Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile (PROOF): Study Protocol of a Phase IIb Trial.

Poli, Sven; Mbroh, Joshua; Baron, Jean-Claude; Singhal, Aneesh B; Strbian, Daniel; Molina, Carlos; Lemmens, Robin; Turc, Guillaume; Mikulik, Robert; Michel, Patrik; Tatlisumak, Turgut; Audebert, Heinrich J; Dichgans, Martin; Veltkamp, Roland; Hüsing, Johannes; Graessner, Holm; Fiehler, Jens; Montaner, Joan; Adeyemi, Adedolapo Kamaldeen; Althaus, Katharina; ... (2024). Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile (PROOF): Study Protocol of a Phase IIb Trial. International journal of stroke, 19(1), pp. 120-126. SAGE 10.1177/17474930231185275

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RATIONALE

Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs.

AIMS

PROOF investigates the use of normobaric oxygen therapy (NBO) within six hours of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior circulation occlusion.

METHODS AND DESIGN

Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial.

STUDY OUTCOMES

Primary outcome is ischemic core growth (mL) from baseline to 24 hours (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 hours, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers are conducted.

SAMPLE SIZE

Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation.

DISCUSSION

By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 hours on follow-up imaging reduces potential bias due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia.

TRIAL REGISTRATIONS

ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology
UniBE Contributor:	Nedeltchev, Krassen
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1747-4949
Publisher:	SAGE
Language:	English
Submitter:	Pubmed Import
Date Deposited:	02 Aug 2023 12:32
Last Modified:	03 Jan 2024 00:12
Publisher DOI:	10.1177/17474930231185275
PubMed ID:	37515459
Uncontrolled Keywords:	NBO Neuroprotection hyperoxygenation ischemic stroke normobaric oxygen therapy penumbra thrombectomy
URI:	https://boris.unibe.ch/id/eprint/185125