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

Acute Ischemic Stroke Clinical Trial

— Urico-Ictus  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00860366
• Other study ID #: URICOICTUS-1-2007
• Secondary ID: EudraCT 2007-002
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: March 11, 2009
• Last updated: March 9, 2015
• Start date: June 2011
• Est. completion date: October 2013

Study information

• Verified date: March 2015
• Source: Fundacion Clinic per a la Recerca Biomédica
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 421
• Est. completion date: October 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Ischemia
• Stroke

Intervention

Drug:
• Uric Acid
1 gram dissolved in a vehicle containing 500 ml of 0'1% Lithium Carbonate and 5% Mannitol, IV (in the vein), single dose.

Other:
• Vehicle
Single intravenous infusion of a 500 ml vehicle containing 0'1% Lithium Carbonate and 5% Mannitol.

Locations

Country	Name	City	State
Spain	Hospital General Universitario de Albacete	Albacete
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu y Sant Pau	Barcelona
Spain	Hospital Universitari de Bellvitge	Bellvitge	Barcelona
Spain	Hospital Dr Josep Trueta	Girona
Spain	Hospital de Navarra	Pamplona	Navarra
Spain	Corporació Sanitària del Parc Taulí	Sabadell	Barcelona
Spain	Hospital Universitari Mútua de Terrassa	Terrassa	Barcelona
Spain	Hospital Clínico Universitario de Valladolid	Valladolid

Sponsors (2)

Lead Sponsor	Collaborator
Angel Chamorro, MD	Carlos III Health Institute

Country where clinical trial is conducted

Spain, 

References & Publications (8)

Amaro S, Chamorro Á. 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. — View 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. Review. — View 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. Epub 2007 May 24. — View Citation

Amaro S, Urra X, Gómez-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. — View 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. — View 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. — View 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. Epub 2003 Dec 11. — View 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. Epub 2006 Apr 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		90 days after the inclusion.	No
Secondary	Proportion of patients with NIHSS <2 at 2 hours after completing the experimental treatment.		2 hours after completing the experimental treatment	No
Secondary	Proportion of patients with NIHSS <1 at day 90.		Day 90	No
Secondary	Proportion of patients achieving a Barthel scale of 95 to 100 at day 90		Day 90	No
Secondary	All-cause mortality within the first 90 days.		Day 90	Yes
Secondary	Final Infarction Volume measured by means of MRI or multimodal CT at 72 hours of onset (in specific centers)		72 hours	No
Secondary	Proportion of patients with an intracranial hemorrhage associated to a worsening of 4 points in the NIHSS within the first 36 hours of treatment.		36 hours.	Yes