Remote Ischemic Conditioning for the Treatment of Intracerebral Hemorrhage (RICH-2)

The Safety and Efficacy of Remote Ischemic Conditioning for the Treatment of Intracerebral Hemorrhage: A Multicenter, Randomized, Controlled Study

Intracerebral hemorrhage (ICH) results from the rupture of small vessels damaged by chronic hypertension, amyloid angiopathy or other disease. Currently, ICH has been a devastating type of stroke that lacking effective therapy. Remote ischemic conditioning (RIC), a systematically protective strategy, has been found to have neuroprotective effects by in patients with ischemic stroke. In addition, animal studies show that RIC is safe in ICH model and it could accelerate the absorption of hematoma. In a previous clinical study (RICH-1), RIC have been found to be safe and well-tolerated in patients with ICH. Therefore, the investigators plan to undertake this study to further evaluate the safety and efficacy of RIC in patients with ICH.

The investigators hypothesize that treatment with RIC will accelerate the absorption of hematoma and improve patients' functional outcomes. Results of this study can potentially bring into account new means to improve the outcomes of ICH patients.

Study Overview

• Status: Recruiting
• Conditions: Acute Stroke; Intracerebral Hemorrhage
• Intervention / Treatment: Device: Remote ischemic conditioning; Drug: Standard medication therapy; Device: Sham remote ischemic conditioning

• Study Type: Interventional
• Enrollment (Anticipated): 452
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Xunming Ji, MD, PhD; Phone Number: 010-83199430; Email: jixm@ccmu.edu.cn
• Study Contact Backup: Name: Wenbo Zhao, MD, PhD; Phone Number: 86-13120136877; Email: zhaowb@xwh.ccmu.edu.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100053
      • Active, not recruiting
      • Xuanwu Hospital, Capital Medical University
    • Beijing, Beijing, China
      • Active, not recruiting
      • Beijing Red Cross Emergency Rescue Center
  • Beijng
    • Beijing, Beijng, China
      • Not yet recruiting
      • Beijing Renhe Hospital
      • Contact: Na Li, M.D.
  • Hebei
    • Chengde, Hebei, China
      • Recruiting
      • Chengde Central Hospital
      • Contact: Jiangtao Zhang
    • Hengshui, Hebei, China
      • Recruiting
      • The Six People's Hospital of Hengshui
      • Contact: Xinjing Gao
  • Henan
    • Nanyang, Henan, China
      • Recruiting
      • Nanshi Hospital of Nanyang
      • Contact: Rongyao Ma
  • Inner Mongolia Autonomous Region
    • Tongliao, Inner Mongolia Autonomous Region, China
      • Not yet recruiting
      • Tongliao Municipal Hosptial
  • Jiangsu
    • Changzhou, Jiangsu, China
      • Recruiting
      • The First People's Hospital of Changzhou
      • Contact: Song Yang, M.D.
    • Xuzhou, Jiangsu, China
      • Recruiting
      • The Affiliated Hospital of Xuzhou Medical University
      • Contact: Deqin Geng, MD
  • Tianjin
    • Tianjin, Tianjin, China, 300350
      • Recruiting
      • Tianjin Huanhu Hospital
      • Contact: Ming Wei, MD
  • Zhejiang
    • Jiaxing, Zhejiang, China
      • Not yet recruiting
      • Jiaxing Second Hospital
      • Contact: Jianguo Shen
    • Shaoxing, Zhejiang, China, 312000
      • Recruiting
      • Shaoxing People's Hospital
      • Contact: Xuebin Yu, MD
    • Zhuji, Zhejiang, China
      • Active, not recruiting
      • Zhuji People's Hospital of Zhejaing Province

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 and ≤ 80 years
2. The diagnosis of supratentorial ICH is confirmed by brain CT scan
3. Hematoma volume of 10 to 30 ml and Glasgow Coma Score (GCS)>8 at randomization.
4. National Institutes of Health Stroke Scale (NIHSS)≥6 and ≤20 points at randomization.
5. Randomization and starting treatment between 24 and 48 hours of symptom ictus.
6. Signed and dated informed consent is obtained.

Exclusion Criteria:

1. Planned surgical evacuation of ICH prior to administration of investigational intervention
2. ICH concomitant with subarachnoid hemorrhage or intraventricular hemorrhage
3. Suspected secondary ICH related to tumor, ruptured aneurysm or arteriovenous malformation, hemorrhagic transformation of an ischemic infarct, or venous sinus thrombosis
4. Patients with a pre-existing neurological deficit (mRS>1) or psychiatric disease that would confound the neurological or functional evaluations.
5. 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
6. Severe renal disease (i.e., renal disorder requiring dialysis ) or eGFR <30ml/min/1.73m2
7. Severe liver disorder, or ALT >3 times or bilirubin >2 times upper limit of normal
8. Known severe hearing loss or cognitive impairment
9. Known pregnancy, or positive pregnancy test, or breastfeeding
10. Patients known or suspected of not being able to comply with the study protocol due to alcoholism, noncompliance or any other cause
11. Life expectancy of less than 90 days due to co-morbid conditions
12. Concurrent participation in another research protocol for investigation of another experimental therapy
13. Severe, sustained hypertension (Systolic blood pressure> 180 mmHg or diastolic blood pressure> 110 mmHg).
14. Contraindication for remote ischemic conditioning: severe soft tissue injury, fracture, or peripheral vascular disease in the upper limbs.
15. Any condition which, in the judgement of the investigator, might increase the risk to the patient.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention group; Subjects in the intervention group will receive remote ischemic conditioning and standard background medical treatment.	Device: Remote ischemic conditioning; RIC is a non-invasive therapy that performed by an electric autocontrol device with cuff placed on arm. RIC procedures consist of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuff on one arm. The procedure will be performed once daily for consecutive 7 days after enrollment.; Other Names: RIC; Drug: Standard medication therapy; Standard medication therapy will be performed according to the national and international guidelines.
PLACEBO_COMPARATOR: Sham group; Subjects in the placebo group will receive sham remote ischemic conditioning and standard background medical treatment alone.	Drug: Standard medication therapy; Standard medication therapy will be performed according to the national and international guidelines.; Device: Sham remote ischemic conditioning; Sham RIC will be performed by the same electric autocontrol device with cuff placed on arm. Sham RIC procedures consist of five cycles of 5-min inflation (30 mmHg) and 5-min deflation of cuff on one arm. The procedure will be performed once daily for consecutive 7 days after enrollment.; Other Names: Sham RIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Modified Rankin Scale (mRS) Score 0-2 at 90 Days	The mRS ranges from 0 to 6, with higher scores indicating worse outcome. The primary outcome measure is the mRS score, dichotomized to define favorable functional outcome as mRS 0-2 at 90 days.	0-90 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Experiencing Serious Adverse Events	Number of subjects experiencing Serious adverse events at any time from randomization through day 90	90 days
Number of Subjects With Serious Adverse Events Within 7 Days	Number of Subjects Experiencing Serious Adverse Events within 7 days of randomization	7 days
Proportion of Patients With mRS Score 0-3 at 90 Days	The mRS ranges from 0 to 6, with higher scores indicating worse outcome. Another measure of efficacy is the mRS score, dichotomized to define good functional outcome as mRS 0-3 at 90 days.	90 days
Proportion of Patients With mRS Score 0-2 at 180 Days	The mRS ranges from 0 to 6, with higher scores indicating worse outcome. Another measure of efficacy is the mRS score, dichotomized to define good functional outcome as mRS 0-2 at 180 days.	180 days
Proportion of Patients With mRS Score 0-3 at 180 Days	The mRS ranges from 0 to 6, with higher scores indicating worse outcome. Another measure of efficacy is the mRS score, dichotomized to define good functional outcome as mRS 0-3 at 180 days.	180 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of intracerebral hematoma volume	Intracerebral hematoma volume (ml) is assessed by CT brain scan	0-7 days after enrollment.
Changes of perihematomal edema volume	Perihematomal edema volume (ml) is assessed by CT brain scan	0-7 days after enrollment.
Ordinal Distribution of Scores on mRS at Day 90	The overall ordinal distribution of scores on mRS at 90 days in all subjects of two groups will be determined.	90 days
Ordinal Distribution of Scores on mRS at Day 180	The overall ordinal distribution of scores on mRS at 180 days in all subjects of two groups will be determined.	180 days

Collaborators and Investigators

• Sponsor: Capital Medical University

Publications and helpful links

General Publications

• Shoamanesh A, Patrice Lindsay M, Castellucci LA, Cayley A, Crowther M, de Wit K, English SW, Hoosein S, Huynh T, Kelly M, O'Kelly CJ, Teitelbaum J, Yip S, Dowlatshahi D, Smith EE, Foley N, Pikula A, Mountain A, Gubitz G, Gioia LC. Canadian stroke best practice recommendations: Management of Spontaneous Intracerebral Hemorrhage, 7th Edition Update 2020. Int J Stroke. 2021 Apr;16(3):321-341. doi: 10.1177/1747493020968424. Epub 2020 Nov 11.
• 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.
• Zhao W, Jiang F, Li S, Liu G, Wu C, Wang Y, Ren C, Zhang J, Gu F, Zhang Q, Gao X, Gao Z, Song H, Ma Q, Ding Y, Ji X; RICH-1 Investigators. Safety and efficacy of remote ischemic conditioning for the treatment of intracerebral hemorrhage: A proof-of-concept randomized controlled trial. Int J Stroke. 2022 Apr;17(4):425-433. doi: 10.1177/17474930211006580. Epub 2021 Apr 7.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 22, 2021
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): June 30, 2023

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (ACTUAL): December 8, 2020

Study Record Updates

• Last Update Posted (ACTUAL): July 19, 2022
• Last Update Submitted That Met QC Criteria: July 16, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Therapy; Neuroprotection
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Stroke; Hemorrhage; Cerebral Hemorrhage
• Other Study ID Numbers: RICH-2

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