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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Cerebrovascular Disorders, Pontine Hemorrhage, Primary, Surgery

Intervention / Treatment
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* Procedure: hematoma evacuation by craniotomy
* Procedure: hematoma evacuation by stereotactic puncture
* Procedure: hematoma evacuation by neuroendoscopy
* Other: life support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of PPH: patients have acute hemorrhage mainly in pons with a definite history of hypertension. GCS 5 7 and HV≥5ml on admission (the HV in intraventricular system being excluded). Family members consenting to randomize and signing informed consent form (ICF). Time from onset to admission less than 24 hours. Age:18 years or older. Exclusion Criteria: Structural lesions such as brainstem cavernous malformation, arteriovenous malformation, aneurysm, tumor apoplexy. GCS≥8 and HV<5ml. Time from onset to admission over 24 hours. Patients with platelet count < 100,000, International Normalized Ratio (INR)> 1.4, or an elevated prothrombin time (PT) and activated partial thromboplastin time (APTT). Multiple ICH. Accompanying hydrocephalus that requires surgical management Irreversible brainstem failure (bilateral fixed, dilated pupils and extensor motor posturing, GCS≤4). A previous history of ICH. Any serious concurrent illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease. Pregnant patients. Patients' family members refuse HE. Any other condition that the investigator believes would present a significant hazard to the subject if the investigational therapy were initiated. Participating in another simultaneous trial of ICH treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A sample size of 60 would be required to demonstrate a significant level of 5% (two-sided) with 80% power. Considering the 6% missing rate during follow-up, the total sample size was 64 cases with 16 and 48 cases in MT and HE group, respectively.
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 |