Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke

Condition(s) targeted: Acute Ischemic Stroke

Intervention: Uric Acid (Drug); Vehicle (Other)

Phase: Phase 2/Phase 3

Status: Not yet recruiting

Sponsored by: Fundacion Clinic per a la Recerca Biomédica

Official(s) and/or principal investigator(s):
Angel Chamorro, MD, PhD., Study Director, Affiliation: Comprehensive Stroke Center, Hospital Clínic Barcelona, Spain.

Overall contact:
Ángel Chamorro, MD, PhD., Phone: +34 932275400, Ext: 2424, Email: mvargas@clinic.ub.es

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.

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 design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: 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

Secondary outcome:

Proportion of patients with NIHSS <2 at 2 hours after completing the experimental treatment.

Proportion of patients with NIHSS <1 at day 90.

Proportion of patients achieving a Barthel scale of 95 to 100 at day 90

All-cause mortality within the first 90 days.

Final Infarction Volume measured by means of MRI or multimodal CT at 72 hours of onset (in specific centers)

Proportion of patients with an intracranial hemorrhage associated to a worsening of 4 points in the NIHSS within the first 36 hours of treatment.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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).

Ángel Chamorro, MD, PhD., Phone: +34 932275400, Ext: 2424, Email: mvargas@clinic.ub.es

Hospital General Universitario de Albacete, Albacete 02006, Spain

Hospital Clínic de Barcelona, Barcelona 08036, Spain

Hospital de la Santa Creu y Sant Pau, Barcelona 08025, Spain

Hospital Dr Josep Trueta, Girona 17007, Spain

Corporació Sanitària del Parc Taulí, Sabadell, Barcelona 08208, Spain

Hospital de Navarra, Pamplona, Navarra 31008, Spain

Related publications:

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.

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. Epub 2003 Dec 11. No abstract available.

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.

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. Epub 2006 Apr 5.

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. Epub 2007 May 24.

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. Review.

Starting date: September 2009
Ending date: September 2012
Last updated: March 11, 2009