Thrombolysis and Deferoxamine in Middle Cerebral Artery Occlusion (TANDEM-1)

• ClinicalTrials.gov Identifier: NCT00777140
• Recruitment Status: Completed
• First Posted: October 22, 2008
• Last Update Posted: July 6, 2012
• Sponsor: Germans Trias i Pujol Hospital
• Collaborator: Fundació Institut Germans Trias i Pujol
• Information provided by (Responsible Party): Monica Millan Torne, Germans Trias i Pujol Hospital

Tracking Information

• First Submitted Date: October 21, 2008
• First Posted Date: October 22, 2008
• Last Update Posted Date: July 6, 2012
• Study Start Date: September 2008
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: October 21, 2008): Clinical and Analytical Adverse Events (anemia, hypotension, renal failure, mortality, hemorrhagic transformation, cerebral edema, other severe adverse events) [ Time Frame: 3 months ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 21, 2008)

• Neurological status (NIHSS, Barthel and Rankin scales), final ischemic lesion volume on CTscan. [ Time Frame: 24h, 7days and 3 months ]
• Deferoxamine and ferritin levels in serum (pharmacokinetics). [ Time Frame: 72h ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Thrombolysis and Deferoxamine in Middle Cerebral Artery Occlusion
• Official Title: Double-blind, Randomized, Placebo Controlled, Dose-finding Phase 2 Clinical Trial of Intravenous Deferoxamine in Patients With Acute Ischemic Stroke Treated With Tissue Plasminogen Activator

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Acute Ischemic Stroke

Intervention

Drug: 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.

Study Arms

• Active Comparator: 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.
  Intervention: Drug: Deferoxamine
• Placebo Comparator: 2. Placebo
  Saline solution: Bolus and perfusion during 72h. 5 patients in the placebo arm in each step (randomization 3:1)
  Intervention: Drug: Deferoxamine

Publications *

• Kontos HA. Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke. 2001 Nov;32(11):2712-6.
• Selim MH, Ratan RR. The role of iron neurotoxicity in ischemic stroke. Ageing Res Rev. 2004 Jul;3(3):345-53. Review.
• Castellanos M, Puig N, Carbonell T, Castillo J, Martinez J, Rama R, Dávalos A. Iron intake increases infarct volume after permanent middle cerebral artery occlusion in rats. Brain Res. 2002 Oct 11;952(1):1-6.
• Millan M, Sobrino T, Castellanos M, Nombela F, Arenillas JF, Riva E, Cristobo I, García MM, Vivancos J, Serena J, Moro MA, Castillo J, Dávalos A. Increased body iron stores are associated with poor outcome after thrombolytic treatment in acute stroke. Stroke. 2007 Jan;38(1):90-5. Epub 2006 Nov 30.
• Dávalos 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.
• Dávalos A, Fernandez-Real JM, Ricart W, Soler S, Molins A, Planas E, Genís D. Iron-related damage in acute ischemic stroke. Stroke. 1994 Aug;25(8):1543-6. Erratum in: Stroke 1994 Nov;25(11):2300.
• Erdemoglu AK, Ozbakir S. Serum ferritin levels and early prognosis of stroke. Eur J Neurol. 2002 Nov;9(6):633-7.
• Soloniuk DS, Perkins E, Wilson JR. Use of allopurinol and deferoxamine in cellular protection during ischemia. Surg Neurol. 1992 Aug;38(2):110-3.
• 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.
• Palmer C, Roberts RL, Bero C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke. 1994 May;25(5):1039-45.
• 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.
• 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.
• 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. Epub 2006 May 12.
• 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.
• 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.
• 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:CD009280. doi: 10.1002/14651858.CD009280.pub3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 4, 2012): 62
• Original Estimated Enrollment (submitted: October 21, 2008): 60
• Actual Study Completion Date: December 2011
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT00777140
• Other Study ID Numbers: TANDEM-1; EUDRACT: 2007-006731-31
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Monica Millan Torne, Germans Trias i Pujol Hospital
• Study Sponsor: Germans Trias i Pujol Hospital
• Collaborators: Fundació Institut Germans Trias i Pujol

Investigators

• Principal Investigator: Monica Millán Torné, MD; Germans Trias i Pujol Hospital

• PRS Account: Germans Trias i Pujol Hospital
• Verification Date: July 2012