Nimsai Herbal for Grade 2-3 Hemorrhoids: A Quadruple-Blind Placebo-Controlled Mechanistic Trial

This is a prospective, single-center, quadruple-blind, placebo-controlled, parallel-group randomized controlled trial designed as a mechanistic signal-detection study. The trial evaluates the War-Drill Model of hemorrhoid pathogenesis, which proposes that venous congestion, rather than primary vascular deformation, constitutes the indispensable initiating event in hemorrhoid formation. The model distinguishes two hemodynamic phenotypes: War Mode, associated with systemic inflammation and sustained venous congestion, and Drill Mode, characterized by hormonally mediated transient venous engorgement.

A total of 50 participants with endoscopically confirmed Grade 2-3 internal hemorrhoids and symptom duration exceeding 6 weeks will be randomized 1:1 to Nimsai Herbal (600 mg once daily) or matching placebo for 10 consecutive days. The study employs quadruple blinding, with participants, care providers, investigators, and outcomes assessors all masked to treatment assignment. An independent Data Safety Monitoring Board will provide ongoing safety oversight.

The primary outcome is hemorrhoid regression rate at Day 10, defined as either reduction in Goligher grade or ≥75% reduction in composite severity score. Secondary outcomes include mean change in self-reported symptom severity (VAS) and complete symptom resolution rate. Safety outcomes include incidence of mild gastrointestinal discomfort, serious adverse events, and withdrawals due to adverse events. Diabetic participants will be specifically monitored for transient diarrhea during Days 1-3.

The Parola Phenomenon, a patient-reported clinical indicator, will be assessed at baseline to stratify participants into War Mode and Drill Mode phenotypes for exploratory subgroup analyses.

The trial is prospectively registered on ClinicalTrials.gov and approved by the Nimsai Academia Ethics Committee. Written informed consent will be obtained from all participants. The complete study protocol, statistical analysis plan, and de-identified individual participant data will be made publicly available through the Dryad Digital Repository.

• Nimsai Herbal (Dietary supplement): 600 mg oral capsule taken once daily. Contains a proprietary blend of Centella asiatica extract, Curcuma longa extract, and Piper nigrum extract.
• Placebo (Other): Identical-appearing oral capsule containing inert ingredients, matched for taste and packaging.

Primary outcomes

• Hemorrhoid Regression Rate [Day 10]: Percentage of participants achieving a clinical response at Day 10, defined as either a reduction in Goligher grade or a ≥75% reduction in composite hemorrhoid severity score from baseline. The composite score is the sum of clinician-assessed scores for pain, bleeding, itching, and swelling, each rated on a 0-10 Visual Analog Scale (total range 0-40).

Secondary outcomes

• Visual Analog Scale Symptom Score Change [Baseline to Day 10]: Mean change from baseline in self-reported overall hemorrhoid symptom severity at Day 10, measured on a 0-10 Visual Analog Scale (0 = no symptoms, 10 = most severe symptoms).
• Symptom Resolution Rate [Day 10]: Percentage of participants achieving complete resolution of all baseline hemorrhoid symptoms (composite severity score = 0) at Day 10.

Other outcomes

• Incidence of Mild Gastrointestinal Discomfort [Baseline to Day 10]: Percentage of participants reporting mild gastrointestinal adverse events (nausea, bloating, dyspepsia) during the 10-day intervention period.
• Incidence of Serious Adverse Events [Baseline to Day 10]: Percentage of participants experiencing serious adverse events as defined by ICH GCP guidelines during the 10-day intervention period.
• Incidence of Transient Diarrhea in Diabetic Participants [Days 1-3]: Number of diabetic participants experiencing transient diarrhea resolving spontaneously within 24-48 hours during the first three days of the intervention.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Endoscopically confirmed Grade 2 or 3 internal hemorrhoids

History of hemorrhoidal symptoms persisting for more than 6 weeks prior to screening

Age 18 to 70 years inclusive at time of informed consent

Willingness and ability to provide written informed consent

Willingness and ability to comply with all study procedures, schedules, and follow-up requirements

Exclusion Criteria:

* Diagnosis of Grade 1 or Grade 4 hemorrhoids

Any known anorectal malignancy or suspicion of malignancy

Active bleeding from sources other than hemorrhoids

Currently pregnant or lactating women, or women of childbearing potential not using effective contraception

Known hypersensitivity or allergy to any component of Nimsai Herbal or placebo

Significant systemic diseases including severe cardiovascular disease, severe renal impairment, severe hepatic dysfunction, or uncontrolled diabetes mellitus (HbA1c > 9%)

Any medical or psychiatric condition that might compromise participant safety or data integrity

Participation in another interventional clinical trial within 30 days prior to screening

Use of concurrent treatments for hemorrhoids within 7 days prior to screening

History of hemorrhoidectomy or other invasive hemorrhoid procedures within the last 6 months

• Atabiner C. The War-Drill Model of Hemorrhoid Pathogenesis. Research Square. 2025. doi:10.21203/rs.3.rs-6607959/v1