Clinical trial NCT00860366: Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke
Official title: Randomized, Double Blind Study Assessing the Clinical Efficacy of Combined Treatment With Uric Acid and rtPA Administered Intravenously in Acute Ischemic Stroke Patients Within the First 4.5 Hours of Symptoms Onset
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Ischemic Stroke
Keywords: Acute ischemic stroke
thrombolysis
alteplase
uric acid
neuroprotection
oxidative stress
Lead sponsor: Fundacion Clinic per a la Recerca Biomédica
Sponsor class: OTHER
Collaborators: name: Carlos III Health Institute
First posted: 2009-03-12
Enrollment: 421
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether the combined treatment with Uric Acid and rtPA is superior to rtPA alone in terms of clinical efficacy in acute ischemic stroke patients treated within the first 4.5 hours of symptoms onset.

Detailed description: Oxidative stress is a major contributor to brain damage in patients with ischemic stroke. Uric acid (UA) is an endogenous product derived from the metabolism of purins which in man is responsable of the 60% of the total antioxidant capacity of the organism. Recent experimental evidences gathered by our and other research groups have shown that the exogenous administration of UA is neuroprotective both in cortical and subcortical brain areas as the result of its antioxidant properties. In these studies, animals treated with UA disclosed smaller brain infarction after transient focal ischemia, both using the intraluminal model or after the injection of autologous clots. Moreover, our group first described greater neuroprotection in animals pretreated with rtPA (alteplase). Likewise, we have recently shown that the administration of UA was free of serious adverse effects in stroke patients receiving rtPA within 3 hours of stroke onset. Yet, preliminary data suggested that this intervention might translate into clinical benefits at 3 months follow-up. Based on these data, we aim to conduct a phase 3, randomized, double-blind, controlled trial assessing the clinical efficacy of UA administration in acute ischemic stroke patients. Currently, rtPA is the only approved therapy for stroke patients within the first hours of clinical onset, and oxidative stress is thought particularly relevant following ischemia/reperfusion. Based on this ground, we aim to conduct this phase 3 clinical trial in ischemic stroke patients which are currently treated with rtPA within the 4'5 hour window.

Eligibility criteria: Inclusion criteria:

* Age older than 18 years old.
* Acute ischemic stroke treated with rtPA within the first 4.5 hours of clinical onset. Baseline National Institute of Health Stroke Scale (NIHSS) \>6 and \<25, and modified Rankin Scale (mRS) of 2 prior to the stroke.
* Cranial CT disclosing the absence of blood in the CNS.
* Informed consent.

Exclusion criteria:

* Presence of any of the valid exclusion criteria for the administration of rtPA in the current clinical practise.
* History of gout with or without history of gouty nephropathy, or uric lithiasis. Asymptomatic hiperuricemia under chronic treatment with allopurinol, or chronic treatment with lithium.
* Chronic renal insufficiency (baseline creatinine \> 1,5mg/dl).

Primary outcomes:
measure: Proportion of patients achieving a mRS of 0 to 1 at 3 months after treatment, or 2 in those patients with a mRS 2 prior to the inclusion in the study
timeFrame: 90 days after the inclusion.
Secondary outcomes:
measure: Proportion of patients with NIHSS <2 at 2 hours after completing the experimental treatment.
timeFrame: 2 hours after completing the experimental treatment
measure: Proportion of patients with NIHSS <1 at day 90.
timeFrame: Day 90
measure: Proportion of patients achieving a Barthel scale of 95 to 100 at day 90
timeFrame: Day 90
measure: All-cause mortality within the first 90 days.
timeFrame: Day 90
measure: Final Infarction Volume measured by means of MRI or multimodal CT at 72 hours of onset (in specific centers)
timeFrame: 72 hours
measure: Proportion of patients with an intracranial hemorrhage associated to a worsening of 4 points in the NIHSS within the first 36 hours of treatment.
timeFrame: 36 hours.
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Bellvitge
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: Sabadell
country: Spain
facility: Corporació Sanitària del Parc Taulí
state: Barcelona
city: Terrassa
country: Spain
facility: Hospital Universitari Mútua de Terrassa
state: Barcelona
city: Pamplona
country: Spain
facility: Hospital de Navarra
state: Navarra
city: Albacete
country: Spain
facility: Hospital General Universitario de Albacete
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu y Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Girona
country: Spain
facility: Hospital Dr Josep Trueta
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
Study officials:
affiliation: Comprehensive Stroke Center, Hospital Clínic Barcelona, Spain.
name: Angel Chamorro, MD, PhD.
role: STUDY_DIRECTOR
References:
citation: Chamorro A, Obach V, Cervera A, Revilla M, Deulofeu R, Aponte JH. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke. 2002 Apr;33(4):1048-52. doi: 10.1161/hs0402.105927.
citation: Chamorro A, Planas AM. Yin and yang of uric acid in patients with stroke. Stroke. 2004 Jan;35(1):e11-2; author reply e11-2. doi: 10.1161/01.STR.0000107762.79571.7D. Epub 2003 Dec 11. No abstract available.
citation: Chamorro A, Planas AM, Muner DS, Deulofeu R. Uric acid administration for neuroprotection in patients with acute brain ischemia. Med Hypotheses. 2004;62(2):173-6. doi: 10.1016/S0306-9877(03)00324-4.
citation: Romanos E, Planas AM, Amaro S, Chamorro A. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2007 Jan;27(1):14-20. doi: 10.1038/sj.jcbfm.9600312. Epub 2006 Apr 5.
citation: Amaro S, Soy D, Obach V, Cervera A, Planas AM, Chamorro A. A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke. Stroke. 2007 Jul;38(7):2173-5. doi: 10.1161/STROKEAHA.106.480699. Epub 2007 May 24.
citation: Amaro S, Planas AM, Chamorro A. Uric acid administration in patients with acute stroke: a novel approach to neuroprotection. Expert Rev Neurother. 2008 Feb;8(2):259-70. doi: 10.1586/14737175.8.2.259.
citation: Amaro S, Chamorro A. Translational stroke research of the combination of thrombolysis and antioxidant therapy. Stroke. 2011 May;42(5):1495-9. doi: 10.1161/STROKEAHA.111.615039. Epub 2011 Apr 7.
citation: Amaro S, Urra X, Gomez-Choco M, Obach V, Cervera A, Vargas M, Torres F, Rios J, Planas AM, Chamorro A. Uric acid levels are relevant in patients with stroke treated with thrombolysis. Stroke. 2011 Jan;42(1 Suppl):S28-32. doi: 10.1161/STROKEAHA.110.596528. Epub 2010 Dec 16.
citation: Amaro S, Renu A, Laredo C, Castellanos M, Arenillas JF, Llull L, Rudilloso S, Urra X, Obach V, Chamorro A; on behalf of the URICO-ICTUS investigators. Relevance of Collaterals for the Success of Neuroprotective Therapies in Acute Ischemic Stroke: Insights from the Randomized URICO-ICTUS Trial. Cerebrovasc Dis. 2019;47(3-4):171-177. doi: 10.1159/000500712. Epub 2019 Jun 4.
citation: Amaro S, Laredo C, Renu A, Llull L, Rudilosso S, Obach V, Urra X, Planas AM, Chamorro A; URICO-ICTUS Investigators. Uric Acid Therapy Prevents Early Ischemic Stroke Progression: A Tertiary Analysis of the URICO-ICTUS Trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke). Stroke. 2016 Nov;47(11):2874-2876. doi: 10.1161/STROKEAHA.116.014672. Epub 2016 Oct 6.
citation: Chamorro A, Amaro S, Castellanos M, Gomis M, Urra X, Blasco J, Arenillas JF, Roman LS, Munoz R, Macho J, Canovas D, Marti-Fabregas J, Leira EC, Planas AM; URICO-ICTUS Investigators. Uric acid therapy improves the outcomes of stroke patients treated with intravenous tissue plasminogen activator and mechanical thrombectomy. Int J Stroke. 2017 Jun;12(4):377-382. doi: 10.1177/1747493016684354. Epub 2016 Dec 20.
citation: Llull L, Laredo C, Renu A, Perez B, Vila E, Obach V, Urra X, Planas A, Amaro S, Chamorro A. Uric Acid Therapy Improves Clinical Outcome in Women With Acute Ischemic Stroke. Stroke. 2015 Aug;46(8):2162-7. doi: 10.1161/STROKEAHA.115.009960. Epub 2015 Jul 9.
citation: Chamorro A, Amaro S, Castellanos M, Segura T, Arenillas J, Marti-Fabregas J, Gallego J, Krupinski J, Gomis M, Canovas D, Carne X, Deulofeu R, Roman LS, Oleaga L, Torres F, Planas AM; URICO-ICTUS Investigators. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol. 2014 May;13(5):453-60. doi: 10.1016/S1474-4422(14)70054-7. Epub 2014 Apr 2.