients with heterogeneous emphysema and without interlobar collateral ventilation: open label treatment following the BeLieVeR-HIFi study. Thorax. 2017 Mar;72(3):277-279. doi: 10.1136/thoraxjnl-2016-208865. Epub 2016 Dec 20.
citation: Nolan CM, Maddocks M, Canavan JL, Jones SE, Delogu V, Kaliaraju D, Banya W, Kon SSC, Polkey MI, Man WD. Pedometer Step Count Targets during Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease. A Randomized Controlled Trial. Am J Respir Crit Care Med. 2017 May 15;195(10):1344-1352. doi: 10.1164/rccm.201607-1372OC.
citation: Demeyer H, Gimeno-Santos E, Rabinovich RA, Hornikx M, Louvaris Z, de Boer WI, Karlsson N, de Jong C, Van der Molen T, Vogiatzis I, Janssens W, Garcia-Aymerich J, Troosters T, Polkey MI; PROactive consortium. Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used. PLoS One. 2016 Mar 14;11(3):e0151255. doi: 10.1371/journal.pone.0151255. eCollection 2016.