Hemorrhoidal Disease, Hemorrhoids
Conditions
Keywords
Hemorrhoids, Hemorrhoidal Disease, Pathogenesis, War-Drill Model, Sine Qua Non Hypothesis, Venous Congestion, Nimsai Herbal, Randomized Controlled Trial, Clinical Trial, Treatment, Early Diagnosis, Biological Early-Warning System, Inflammatory Bowel Disease, Anal Fissure, Rectal Polyps, Hormonal Fluctuations, Parola Phenomenon, Systemic Therapy, Gastroenterology
Brief summary
This study investigated a new understanding of hemorrhoid formation and evaluated a novel systemic treatment. For 200 years, hemorrhoids were conventionally understood as isolated swollen veins. However, our new War-Drill Model proposes that hemorrhoids are primarily caused by blood pooling (venous congestion) in the anal region, which then secondarily leads to vascular deformation. This congestion is hypothesized to arise from either underlying health issues (War Mode) or natural physiological and hormonal changes (Drill Mode). We conducted a double-blind, placebo-controlled randomized controlled trial on 300 patients with Grade 2-3 hemorrhoids to evaluate the efficacy and safety of Nimsai Herbal. This study explores the potential for War Mode hemorrhoids to serve as an early warning sign for other serious underlying conditions and aims to validate a novel systemic therapeutic approach.
Detailed description
The current understanding of hemorrhoid pathogenesis has remained largely unchanged for over two centuries, positing hemorrhoids primarily as isolated venous dilatations or prolapses. This traditional view, however, fails to adequately explain the high recurrence rates post-treatment, the limited efficacy of topical agents, and the often-debilitating symptomatology. Our extensive research, culminating in the War-Drill Model and the Sine Qua Non Hypothesis, fundamentally challenges this conventional paradigm. We propose that hemorrhoids are not primarily structural abnormalities but rather a manifestation of underlying venous congestion, which then secondarily leads to vascular deformation and associated symptoms. This congestion acts as the indispensable (sine qua non) prerequisite for the development of both symptomatic and asymptomatic hemorrhoidal disease. The War-Drill Model further categorizes this venous congestion based on its etiology: War Mode Hemorrhoids: These are hypothesized to arise from chronic or passive venous congestion triggered by an underlying systemic or local inflammatory process or pathology. Examples include inflammatory bowel diseases (Crohn's disease, ulcerative colitis), anal fissures, rectal polyps, liver diseases causing portal hypertension, and various other systemic conditions affecting vascular flow or integrity. Crucially, War Mode hemorrhoids may serve as a critical biological early-warning system, prompting investigations that could lead to the early diagnosis of up to 20 distinct and potentially severe internal diseases. Drill Mode Hemorrhoids: These are hypothesized to be transient vascular engorgements resulting from physiological hormonal fluctuations, typically observed during periods of significant endocrine change such as adolescence, pregnancy, lactation, menopause, and andropause. These episodes are often self-limiting, resolving as hormonal balance stabilizes. To validate a systemic therapeutic approach based on this new model, we conducted a double-blind, placebo-controlled, parallel-group Randomized Controlled Trial (RCT) (Protocol ID: NA-2024-01). The study enrolled 300 participants aged 18-70 years with endoscopically confirmed Grade 2-3 internal hemorrhoids and a history of symptoms for over 6 weeks. Participants were randomized to receive either Nimsai Herbal (a novel systemic botanical formulation, 600 mg daily) or an identical placebo for 10 consecutive days. The primary outcome measure was hemorrhoid regression rate, defined as a reduction of at least one Goligher grade by Day 10, assessed via anoscopic examination and clinical evaluation. Secondary outcomes included incidence of adverse events. The study utilized the Parola Phenomenon, a simple clinical maneuver designed by Atabiner, as part of patient assessment, aiming to differentiate War Mode from Drill Mode hemorrhoids.
Interventions
DIETARY_SUPPLEMENTNimsai Herbal
Oral Nimsai Herbal is a novel botanical formulation, administered as one 600 mg capsule per day for a duration of 10 consecutive days. It is specifically designed to target the underlying venous congestion hypothesized by the War-Drill Model, aiming to promote hemorrhoid regression and symptom resolution.
DIETARY_SUPPLEMENTPlacebo
This intervention consisted of an oral placebo, formulated to be identical in appearance, taste, and packaging to Nimsai Herbal. It was administered as one capsule per day for 10 consecutive days to ensure blinding and serve as a control for comparison.
Sponsors
Nimsai Academia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study employed a robust double-blind design where the Nimsai Herbal and placebo treatments were identical in appearance, taste, and packaging. In addition to participants, care providers, investigators, and outcomes assessors, the independent data monitoring committee and third-party statisticians involved in the primary data analysis were also masked to treatment assignments. The unblinding codes were securely held by a designated unmasked statistician who was not involved in the interim analyses or daily study conduct.
Intervention model description
Participants were randomized to either the Nimsai Herbal group or the placebo group, with both groups receiving treatment concurrently.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Endoscopically confirmed Grade 2 or 3 internal hemorrhoids. History of hemorrhoidal symptoms \>6 weeks. Age 18-70 years at the time of enrollment. Provided written informed consent prior to any study-related procedures. Willingness and ability to comply with all study procedures and follow-up visits.
Exclusion criteria
Grade 1 or 4 hemorrhoids. Any known anorectal malignancy or suspicion of malignancy. Pregnancy or lactation. Known hypersensitivity or allergy to Nimsai Herbal components or placebo ingredients. Significant systemic diseases (e.g., severe cardiovascular, renal, hepatic, or hematological disorders) that could affect study participation or safety. Participation in another clinical trial within 30 days prior to screening. Any condition that, in the opinion of the investigator, might compromise the safety of the participant or the integrity of the study data.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemorrhoid Regression Rate | Day 10 (end of treatment period) | Hemorrhoid regression was defined as a reduction of at least one Goligher grade or a ≥75% reduction in composite hemorrhoid severity score by Day 10. (The Goligher Classification of Hemorrhoids is a 4-point scale (Grade I to IV) used for hemorrhoid severity, where higher scores indicate worse disease.) |
Countries
Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nimsai Herbal Group Participants in this arm received oral Nimsai Herbal (600 mg, one capsule per day) for 10 consecutive days.
Nimsai Herbal: Oral Nimsai Herbal is a novel botanical formulation, administered as one 600 mg capsule per day for a duration of 10 consecutive days. It is specifically designed to target the underlying venous congestion hypothesized by the War-Drill Model, aiming to promote hemorrhoid regression and symptom resolution. | 150 |
| Placebo Group Participants in this arm received oral placebo (identical in appearance, taste, and packaging to Nimsai Herbal) for 10 consecutive days.
Nimsai Herbal: This intervention consisted of an oral placebo, formulated to be identical in appearance, taste, and packaging to Nimsai Herbal. It was administered as one capsule per day for 10 consecutive days to ensure blinding and serve as a control for comparison. | 150 |
| Total | 300 |
Baseline characteristics
| Characteristic | Nimsai Herbal Group | Placebo Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 149 Participants | 150 Participants | 299 Participants |
| Age, Continuous | 45.2 Years STANDARD_DEVIATION 12.3 | 45.7 Years STANDARD_DEVIATION 12.5 | 45.45 Years STANDARD_DEVIATION 12.4 |
| Composite Severity Score at Baseline | 24.8 units on a scale STANDARD_DEVIATION 6.7 | 24.5 units on a scale STANDARD_DEVIATION 6.5 | 24.65 units on a scale STANDARD_DEVIATION 6.6 |
| Diabetes (%) | 15 Participants | 15 Participants | 30 Participants |
| Hemorrhoid Grade at Baseline Grade 2 Hemorrhoids | 105 Participants | 105 Participants | 210 Participants |
| Hemorrhoid Grade at Baseline Grade 3 Hemorrhoids | 45 Participants | 45 Participants | 90 Participants |
| Overall Symptom VAS Score at Baseline | 6.5 units on a scale STANDARD_DEVIATION 1.9 | 6.4 units on a scale STANDARD_DEVIATION 1.8 | 6.45 units on a scale STANDARD_DEVIATION 1.85 |
| Participants with War Mode Hemorrhoids (via Parola Phenomenon) | 60 Participants | 57 Participants | 117 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Turkey | 150 Participants | 150 Participants | 300 Participants |
| Sex: Female, Male Female | 78 Participants | 78 Participants | 156 Participants |
| Sex: Female, Male Male | 72 Participants | 72 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 150 | 0 / 150 |
| other Total, other adverse events | 6 / 150 | 3 / 150 |
| serious Total, serious adverse events | 0 / 150 | 0 / 150 |
Outcome results
Primary
Hemorrhoid Regression Rate
Hemorrhoid regression was defined as a reduction of at least one Goligher grade or a ≥75% reduction in composite hemorrhoid severity score by Day 10. (The Goligher Classification of Hemorrhoids is a 4-point scale (Grade I to IV) used for hemorrhoid severity, where higher scores indicate worse disease.)
Time frame: Day 10 (end of treatment period)
Population: All randomized participants who completed the study (Full Analysis Set).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nimsai Herbal Group | Hemorrhoid Regression Rate | 117 Participants |
| Placebo Group | Hemorrhoid Regression Rate | 33 Participants |
Comparison: Powered for 56% difference (80% power, alpha=0.05) to detect the anticipated difference in hemorrhoid regression rates between groups. The sample size of N=300 (150 participants per arm) was calculated based on an expected regression rate of 22% in the placebo group and 78% in the Nimsai Herbal group. This ensured sufficient statistical power for the primary efficacy analysis.p-value: <0.00195% CI: [48, 64]Chi-squared