Clinical trial NCT05258370: Fibroblast Growth Factor 23 in Chronic Respiratory Failure
Official title: "Exploration of the Role of Intact Fibroblast Growth Factor 23 and Its C-terminal Fragment in Chronic Respiratory Failure "
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Chronic Respiratory Failure
Keywords: fibroblast growth factor 23
erythropoietin
cardiac hypertrophy
pulmonary hypertension
oxygen therapy
chronic respiratory failure
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Fondation Université de Paris
First posted: 2022-02-28
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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.

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: circulating C-terminal FGF23 (FGF23Ct)
timeFrame: at inclusion (before oxygen therapy)
measure: circulating intact FGF23 (FGF23i)
timeFrame: at inclusion (before oxygen therapy)
Secondary outcomes:
measure: circulating FGF23Ct
timeFrame: at month 3 and month 12
measure: circulating FGF23i
timeFrame: at month 3 and month 12
measure: circulating erythropoietin
timeFrame: at inclusion, month 3 and month 12
measure: arterial O2 saturation
timeFrame: at inclusion, month 3 (without and with 02 therapy) and month 12 (without and with 02 therapy)
measure: PaO2 (arterial partial oxygen pressure)
timeFrame: at inclusion, month 3 (without and with 02 therapy) and month 12 (without and with 02 therapy)
measure: Assessment of systolic function
timeFrame: at inclusion and month 12
measure: left ventricular mass indexed for body surface area
timeFrame: at inclusion and month 12
measure: Assessment of diastolic function
timeFrame: at inclusion and month 12
measure: Assessment of pulmonary artery pressure
timeFrame: at inclusion and month 12
Other outcomes:
Locations:
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Marie COURBEBAISSE, MD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Nicolas ROCHE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.