Efficacy and Safety of Minocycline in Acute Spontaneous Intracerebral Hemorrhage

Official title

Efficacy and Safety of Minocycline in Patients With Acute Spontaneous Intracerebral Hemorrhage: A Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Phase III Trial

Overview

This is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. It aims to evaluate the efficacy and safety of oral minocycline in patients with acute spontaneous intracerebral hemorrhage within 48 hours of onset.

Detailed description

The aim of this study was to evaluate the efficacy and safety of 5-day Minocycline versus placebo in patients with acute intracerebral hemorrhage within 48 hours of onset. In addition, we will explore the effect of Minocycline versus placebo on indicators of venous neuroinflammation at different time points in patients with acute intracerebral hemorrhage within 48 hours of onset.

A total of 1192 participants will be randomized 1:1 to receive either minocycline or matching placebo for 5 days, in addition to guideline-based standard medical care.

The primary objective is to evaluate the effect of Minocycline in improving the level of 90-day mRS score to 0-3 in patients with acute intracerebral hemorrhage within 48 hours of onset.

The trial is divided into three phases: screening/baseline period, treatment period, and follow-up period. The visit schedule is as follows: Randomized participants are interviewed at screening/baseline period, 72±12 hours, 7±1 days, 90±7 days,180±7 days after randomization, and when events occur.

Interventions

• Drug Minocycline hydrochloride capsules
  50 mg per capsule, containing 50mg of Minocycline Hydrochloride
• Drug Placebo capsules of Minocycline hydrochloride capsules
  50 mg per capsule, containing 0 mg of Minocycline Hydrochloride

Primary outcome measures

• mRS score 0-3 [Time frame: At 90±7 days after randomization]

Secondary outcome measures (9)

• mRS score [Time frame: At 90±7 days and 180±7 days after randomization]
• Changes in NIHSS score compared with baseline score [Time frame: At 72±12 hours and 7±1 days after randomization]
• Changes in Glasgow Coma Scale score compared with baseline score [Time frame: At 72±12 hours and 7±1 days after randomization]
• Early neurological deterioration [Time frame: At 72±12 hours and 7±1 days after randomization]
• Changes in hs-CRP level compared with baseline level [Time frame: At 72±12 hours and 7±1 days after randomization]
• Volume of perihematomal edema (PHE) [Time frame: At 7±1 days after randomization]
• EQ-5D-5L utility score [Time frame: At 90±7 days and 180±7 days after randomization]
• Recurrent stroke [Time frame: At 90±7 days and 180±7 days after randomization]
• Combined vascular events [Time frame: At 90±7 days and 180±7 days after randomization]

Eligibility criteria

Inclusion criteria

• CT-confirmed spontaneous supratentorial intracerebral hemorrhage;
• Aged 18 to 80 years;
• Within 48 hours of symptom onset;
• Hematoma volume 15-40 ml;
• NIHSS score 8-24, with item 1a ≤ 2;
• Signed informed consent by the patient or legal representative.

Exclusion criteria

• Secondary intracerebral hemorrhage (traumatic, tumor-related, vascular malformation, aneurysm, coagulation disorder, etc.);
• Intraventricular hemorrhage filling one entire lateral ventricle, third ventricle, or fourth ventricle, or more than half of two lateral ventricles;
• Significant subarachnoid hemorrhage (Fisher grade ≥ 3) or subdural hemorrhage;
• Patients with uncontrollable hypertension ( systolic blood pressure persistently ≥ 180 mmHg despite intensive antihypertensive treatment);
• Progressive neurological or other severe systemic diseases;
• Planned surgical intervention for the intracerebral hemorrhage;
• Pre-stroke disability (modified Rankin Scale score > 1);
• Severe cardiac insufficiency (NYHA Class III-IV), severe liver disease (ALT or AST > 3 times the normal upper limit value), severe renal insufficiency (serum creatinine > 2 times the normal upper limit value, or glomerular filtration rate < 45 ml/min), or malignancy with life expectancy < 1 year;
• Moderate to severe anemia (hemoglobin < 90 g/L), thrombocytopenia (platelet count < 100×10\^9/L), leukopenia (white blood cell count < 2×10\^9/L), or coagulopathy (INR > 1.5);
• Allergy or intolerance to minocycline or other tetracycline antibiotics;
• History of pseudomembranous enteritis or antibiotic-associated enteritis;
• Use of tetracycline antibiotics within the past week;
• Intracranial or spinal surgery within the past 3 months;
• Any major surgery or severe physical trauma within the past month;
• Females who are pregnant, within 30 days postpartum, or in the lactation period.
• Participated in other interventional clinical trials within the past 3 months;
• Inability to obtain signed informed consent from the patient or representative;
• Other conditions that are not suitable for participating in this clinical trial, such as inability to understand and/or follow the research procedures due to mental, cognitive, emotional, or physical disorders, etc.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 41 centers

• Beijing Tiantan Hospital — Beijing
• Chongqing Tongnan District People's Hospital — Chongqing
• The Second People's Hospital of Guangdong Province — Guangzhou
• Baoding Fourth Central Hospital (Tangxian, Hebei) — Baoding
• Zhangjiakou First Hospital — Zhangjiakou
• Zunhua People's Hospital — Zunhua
• Mengzhou Fuxing Hospital — Mengzhou
• Nanle County People's Hospital — Nanle
• … and 33 more centers

Publications

• Chang JJ, Kim-Tenser M, Emanuel BA, Jones GM, Chapple K, Alikhani A, Sanossian N, Mack WJ, Tsivgoulis G, Alexandrov AV, Pourmotabbed T. Minocycline and matrix metalloproteinase inhibition in acute intracerebral hemorrhage: a pilot study. Eur J Neurol. 2017 Nov;24(11):1384-1391. doi: 10.1111/ene.13403. Epub 2017 Sep 20. PMID 28929560
• Lu Y, Guan L, Zhang M, Yang Q, Qiu B, Zhou D, Wang Y, Pan Y, Wang L, Zhou X, Qu H, Liao X, Liu L, Zhao X, Bath PM, Johnston SC, Amarenco P, Wang Y, Wang Y. Rationale and Study Design to Assess the Efficacy and Safety of Minocycline in Patients with Moderate to Severe Acute Ischaemic Stroke (EMPHASIS). Stroke Vasc Neurol. 2025 Dec 23;10(6):786-792. doi: 10.1136/svn-2024-003577. PMID 40147820
• Fouda AY, Newsome AS, Spellicy S, Waller JL, Zhi W, Hess DC, Ergul A, Edwards DJ, Fagan SC, Switzer JA. Minocycline in Acute Cerebral Hemorrhage: An Early Phase Randomized Trial. Stroke. 2017 Oct;48(10):2885-2887. doi: 10.1161/STROKEAHA.117.018658. Epub 2017 Sep 8. PMID 28887388
• Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology. 2007 Oct 2;69(14):1404-10. doi: 10.1212/01.wnl.0000277487.04281.db. PMID 17909152
• Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002 Mar 1;22(5):1763-71. doi: 10.1523/JNEUROSCI.22-05-01763.2002. PMID 11880505
• Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem. 2005 Aug;94(3):819-27. doi: 10.1111/j.1471-4159.2005.03219.x. PMID 16033424
• Lee JM, Yin K, Hsin I, Chen S, Fryer JD, Holtzman DM, Hsu CY, Xu J. Matrix metalloproteinase-9 in cerebral-amyloid-angiopathy-related hemorrhage. J Neurol Sci. 2005 Mar 15;229-230:249-54. doi: 10.1016/j.jns.2004.11.041. Epub 2004 Dec 29. PMID 15760647
• Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500. doi: 10.1073/pnas.96.23.13496. PMID 10557349

Identifiers

NCT: NCT07338175 · MISTICH

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗