Thrombolysis and Deferoxamine in Middle Cerebral Artery Occlusion

NCT00777140 | Completed Phase 2 DMC

• 2 other identifiers: TANDEM-1EUDRACT: 2007-006731-31
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 4

Brief Summary

Iron overload has been associated with greater brain injury in ischemia/reperfusion experimental stroke models and ischemic stroke patients, especially in those treated with thrombolytic treatment. Deferoxamine administration, an iron chelator, offers a neuroprotective action in ischemia/reperfusion animal models. Primary objective: To evaluate the security and tolerability of deferoxamine endovenous treatment in acute ischemic stroke patients treated with iv. tPA. Secondary objectives: To study pharmacokinetics of deferoxamine given by endovenous bolus (10 mg/Kg) followed by 72-hour continuous intravenous infusion (20, 40 o 60 mg/Kg). To evaluate the deferoxamine effect in clinical outcome, infarct volume and hemorrhagic transformation and brain edema development. Methodology: Double-blind, randomized, placebo controlled, dose-finding phase II clinical trial. Study stages: 1st: bolus+20 mg/Kg/day vs. Placebo (n=15:5); 2nd: bolus+40 mg/Kg/day vs. Placebo (n=15:5); 3rd: bolus+60 mg/Kg/day vs placebo (n=15:5). These doses will be increased according to security results of the previous stage. Patients will be continuously monitored in stroke units. Laboratory parameters will be measured at baseline, 24h, 72h and 30 days to evaluate adverse events related to the drug. Serum deferoxamine and feroxamine concentrations will be measured along time after the injection in a subgroup of patients to the pharmacokinetics study. CT scan will be performed at 24-36h to assess hemorrhagic transformation and brain edema. The NIH Stroke Scale will be evaluated during hospitalization, and the Rankin score at discharge and 3 months. If deferoxamine demonstrate to be secure and well tolerated treatment in acute stroke patients, it may be a new therapy option to lower the brain injury after ischemia and reperfusion.

Conditions

Ischemic Stroke, Acute

Keywords

Stroke; Ischemic Stroke; Thrombolytic treatment; Middle cerebral artery occlusion; Deferoxamine; Iron chelator; Acute Ischemic Stroke treated with Intravenous Thrombolytic

Outcome Measures

Primary Outcomes (1)

• Clinical and Analytical Adverse Events (anemia, hypotension, renal failure, mortality, hemorrhagic transformation, cerebral edema, other severe adverse events)

  3 months

Secondary Outcomes (2)

• Neurological status (NIHSS, Barthel and Rankin scales), final ischemic lesion volume on CTscan.

  24h, 7days and 3 months

• Deferoxamine and ferritin levels in serum (pharmacokinetics).

  72h

Study Arms (2)

1. Deferoxamine

ACTIVE COMPARATOR

Intravenous deferoxamine: bolus of 10mg/Kg (initiated during tPA infusion) and perfusion of 20/40/60 mg/Kg/day during 72h. Three different doses (3 steps), 15 patient in the active arm for each dose.

Drug: Deferoxamine

2. Placebo

PLACEBO COMPARATOR

Saline solution: Bolus and perfusion during 72h. 5 patients in the placebo arm in each step (randomization 3:1)

Drug: Deferoxamine

Interventions

Deferoxamine DRUG

Intravenous deferoxamine: bolus 10mg/Kg (initiated during thrombolytic infusion, iv tPA), followed by intravenous perfusion of 20/40/60mg/Kg during 72h. It's a dose-finding study with 3 different doses of deferoxamine, with 20 patients (15 active:5 placebo) in each step. Bolus + 72h perfusion of saline solution for the placebo group.

1. Deferoxamine; 2. Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-80 years old
• Acute Ischemic Stroke on the middle cerebral artery territory
• Treatment with iv tPA in the first 3 hours from symptoms onset

You may not qualify if:

• Modified Rankin Scale more or equal to 2
• Infectious, inflammatory, neoplastic or hematologic disease
• Anemia (Hto\<34% or Hb\<10g/dl)
• Previous renal failure
• Previous treatment with oral iron supplement
• Minor stroke (NIHSS less than 4), lacunar or posterior territory
• Alcohol consumption (more than 40mg/Kg)
• Pregnancy
• Participation in other clinical trials

Sponsors & Collaborators

• Germans Trias i Pujol Hospital: lead
• Fundació Institut Germans Trias i Pujol: collaborator

Study Sites (4)

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Clínico Universitario de Santiago de Compostela

Santiago de Compostela, La Coruña, Galicia, 15706, Spain

Location

Hospital Universitari Josep Trueta

Girona, 17007, Spain

Location

Hospital Universitario de la Princesa

Madrid, 28006, Spain

Location

Related Publications (17)

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  PMID: 11692043 BACKGROUND

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  PMID: 15231241 BACKGROUND

• Castellanos M, Puig N, Carbonell T, Castillo J, Martinez J, Rama R, Davalos A. Iron intake increases infarct volume after permanent middle cerebral artery occlusion in rats. Brain Res. 2002 Oct 11;952(1):1-6. doi: 10.1016/s0006-8993(02)03179-7.

  PMID: 12363398 BACKGROUND

• Millan M, Sobrino T, Castellanos M, Nombela F, Arenillas JF, Riva E, Cristobo I, Garcia MM, Vivancos J, Serena J, Moro MA, Castillo J, Davalos A. Increased body iron stores are associated with poor outcome after thrombolytic treatment in acute stroke. Stroke. 2007 Jan;38(1):90-5. doi: 10.1161/01.STR.0000251798.25803.e0. Epub 2006 Nov 30.

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• Patt A, Horesh IR, Berger EM, Harken AH, Repine JE. Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains. J Pediatr Surg. 1990 Feb;25(2):224-7; discussion 227-8. doi: 10.1016/0022-3468(90)90407-z.

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  PMID: 7709418 BACKGROUND

• Freret T, Valable S, Chazalviel L, Saulnier R, Mackenzie ET, Petit E, Bernaudin M, Boulouard M, Schumann-Bard P. Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat. Eur J Neurosci. 2006 Apr;23(7):1757-65. doi: 10.1111/j.1460-9568.2006.04699.x.

  PMID: 16623832 BACKGROUND

• Kim HJ, Hida H, Jung CG, Miura Y, Nishino H. Treatment with deferoxamine increases neurons from neural stem/progenitor cells. Brain Res. 2006 May 30;1092(1):1-15. doi: 10.1016/j.brainres.2006.02.046. Epub 2006 May 12.

  PMID: 16697980 BACKGROUND

• Summers MR, Jacobs A, Tudway D, Perera P, Ricketts C. Studies in desferrioxamine and ferrioxamine metabolism in normal and iron-loaded subjects. Br J Haematol. 1979 Aug;42(4):547-55. doi: 10.1111/j.1365-2141.1979.tb01167.x.

  PMID: 476006 BACKGROUND

• Allain P, Mauras Y, Chaleil D, Simon P, Ang KS, Cam G, Le Mignon L, Simon M. Pharmacokinetics and renal elimination of desferrioxamine and ferrioxamine in healthy subjects and patients with haemochromatosis. Br J Clin Pharmacol. 1987 Aug;24(2):207-12. doi: 10.1111/j.1365-2125.1987.tb03163.x.

  PMID: 3620295 BACKGROUND

• Millan M, DeGregorio-Rocasolano N, Perez de la Ossa N, Reverte S, Costa J, Giner P, Silva Y, Sobrino T, Rodriguez-Yanez M, Nombela F, Campos F, Serena J, Vivancos J, Marti-Sistac O, Cortes J, Davalos A, Gasull T. Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial. Antioxidants (Basel). 2021 Aug 10;10(8):1270. doi: 10.3390/antiox10081270.

  PMID: 34439518 DERIVED

• Van der Loo LE, Aquarius R, Teernstra O, Klijn K, Menovsky T, van Dijk JMC, Bartels R, Boogaarts HD. Iron chelators for acute stroke. Cochrane Database Syst Rev. 2020 Nov 24;11(11):CD009280. doi: 10.1002/14651858.CD009280.pub3.

  PMID: 33236783 DERIVED

MeSH Terms

Conditions

Ischemic Stroke; Stroke; Infarction, Middle Cerebral Artery

Interventions

Deferoxamine

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Cerebral Infarction; Brain Infarction; Brain Ischemia; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids

Study Officials

• Monica Millán Torné, MD

  Germans Trias i Pujol Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Doctor

Study Record Dates

• First Submitted: October 21, 2008
• First Posted: October 22, 2008
• Study Start: September 1, 2008
• Primary Completion: December 1, 2011
• Study Completion: December 1, 2011
• Last Updated: August 8, 2022

Record last verified: 2022-08

Locations

ES (4)