BUTCH
Effect of DL-3-n-Butylphthalide on Cerebral Hypoperfusion Due to Atherosclerotic Stenosis: A Multicenter, Double-Blind, Randomized Controlled, Preliminary Trial
Bottom Line
In this preliminary multicenter RCT, NBP 600 mg/day for 4 weeks significantly increased the proportion of patients with cerebral blood flow amelioration at 12 weeks (adjusted RR 1.32, p=0.006) without an increase in adverse events, supporting NBP as a candidate medical therapy for chronic cerebral hypoperfusion in patients ineligible for or declining revascularization.
Major Points
- Primary endpoint (CBF amelioration ≥10% on CTP at 12 weeks) was met: 55.4% NBP vs 43.9% placebo; adjusted RR 1.32 (95% CI 1.08–1.61), p=0.006.
- Secondary perfusion measures (CBV, MTT, TTP amelioration; continuous perfusion changes) did not show significant differences between groups.
- Clinical cerebral ischemic events were rare and similar between arms (any territory: 1.23% NBP vs 2.30% placebo, p=0.521).
- Safety was comparable: total AEs 6.1% vs 5.0% (p=0.575); serious AEs 0.8% vs 0.8% (p=0.990).
- Authors characterize this as a preliminary trial; a larger confirmatory study is registered (ChiCTR2500104739).
- Population was almost entirely Han Chinese, enrolled across 38 Chinese centers, limiting generalizability.
Design
Study Type: Multicenter, double-blind, randomized, placebo-controlled preliminary trial
Randomization: 1
Blinding: Double-blind (patients, investigators, and drug administrators blinded)
Enrollment Period: January 14, 2022 – April 11, 2024
Follow-up Duration: 12 weeks (with 4 weeks of active treatment)
Centers: 38
Countries: China
Sample Size: 485
Analysis: Comparison of completers with CTP at 12 weeks (n=416); sensitivity analyses with multiple imputation
Inclusion Criteria
- Age 35–85 years
- ≥70% stenosis or occlusion in unilateral internal carotid artery (ICA) or M1 segment of middle cerebral artery (MCA)
- Documented cerebral hypoperfusion in the ipsilateral MCA territory on imaging
- No transient ischemic attack or ischemic stroke within the previous 2 weeks
- Signed informed consent from patient or surrogate
Exclusion Criteria
- ≥50% stenosis or occlusion in the contralateral ICA or M1 MCA
- ≥50% stenosis or occlusion in bilateral carotid arteries or innominate artery
- Patient preference for carotid artery stenting, carotid endarterectomy, or other revascularization
- ≥10 mm infarction in both MCA territories on CT or MRI
- Other cerebral diseases affecting perfusion (infection, degeneration, demyelination, tumor, trauma)
- Use of NBP or vasodilatation therapy within the prior 30 days
- Pregnant or lactating women
- Severe cardiac, pulmonary, alimentary, or neoplastic disease; life expectancy ≤6 months
- Serum creatinine ≥140 µmol/L or transaminases ≥3× upper limit of normal
- Cerebral stenosis from non-atherosclerotic causes (dissection, vasculitis, moyamoya)
- Allergy to NBP or to Apium graveolens
- Participation in another clinical trial within the prior 3 months
- Other situations deemed unsuitable for inclusion by investigators
Arms
| Field | DL-3-n-Butylphthalide (NBP) | Control |
|---|---|---|
| Intervention | NBP 200 mg orally three times daily (600 mg/day) | Matching placebo 20 mg orally three times daily (60 mg/day, designed as no-effect level) |
| Duration | 4 weeks of treatment; imaging follow-up at 12 weeks | 4 weeks of treatment; imaging follow-up at 12 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Proportion of patients achieving cerebral blood flow (CBF) amelioration on CT perfusion at 12 weeks (defined as rCBF_after/rCBF_before − 1 ≥ 10%) | Primary | 43.9% (93/212) | 55.4% (113/204) | RR 1.32 (adjusted); RR 1.26 (unadjusted) | 0.006 (adjusted); 0.020 (unadjusted) |
| CBV amelioration at 12 weeks (≥10%) | Secondary | 40.6% (86/212) | 44.6% (91/204) | RR 1.10 (adj 1.19) | 0.255 (adj 0.418) |
| MTT amelioration at 12 weeks (≥10%) | Secondary | 35.9% (76/212) | 33.3% (68/204) | RR 0.93 (adj 0.99) | 0.572 (adj 0.583) |
| TTP amelioration at 12 weeks (≥10%) | Secondary | 17.5% (37/212) | 21.1% (43/204) | RR 1.20 (adj 1.22) | 0.793 (adj 0.917) |
| Median rCBF change (%) | Secondary | 5.6 (−7.7 to 19.7) | 9.9 (−0.6 to 20.7) | Median diff 3.7 (−0.1 to 7.4) | 0.059 |
| Median rCBV change (%) | Secondary | 4.9 (−9.1 to 16.6) | 6.9 (−3.9 to 20.0) | Median diff 2.9 (−1.0 to 7.1) | 0.141 |
| Median rMTT change (%) | Secondary | 1.8 (−8.3 to 12.6) | 1.5 (−8.2 to 11.7) | Median diff −0.1 (−3.3 to 3.3) | 0.980 |
| Median rTTP change (%) | Secondary | 0.2 (−3.5 to 5.1) | 1.5 (−2.3 to 5.5) | Median diff 0.7 (−0.7 to 2.1) | 0.335 |
| Cerebral ischemic event in stenotic territory | Secondary | 1.24% (3/241) | 1.23% (3/244) | RR 1.04 (0.21–5.11) | 0.959 |
| Cerebral ischemic event in any territory | Secondary | 2.30% (5/241) | 1.23% (3/244) | RR 0.63 (0.15–2.60) | 0.521 |
| Total Adverse Events | Adverse | 6.1% (15/244) NBP vs 5.0% (12/241) placebo; RR 1.24 (0.59–2.58), p=0.575 | |||
| Serious Adverse Events | Adverse | 0.8% (2/244) vs 0.8% (2/241); RR 0.99 (0.14–6.96), p=0.990 | |||
| Cerebral Ischemic Events (any territory) | Adverse | 1.23% vs 2.30%; RR 0.63 (0.15–2.60), p=0.521 | |||
| Cerebral Ischemic Events (stenotic territory) | Adverse | 1.23% vs 1.24%; RR 1.04 (0.21–5.11), p=0.959 | |||
Subgroup Analysis
Sensitivity analyses using multiple imputation for missing CTP follow-up data confirmed the primary result; detailed prespecified subgroups (e.g., ICA vs MCA, severe stenosis vs occlusion) were not reported as formal interaction analyses.
Criticisms
- Self-described as a preliminary trial; sample size modest with ~14% loss to imaging follow-up (485 randomized but only 416 had 12-week CTP).
- Population almost exclusively Han Chinese across 38 Chinese centers, limiting generalizability to other ethnic groups and healthcare settings.
- Short treatment course (only 4 weeks of active drug) with surrogate imaging endpoint (CT perfusion CBF amelioration) at 12 weeks; clinical outcomes (recurrent ischemia, cognition, function) were not powered endpoints.
- Only the primary perfusion measure (CBF) was significant; other perfusion parameters (CBV, MTT, TTP) showed no difference, raising questions about mechanism and robustness.
- Placebo arm received a low (20 mg TID) NBP dose described as a 'no-effect level' rather than a true placebo, which is unusual and may have biased the comparison.
- Patients eligible for revascularization (CAS/CEA) were excluded, so results do not apply to typical surgical/endovascular candidates.
- Funding from a single PLA institution and no industry sponsorship listed, but external validity for non-Chinese populations and longer-term safety remain unclear.
Funding
Clinical Research Project of Air Force Medical Center, Chinese PLA (No. 2021LC002). Trial registration: ChiCTR2100053112. Authors declared no conflicts of interest.
Based on: BUTCH (CNS Drugs, 2026)
Authors: Chen D, et al.
Citation: CNS Drugs. 2026 Jul (epub 2026 Apr 30). doi:10.1007/s40263-026-01293-w. PMID: 42062656; PMCID: PMC13303579.
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