A Clinical Trial About the Safety of Surgical Treatment in Severe Primary Pontine Hemorrhage (STIPE)

Safety of Surgical Treatment In Severe Primary Pontine Hemorrhage Evacuation (STIPE): a Multicentric, Randomized, Controlled, Open-label Trial

Primary pontine hemorrhage (PPH) is not common but is the most catastrophic subtype of intracerebral hemorrhage, with acute mortality between 30% and 60%. For severe PPH, defined as Glasgow Coma score (GCS) <8 and hematoma volume≥5ml, the mortality rate is as high as 80-100%. Guidelines from the American Heart Association and European Stroke Organization do not make definite specifications. More than a century after Finkelnburg first explored the brainstem for hematoma, however, plenty of researches have shown surgery can save lives and improve the prognosis for selective patients and can be an effective and safe treatment. This study is proposed to validate the safety of surgical treatment in severe primary pontine hemorrhage.

Study Overview

• Status: Recruiting
• Conditions: Cerebrovascular Disorders; Surgery; Primary; Pontine Hemorrhage
• Intervention / Treatment: Other: life support; Procedure: hematoma evacuation by craniotomy; Procedure: hematoma evacuation by stereotactic puncture; Procedure: hematoma evacuation by neuroendoscopy

Detailed Description

The study is being conducted from Jan 2022 to Nov 2024 in 20 neurosurgical units. This STIPE trial is an investigator-initiated, parallel (3:1 to surgical HE or MT), multi-centre, randomized controlled open-label trial following the Consolidated Standards of Reporting Trials (CONSORT) guidelines and will be conducted from Jan 2022 to Nov 2024 in 20 Tertiary hospitals in China. The flow chart of the clinical trial is presented in Figure 1. Neurosurgeons involved in the study are senior investigators with good clinical experience in sPPH management. Moreover, all investigators are well trained centrally according to the requirements.

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chao You, MD; Phone Number: +86 028-85422488; Email: youchao@vip.126.com
• Study Contact Backup: Name: Qiang He, MD; Phone Number: +86 15099189463; Email: heqiang629@126.com

Study Locations

• China
  • Baoji, China
    • Recruiting
    • The Third Hospital of the People's Liberation Army
    • Contact: Rongjun Zhang
  • Beijing, China
    • Recruiting
    • The seventh medical center of the Army General Hospital
    • Contact: Hongtian Zhang, MD
  • Hangzhou, China
    • Recruiting
    • Second Affiliated Hospital of Zhejiang University School of Medicine
    • Contact: Fengqiang Liu
  • Shanghai, China
    • Recruiting
    • Huashan Hospital of Fudan University
    • Contact: Jian Yu, MD
  • Shanghai, China
    • Recruiting
    • Shanghai No.10 hospital
    • Contact: Liang Gao, MD
  • Shanghai, China
    • Recruiting
    • Xuhui Hospital of Zhongshan Hospital affiliated to Fudan
    • Contact: Shujie Sun, MD
  • Anhui
    • Hefei, Anhui, China
      • Recruiting
      • The First Affiliated Hospital of Anhui Medical University
      • Contact: Hongwei Cheng, MD
  • Fujian
    • Fuzhou, Fujian, China
      • Recruiting
      • The First Affiliated Hospital Of Fujian Medical University
      • Contact: Dezhi Kang, MD
  • Guangdong
    • Gaozhou, Guangdong, China
      • Recruiting
      • Gaozhou Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine
      • Contact: Jinhua Yang, MD
    • Guangzhou, Guangdong, China
      • Recruiting
      • Guangdong Sanjiu Brain Hospital
      • Contact: Linsen Mu, MD
    • Shenzhen, Guangdong, China, 518000
      • Recruiting
      • University of Chinese Academy of Sciences Shenzhen Hospital
      • Contact: Xuezheng Fan, MD; Phone Number: 18126081550; Email: 835646710@qq.com
    • Shenzhen, Guangdong, China
      • Recruiting
      • The Second Affiliated Hospital of South China University of Technology
      • Contact: Jiangang Liu, MD
    • Zhuhai, Guangdong, China
      • Recruiting
      • Zhuhai People's Hospital
      • Contact: Gang Chen, MD
  • Heilongjiang
    • Harbin, Heilongjiang, China
      • Recruiting
      • The First Affiliated Hospital Of Harbin Medical University
      • Contact: Hongsheng Liang, MD
  • Henan
    • Zhengzhou, Henan, China
      • Recruiting
      • The Second Affiliated Hospital Of Zhengzhou University
      • Contact: Zhan Liu, MD
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Recruiting
      • General Hospital of the Eastern Theater
      • Contact: Chiyuan Ma, MD
  • Shanxi
    • Taiyuan, Shanxi, China
      • Recruiting
      • Shanxi Bethune Hospital
      • Contact: Xinming Ding, MD
  • Sichuan
    • Chengdu, Sichuan, China
      • Recruiting
      • West China Hospital of Sichuan University
      • Contact: Chao You, MD
    • Mianyang, Sichuan, China
      • Recruiting
      • Mianyang Central Hospital
      • Contact: Zongping Li, MD
    • Nanchong, Sichuan, China
      • Recruiting
      • Affiliated Hospital of North Sichuan Medical College
      • Contact: Xiaoping Tang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Clinical diagnosis of PPH: patients have acute hemorrhage mainly in pons with a definite history of hypertension.
2. GCS 5~7 and HV≥5ml on admission (the HV in intraventricular system being excluded).
3. Family members consenting to randomize and signing informed consent form (ICF).
4. Time from onset to admission less than 24 hours.
5. Age:18 years or older.

Exclusion Criteria:

1. Structural lesions such as brainstem cavernous malformation, arteriovenous malformation, aneurysm, tumor apoplexy.
2. GCS≥8 and HV<5ml.
3. Time from onset to admission over 24 hours.
4. Patients with platelet count < 100,000, International Normalized Ratio (INR)> 1.4, or an elevated prothrombin time (PT) and activated partial thromboplastin time (APTT).
5. Multiple ICH.
6. Accompanying hydrocephalus that requires surgical management
7. Irreversible brainstem failure (bilateral fixed, dilated pupils and extensor motor posturing, GCS≤4).
8. A previous history of ICH.
9. Any serious concurrent illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease.
10. Pregnant patients.
11. Patients' family members refuse HE.
12. Any other condition that the investigator believes would present a significant hazard to the subject if the investigational therapy were initiated.
13. Participating in another simultaneous trial of ICH treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: medical group; Patients receive only medical treatment including active life support, nutritional support, homeostasis maintenance of the internal environment, and other symptomatic treatment.	Other: life support; The treatments in medical group includes life support, nutrition support, and rehabilitation therapy。
Experimental: surgical group; Patients receive intervention such as the evacuation of hematoma under craniotomy or by stereotactic puncture or neuroendoscopy.	Procedure: hematoma evacuation by craniotomy; The intervention method of hematoma evacuation is under craniotomy.; Procedure: hematoma evacuation by stereotactic puncture; The intervention method of hematoma evacuation is under stereotactic puncture.; Procedure: hematoma evacuation by neuroendoscopy; The intervention method of hematoma evacuation is under neuroendoscopy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome Number 1: Rate of Mortality	Percentage of participants who died during the first 30 days after randomization.	30 days from randomization
Safety Outcome Number 2: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis	Percentage of participants who had a bacterial brain infection (cerebritis, meningitis, ventriculitis) within 30 days of randomization.	30 days from randomization
Safety Outcome Number 3: Rate of Symptomatic Rebleeding	The difference in the rate of symptomatic rebleeding 72 hours post surgery.	72 hours post surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the rate of hematoma clearance 3 days after surgery	the rate of hematoma clearance 3 days after surgery	3 days after surgery
all-cause mortality at 365 days	all-cause mortality at 365 days	365 days after surgery
neurological functional status of 30 days, 90 days, 180 days, and 365 days measured by Modified Rankin Scale (mRS), GCS and GOS.	neurological functional status of 30 days, 90 days, 180 days, and 365 days measured by Modified Rankin Scale (mRS), GCS and GOS.	30 days, 90 days, 180 days, and 365 days after surgery
The Extended Glasgow Outcome Scale (EGOS) at 180 days and 365 days	The Extended Glasgow Outcome Scale (EGOS) at 180 days and 365 days	180 days and 365 days after surgery
The 5-level EuroQol five dimensions questionnaire (EQ-5D) version (EQ-5D-5L) at 180 days and 365 days	The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The former descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The latter is numbered from 0 to 100. 100 means the best health you can imagine. 0 means the worst health you can imagine.	180 days and 365 days after surgery
the National Institutes of Health Stroke Scale (NIHSS) at 180 days and 365 days	the National Institutes of Health Stroke Scale (NIHSS) at 180 days and 365 days	180 days and 365 days after surgery

Collaborators and Investigators

• Sponsor: West China Hospital
• Investigators: Principal Investigator: Chao You, MD, West China Hospital

Publications and helpful links

General Publications

• Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, Fung GL, Goldstein JN, Macdonald RL, Mitchell PH, Scott PA, Selim MH, Woo D; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015 Jul;46(7):2032-60. doi: 10.1161/STR.0000000000000069. Epub 2015 May 28.
• Morotti A, Jessel MJ, Brouwers HB, Falcone GJ, Schwab K, Ayres AM, Vashkevich A, Anderson CD, Viswanathan A, Greenberg SM, Gurol ME, Romero JM, Rosand J, Goldstein JN. CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage. Neurocrit Care. 2016 Aug;25(1):79-85. doi: 10.1007/s12028-016-0241-2.
• Ye Z, Huang X, Han Z, Shao B, Cheng J, Wang Z, Zhang Z, Xiao M. Three-year prognosis of first-ever primary pontine hemorrhage in a hospital-based registry. J Clin Neurosci. 2015 Jul;22(7):1133-8. doi: 10.1016/j.jocn.2014.12.024. Epub 2015 May 14.
• Tao C, Li H, Wang J, You C. Predictors of Surgical Results in Patients with Primary Pontine Hemorrhage. Turk Neurosurg. 2016;26(1):77-83. doi: 10.5137/1019-5149.JTN.12634-14.1.
• Huang K, Ji Z, Sun L, Gao X, Lin S, Liu T, Xie S, Zhang Q, Xian W, Zhou S, Gu Y, Wu Y, Wang S, Lin Z, Pan S. Development and Validation of a Grading Scale for Primary Pontine Hemorrhage. Stroke. 2017 Jan;48(1):63-69. doi: 10.1161/STROKEAHA.116.015326. Epub 2016 Dec 8.
• Indredavik B, Bakke F, Slordahl SA, Rokseth R, Haheim LL. Stroke unit treatment. 10-year follow-up. Stroke. 1999 Aug;30(8):1524-7. doi: 10.1161/01.str.30.8.1524.
• Steiner T, Al-Shahi Salman R, Beer R, Christensen H, Cordonnier C, Csiba L, Forsting M, Harnof S, Klijn CJ, Krieger D, Mendelow AD, Molina C, Montaner J, Overgaard K, Petersson J, Roine RO, Schmutzhard E, Schwerdtfeger K, Stapf C, Tatlisumak T, Thomas BM, Toni D, Unterberg A, Wagner M; European Stroke Organisation. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014 Oct;9(7):840-55. doi: 10.1111/ijs.12309. Epub 2014 Aug 24.
• Lui TN, Fairholm DJ, Shu TF, Chang CN, Lee ST, Chen HR. Surgical treatment of spontaneous cerebellar hemorrhage. Surg Neurol. 1985 Jun;23(6):555-8. doi: 10.1016/0090-3019(85)90002-3.
• Ichimura S, Bertalanffy H, Nakaya M, Mochizuki Y, Moriwaki G, Sakamoto R, Fukuchi M, Fujii K. Surgical Treatment for Primary Brainstem Hemorrhage to Improve Postoperative Functional Outcomes. World Neurosurg. 2018 Dec;120:e1289-e1294. doi: 10.1016/j.wneu.2018.09.055. Epub 2018 Sep 19.
• Mangiardi JR, Epstein FJ. Brainstem haematomas: review of the literature and presentation of five new cases. J Neurol Neurosurg Psychiatry. 1988 Jul;51(7):966-76. doi: 10.1136/jnnp.51.7.966.
• Rohde V, Berns E, Rohde I, Gilsbach JM, Ryang YM. Experiences in the management of brainstem hematomas. Neurosurg Rev. 2007 Jul;30(3):219-23; discussion 223-4. doi: 10.1007/s10143-007-0081-9. Epub 2007 May 8.
• Murata Y, Yamaguchi S, Kajikawa H, Yamamura K, Sumioka S, Nakamura S. Relationship between the clinical manifestations, computed tomographic findings and the outcome in 80 patients with primary pontine hemorrhage. J Neurol Sci. 1999 Aug 15;167(2):107-11. doi: 10.1016/s0022-510x(99)00150-1.
• Cao S, Zheng M, Hua Y, Chen G, Keep RF, Xi G. Hematoma Changes During Clot Resolution After Experimental Intracerebral Hemorrhage. Stroke. 2016 Jun;47(6):1626-31. doi: 10.1161/STROKEAHA.116.013146. Epub 2016 Apr 28.
• Wilkinson DA, Keep RF, Hua Y, Xi G. Hematoma clearance as a therapeutic target in intracerebral hemorrhage: From macro to micro. J Cereb Blood Flow Metab. 2018 Apr;38(4):741-745. doi: 10.1177/0271678X17753590. Epub 2018 Jan 19.
• Parraga RG, Possatti LL, Alves RV, Ribas GC, Ture U, de Oliveira E. Microsurgical anatomy and internal architecture of the brainstem in 3D images: surgical considerations. J Neurosurg. 2016 May;124(5):1377-95. doi: 10.3171/2015.4.JNS132778. Epub 2015 Oct 30.
• He Q, Wang J, Ma L, Li H, Tao C, You C. Safety of surgical Treatment In severe primary Pontine haemorrhage Evacuation (STIPE): study protocol for a multi-centre, randomised, controlled, open-label trial. BMJ Open. 2022 Aug 23;12(8):e062233. doi: 10.1136/bmjopen-2022-062233.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: November 17, 2020
• First Submitted That Met QC Criteria: November 22, 2020
• First Posted (Actual): November 30, 2020

Study Record Updates

• Last Update Posted (Actual): December 8, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hemorrhage; Cerebrovascular Disorders
• Other Study ID Numbers: STIPE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No