Clinical trial NCT06297863: Head Down Tilt 15° to Increase Collateral Flow in Acute Ischemic Stroke
Official title: Head Down Tilt 15° to Increase Collateral Flow in Acute Ischemic Stroke: a Multicenter, Randomised, Proof of Concept, Phase 2a/b Trial in Patients Treated With Mechanical Thrombectomy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Ischemic Stroke
Keywords: Collaterals
Cerebral hemodynamics
Head down positioning
Lead sponsor: University of Milano Bicocca
Sponsor class: OTHER
Collaborators: name: Fondazione IRCCS San Gerardo dei Tintori
name: Azienda Ospedaliero-Universitaria Careggi
name: Azienda Ospedaliera Universitaria Gaetano Martino, Messina
name: Azienda Ospedaliero Universitaria, Santa Maria della Misericordia di Udine, Italy
name: Università degli Studi dell'Aquila
name: Azienda Ospedaliero Universitaria Policlinico Umberto I, Roma
First posted: 2024-03-07
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The DOWN-SUITE trial is a prospective, multicenter, proof of concept, randomised, controlled, open label, phase 2a/b clinical trial with blinded outcome assessment, comparing cerebral collateral status in patients with acute ischemic stroke due to middle cerebral artery occlusion (M1 segment) treated with in-hospital application of HDT15 (-10° to -15°) versus usual positioning (0° to +30°), before and during mechanical thrombectomy.
Primary purpose: TREATMENT

Brief summary: The DOWN-SUITE study is multicenter, randomised, controlled, open-label clinical trial with blinded outcome assessment comparing collateral status in patients with acute ischemic stroke treated with an in-hospital application of head down tilt -10° to -15° (HDT15) versus usual positioning (0° to +30°) before endovascular mechanical thrombectomy.

This study will involve adult patients who are eligible for mechanical thrombectomy and who have acute ischemic stroke due to left or right middle cerebral artery occlusion (M1 segment).

The investigators hypothesise that HDT15, applied in acute ischemic stroke patients with a large vessel occlusion, will improve collateral circulation, prolong the survival of the ischemic penumbra and improve the clinical benefit from mechanical thrombectomy compared with standard of care (usual positioning 0° to +30°).

Detailed description: Investigating, developing and implementing a collateral therapeutic is a major objective in stroke research. The aim is to increase the amount of potentially salvageable penumbral tissue and expand the tissue time window, thus increasing the efficacy of reperfusion therapies and improving clinical outcomes.

Head down tilt 15° (HDT15) is a positional therapy consisting of tilting the patient with the head 15 degrees below the rest of the body. Experimental studies from an Italian-French group (Dr. Simone Beretta, Fondazione IRCCS San Gerardo dei Tintori and Prof. Tae-Hee Cho, Hospices Civils de Lyon) showed that HDT15 increased cerebral blood flow and improved functional outcome and infarct volume in randomised rats with middle cerebral artery (MCA) occlusion followed by reperfusion. Subsequent perfusion MRI experiments using the same stroke model by our group confirmed that HDT15 application for 60 minutes significantly increases collateral flow in the ischemic area.

There is no consensus in current clinical practice regarding the most appropriate head position for acute ischemic stroke (AIS) patients. The sitting position at +30° is the most common. An international cluster-randomised trial, HeadPoST, randomised over 11000 patients with acute stroke (85% ischemic) to either a lying-flat position or a sitting-up position (head elevated to at least 30°), maintained for 24 hours. No difference in the primary efficacy outcome (disability at 90 days measured with the modified Rankin Scale (mRS)), mortality, or rates of other serious adverse events, including pneumonia, were observed. However, the HeadPoST trial primarily targeted patients with mild symptoms without a large vessel occlusion (LVO), who were randomised beyond the usual time window of reperfusion therapies.

One retrospective study (pre-thrombectomy era) compared two cohorts of AIS patients with a LVO: patients with a standard position (0 to 30°; N=119), versus those with a HDT15 position (0 to -15°; N=90). The results suggested that HDT15 promotes neurological improvement compared to the standard position. No difference in serious adverse events was observed between the two cohorts.

A recent randomized, pilot clinical trial showed promising results of -20° head down positioning on long-term disability and an excellent safety profile.

Thus, the available clinical evidence raised no safety concern for HDT15 in AIS patients, but data on its efficacy, notably among AIS patients treated by MT, remains insufficient. HDT15, for its simplicity, low cost and feasibility, might be an optimal collateral therapeutic candidate to prolong the survival of the ischemic penumbra and improve the clinical benefit from reperfusion therapies with disability reduction. HDT15 is readily feasible by Emergency Services in the prehospital phase of AIS, before reperfusion therapies.

The DOWN-SUITE study will be the first multicenter, randomised, controlled, open-label clinical trial with blinded outcome assessment comparing collateral status in patients with AIS treated with an in-hospital application of HDT15 versus usual positioning before MT. The duration of HDT15 application (approximately 60-90 minutes) is expected to be long enough to detect significant changes in cerebral hemodynamics. Building from preclinical experiments on rodent and non-human primate stroke models carried out by our French-Italian group, it will provide for the first time the translation of HDT15 efficacy on cerebral hemodynamics and clinical outcome from animal models to AIS patients.

No therapeutic intervention is currently available to enhance collaterals in AIS.

The DOWN-SUITE trial will provide robust, high-quality evidence on the safety, feasibility and efficacy of HDT15 as a low-cost collateral therapeutic for AIS.

The investigators hypothesise that HDT15 (-10° to -15°), applied in AIS patients with an LVO, will improve collateral circulation, prolong the survival of the ischemic penumbra and improve the clinical benefit from MT compared with standard of care (usual positioning: 0° to +30°).

The investigators aim to perform a prospective, multicenter, proof of concept, randomised, controlled, open-label study. As a double-blind is not possible, a blinded central imaging core lab, whose members will be unaware of the procedure assignments, will assess all imaging outcomes, including the primary efficacy outcome.

This study will involve adult patients who are eligible for MT and who have AIS due to left or right MCA occlusion (M1 segment).

Benefit/risk ratio The investigators hypothesise that HDT15 would improve cerebral collaterals in patients randomised in the intervention group, which could subsequently reduce the ischemic injury and improve the clinical outcome.

No harm from participating in DOWN-SUITE is expected for patients in the intervention or control groups. Previous clinical data on HDT15 raised no safety concerns. No difference in post-stroke complications, including cerebral oedema or haemorrhage, pneumonia or mortality, was observed in a retrospective observational study. HDT15 is not expected to interfere with standard care, including the procedural steps of MT. Mild discomfort related to the tilted position may occur in some patients. The treating physician will continuously monitor all patients during the entire duration of the HDT15 application. No additional risk is expected in patients in the control group, as they will receive standard care.

Overall, this study's benefit/risk ratio is considered very favourable.

This study could potentially establish HDT15 as the first evidence-based collateral therapeutic for AIS. No therapeutic intervention is currently available to enhance collaterals in the acute phase of ischemic stroke. Such a collateral-enhancing therapy is necessary to expand the time window and increase the probability of successful reperfusion with IVT and MT, resulting in better clinical outcomes.

The results of the DOWN-SUITE trial may pave the way for larger randomised controlled trials of HDT15 in a wider stroke patient population, such as patients transferred from spoke hospitals to hub stroke centers to receive thrombectomy and unselected patients with suspected AIS in the prehospital setting.

Eligibility criteria: Inclusion Criteria:

* Acute ischemic stroke due to left or right MCA occlusion of the M1 segment (excluding occlusion of the internal carotid artery terminus + M1)
* Decision to treat with mechanical thrombectomy (with or without intravenous thrombolysis)
* Informed consent obtained from patient or patient's next of kin, or emergency consent procedure

Exclusion Criteria:

* Impaired consciousness, defined as NIHSS score of 2 or 3 of the item 1a (level of consciousness): not alert, requires repeated stimulation or unresponsive.
* Vomiting upon stroke onset.
* History of glaucoma.
* History or imaging findings of intracranial hypertension of any aetiology
* Major breath disorders, defined as follows:

  * oxygen saturation ≤92% in room air at admission
  * severe chronic obstructive pulmonary disease (COPD) treated with long-term oxygen therapy.
  * severe heart failure with NYHA class 3 or 4 (breathlessness during ordinary physical activity or at rest).
* Severe obesity, defined as body mass index (BMI) \> 35.
* Patients participating in another interventional trial that would interfere with this study.
* Female patients who are pregnant

Primary outcomes:
measure: Good collateral status
timeFrame: Day 0 (during mechanical thrombectomy)
Secondary outcomes:
measure: Feasibility of HDT15
timeFrame: Day 0 (in the emergency room and angio suite)
measure: Delay to thrombectomy
timeFrame: Day 0 (in the emergency room and angio suite)
measure: Vomiting
timeFrame: Day 0 (in the emergency room and angio suite)
measure: Early neurological deterioration
timeFrame: 1 day (24±12 hours)
measure: Symptomatic intracranial hemorrhage
timeFrame: 1 day (24±12 hours)
measure: Aspiration pneumonia
timeFrame: 1 day (24±12 hours)
measure: Neurological disability
timeFrame: 3 months
measure: Systolic blood pressure
timeFrame: Day 0 (in the emergency room and angio suite)
measure: Diastolic blood pressure
timeFrame: Day 0 (in the emergency room and angio suite)
measure: Oxygen saturation
timeFrame: Day 0 (in the emergency room and angio suite)
Other outcomes:
Locations:
city: Avezzano
country: Italy
facility: Ospedale Civile SS. Nicola e Filippo Avezzano Pronto Soccorso
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Messina
country: Italy
facility: Azienda Ospedaliera Policlinico Universitario "G. Martino"
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori Monza
city: Roma
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico Umberto I
city: Udine
country: Italy
facility: Ospedale Santa Maria della Misericordia
Study officials:
affiliation: University of Milano Bicocca
name: Simone Beretta, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beretta S, Versace A, Carone D, Riva M, Dell'Era V, Cuccione E, Cai R, Monza L, Pirovano S, Padovano G, Stiro F, Presotto L, Paterno G, Rossi E, Giussani C, Sganzerla EP, Ferrarese C. Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies. J Cereb Blood Flow Metab. 2017 Oct;37(10):3344-3354. doi: 10.1177/0271678X16688705. Epub 2017 Jan 23.
citation: Diamanti S, Mariani J, Versace A, Riva M, Cuccione E, Cai R, Monza L, Vigano M, Bolbos R, Chauveau F, Cho TH, Carone D, Ferrarese C, Beretta S. Head down tilt 15 degrees to preserve salvageable brain tissue in acute ischemic stroke: A pre-clinical pooled analysis, with focus on cerebral hemodynamics. Eur J Neurosci. 2023 Jun;57(12):2149-2159. doi: 10.1111/ejn.15852. Epub 2022 Nov 4.
citation: Anderson CS, Arima H, Lavados P, Billot L, Hackett ML, Olavarria VV, Munoz Venturelli P, Brunser A, Peng B, Cui L, Song L, Rogers K, Middleton S, Lim JY, Forshaw D, Lightbody CE, Woodward M, Pontes-Neto O, De Silva HA, Lin RT, Lee TH, Pandian JD, Mead GE, Robinson T, Watkins C; HeadPoST Investigators and Coordinators. Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke. N Engl J Med. 2017 Jun 22;376(25):2437-2447. doi: 10.1056/NEJMoa1615715.
citation: Gauthier A, Gerardin P, Renou P, Sagnier S, Debruxelles S, Poli M, Rouanet F, Olindo S, Sibon I. Trendelenburg Positioning in Large Vessel Ischaemic Stroke: A Pre-Post Observational Study Using Propensity Score Matching. Cerebrovasc Dis. 2018;46(1-2):24-32. doi: 10.1159/000490423. Epub 2018 Jul 27.
citation: Chen HS, Zhang NN, Cui Y, Li XQ, Zhou CS, Ma YT, Zhang H, Jiang CH, Li RH, Wan LS, Jiao Z, Xiao HB, Li Z, Yan TG, Wang DL, Nguyen TN. A randomized trial of Trendelenburg position for acute moderate ischemic stroke. Nat Commun. 2023 May 5;14(1):2592. doi: 10.1038/s41467-023-38313-y.