Clinical trial NCT02175225: Intracerebral Hemorrhage Deferoxamine Trial - iDEF Ttrial
Official title: Study of Deferoxamine Mesylate in Intracerebral Hemorrhage
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Intracerebral Hemorrhage
Keywords: Brain hemorrhage
Cerebral hemorrhage
Bleeding in the brain
Deferoxamine
iDEF trial
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Medical University of South Carolina
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Massachusetts General Hospital
name: University of Massachusetts, Worcester
name: University of Pennsylvania
name: Johns Hopkins University
name: Duke University
name: University of North Carolina
name: University of Florida
name: Henry Ford Hospital
name: Ohio State University
name: St. Joseph's Hospital and Medical Center, Phoenix
name: University of California, San Francisco
name: Oregon Health and Science University
name: Yale New Haven Health System Center for Healthcare Solutions
name: University of Iowa
name: Hartford Hospital
name: The University of Texas Health Science Center, Houston
name: Rhode Island Hospital
name: Stanford University
name: University of Washington
name: University of Calgary
name: Hopital de l'Enfant-Jesus
name: University of Alberta
name: Rush University Medical Center
name: University Hospitals Cleveland Medical Center
name: Columbia University
name: Weill Medical College of Cornell University
name: NYU Langone Health
name: Mount Sinai Hospital, New York
name: Loyola University
First posted: 2014-06-26
Enrollment: 294
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The investigators hypothesize that treatment with the iron chelator, Deferoxamine Mesylate, improves the outcome of patients with brain hemorrhage.

The purpose of this study is to determine whether treatment with Deferoxamine Mesylate is of sufficient promise to improve outcome before pursuing a larger clinical trial to examine its effectiveness as a treatment for intracerebral hemorrhage.

Detailed description: This is a prospective, multi-center, double-blind, randomized, placebo-controlled, phase-II clinical trial.

Subjects will be randomized to either deferoxamine mesylate (DFO) at 32 mg/kg/day (up to a maximum daily dose of 6000 mg/day), or saline placebo, given by IV infusion for 3 consecutive days.

Treatment will be initiated within 24 hours after ICH symptom onset. Randomization will control baseline imbalances associated with baseline ICH score, ICH onset-to-treatment time (OTT), ICH volume, baseline NIHSS score, and warfarin use.

All subjects will be followed for 6 months and will receive standard of care therapy while participating in the study.

Throughout the study, we will continue to assess the safety of DFO. At the conclusion of the study, the proportion of DFO-treated subjects with a good clinical outcome at 3 months (defined as modified Rankin Scale (mRS) score of 0-2) will be compared to the placebo proportion in a futility analysis to determine if it is futile to move DFO forward to Phase III efficacy evaluation.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 and ≤ 80 years
* The diagnosis of ICH is confirmed by brain CT scan
* NIHSS score ≥6 and GCS \>6 upon presentation
* The first dose of the study drug is expected to be administered within 24h of ICH symptom onset
* Functional independence prior to ICH, defined as pre-ICH mRS ≤1
* Signed and dated informed consent is obtained.

Exclusion Criteria:

* Previous chelation therapy or known hypersensitivity to DFO products
* Known severe iron deficiency anemia (defined as hemoglobin concentration \< 7g/dL or requiring blood transfusions)
* Abnormal renal function, defined as serum creatinine \>2 mg/dL
* Planned surgical evacuation of ICH prior to administration of study drug (placement of a catheter for ventricular drainage is not a contraindication to enrollment)
* SUSPECTED secondary ICH related to tumour, ruptured aneurysm or arteriovenous malformation, hemorrhagic transformation of an ischemic infarct, or venous sinus thrombosis
* Infratentorial hemorrhage
* Irreversibly impaired brainstem function (bilateral fixed and dilated pupils and extensor motor posturing)
* Complete unconsciousness, defined as a score of 3 on item 1a of the NIHSS (Responds only with reflex motor or autonomic effects or totally unresponsive, and flaccid)
* Pre-existing disability, defined as pre-ICH mRS ≥2
* Coagulopathy - defined as elevated aPTT or INR \>1.3 upon presentation; concurrent use of direct thrombin inhibitors (such as dabigatran), direct factor Xa inhibitors (such as rivaroxaban or apixaban), or low-molecular-weight heparin
* Patients with confirmed aspiration, pneumonia, or evident bilateral pulmonary infiltrates on chest x-ray or CT scan prior to enrollment
* Patients with significant respiratory disease such as chronic obstructive pulmonary disease, pulmonary fibrosis, or any use (chronic or intermittent) of inhaled O2 at home
* FiO2 \>0.35 (\>4 L/min) prior to enrollment
* Sepsis (present source of infection ± lactic acidosis); Systemic Inflammatory Response Syndrome (Temp \>100.4F or \<96.8F; Heart rate \>90; Respiratory rate \>20 or PaCo2 \<32 mmHg; WBC \>12, \<4, or bands \>10%); or shock (SBP \<90 mmHg) at presentation
* The presence of 4 or more of the following risk modifiers for ARDS prior to enrollment:

  1. Tachypnea (respiratory rate \>30)
  2. SpO2 \<95%
  3. Obesity (BMI \>30)
  4. Acidosis (pH \<7.35)
  5. Hypoalbuminemia (albumin \<3.5 g/dL)
  6. Concurrent use of chemotherapy
* Taking iron supplements containing ≥ 325 mg of ferrous iron, or prochlorperazine
* Patients with heart failure taking \> 500 mg of vitamin C daily
* Known severe hearing loss
* Known pregnancy, or positive pregnancy test, or breastfeeding
* Positive drug screen for cocaine upon presentation
* Patients known or suspected of not being able to comply with the study protocol due to alcoholism, drug dependency, noncompliance, living in another state or any other cause
* Any condition which, in the judgement of the investigator, might increase the risk to the patient
* Life expectancy of less than 90 days due to co-morbid conditions
* Concurrent participation in another research protocol for investigation of another experimental therapy
* Indication that a new DNR or Comfort Measures Only (CMO) order will be implemented within the first 72 hours of hospitalization

Primary outcomes:
measure: Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 90 Days
timeFrame: 90 days
measure: Number of Subjects Experiencing Serious Adverse Events
timeFrame: 90 days
measure: Number of Subjects With Serious Adverse Events Within 7 Days
timeFrame: 7 days
Secondary outcomes:
measure: Proportion of Patients With mRS Score 0-3 at 90 Days
timeFrame: 90 days
measure: Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 180 Days
timeFrame: 180 days
measure: Proportion of Patients With Modified Rankin Scale (mRS) Score 0-3 at 180 Days
timeFrame: 180 days
measure: Proportion of Subjects With Good Outcome (mRS 0-2) in the Early vs. Delayed Treatment Time Windows
timeFrame: 90 days
Other outcomes:
measure: Ordinal Distribution of Scores on mRS at Day 90
timeFrame: 90 days
measure: Ordinal Distribution of Scores on mRS at 180 Days
timeFrame: 180 days
measure: Adverse Event of Special Interest: Number of Patients With Allergic Reactions (During Infusion of Study Drug)
timeFrame: during the study infusion
measure: Adverse Event of Special Interest: Number of Patients With Hypotension
timeFrame: during the study infusion
measure: Adverse Event of Special Interest: Number of Patients With New Visual or Auditory Changes
timeFrame: after initiation of study infusion
measure: Adverse Event of Special Interest: Number of Patients With Respiratory Compromise
timeFrame: 7 days
measure: Number of Patients With Symptomatic Cerebral Edema
timeFrame: 7 days
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital / Barrow Neurological Institute
state: Arizona
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Chicago
country: United States
facility: RUSH University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Medical Center
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas Health Sciences Center
state: Texas
city: Calgary
country: Canada
facility: Foothills Hospital - University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta - Mackenzie Health Sciences Centre
state: Alberta
city: Québec
country: Canada
facility: CHU de Québec - Hôpital de l'Enfant-Jésus
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Magdy Selim, MD, PhD
role: STUDY_CHAIR
References:
citation: Yeatts SD, Palesch YY, Moy CS, Selim M. High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. Neurocrit Care. 2013 Oct;19(2):257-66. doi: 10.1007/s12028-013-9861-y.
citation: Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, Morgenstern LB, Schlaug G, Torbey M, Waldman B, Xi G, Palesch Y; Deferoxamine Mesylate in Intracerebral Hemorrhage Investigators. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke. 2011 Nov;42(11):3067-74. doi: 10.1161/STROKEAHA.111.617589. Epub 2011 Aug 25.
citation: Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke. 2009 Mar;40(3 Suppl):S90-1. doi: 10.1161/STROKEAHA.108.533125. Epub 2008 Dec 8.
citation: Hatakeyama T, Okauchi M, Hua Y, Keep RF, Xi G. Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats. Transl Stroke Res. 2013 Oct;4(5):546-53. doi: 10.1007/s12975-013-0270-5.
citation: Xie Q, Gu Y, Hua Y, Liu W, Keep RF, Xi G. Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. Stroke. 2014 Jan;45(1):290-2. doi: 10.1161/STROKEAHA.113.003033. Epub 2013 Oct 30.
citation: Okauchi M, Hua Y, Keep RF, Morgenstern LB, Schallert T, Xi G. Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke. 2010 Feb;41(2):375-82. doi: 10.1161/STROKEAHA.109.569830. Epub 2009 Dec 31.
citation: Sonni S, Lioutas VA, Selim MH. New avenues for treatment of intracranial hemorrhage. Curr Treat Options Cardiovasc Med. 2014 Jan;16(1):277. doi: 10.1007/s11936-013-0277-y.
citation: Lee KH, Lioutas VA, Marchina S, Selim M; iDEF Investigators. The Prognostic Roles of Perihematomal Edema and Ventricular Size in Patients with Intracerebral Hemorrhage. Neurocrit Care. 2022 Oct;37(2):455-462. doi: 10.1007/s12028-022-01532-0. Epub 2022 Jun 8.
citation: Foster L, Robinson L, Yeatts SD, Conwit RA, Shehadah A, Lioutas V, Selim M; i-DEF Investigators. Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial. Stroke. 2022 Jul;53(7):2204-2210. doi: 10.1161/STROKEAHA.121.037298. Epub 2022 Mar 21.
citation: Wei C, Wang J, Foster LD, Yeatts SD, Moy C, Mocco J, Selim M; i-DEF Investigators. Effect of Deferoxamine on Outcome According to Baseline Hematoma Volume: A Post Hoc Analysis of the i-DEF Trial. Stroke. 2022 Apr;53(4):1149-1156. doi: 10.1161/STROKEAHA.121.035421. Epub 2021 Nov 18.
citation: Lun R, Yogendrakumar V, Ramsay T, Shamy M, Fahed R, Selim MH, Dowlatshahi D. Predicting long-term outcomes in acute intracerebral haemorrhage using delayed prognostication scores. Stroke Vasc Neurol. 2021 Dec;6(4):536-541. doi: 10.1136/svn-2020-000656. Epub 2021 Mar 23.
citation: Selim M, Foster LD, Moy CS, Xi G, Hill MD, Morgenstern LB, Greenberg SM, James ML, Singh V, Clark WM, Norton C, Palesch YY, Yeatts SD; i-DEF Investigators. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2019 May;18(5):428-438. doi: 10.1016/S1474-4422(19)30069-9. Epub 2019 Mar 18.