BUTCH
(2026)Objective
To test whether DL-3-n-butylphthalide (NBP) improves cerebral blood flow in patients with chronic cerebral hypoperfusion from severe unilateral atherosclerotic stenosis of the internal carotid system.
Study Summary
• No significant differences in CBV, MTT, or TTP amelioration or in continuous perfusion change measures.
• Adverse events (6.1% vs 5.0%) and serious adverse events (0.8% vs 0.8%) were comparable between groups; cerebral ischemic events were rare and similar.
Intervention
Oral DL-3-n-butylphthalide (NBP) 200 mg three times daily (600 mg/day) for 4 weeks, vs matching placebo 20 mg three times daily (no-effect level), in addition to guideline-directed medical therapy.
Inclusion Criteria
Age 35–85 years; ≥70% stenosis or occlusion of unilateral ICA or M1 MCA; documented cerebral hypoperfusion in ipsilateral MCA territory; no TIA or ischemic stroke within 2 weeks; informed consent.
Study Design
Arms: NBP 600 mg/day vs matching placebo 60 mg/day, both for 4 weeks with 12-week imaging follow-up.
Patients per Arm: 244 NBP / 241 placebo (485 randomized; 416 with follow-up CTP)
Outcome
• Secondary perfusion endpoints (CBV, MTT, TTP amelioration) not significantly different.
• Safety: total AEs 6.1% vs 5.0% (p=0.575); serious AEs 0.8% vs 0.8% (p=0.990); cerebral ischemic events 1.23% vs 2.30% across any territory.
Clinical Question
In patients with chronic cerebral hypoperfusion from severe unilateral atherosclerotic stenosis of the internal carotid system who are not undergoing revascularization, does 4 weeks of oral DL-3-n-butylphthalide (NBP) 600 mg/day improve cerebral blood flow on CT perfusion at 12 weeks compared with placebo?
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.
Study Design
- Study Type
- Multicenter, double-blind, randomized, placebo-controlled preliminary trial
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, and drug administrators blinded)
- Sample Size
- 485
- Follow-up
- 12 weeks (with 4 weeks of active treatment)
- Centers
- 38
- Countries
- China
Primary Outcome
Definition: Proportion of patients achieving cerebral blood flow (CBF) amelioration on CT perfusion at 12 weeks (defined as rCBF_after/rCBF_before − 1 ≥ 10%)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 43.9% (93/212) | 55.4% (113/204) | RR 1.32 (adjusted); RR 1.26 (unadjusted) (1.08–1.61 (adjusted); 1.04–1.54 (unadjusted)) | 0.006 (adjusted); 0.020 (unadjusted) |
Limitations & 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.
Citation
CNS Drugs. 2026 Jul (epub 2026 Apr 30). doi:10.1007/s40263-026-01293-w. PMID: 42062656; PMCID: PMC13303579.