Fibroblast Growth Factor 23 in Chronic Respiratory Failure (EFIC-RES)

"Exploration of the Role of Intact Fibroblast Growth Factor 23 and Its C-terminal Fragment in Chronic Respiratory Failure "

Fibroblast growth factor 23 (FGF23) is a key hormone of the mineral metabolism produced in bone and acting on the kidney to lower phosphatemia. FGF23 is subject to inactivating proteolytic cleavage which results in the presence of C-terminal and N-terminal fragments heretofore described as inactive.

We recently showed an increase in FGF23Ct in sickle cell patients, its association with left ventricular mass as well as a direct, pro-hypertrophic effect of FGF23Ct on rat cardiomyocytes. Data from the literature suggest that hypoxia (linked or not to anemia) is responsible for an increase in the production and cleavage of FGF23, either via the hypoxia inducible factor (HIF1α) or via the increase in erythropoietin (EPO).

We hypothesize that the FGF23Ct / FGF23i ratio is increased in response to chronic tissue hypoxia, in the absence of anemia, in patients with chronic respiratory failure (CRF) either due to a direct response to hypoxia via the stimulation of HIF1α, or indirectly via the increase in the circulating concentration of EPO. This elevation, if proven, could contribute to the increased risk of heart disease seen in some populations of CRF.

We propose to test this hypothesis by assaying FGF23Ct and FGF23i in a cohort of adult CRF patients before and after initiation of oxygen therapy.

The object of the present study is to study the FGF23Ct / FGF23i ratio in incident patients presenting with a non treated CRF as well as the modifications of this ratio under oxygen therapy and to study the correlations between FGF23 Ct and FGF23 and i) oxygen saturation and PaO2 ii) echocardiographic parameters and iii) EPO concentrations.

Three visits are planned: Baseline (before initiation of oxygen therapy), and two visits after initiation of oxygen therapy, at 3 months (M3) and at 12 months (M12).

For each visit, anthropometric and clinical data, treatment and biological results will be collected. FGF23 intact , FGF23 C-terminal and Erythropoietin will be measured. A cardiac ultrasound will be performed at baseline and at M12.

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Respiratory Failure
• Intervention / Treatment: Other: Dosage; Other: Cardiac echography

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Natacha Nohilé; Phone Number: 331 56 09 59 82; Email: natacha.nohile@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

adult patients with untreated chronic respiratory Ffilure with an indication to oxygen therapy and free from chronic kidney disease.

Description

Inclusion Criteria:

• Patient informed and not opposed to participating in the research
• Age ≥ 18 years old
• Severe chronic respiratory failure defined by PaO2 <60 mmHg, whatever the cause, and justifying the initiation of long-term oxygen therapy
• Not yet treated or with stopping oxygen therapy for at least 6 weeks
• Be affiliated with a social security scheme or be a beneficiary of such a scheme
• Be able to understand the interest and the constraints of the study

Exclusion Criteria:

• Exacerbation of respiratory failure in the 6 weeks prior to inclusion
• Chronic kidney disease defined by a glomerular filtration rate (GFR) estimated by CKD-EPI <60 mL / min / 1.73m2
• Anemia at the time of inclusion whatever the cause (sickle cell anemia, thalassemia, hemolytic anemia, chronic iron deficiency, others)
• Pregnancy
• Breastfeeding women
• Simultaneous participation in another therapeutic trial
• Patient under guardianship or curatorship
• Patient under medical help from the French government

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
incident patients with chronic respiratory failure; adult patients with untreated chronic respiratory failure	Other: Dosage; Evaluation of circulating C-terminal FGF23 (FGF23Ct) rate, circulating intact FGF23 (FGF23i) rate and Erythropoietin; Other: Cardiac echography; 12 months after patient enrollment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
circulating C-terminal FGF23 (FGF23Ct)	ELISA method	at inclusion (before oxygen therapy)
circulating intact FGF23 (FGF23i)	ELISA method	at inclusion (before oxygen therapy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
circulating FGF23Ct	ELISA method	at month 3 and month 12
circulating FGF23i	ELISA method	at month 3 and month 12
circulating erythropoietin	ELISA method	at inclusion, month 3 and month 12
arterial O2 saturation	assessed using an arterial sampling	at inclusion, month 3 (without and with 02 therapy) and month 12 (without and with 02 therapy)
PaO2 (arterial partial oxygen pressure)	assessed using an arterial sampling	at inclusion, month 3 (without and with 02 therapy) and month 12 (without and with 02 therapy)
Assessment of systolic function	left ventricular ejection fraction assessed using cardiac ultrasound	at inclusion and month 12
left ventricular mass indexed for body surface area	using cardiac ultrasound	at inclusion and month 12
Assessment of diastolic function	Recording of mitral filling flow using cardiac ultrasound	at inclusion and month 12
Assessment of pulmonary artery pressure	with measure, using cardiac ultrasound, of; The Vmax of the tricuspid insufficiency flow which gives the systolic gradient right heart ventricle/right heart atrium; And the diameter the inferior vena cava	at inclusion and month 12

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fondation Université de Paris
• Investigators: Study Director: Marie COURBEBAISSE, MD, Assistance Publique - Hopitaux de Paris

Publications and helpful links

General Publications

• Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011 Nov;121(11):4393-408. doi: 10.1172/JCI46122. Epub 2011 Oct 10.
• Courbebaisse M, Mehel H, Petit-Hoang C, Ribeil JA, Sabbah L, Tuloup-Minguez V, Bergerat D, Arlet JB, Stanislas A, Souberbielle JC, Le Clesiau H, Fischmeister R, Friedlander G, Prie D. Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease. Haematologica. 2017 Feb;102(2):e33-e35. doi: 10.3324/haematol.2016.150987. Epub 2016 Oct 27. No abstract available.
• Clinkenbeard EL, Hanudel MR, Stayrook KR, Appaiah HN, Farrow EG, Cass TA, Summers LJ, Ip CS, Hum JM, Thomas JC, Ivan M, Richine BM, Chan RJ, Clemens TL, Schipani E, Sabbagh Y, Xu L, Srour EF, Alvarez MB, Kacena MA, Salusky IB, Ganz T, Nemeth E, White KE. Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica. 2017 Nov;102(11):e427-e430. doi: 10.3324/haematol.2017.167882. Epub 2017 Aug 17. No abstract available.
• Zhang Q, Doucet M, Tomlinson RE, Han X, Quarles LD, Collins MT, Clemens TL. The hypoxia-inducible factor-1alpha activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res. 2016 Jul 5;4:16011. doi: 10.1038/boneres.2016.11. eCollection 2016.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2023
• Primary Completion (Anticipated): May 1, 2026
• Study Completion (Anticipated): May 1, 2026

Study Registration Dates

• First Submitted: February 17, 2022
• First Submitted That Met QC Criteria: February 17, 2022
• First Posted (Actual): February 28, 2022

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 14, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: erythropoietin; pulmonary hypertension; cardiac hypertrophy; oxygen therapy; fibroblast growth factor 23; chronic respiratory failure
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: APHP201305; 2020-A02607-32 (Other Identifier: ID-RCB Number - ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared
• IPD Sharing Time Frame: Two years after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.

Data sharing must respect the agreements made with funders. Teams wishing obtain IPD must meet the sponsor and IP team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractual agreement.

Processing of shared data must comply with European General Data Protection Regulation (GDPR).

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No