Thrombolysis and Deferoxamine in Middle Cerebral Artery Occlusion

NCT ID: NCT00777140

Last Updated: 2022-08-08

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

62 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-09-30

Study Completion Date

2011-12-31

Brief Summary

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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.

Detailed Description

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Conditions

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Ischemic Stroke, Acute

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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1. Deferoxamine

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.

Group Type ACTIVE_COMPARATOR

Deferoxamine

Intervention Type 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.

2. Placebo

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

Group Type PLACEBO_COMPARATOR

Deferoxamine

Intervention Type 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.

Interventions

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Deferoxamine

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.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* 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

Exclusion Criteria

* 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
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Fundació Institut Germans Trias i Pujol

OTHER

Sponsor Role collaborator

Germans Trias i Pujol Hospital

OTHER

Sponsor Role lead

Responsible Party

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Monica Millan Torne

Medical Doctor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Monica Millán Torné, MD

Role: PRINCIPAL_INVESTIGATOR

Germans Trias i Pujol Hospital

Locations

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Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain

Site Status

Hospital Clínico Universitario de Santiago de Compostela

Santiago de Compostela, La Coruña, Galicia, Spain

Site Status

Hospital Universitari Josep Trueta

Girona, , Spain

Site Status

Hospital Universitario de la Princesa

Madrid, , Spain

Site Status

Countries

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Spain

References

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Kontos HA. Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke. 2001 Nov;32(11):2712-6. doi: 10.1161/hs1101.098653.

Reference Type BACKGROUND
PMID: 11692043 (View on PubMed)

Selim MH, Ratan RR. The role of iron neurotoxicity in ischemic stroke. Ageing Res Rev. 2004 Jul;3(3):345-53. doi: 10.1016/j.arr.2004.04.001.

Reference Type BACKGROUND
PMID: 15231241 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 12363398 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17138950 (View on PubMed)

Davalos A, Castillo J, Marrugat J, Fernandez-Real JM, Armengou A, Cacabelos P, Rama R. Body iron stores and early neurologic deterioration in acute cerebral infarction. Neurology. 2000 Apr 25;54(8):1568-74. doi: 10.1212/wnl.54.8.1568.

Reference Type BACKGROUND
PMID: 10762495 (View on PubMed)

Davalos A, Fernandez-Real JM, Ricart W, Soler S, Molins A, Planas E, Genis D. Iron-related damage in acute ischemic stroke. Stroke. 1994 Aug;25(8):1543-6. doi: 10.1161/01.str.25.8.1543.

Reference Type BACKGROUND
PMID: 8042204 (View on PubMed)

Erdemoglu AK, Ozbakir S. Serum ferritin levels and early prognosis of stroke. Eur J Neurol. 2002 Nov;9(6):633-7. doi: 10.1046/j.1468-1331.2002.00472.x.

Reference Type BACKGROUND
PMID: 12453079 (View on PubMed)

Soloniuk DS, Perkins E, Wilson JR. Use of allopurinol and deferoxamine in cellular protection during ischemia. Surg Neurol. 1992 Aug;38(2):110-3. doi: 10.1016/0090-3019(92)90087-4.

Reference Type BACKGROUND
PMID: 1509342 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 2303992 (View on PubMed)

Palmer C, Roberts RL, Bero C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke. 1994 May;25(5):1039-45. doi: 10.1161/01.str.25.5.1039.

Reference Type BACKGROUND
PMID: 8165675 (View on PubMed)

Hurn PD, Koehler RC, Blizzard KK, Traystman RJ. Deferoxamine reduces early metabolic failure associated with severe cerebral ischemic acidosis in dogs. Stroke. 1995 Apr;26(4):688-94; discussion 694-5. doi: 10.1161/01.str.26.4.688.

Reference Type BACKGROUND
PMID: 7709418 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16623832 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16697980 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 476006 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 3620295 (View on PubMed)

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.

Reference Type DERIVED
PMID: 34439518 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33236783 (View on PubMed)

Other Identifiers

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EUDRACT: 2007-006731-31

Identifier Type: -

Identifier Source: secondary_id

TANDEM-1

Identifier Type: -

Identifier Source: org_study_id

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