Fufang Tongluo Decoction as an Adjunct to Aspirin and Atorvastatin for Ischemic Moyamoya Disease

1. Study Design

   This is a multicenter, randomized, double-blind, placebo-controlled, investigator-initiated clinical trial, conducted under the National Major and Difficult Diseases Integrated Chinese and Western Medicine Clinical Collaboration Project - Moyamoya Disease Project (Project No. ZDYN-2024-A-130). The project comprises 10 core collaborative units and 22 auxiliary collaborative traditional Chinese medicine hospital units. Jiangsu Province Hospital (The First Affiliated Hospital of Nanjing Medical University) serves as the sponsor and primary center; the remaining centers serve as sub-centers and have formed a Moyamoya Disease Specialty Alliance and a Moyamoya Disease Specialty Outpatient Alliance. Patients meeting the eligibility criteria at sub-center outpatient clinics are reported to the primary center and referred to the Integrated Chinese and Western Medicine Moyamoya Disease Outpatient Clinic of the primary center, where examinations are completed (complete blood count, urinalysis, fecal routine and occult blood panel, liver and kidney function tests, comprehensive metabolic panel, coagulation function, head CT, chest CT, and 3T moyamoya MRI [non-contrast and contrast-enhanced]).

2. Study Population

   2.1 Inclusion Criteria

   1. Age 18-60 years.
   2. Meets the Western medicine diagnostic criteria for moyamoya disease per the 2024 Chinese Expert Consensus on the Diagnosis and Treatment of Moyamoya Disease and Moyamoya Syndrome: confirmed diagnosis of moyamoya disease (ICD-11 code 8B22.B) and stroke (A07.01.01). (1) DSA findings: stenosis or occlusion of the terminal internal carotid artery (ICA) and/or the proximal anterior cerebral artery (ACA) and/or the proximal middle cerebral artery (MCA), with abnormal vascular networks at the skull base in the arterial phase. (2) MRI and MRA findings: stenosis or occlusion of the terminal ICA and/or proximal ACA and/or proximal MCA, with abnormal vascular networks in the basal ganglia region (more than 2 prominent flow voids in the basal ganglia on a single scan slice). (3) Other diseases that must be excluded for the diagnosis of moyamoya disease are ruled out.
   3. Meets the traditional Chinese medicine syndrome differentiation criteria: "stroke" with the phlegm-stasis obstructing the collaterals syndrome, with tongue signs (dark tongue with white-greasy or yellow-greasy coating) and pulse signs (wiry-slippery or thin-choppy); diagnosis requires at least 2 primary symptoms, or 1 primary symptom plus 2 secondary symptoms.
   4. Stable baseline treatment for at least 1 month (e.g., antiplatelet therapy and treatment for atherosclerosis, hypertension, or coronary heart disease), with underlying diseases well controlled and no need for additional medications during the intervention period.

   5. Able to understand and agree to comply with the study requirements and restrictions.

      2.2 Exclusion Criteria

      1. Comorbid cognitive impairment or severe psychiatric disorders (ICD-10: F20-F48, F60-F69), such as Alzheimer's disease, other neurodegenerative diseases, Parkinson's disease, multiple sclerosis, demyelinating or hereditary central nervous system disorders, neurodevelopmental abnormalities, uncontrolled epilepsy, or other neurological conditions that in the investigator's judgment may significantly affect motor or cognitive function.
      2. Pregnant or breastfeeding patients.
      3. Severe dysfunction of major organs (heart, liver, kidney, or lung); severe congenital malformations; hematological disorders; severe infections or malignancies; seropositivity for HIV, syphilis, hepatitis B, or hepatitis C.
      4. Currently participating in another drug clinical trial.
      5. History of intolerance or allergy to any component of the investigational medications.
      6. Ischemic stroke within 12 months before enrollment, or a history of hemorrhagic moyamoya disease or other subtypes of moyamoya disease.
      7. Use of protocol-prohibited medications within 30 days before enrollment, or alcohol or drug dependence.
      8. Anticipated need for cervical or cerebrovascular surgery (including interventional procedures) during the study period.

      2.3 Subject Withdrawal Criteria A subject may be withdrawn for: inability to adhere to protocol requirements (e.g., failure to take medication on time or missed visits, making continuation impossible); voluntary withdrawal by the subject or legal guardian with a signed withdrawal statement; serious adverse events where continued participation may endanger the subject's health per medical assessment; the investigator's clinical judgment that continued participation poses a significant risk to the subject's health; or discovery during the study of a violation of the inclusion or exclusion criteria.

      2.4 Suspension/Termination Criteria The study may be suspended or terminated upon: occurrence of serious adverse events (e.g., death, life-threatening reactions, or side effects requiring hospitalization), with a comprehensive assessment of all subjects during suspension to determine whether the study can continue; unforeseen study risks (e.g., severe adverse reactions due to drug interactions or unexpected side effects) requiring reassessment of study safety; major protocol deviations (unforeseen technical deviations or operational errors compromising data integrity or validity); or an Ethics Committee decision during interim review that continuation poses unacceptable risks to subjects.

      2.5 Termination Criteria The study may be terminated if: study objectives cannot be achieved (adjunctive therapy shows no significant efficacy in improving ischemic moyamoya disease and the anticipated benefits cannot be met); major adverse reactions or safety concerns occur that are uncontrollable or seriously compromise subject safety; external factors (regulatory changes, funding issues, or major changes in research personnel or institutions) make continuation unfeasible; or the study team fails to conduct the study according to the approved protocol, compromising data validity or subject safety.

      2.6 Sample Size Calculation Based on 3T moyamoya MRI (non-contrast and contrast-enhanced) examinations, four parameters (time to peak, TTP; mean transit time, MTT; relative cerebral blood flow, rCBF; relative cerebral blood volume, rCBV) classify perfusion in ischemic moyamoya disease from worst to best as II2, II1, I2, and I1, scored 1, 2, 3, and 4 respectively (ordinal data). An increase of ≥1 point in the perfusion score after intervention is defined as improvement. The expected improvement rate is 50% in the control group (aspirin + atorvastatin + placebo) and 75% in the experimental group (aspirin + atorvastatin + Fufang Tongluo Decoction). With alpha = 0.05 (two-sided) and a statistical power of 80%, sample size estimation for comparing two independent proportions yields approximately 58 subjects per group. Allowing for a 10% dropout rate, 64 subjects per group are planned, for a total of 128 subjects.

3. Study Intervention

   3.1 Regimens for the Experimental and Control Groups Experimental group: aspirin 100 mg enteric-coated tablets (Bayaspirin, Bayer Healthcare; approval number J20130078), once daily, one tablet; atorvastatin calcium tablets 10 mg (Lipitor, Pfizer), once daily, one tablet; Fufang Tongluo Decoction, one dose (200 mL), twice daily. Treatment duration: 3 months.

   Control group: aspirin and atorvastatin as above, plus matched placebo, one dose (200 mL), twice daily. Treatment duration: 3 months.

   Fufang Tongluo Decoction is prepared by Nanjing Hospital of Chinese Medicine. The formula comprises prepared Polygonum multiflorum, Gastrodia elata, prepared Polygonatum sibiricum, fried Bombyx Batryticatus, Sargassum, and Euonymus alatus (each 10 g) and fried Hirudo (6 g). The formula is dispensed and processed into powder form by the Pharmacy Department of Nanjing Hospital of Chinese Medicine. Subjects dissolve one dose of the powder in 200 mL of warm water and consume it in a single administration, at least 1 hour before or after meals; one dose is taken twice daily (morning and evening).

   Fufang Tongluo Decoction placebo: composed of 10% of the original herbal formula mixed with rice flour and edible flavoring agents to match the color, taste, and consistency of the active treatment. Appearance, labeling, and packaging are matched to the investigational product to maintain blinding.

   Both the Fufang Tongluo Decoction and the placebo are centrally prepared by Nanjing Hospital of Chinese Medicine according to a unified prescription and standard operating procedures; its Pharmacy Department performs dispensing, labeling, and quality release based on pre-generated randomization codes. The primary center does not participate in the preparation of the investigational drugs; with the assistance of its Department of Traditional Chinese Medicine, it is responsible only for receiving, storing, and dispensing the blinded medication. The specific processing details involve intellectual property rights of the collaborating party at Nanjing Hospital of Chinese Medicine and cannot be elaborated upon.

   3.2 Randomization and Blinding Centralized randomization is implemented via the Interactive Web Response System (IWRS) provided by Taimei Medical Technology, at a 1:1 ratio (investigational drug: placebo) using stratified block randomization (stratification factors: age group and sex). The randomization list is generated by an independent statistician not involved in the clinical conduct, using a prespecified random seed and concealed block lengths; the version-controlled list is archived by the quality unit of Jiangsu Province Hospital.

   Workflow: (1) After subjects complete screening and eligibility is confirmed, the investigator logs into the IWRS, enters basic subject information and key baseline data, and the system performs centralized randomization automatically, generating a unique subject randomization number and the corresponding drug number/kit number. (2) The IWRS records the linkage between the subject and the drug number and prompts the research site pharmacy to dispense the corresponding study medication; the pharmacy verifies and dispenses the medication based on the drug number indicated by the IWRS from the inventory of received blinded medication, without knowledge of the specific treatment assignment. (3) The pharmacy is responsible for receiving, registering, temperature and humidity monitoring, inventory management, and dispensing records, with periodic reconciliation against medication data exported from the IWRS to ensure traceability and consistency. (4) If a subject withdraws from the trial or discontinues medication, the investigator notifies the pharmacy to retrieve unused medication; the pharmacy performs counting, documentation, and disposal in accordance with the protocol and GCP requirements.

   Nanjing Hospital of Chinese Medicine is responsible for the centralized preparation, quality control, and randomized coded packaging of the investigational drugs, ensuring consistency in composition and quality across sites; the primary center's pharmacy manages and dispenses medication based on the centralized randomization results from the IWRS without participating in preparation or coding, minimizing selection and operational bias. The study employs competitive enrollment without center-specific quotas. The IWRS maintains real-time logic for enrollment, dispensing, returns, replacements, and inventory replenishment across centers (including safety stock and reorder points) and generates a complete audit trail (operator, timestamp, transaction type, and reason).

   Emergency unblinding is permitted only for medical necessity (e.g., affecting immediate medical management) or upon documented request from ethics or regulatory authorities. It must be performed by an investigator with unblinding privileges in the IWRS via the emergency unblinding function; the system automatically logs the reason, operator, and timestamp, and promptly notifies the sponsor and the monitor. Subsequent handling of the unblinded subject (whether treatment continues and how efficacy and safety data are included) follows the protocol and the statistical analysis plan. Data are collected via an electronic data capture system and fully documented and archived.

   3.3 Concomitant Medications Stable pre-existing baseline treatments are permitted to continue. The following medications/supplements are prohibited during the study: preparations containing succinic acid and its salts (e.g., reamberin, remaxol, cytoflavin); vitamin B6 and its derivatives; antioxidant/antihypoxic drugs (including 3-hydroxypyridine derivatives); and various classes of nootropic agents (e.g., citicoline, alpha-glycerylphosphorylcholine, piracetam, pyridoxine derivatives, GABA derivatives or analogues, Ginkgo biloba, neuropeptide/polypeptide preparations, cerebral circulation enhancers such as vinpocetine and cinnarizine, and plant-derived adaptogens).

4. Follow-up

   4.1 Follow-up Schedule and Frequency Two on-site follow-up visits for 3T moyamoya MRI (non-contrast and contrast-enhanced) are conducted at the primary center: the first before the intervention, and the second on the day after completion of the 3-month treatment course, with imaging appointments scheduled in advance via telephone. In addition, a three-year telephone follow-up is conducted every two weeks by a clinical physician from the research team to assess medication adherence and monitor adverse events.

   4.2 Follow-up Content Clinical examination: detailed medical history and medication review, measurement of vital signs, and recording of adverse clinical events. Scale assessments: pre-specified functional rating scales (clinical symptom assessment, Fugl-Meyer Assessment, Modified Barthel Index, and Montreal Cognitive Assessment) are completed at each follow-up visit, using the same assessment tools and raters at similar times of day to minimize measurement bias. Imaging examination: a standardized MRI protocol with the same scanner model and fixed scanning parameters; scans are performed once before the intervention and once after completion of the treatment course; experienced radiologists blinded to group allocation interpret the images and record the pre-specified imaging parameters (TTP, MTT, rCBF, rCBV). Safety monitoring: all adverse events and serious adverse events are recorded on the pre-designed safety follow-up log (time of onset, severity, management measures, relationship to the investigational drug, and outcome) and summarized periodically. If a serious adverse event occurs, the investigator provides appropriate clinical management immediately and reports the event to the principal investigator and the Ethics Committee within 24 hours in accordance with GCP and ethical requirements.

   4.3 Handling of Loss to Follow-up and Withdrawals If a subject discontinues medication or withdraws from the study prematurely, the investigator arranges for the subject to complete the end-of-treatment clinical and imaging assessments whenever possible to obtain key outcome data; for subjects who cannot complete these assessments, the reason for loss to follow-up is documented and the data are included in the follow-up statistical analysis.

5. Evaluation Criteria / Study Endpoints

5.1 Primary Endpoint Imaging-based treatment effectiveness: the percentage of participants whose cerebral perfusion staging score increases by ≥1 point after intervention compared with the pre-intervention score. 3T moyamoya MRI (non-contrast and contrast-enhanced) records cerebral artery parameters, including mean transit time (MTT), cerebral blood flow (CBF), time to peak (TTP), and cerebral blood volume (CBV). Reference values: CBF, gray matter approximately 50-80 mL/100g/min and white matter approximately 20-30 mL/100g/min; CBV, gray matter approximately 4-5 mL/100g and white matter approximately 2-3 mL/100g; MTT normally 3-5 seconds, with values over 6 seconds suggesting a perfusion abnormality; TTP is compared with the contralateral healthy region, with a difference within 2 seconds considered normal.

Based on the degree of change in regional cerebral microcirculation and perfusion imaging findings, the pre-infarction stage is divided into 2 stages and 4 subtypes: stage I1, prolonged TTP with normal MTT, rCBF, and rCBV; stage I2, prolonged TTP and MTT with normal rCBF and normal or mildly elevated rCBV; stage II1, prolonged TTP and MTT with decreased rCBF and normal or mildly decreased rCBV; stage II2, prolonged TTP and MTT with decreased rCBF and rCBV. Ranked from worst to best (II2, II1, I2, I1), these stages are scored 1, 2, 3, and 4 respectively as ordinal data. The primary outcome measure is the change in perfusion stage between the pre-intervention and post-intervention MRI; a post-intervention cerebral perfusion score at least 1 point higher than the pre-intervention score is considered effective, and the effectiveness rate is calculated separately for each group.

5.2 Secondary Endpoints Motor function and activities of daily living: the Fugl-Meyer Assessment evaluates motor function, the Modified Barthel Index evaluates self-care ability and activities of daily living, and the Montreal Cognitive Assessment evaluates cognitive function. All three assessments are scored independently by the attending physician before the intervention, recorded using only the subject's unique study ID, and re-scored after the intervention by a separate group of physicians. Effective is defined as a score increase compared with baseline; ineffective is defined as an unchanged or decreased score.

Clinical efficacy is graded by change in NIHSS score: excellent, a decrease of 50% or more; good, a decrease of 30% or more; fair, a decrease of 20% or more; poor, not meeting the above criteria. The NIHSS comprises 11 items (level of consciousness 1a, 1b, and 1c; gaze; visual fields; facial palsy; motor arm; motor leg; limb ataxia; sensory; best language; dysarthria; and extinction/inattention), with a total score of 0-42; higher scores indicate more severe neurological deficit. The Modified Barthel Index comprises 10 items (feeding, bathing, grooming, dressing, bowels, bladder, toilet use, bed-to-chair transfers, ambulation, and stairs), with a total score of 0-100; higher scores indicate greater independence in daily living.

5.3 Long-Term Clinical Endpoints In addition to the short-term imaging (3-month) and functional scale outcomes, survival analysis of long-term clinical outcomes is pre-specified, defined as the incidence from the date of randomization to the first occurrence of any of the following events: new-onset cerebral hemorrhage, recurrent or new cerebral infarction, and all-cause death.