18 Haz Clinical Trial Study Protocol
Protocol Title: A Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Randomized Clinical Trial Investigating the Efficacy and Safety of a 10-Day Oral Nimsai Herbal Treatment in Patients with Grade 2-3 Hemorrhoids, Based on the War-Drill Model and the Sine Qua Non Hypothesis
Protocol Number: NA-2024-01
Protocol Version: 1.1
Date: October 14, 2021
Sponsor/Institution: Nimsai Academia, Türkiye
Principal Investigator: Cem Atabiner
Contact Email: info@nimsai.com
1. Background and Rationale
Hemorrhoidal disease (HD) remains a significant global health burden, with conventional treatments often proving insufficient or invasive. This study is grounded in the novel War-Drill Model and the Sine Qua Non Hypothesis, which fundamentally reinterprets hemorrhoid pathogenesis. We posit that venous congestion is the sine qua non for hemorrhoid formation, preceding and causing vascular deformation, thereby correcting a 200-year-old conceptual error in the literature. This congestion manifests through two distinct mechanisms: “War Mode” (driven by underlying systemic or local pathologies) and “Drill Mode” (triggered by transient hormonal fluctuations).
Nimsai Herbal is a novel systemic therapeutic intervention specifically developed to target vascular dysregulation and resolve venous congestion, offering a non-invasive approach to hemorrhoid management. This randomized controlled trial (RCT) aims to rigorously evaluate the efficacy and safety of Nimsai Herbal in patients with Grade 2-3 hemorrhoids, providing robust clinical validation for the proposed War-Drill Model.
2. Study Objectives
2.1. Primary Objective:
To assess the hemorrhoid regression rate (defined as a reduction of ≥1 Goligher grade) at Day 10 in patients treated with oral Nimsai Herbal compared to placebo.
2.2. Secondary Objectives:
To evaluate symptom improvement (pain, bleeding, itching) using Visual Analog Scale (VAS) scores (0–10) from baseline to Day 10.
To assess the rate of complete symptom resolution (VAS score of 0 for all primary symptoms) at Day 10.
To monitor and systematically record all adverse events (AEs) to assess the safety and tolerability of Nimsai Herbal.
To explore the efficacy of Nimsai Herbal in prespecified subgroups based on age and gender.
3. Study Design
This was a multicenter, prospective, double-blind, placebo-controlled, parallel-group randomized clinical trial. The trial was designed as a superiority trial to demonstrate the greater efficacy of Nimsai Herbal over placebo.
Randomization Ratio: 1:1 (Nimsai Herbal : Placebo).
Blinding: Participants, investigators, outcome assessors, and data analysts were blinded to treatment allocation.
Duration per Participant: 10 days.
4. Study Population
4.1. Inclusion Criteria:
Age: 18–65 years.
Diagnosis of Grade 2 or 3 internal hemorrhoids confirmed by anoscopic examination and clinical evaluation according to the Goligher classification.
History of hemorrhoidal symptoms for >6 weeks.
Willingness and ability to provide written informed consent.
4.2. Exclusion Criteria:
Diagnosis of Grade 1 or 4 hemorrhoids.
Confirmed anorectal malignancy.
Pregnancy or lactation.
Known hypersensitivity to Nimsai Herbal components or placebo.
Recent participation in other clinical trials (within the last 30 days).
Serious comorbidities or other medical conditions that, in the opinion of the investigator, might interfere with the study procedures or compromise patient safety.
4.3. Recruitment and Setting:
A total of 300 participants were assessed for eligibility and randomized. Participants were recruited from outpatient clinics of five independent tertiary care medical centers in Türkiye. Participant recruitment took place from October 14, 2021 to November 14, 2021
-5. Intervention
5.1. Nimsai Herbal Group:
Participants received oral Nimsai Herbal capsules at a dose of 600 mg once daily for 10 consecutive days.
5.2. Placebo Group:
Participants received matching placebo capsules orally once daily for 10 consecutive days. Nimsai Herbal and placebo capsules were identical in appearance, taste, and packaging.
5.3. Intervention Administration and Adherence:
Interventions were dispensed by blinded pharmacists at each study site. Participant adherence was monitored by daily self-reported logs and return of unused medication at the final visit. Care provider fidelity was ensured through standardized training sessions and regular site monitoring visits. Participants were considered ‘treated as planned’ if they completed at least 80% of the prescribed dosage.
5.4. Concomitant Care:
Participants were instructed to maintain their usual diet and lifestyle. No other hemorrhoid-specific treatments (topical, oral, or surgical) were permitted during the 10-day study period. No dose modifications were permitted. Discontinuation criteria included participant request, serious adverse events, or protocol deviation.
6. Outcome Measures
6.1. Primary Endpoint:
Hemorrhoid grade regression (reduction of ≥1 Goligher grade) at Day 10, assessed by anoscopic examination and clinical evaluation.
6.2. Secondary Endpoints:
Change in VAS scores (pain, bleeding, itching; 0–10) from baseline to Day 10.
Complete symptom resolution (VAS score of 0 for all primary symptoms) at Day 10.
Frequency and severity of adverse events.
7. Sample Size
A total of 300 participants (150 per arm) were enrolled and randomized. The sample size was determined to achieve 80% power to detect a clinically significant difference of 56% in hemorrhoid regression rate between groups assuming a baseline regression rate of 22% in the placebo group and aiming for 78% in the Nimsai Herbal group), with a two-sided alpha level of 0.05. The primary outcome on which the calculations are based is hemorrhoid regression rate. Sample size calculation was performed using G*Power v3.1.9.4 . No adjustments for missing data were deemed necessary as there were no losses to follow-up.
8. Randomization and Blinding
8.1. Randomization Sequence Generation:
The random allocation sequence was generated by an independent statistician using a computer-generated algorithm in R statistical software. Block randomization with variable block sizes 4 or 6 was used to ensure balanced group sizes at each site.
8.2. Allocation Concealment Mechanism:
Allocation concealment was maintained by using sequentially numbered, opaque, sealed envelopes (SNOSE) containing the treatment assignment, prepared by an unblinded third party (e.g., a central pharmacy) that was not involved in participant recruitment or intervention assignment.
8.3. Implementation:
Participants were enrolled by trained research coordinators at each medical center. Interventions were assigned by site pharmacists. Neither enrolling personnel nor those assigning interventions had access to the random allocation sequence.
8.4. Blinding:
This was a double-blind trial. Participants, care providers, outcome assessors, and data analysts were blinded to treatment allocation. Blinding was maintained by using Nimsai Herbal and placebo capsules that were identical in appearance, taste, and packaging, prepared by an unblinded third party. No formal procedures were used to evaluate blinding during the trial. No instances of unblinding were reported, and no emergency unblinding procedures were activated as no serious adverse events occurred requiring knowledge of treatment allocation.
9. Data Collection and Management
Data were recorded using standardized Case Report Forms (CRFs) at baseline and daily during the 10-day intervention period. Daily symptom logs were maintained by participants. Data entry was performed by trained personnel. Data quality control measures included logical checks within the database, periodic review of CRFs. All data were stored securely and confidentially on a password-protected server, with access limited to authorized personnel.
10. Statistical Analysis
All randomized participants (n=300) were included in the intention-to-treat analysis for primary and secondary outcomes, analyzed in their originally assigned groups (as-randomised). Missing data were not present for primary outcomes, thus no specific handling methods were applied, and no sensitivity analyses for missing data were conducted. All analyses presented were prespecified in the statistical analysis plan.
Primary Endpoint Analysis: Hemorrhoid regression rate (categorical variable) was compared between groups using the Chi-square test.
Secondary Endpoints Analysis:
Change in VAS scores (continuous variable) was compared using the Mann-Whitney U test.
Complete symptom resolution rate (categorical variable) was compared using the Chi-square test.
Multiplicity: Bonferroni correction for multiple comparisons was applied for primary and secondary outcomes to control for Type I error.
Subgroup Analysis: Prespecified subgroup analyses by age (<40 vs ≥40) and gender were conducted to assess consistency of efficacy. Descriptive subgroup analysis was employed.
Software: Statistical analyses were performed using R statistical software v4.5.1
Significance Level: A two-sided alpha level of 0.05 was used for all primary and secondary outcomes.
11. Ethical Considerations
This study complied with the Declaration of Helsinki principles and International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines. The protocol was approved by the Nimsai Academia Ethics Committee October 10, 2021 . Written informed consent was secured from all participants prior to any study procedures. An independent data monitoring committee oversaw the trial. The trial concluded as planned after all participants completed the 10-day intervention and follow-up, with no premature stopping. Data privacy and confidentiality were maintained throughout the study.
Trial Identification: This trial is identified by its internal protocol number NA-2024-01, approved by the Nimsai Academia Ethics Committee. As an internally funded and conducted study directly associated with the Nimsai Academia research team and Nimsai Herbal, this trial was not registered with an external, public clinical trial registry
12. Dissemination Plan
The findings of this trial will be submitted for publication in peer-reviewed medical journals and presented at relevant scientific conferences, regardless of the outcome. Participant confidentiality will be maintained throughout the dissemination process. De-identified data and statistical code will be made available upon reasonable request from the corresponding author. Requests for data will be reviewed by the Nimsai Academia Ethics Committee.
13. Appendices
Appendix A: Informed Consent Form
Appendix B: Case Report Forms (CRFs)
Appendix C: Investigator Brochure for Nimsai Herbal
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