Deferoxamine and Xingnaojing Injection Treatment in Intracerebral Hemorrhage

Intracerebral Hemorrhage Clinical Trial

Official title:

Safety and Effectiveness Study of Deferoxamine and Xingnaojing Injection in Intracerebral Hemorrhage

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02367248
• Other study ID #: MHe
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: February 13, 2015
• Last updated: May 14, 2015
• Start date: March 2015
• Est. completion date: December 2016

Study information

• Verified date: May 2015
• Source: Capital Medical University
• Contact: Maolin He, MD
• Phone: 0086-010-63926550
• Email: maolinh[@]sina.com
• Is FDA regulated: No
• Health authority: China: Beijing Municipal Science and Technology Commission
• Study type: Interventional

Clinical Trial Summary

The main purpose of this study is to determine whether deferoxamine and xingnaojing injection is effective and safe as a treatment for intracerebral hemorrhage.

Description:

Research shows that more than 1/3 of patients with acute cerebral hemorrhage in the first 24 hours will be expanding hematoma. The treatment of acute cerebral hemorrhage has two main targets: prevention of hematoma enlargement in primary brain damage; Reduce hematoma secondary brain damage caused by blood toxicity degradation products. At present, the curative effect of drug treatment of acute cerebral hemorrhage remains limited, using drug therapy to treat hematoma caused by blood toxicity degradation products secondary brain damage, is one of the main current international research direction and hotspot. Recent studies have found that iron overload in cells in acute cerebral hemorrhage stove weeks edema secondary lesion plays a very important role. Acute cerebral hemorrhage animal model research and small sample clinical study has shown that the iron chelator deferoxamine has good curative effect and security. Currently ongoing international HI-DEF test plans to assess the efficacy and safety of high-dose deferoxamine treatment within 24 h of patients with acute cerebral hemorrhage.

Basic research shows Xingnaojing injection can inhibit inflammatory reaction, scavenging free radicals, relieve acute cerebral hemorrhage hematoma surrounding edema and has a variety of brain protection mechanism. The current study builds on these results to assess the potential utility of deferoxamine and Xingnaojing injection as a therapeutic intervention in ICH.

This is a prospective, multi-center, double-blind, randomized, placebo-armed clinical study to test the safety and effectiveness of deferoxamine and Xingnaojing injection treatment in intracerebral hemorrhage. The investigators will randomize 180 subjects with ICH equally (1:1:1) to either DFO at 40mg/kg/day (up to a maximum daily dose of 6000 mg/day), or Xingnaojing injection, or saline placebo, given by continuous IV infusion for 5 consecutive days. Treatment will be initiated within 12 hours after ICH symptom onset.

The main objectives are:

1. Examining the effects of DFO and Xingnaojing injection on peri-hematoma edema (PHE) volume progression between baseline and post-treatment CT/MRI scans and the residual cavity volume at 90 days.

2. Obtaining data on the National Institute of Health Stroke Scale (NIHSS) to explore the effects of treatment on neurological functions.

3. Examining the effects of DFO and Xingnaojing injection on biomarkers of acute cerebral hemorrhage such as ferritin, interleukin - 6, matrix metalloproteinase 9, tumor necrosis factor alpha and so on.

4. Study the traditional Chinese medicine(TCM)curative effect evaluation of the roles of different treatment methods on secondary damage after ICH.

Secondary and exploratory objectives include:

1. Exploring whether the effect of DFO on outcome is dependent on initial ICH volume, after adjusting for other prognostic variables, to determine if specific limits for ICH volume should be specified as exclusion/inclusion criteria for future studies.

2. Exploring the differences between early (≤12h) and late (>12-24h) OTT windows in DFO treatment effect on functional outcome.

Exploratory study shows that iron chelator deferoxamine is effective and safe in the treatment of acute cerebral hemorrhage. We choose within 12 hours as the treatment time window, different from within 24 hours in the current international ongoing HI-DEF test. In theory, the earlier, the better curative effect. So this experiment is more likely to get a better curative effect. Xingnaojing injection is widely used in clinical in china, but lack of rigorous randomized controlled trial to prove its brain protection effect currently. Successful completion of this study will provide a crucial, reliable experimental evidence for a new treatment for acute cerebral hemorrhage. ICH is one of main causes of disability and death. A successful study demonstrating the efficacy of DFO and xingnaojing injection would be of considerable public health significance.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: December 2016
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Age = 18 and = 80 years

2. The diagnosis of ICH is confirmed by brain CT scan

3. NIHSS score = 6 and GCS > 6 upon presentation

4. The first dose of the study drug can be administered within 12h of ICH symptom onset

5. Functional independence prior to ICH, defined as pre-ICH mRS = 1

6. Signed and dated informed consent is obtained.

Exclusion Criteria:

1. Known hypersensitivity to deferoxamine or xingnaojing injection

2. Known severe iron deficiency anemia (defined as hemoglobin concentration < 7g/dL or requiring blood transfusions)

3. Abnormal renal function, defined as serum creatinine > 2 mg/dL

4. Planned surgical evacuation of ICH prior to administration of study drug

5. Suspected secondary ICH related to tumour, ruptured aneurysm or arteriovenous malformation, hemorrhagic transformation of an ischemic infarct, or venous sinus thrombosis

6. Infratentorial hemorrhage

7. Irreversibly impaired brainstem function (bilateral fixed and dilated pupils and extensor motor posturing)

8. 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)

9. Pre-existing disability, defined as pre-ICH mRS = 2

10. 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 low-molecular-weight heparin

11. Taking iron supplements containing = 325 mg of ferrous iron

12. Patients with heart failure taking > 500 mg of vitamin C daily

13. Known severe hearing loss

14. Known pregnancy, or positive pregnancy test, or breastfeeding

15. 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

16. Life expectancy of less than 90 days due to comorbid conditions

Study Design

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

Related Conditions & MeSH terms

• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage

Intervention

Drug:
• deferoxamine
Deferoxamine mesylate(40 mg/kg/day up to a maximum daily dose of 6000 mg/day) given by a continuous IV infusion for 5 consecutive days beginning within 12 hours of ICH symptom onset.
• Xingnaojing injection
Xingnaojing injection (20 ml/day) given by a continuous IV infusion for 5 consecutive days beginning within 12 hours of ICH symptom onset.
• Normal saline
This is a placebo. Normal saline will be given by a continuous IV infusion for 5 consecutive days beginning within 12 hours of ICH symptom onset.

Locations

Country	Name	City	State
China	Department of Neurology,Beijing Shijitan Hospital,Capital Medical University	Beijing

Sponsors (21)

Lead Sponsor

Collaborator

Capital Medical University

Beijing Aerospace General Hospital, Beijing Ditan Hospital, Beijing Fangshan District Liangxiang Hospital, Beijing Haidian Hospital, Beijing Jishuitan Hospital, Beijing Luhe Hospital, Beijing Neurosurgical Institute, Beijing Pinggu District Hospital, Beijing Shuyi Hospital, Beijing Tiantan Hospital, Beijing Youyi Hospital, Chinese PLA General Hospital, General Hospital of Beijing PLA Military Region, Peking University First Hospital, Peking University People's Hospital, Peking University Third Hospital, People’s Hospital of Beijing Daxing District, The 263 Hospital of PLA, The Second Artillery General Hospital, Xiyuan Hospital of China Academy of Chinese Medical Sciences

Country where clinical trial is conducted

China, 

References & Publications (8)

Chaudhary N, Gemmete JJ, Thompson BG, Xi G, Pandey AS. Iron--potential therapeutic target in hemorrhagic stroke. World Neurosurg. 2013 Jan;79(1):7-9. doi: 10.1016/j.wneu.2012.11.048. Epub 2012 Nov 19. — View Citation

Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Blas YS, Dzialowski I, Kobayashi A, Boulanger JM, Lum C, Gubitz G, Padma V, Roy J, Kase CS, Kosior J, Bhatia R, Tymchuk S, Subramaniam S, Gladstone DJ, Hill MD, Aviv RI; PREDICT/Sunnybrook ICH CTA study group. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol. 2012 Apr;11(4):307-14. doi: 10.1016/S1474-4422(12)70038-8. Epub 2012 Mar 8. Erratum in: Lancet Neurol. 2012 Jun;11(6):483. — View Citation

Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 2009 Jun;40(6):2241-3. doi: 10.1161/STROKEAHA.108.539536. Epub 2009 Apr 16. — View Citation

Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messé SR, Mitchell PH, Selim M, Tamargo RJ; American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010 Sep;41(9):2108-29. doi: 10.1161/STR.0b013e3181ec611b. Epub 2010 Jul 22. — View 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. — View Citation

Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke. 2009 May;40(5):1858-63. doi: 10.1161/STROKEAHA.108.535765. Epub 2009 Mar 12. — View 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. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Numbers of patients with the perihematomal edema (PHE) volume variation.	decreases of more than 20% from initial PHE volumes were defined as "decreased" PHE volume; increases of more than 20% from initial PHE volumes were defined as "increased" PHE volume; changes between -20% and 20% were defined as "unchanged".	7 days	No
Secondary	The residual cavity volume	the variation of residual cavity volume of	90 days	No
Secondary	The variation of the mRS score and the Bathel Index	the variation of mRS score and Bathel Index of different treated subjects from ICH onset to treatment time windows.	90 days	No
Secondary	mortality	the mortality of different treated subjects from ICH onset to treatment time windows.	90 days	Yes
Secondary	Frequency of Treatment-related Adverse Events	The safety endpoints will include all DFO-related adverse events until day-7 or discharge (whichever is earlier), and DFO-related SAEs and through day-90.	90 days	Yes