GLP-1 Receptor Agonist in Primary Intracerebral Hemorrhage: A Phase 2 Randomized Trial (GLICH)
Intracerebral hemorrhage (ICH) is a devastating form of acute stroke with poor clinical outcomes. Although ICH accounted only for 28.8% of incident strokes, it was responsible for nearly half of the long-term burden of stroke measured in disability-adjusted life years . In contrast to the improving outcomes seen in ischemic stroke with advances in reperfusion therapy, outcomes of patients with ICH have shown little progress over the past two decades. Current standard care focuses primarily on blood pressure control and supportive management, yet rate of functional independence remained modest. Randomized evidence suggested that fewer than half of the ICH patients achieved independent activities of daily living even with intensive blood pressure lowering.
A cascade of pathophysiological events is thought to determine the prognosis of ICH. First, the mass effect of the hematoma and its expansion with uncontrolled blood pressure cause primary neuronal injury. Second, neuroinflammation involving blood-brain barrier (BBB) dysfunction, activated microglia and astrocytes, together with neutrophil infiltration in response to extravascular blood, propagates neuronal injury, leading to perihematomal edema. Third, the direct neurotoxicity of blood breakdown products and oxidative stress may further amplify neuroinflammation. Mitigating hematoma expansion through intensive blood pressure control therefore only addresses one of these three pathophysiological processes, and is constrained by a short treatment window, mostly within 6 hours. Therapeutic strategies targeting secondary neuroinflammation should therefore be actively pursued. In addition, multimodal studies incorporating longitudinal imaging and omics markers are needed to elucidate the key pathways mediating neuroinflammation following ICH.
Recent preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RA) may offer neuroprotective benefits in ICH. In animal models of ICH, intracerebroventricular liraglutide suppressed neuroinflammation, prevented brain edema, and reduced neurologic deficits. Previous work from our group has also shown that, across several animal models, GLP-1RA attenuates BBB dysfunction and suppresses neuroinflammatory signaling via microglial modulation. Importantly, a recent translational clinical trial by our team has also provided preliminary evidence that GLP-1RA exerts neuroprotective effects in patients with large vessel occlusion strokes. We therefore hypothesize that compared to standard therapy, administration of GLP-1RA in patients with primary ICH may limit perihaematomal edema, reduce secondary brain injury, and improve neurological outcomes.
In this phase 2, randomized, open-label pilot study with blinded endpoint assessment, we aim to determine the safety and signals for efficacy of GLP-1RA in patients with primary ICH.
調査の概要
詳細な説明
GLP-1RA in Primary Intracerebral Hemorrhage (GLICH) trial is an investigator-initiated, phase 2, multicenter, randomized, open-label trial with blinded endpoint assessment, conducted across centers in Hong Kong Special Administrative Region (HKSAR), Wenzhou and Hefei, China. We aim to recruit 200 patients with primary ICH in the putamen (10-30mL) or thalamus (5-15mL) who present within 24 hours of last-known-well and meet all eligibility criteria. Participants will be randomized in a 1:1 ratio to receive additional semaglutide or just standard therapy after a written informed consent. Patients in the semaglutide group will receive subcutaneous injections of semaglutide on baseline (D0), Day 7 (D7), Day 14 (D14) and Day 21 (D21) after enrollment.
Serial imaging with non-contrast computed tomography (CT) will be performed at baseline, 3+/-1 days, and 7+/-1 days post-enrollment to assess hematoma volume, hematoma expansion, and perihematomal edema (PHE). Brain magnetic resonance imaging (MRI) will be arranged on Day 5-9 (D30) post-ICH to assess the degree of neuronal injury. Blood sampling for omics analysis will be collected at baseline, D3, D7, D14 and D30. Other investigations will be arranged according to clinical requirement. Clinical assessments including National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) will be obtained on D0, Day 90 (D90) and Day 180 (D180). Recruitment targets are 100 patients from Wenzhou, 75 from Hefei and 25 patients from HKSAR according to catchment area size.
研究の種類
入学 (推定)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前：Bonaventure Yiu Ming IP, MB ChB,PhD
- 電話番号：852-28902002
- メール：bonaventureip@cuhk.edu.hk
研究場所
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Anhui
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Hefei、Anhui、中国
- The First Affiliated Hospital of University of Science and Technology China
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コンタクト：
- Wei HU, MD
- メール：andinghu@ustc.edu.cn
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Zhejiang
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Wenzhou、Zhejiang、中国
- The First Affiliated Hospital of Wenzhou Medical University
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コンタクト：
- Xinshi WANG, MD
- メール：wangxinshi@wmu.edu.cn
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Hong Kong、香港
- Chinese University of Hong Kong
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コンタクト：
- Bonaventure Yiu Ming Ip, MBChB, PhD
- 電話番号：852-28902002
- メール：bonaventureip@cuhk.edu.hk
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
Inclusion Criteria:
- 1. Primary spontaneous ICH with hematoma location in putamen (10-30mL) or thalamus (5-15mL) on admission CT imaging. Both locations are selected because they are strongly associated with hypertensive arteriopathy-related ICH and there is limited evidence supporting neurosurgical intervention compared with posterior fossa hemorrhages. The thalamic and putaminal volume cutoffs are based on a recent observational study showing that restricting enrolment to 5-15 mL (thalamus) and 10-30 mL (putamen) enriches for patients with substantial but potentially modifiable prognosis while avoiding extremes with ceiling or floor effects. For patients with hematoma involving both putamen and thalamus, a volume cutoff of 5-30mL will be used.
- 2. National Institutes of Health Stroke Scale (NIHSS) score ≥ 6 AND ≤ 25 at presentation
- 3. Glasgow Coma Scale (GCS) score ≥ 10
- 4. Last-known-well (LKW) to presentation time ≤ 24 hours
- 5. Pre-stroke modified Rankin Scale (mRS) ≤ 2
- 6. Patients deemed not suitable for acute neurosurgical intervention at the time of randomization
- 7. Informed consent obtained from patient (if mentally competent) or legal representative, as per national laws, regulations, and applicable ethics committee requirements
Exclusion Criteria:
- 1. Secondary ICH: ICH due to macrovascular abnormalities (e.g., arteriovenous malformation, aneurysm, arterial dissection, cavernous malformation), coagulopathy, anticoagulant use, antiplatelet overdose, or thrombocytopenia.
- 2. ICH involving locations other than putamen or thalamus (e.g., lobar, brainstem, cerebellar, isolated intraventricular hemorrhage). Extension of hematoma into other structures is allowed if the hematoma centroid is within the thalamus or putamen, and the hematoma volume does not exist the respective thresholds as stated in Inclusion Criterion 1.
- 3. ICH with planned neurosurgical procedure prior to randomization, including hematoma evacuation, external ventricular drainage and decompressive craniectomy.
- 4. Estimated or known body mass index (BMI) < 18 kg/m².
- 5. Pregnancy, lactation, or positive urine or serum beta human chorionic gonadotropin (β-hCG) test. β-hCG testing should be guided by clinical need.
- 6. Creatinine clearance < 30 mL/min (estimated by Cockcroft-Gault equation or measured)
- 7. Severe or fatal comorbid illness with life expectancy < 3 years (e.g., terminal malignancy, advanced organ failure)
- 8. Participation in another clinical trial investigating a drug, medical device, or medical procedure within 30 days preceding trial inclusion.
- 9. Known history of allergy or hypersensitivity to GLP-1RA.
- 10. Family or personal history of multiple endocrine neoplasia (MEN), medullary thyroid carcinoma, or pancreatic carcinoma
- 11. Active sepsis at time of randomization, defined as a body temperature of ≥ 38.5C, or suspected or documented infection and acute organ dysfunction, operationalized as an increase in SOFA score ≥ 2 points from baseline (baseline assumed 0 if no pre-existing organ dysfunction)
- 12. Contraindications to proposed imaging studies (e.g., pacemaker incompatibility with MRI where applicable)
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
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介入なし：標準治療
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アクティブコンパレータ：Semaglutide Group
Patients randomized into the semaglutide group will receive subcutaneous injections of semaglutide on baseline (D0), Day 7 (D7), Day 14 (D14) and Day 21 (D21) after enrollment.
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0.5mg weekly via subcutaneous injection, a total of 4 injections are given, on Day 0 (D0 day of enrollment, within 24 hours of ICH onset), Day 7 (D7), Day 14 (D14) and Day 21 (D21) after enrollment.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Edema extension distance on Day 7
時間枠：Day 7
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The perpendicular distance from the hematoma margin to the outermost extent of perihematomal edema on CT imaging.
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Day 7
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Proportion of patients with excellent functional outcome (mRS 0-1)
時間枠：Day 90±14 and Day 180±14
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Modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 1 no clinically significant disability, 2 slight disability, 3 moderate disability but remaining able to walk unassisted, 4 moderately severe disability, 5 severe disability, and 6 death)
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Day 90±14 and Day 180±14
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Proportion of patients with functional independence (mRS 0-2)
時間枠：Day 90±14 and Day 180±14
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Modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 1 no clinically significant disability, 2 slight disability, 3 moderate disability but remaining able to walk unassisted, 4 moderately severe disability, 5 severe disability, and 6 death)
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Day 90±14 and Day 180±14
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Proportion of patients with ambulatory independence (mRS 0-3)
時間枠：Day 90±14 and Day 180±14
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Modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 1 no clinically significant disability, 2 slight disability, 3 moderate disability but remaining able to walk unassisted, 4 moderately severe disability, 5 severe disability, and 6 death)
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Day 90±14 and Day 180±14
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Ordinal shift of modified Rankin Scale
時間枠：Day 90±14 and Day 180±14
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Modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 1 no clinically significant disability, 2 slight disability, 3 moderate disability but remaining able to walk unassisted, 4 moderately severe disability, 5 severe disability, and 6 death)
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Day 90±14 and Day 180±14
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6. Neurological function of participants assessed by National Institute of Health Stroke Scale
時間枠：Day 3, Day 7, Day 14, Day 30, Day 90 and Day 180
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Zero indicates no stroke symptoms, 1-4 , 5-15, 16-20, 21-42 indicate minor, moderate, moderate to severe, and severe stroke, respectively.
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Day 3, Day 7, Day 14, Day 30, Day 90 and Day 180
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Hematoma expansion
時間枠：Day 3, Day 7
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Absolute increase in hematoma volume by ≥ 6mL OR relative increase in hematoma volume by ≥ 33%
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Day 3, Day 7
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Perihematomal edema volume
時間枠：Day 3, Day 7
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Volume of edema surrounding the intracerebral hematoma
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Day 3, Day 7
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Edema extension distance on Day 3
時間枠：Day 3
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The perpendicular distance from the hematoma margin to the outermost extent of perihematomal edema on CT imaging.
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Day 3
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Need for acute neurosurgical intervention
時間枠：Day 180
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Any neurosurgical intervention performed as a result of neurological or radiological deterioration.
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Day 180
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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Cognitive function by Montreal Cognitive Assessment
時間枠：Day 90, Day 180
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26 - 30: Normal cognitive function; 18 - 25: Mild Cognitive Impairment (MCI) 10 - 17: Moderate Cognitive Impairment / Dementia; ≤ 9: Severe Impairment
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Day 90, Day 180
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Cognitive function by Mini Mental State Examination
時間枠：Day 90, Day 180
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24-30: Normal Cognition (no impairment); 19-23: Mild Cognitive Impairment 10-18: Moderate Cognitive Impairment; ≤9: Severe Cognitive Impairment
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Day 90, Day 180
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Post ICH seizure or epilepsy
時間枠：Day 180
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Post ICH seizure is defined as any seizure that after the ICH event.
Post ICH epilepsy is defined as unprovoked seizures 7 days after the ICH event.
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Day 180
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協力者と研究者
協力者
捜査官
- 主任研究者：Bonaventure Yiu Ming IP, MB ChB,PhD、Chinese University of Hong Kong
- 主任研究者：Wei HU, MD、The First Affiliated Hospital of University of Science and Technology China
- 主任研究者：Xinshi WANG, MD、First Affiliated Hospital of Wenzhou Medical University
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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