Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke - Full Text View

Purpose

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.

Condition	Intervention	Phase
Acute Ischemic Stroke	Drug: Uric Acid Other: Vehicle	Phase 2 Phase 3


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

Resource links provided by NLM:

Drug Information available for: Mannitol Uric Acid Lithium carbonate Alteplase

U.S. FDA Resources

Further study details as provided by Fundacion Clinic per a la Recerca Biomédica:

Primary Outcome Measures:

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 [ Time Frame: 90 days after the inclusion. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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


Enrollment:	421
Study Start Date:	June 2011
Study Completion Date:	October 2013
Primary Completion Date:	August 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Uric Acid Single intravenous infusion of 1 gram of Uric Acid dissolved in vehicle (500 ml of 0'1% Lithium Carbonate and 5% Mannitol).	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.
Placebo Comparator: Vehicle Single intravenous infusion of a 500 ml vehicle containing 0'1% Lithium Carbonate and 5% Mannitol.	Other: Vehicle Single intravenous infusion of a 500 ml vehicle containing 0'1% Lithium Carbonate and 5% Mannitol.

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


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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).

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00860366

Locations


Spain
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain, 08916
Hospital Universitari de Bellvitge
Bellvitge, Barcelona, Spain
Corporació Sanitària del Parc Taulí
Sabadell, Barcelona, Spain, 08208
Hospital Universitari Mútua de Terrassa
Terrassa, Barcelona, Spain, 08221
Hospital de Navarra
Pamplona, Navarra, Spain, 31008
Hospital General Universitario de Albacete
Albacete, Spain, 02006
Hospital de la Santa Creu y Sant Pau
Barcelona, Spain, 08025
Hospital Clínic de Barcelona
Barcelona, Spain, 08036
Hospital Dr Josep Trueta
Girona, Spain, 17007
Hospital Clínico Universitario de Valladolid
Valladolid, Spain, 47005

Sponsors and Collaborators

Angel Chamorro, MD

Carlos III Health Institute

Investigators


Study Director:	Angel Chamorro, MD, PhD.	Comprehensive Stroke Center, Hospital Clínic Barcelona, Spain.

More Information

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.

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. doi: 10.1586/14737175.8.2.259. Review.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Llull L, Laredo C, Renú A, Pérez B, Vila E, Obach V, Urra X, Planas A, Amaro S, Chamorro Á. 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.

Chamorro A, Amaro S, Castellanos M, Segura T, Arenillas J, Martí-Fábregas J, Gállego J, Krupinski J, Gomis M, Cánovas D, Carné X, Deulofeu R, Román 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.


Responsible Party:	Angel Chamorro, MD, MD, PhD, Fundació Clínic per la Recerca Biomèdica
ClinicalTrials.gov Identifier:	NCT00860366 History of Changes
Other Study ID Numbers:	URICOICTUS-1-2007 EudraCT 2007-002687-95 FIS EC07-90276
Study First Received:	March 11, 2009
Last Updated:	March 9, 2015
Health Authority:	Spain: Spanish Agency of Medicines

Keywords provided by Fundacion Clinic per a la Recerca Biomédica:


Acute ischemic stroke thrombolysis alteplase	uric acid neuroprotection oxidative stress

Additional relevant MeSH terms:


Stroke Ischemia Cerebral Infarction Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Vascular Diseases Cardiovascular Diseases Pathologic Processes Brain Infarction Brain Ischemia Mannitol Uric Acid	Lithium Carbonate Diuretics, Osmotic Diuretics Natriuretic Agents Physiological Effects of Drugs Antioxidants Molecular Mechanisms of Pharmacological Action Protective Agents Antidepressive Agents Psychotropic Drugs Enzyme Inhibitors Antimanic Agents Tranquilizing Agents Central Nervous System Depressants

ClinicalTrials.gov processed this record on September 28, 2016

Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke (Urico-Ictus)