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Erythropoietin to Improve Critical Care Patient Outcomes (EPO-ICU-FS)

5. oktober 2022 oppdatert av: University Hospital, Angers

Erythropoietin to Improve Critical Care Patient Outcomes: Feasibility Study of a Multicenter, Randomized, Placebo-controlled Trial of Subcutaneous Erythropoietin Injection for Intensive Care Patients

Recently, the french societies for critical care (SFAR and SRLF) produced guidelines for anemia treatment in critically ill patients that recommend the use of erythropoietin (EPO) in these patients, but the european society (ESICM) recommended against the use of EPO in this patients, despite recent meta analysis showing a lower mortality in patients treated with EPO.

Nevertheless, RCT on EPO in the ICU are quite all, new data are thus needed. Before conducting a large study on EPO in anemic patients in the ICU, we propose to cinduct a feasability RCT to evaluate the feasability of such a study.

Studieoversikt

Status

Aktiv, ikke rekrutterende

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

Anemia is very common in intensive care patients, affecting approximately two-thirds of patients on admission, with a mean admission hemoglobin (Hb) level of 11.0 g/dl. The severity of anemia is associated with increased morbidity and mortality. Its pathophysiology is complex, involving blood loss (from repeated blood sampling, invasive procedures, surgical interventions, etc.) and inflammation. The latter is responsible for a decrease in endogenous erythropoietin (EPO) production and a decreased bone marrow response, which can be very prolonged (half of the patients discharged from ICU with anemia are still anemic at 6 months of discharge, with low levels of EPO, compared to the observed Hb levels). On this basis, several randomized clinical trials (RCTs) evaluating the effect of EPO on the transfusion rate in this population were performed in the 1990s-2000s. The authors showed a modest reduction in blood transfusion, which was not considered clinically relevant in view of the cost of EPO at that time.

Since then, meta-analyses evaluating the benefits and risks of EPO in intensive care patients suggest a positive impact of EPO on mortality. The largest, including 34 studies (and 930,470 patients) reports a reduction in the relative risk of mortality of 0.76, 95% CI [0.61 - 0.92]. Beyond the reduction in red blood cell transfusions, the benefit of EPO could be directly due to its erythropoietic effect (correction of anemia) and/or its anti-inflammatory/anti-apoptotic properties. Based on this literature, the French critical care societies have recently recommended the use of EPO. However, the European Society of Intensive Care Medicine (ESICM) recently recommended against the use of EPO, based on the same literature, but suggested that the benefit of EPO should be evaluated. Indeed, the main obstacle to recommending the use of EPO seems to be economic, whereas the arrival on the market of biosimilar molecules has significantly reduced these costs.

Most of the trials on EPO in critical care patients (and included in the meta-analyses) are quite old (about 15 years) and none of them had mortality as primary endpoint. In addition, transfusion practices and the quality of blood products have changed significantly over the years. In this context of disagreement on the recommendations for the use of EPO in these patients, but of potential benefit on mortality, there is an urgent need to evaluate whether EPO decreases mortality in adult anemic patients admitted to intensive care. However, calculation of the number of patients needed to evaluate the benefit of EPO on mortality in this population yields a number of patients to be included of the order of 1800-2000 patients.

Before considering the implementation of a multicenter study involving such a large number of patients, a pilot study evaluating the feasibility and inclusion capacity for such a study seems indispensable according to the latest CONSORT recommendations.

Studietype

Intervensjonell

Registrering (Faktiske)

42

Fase

  • Fase 3

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Frankrike
      • Cholet, Frankrike
        • Cholet Hospital
      • Tours, Frankrike
        • UH Tours

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år og eldre (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

Inclusion Criteria:

  • Adult patients (age > 18 years),
  • admitted to intensive care for more than 72 hours and less than 7 days
  • who have received invasive ventilatory support and/or treatment with a vasoactive agent for at least one day since admission
  • with an Hb level < 12 g/dl,
  • with consent from the patient or patient's relative (or emergency inclusion procedure).

Exclusion Criteria:

  • Moribund patient,
  • Current hospitalization for acute coronary syndrome,
  • Recent history of thromboembolic event (< 3 months),
  • Uncontrolled hypertension despite adequate antihypertensive therapy,
  • Myelodysplasia or chronic pathology requiring iterative transfusions,
  • EPO treatment within the last 30 days,
  • Participation in another interventional trial of an erythropoiesis-stimulating agent or anemia treatment,
  • Expected discharge from the intensive care unit within 24 hours,
  • Known hypersensitivity to EPO or any of its components,
  • A history of erythroblastopenia following erythropoietin therapy
  • Pregnant, breast-feeding or parturient woman
  • Person deprived of liberty by judicial or administrative decision
  • Person under forced psychiatric care
  • Person under a legal protection measure.

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Trippel

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: erythropoietin
Erythropoietin alpha or theta 40,000 UI (1 ml) sc each week if Hb <12 g/dL (for maximum 5 weeks)
Legemiddel: Erythropoietin

Patients receive a subcutaneous injection of 40,000 IU of erythropoietin alfa or zêta, repeated weekly until Day 28 (if the hemoglobin level is <12 g/dl and the patient remains hospitalized).

The study treatments are administered by an open-label nurse. In both groups, before each injection, iron deficiency (defined as reticulocyte Hb <29 pg, or hepcidin <41 µg/L, or ferritin <100 µg/L, or ferritin <300 µg/L with transferrin saturation <20%) is treated with intravenous iron infusion (depending on the product available at the center). A restrictive transfusion strategy is recommended as long as the patient remains in the ICU, according to recent recommendations.

Six visits are scheduled: V1 for inclusion and the first injection, V2 at Day 7(±2 days) for the second injection, V3 at Day 14(±2 days) for the third injection, V4 at Day 21(±2 days) for the fourth injection, V5 at Day 28(±2 days) for the fifth injection.
Placebo komparator: Placebo
saline sc injection (1 ml) each weeks if Hb <12 g/dL, for a maximum of 5 weeks,
Legemiddel: Placebo

In the control arm, patients receive a subcutaneous injection of placebo (0.9% NaCl) according to the same schedule.

The study treatments are administered by an open-label nurse. In both groups, before each injection, iron deficiency (defined as reticulocyte Hb <29 pg, or hepcidin <41 µg/L, or ferritin <100 µg/L, or ferritin <300 µg/L with transferrin saturation <20%) is treated with intravenous iron infusion (depending on the product available at the center). A restrictive transfusion strategy is recommended as long as the patient remains in the ICU, according to recent recommendations.

Six visits are scheduled: V1 for inclusion and the first injection, V2 at Day 7(±2 days) for the second injection, V3 at Day 14(±2 days) for the third injection, V4 at Day 21(±2 days) for the fourth injection, V5 at Day 28(±2 days) for the fifth injection.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Recruitment rate
Tidsramme: 90 days
≥50% of eligible patients will need to be enrolled, but the trial will not be feasible if the inclusion rate is ≤ 25% or less
90 days
Adherence to allocation groups
Tidsramme: 90 days
A high level of matching of randomization and group allocation should be achieved, with at least 85% of included patients receiving protocol-allocated treatment, but if ≤ 65% patients receive protocol-allocated treatment, the trial is not feasible
90 days
Completion of follow-up of included patients
Tidsramme: 90 days
≥ 85% of patients should be followed through to the end of follow-up, but if <65% patients are followed through to the last visit, the protocol will not be feasible
90 days

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
The proportion of patients lost to follow-up at each visit
Tidsramme: 7, 14, 21, 28 and 90 days
The proportion of patients lost to follow-up at each visit
7, 14, 21, 28 and 90 days
The rate of missing data for mortality outcome
Tidsramme: 90 days
The rate of missing data for mortality outcome
90 days
The rate of compliance with the therapeutic protocol at each visit for inpatients
Tidsramme: 7, 14, 21, and 28 days
The rate of compliance with the therapeutic protocol at each visit for inpatients
7, 14, 21, and 28 days
Mean serum hemoglobin value
Tidsramme: 28 days
Mean serum hemoglobin value
28 days
ICU mortality
Tidsramme: up to 90 days
ICU mortality
up to 90 days
Sykehusdødelighet
Tidsramme: opptil 90 dager
Sykehusdødelighet
opptil 90 dager
ICU length of stay
Tidsramme: up to 90 days
ICU length of stay
up to 90 days
Hospital length of stay
Tidsramme: up to 90 days
Hospital length of stay
up to 90 days
Blood transfusion
Tidsramme: 90 days
Proportion of patients who received at least one red blood cell transfusion
90 days
number of red blood cells transfused
Tidsramme: 90 days
number of red blood cells transfused
90 days
90 days survival analysis
Tidsramme: 90 days
90 days survival analysis
90 days
Occurrence of hospital readmission (censored at 90 days after inclusion),
Tidsramme: 90 days
at least one hospital readmission after the hospital discharge
90 days
Number of days living at home (or previous place of living)
Tidsramme: 90 days
Number of days living at home (or previous place of living) at D90
90 days
Quality of life measured by the EQ-5D 5L scale, EuroQol 5 dimensions
Tidsramme: 90 days
The value from this scale records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine'. The scale is rated from 0 to 100.
90 days
Proportion of patients with a thromboembolic event
Tidsramme: 90 days
Thrombolic event: pulmonary embolism, venous or arterial thrombosis
90 days

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

University Hospital, Angers

Etterforskere

  • Studieleder: Sigismond Lasocki, MD, Angers University hospital

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

28. januar 2022

Primær fullføring (Faktiske)

2. september 2022

Studiet fullført (Forventet)

31. desember 2022

Datoer for studieregistrering

Først innsendt

20. september 2021

Først innsendt som oppfylte QC-kriteriene

1. oktober 2021

Først lagt ut (Faktiske)

15. oktober 2021

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

10. oktober 2022

Siste oppdatering sendt inn som oppfylte QC-kriteriene

5. oktober 2022

Sist bekreftet

1. september 2022

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • EPO-ICU-FS

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

Ubestemt

IPD-planbeskrivelse

Yes

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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