Double-Blind, Placebo-Controlled, Parallel-Group Randomized Controlled Trial to Evaluate the Efficacy and Safety of Nimsai Herbal in Patients With Grade 2-3 Hemorrhoids
Phase: NA
Conditions: Hemorrhoids, Hemorrhoidal Disease
Sponsor: Nimsai Academia

 
 
 
 
 
 
 
Full Clinical Study Protocol: ( Protocol NA-2024-01 ) 
 
Official Title: Double-Blind, Placebo-Controlled, Parallel-Group Randomized Controlled Trial to 
Evaluate the Efficacy and Safety of Nimsai Herbal in Patients with Grade 2-3 Hemorrhoids 
NCT Number: NCT07034820 
Protocol Number: NA-2024-001  
Document Date: October 14, 2021  
Version: 2.0 
Sponsor: Nimsai Academia Bursa, Türkiye 
Principal Investigator: Cem Atabiner Nimsai Academia 
Center Phone: +90 532 459 3292 
Email: cem.atabiner@kecioutdoor.com.tr 
Prepared by: Nimsai Academia Bursa, Türkiye 
Submission Format: PDF/A 
 
Confidentiality Statement: This document contains confidential information and is intended 
solely for authorized personnel, investigators, and regulatory authorities. Unauthorized 
reproduction or distribution is prohibited. No participant names or identifiable information are 
included. 
 
 
 

 
 
 
 
 
 
Table of Contents 
1. 
Introduction 1.1. Background on Hemorrhoidal Disease 1.2. The War-Drill Model and Sine 
Qua Non Hypothesis 1.3. Rationale for Nimsai Herbal Intervention 1.4. Study Rationale 
and Justification 
2. Study Objectives 2.1. Primary Objective 2.2. Secondary Objectives 2.3. Safety 
Objectives 
3. Study Design 3.1. Overall Design 3.2. Study Period and Duration 3.3. Enrollment and 
Sample Size 3.4. Study Flow Diagram 
4. Study Population 4.1. Inclusion Criteria 4.2. Exclusion Criteria 4.3. Participant 
Recruitment 4.4. Screening and Enrollment Procedures 
5. Study Intervention 5.1. Nimsai Herbal Capsules (Active Arm) 5.2. Placebo Capsules 
(Control Arm) 5.3. Administration Schedule and Adherence Monitoring 5.4. Concomitant 
Medications and Prohibited Therapies 
6. Randomization and Blinding 6.1. Randomization Procedure 6.2. Blinding Method 6.3. 
Unblinding Procedures 
7. Outcome Measures 7.1. Primary Outcome Measure 7.2. Secondary Outcome Measures 
7.3. Safety Outcome Measures 
8. Study Procedures and Schedule of Events 8.1. Overview of Visits and Assessments 8.2. 
Detailed Daily Documentation and Procedures (Day 1 to Day 10) 8.3. Post-Treatment 
Follow-up 
9. Data Management and Quality Control 9.1. Data Collection Instruments (CRFs, Diaries) 
9.2. Data Entry and Validation 9.3. Data Quality Assurance 9.4. Source Data Verification 
9.5. Data Security and Confidentiality 
10. Statistical Analysis Plan 10.1. Analysis Populations 10.2. Missing Data Handling 10.3. 
Statistical Software and Significance Level 10.4. Primary Outcome Analysis 10.5. 
Secondary Outcome Analysis 10.6. Safety Outcome Analysis 10.7. Baseline 
Characteristics Analysis 10.8. Subgroup Analyses 
11. Safety Reporting 11.1. Definition of Adverse Events (AEs) and Serious Adverse Events 
(SAEs) 11.2. Reporting Procedures for AEs and SAEs 11.3. Data Safety Monitoring Board 
(DSMB) 
12. Ethical Considerations 12.1. Institutional Review Board (IRB) Approval 12.2. Informed 
Consent Process 12.3. Participant Rights and Confidentiality 12.4. Data Protection 
Regulations 
13. Investigator Responsibilities 13.1. General Responsibilities 13.2. Training and 
Qualification 13.3. Protocol Adherence 
14. Data Handling and Record Retention 14.1. Documentation Standards 14.2. Retention 
Period 
15. Publication Policy 
16. References 
17. Appendices 17.1. Appendix A: Sample Case Report Forms (CRFs) 17.2. Appendix B: 
Sample Participant Daily Diary 17.3. Appendix C: Informed Consent Form (ICF) 
 
 

 
 
Abbreviations 
 
AE: Adverse Event 
 
CRF: Case Report Form 
 
DSMB: Data Safety Monitoring Board 
 
GCP: Good Clinical Practice 
 
ICH: International Conference on Harmonisation 
 
ICF: Informed Consent Form 
 
IPD: Individual Participant Data 
 
IRB: Institutional Review Board 
 
ITT: Intention-to-Treat 
 
LOCF: Last Observation Carried Forward 
 
NCT: National Clinical Trial (ID) 
 
PP: Per-Protocol 
 
RCT: Randomized Controlled Trial 
 
SAE: Serious Adverse Event 
 
SAP: Statistical Analysis Plan 
 
SD: Standard Deviation 
 
VAS: Visual Analog Scale 
1. Introduction 
1.1. Background on Hemorrhoidal Disease Hemorrhoidal disease (HD) is a highly prevalent 
anorectal condition affecting millions globally, characterized by symptoms such as bleeding, 
pain, itching, swelling, and prolapse. Despite its widespread occurrence, the traditional 
understanding of hemorrhoids as mere varicosities or venous dilatations has proven insufficient 
in explaining their complex pathogenesis, high recurrence rates, and the limited efficacy of 
many conventional treatments. Current therapeutic approaches predominantly focus on 
symptomatic relief or surgical removal, often overlooking the underlying mechanisms. 
1.2. The War-Drill Model and Sine Qua Non Hypothesis Nimsai Academia proposes a paradigm 
shift in understanding HD through the "War-Drill Model." This model posits that venous 
congestion, rather than primary venous dilatation, is the fundamental and indispensable 
prerequisite (Sine Qua Non Hypothesis) for the development and progression of hemorrhoidal 
disease. This congestion leads to secondary vascular deformation and the manifest symptoms. 
The model categorizes HD into two distinct modes: 
 
War Mode Hemorrhoids: Characterized by chronic venous congestion often driven by 
systemic or local inflammatory conditions (inflammatory bowel disease, anal fissures, 
liver cirrhosis, chronic constipation). These hemorrhoids may serve as an early 
biological warning system for up to 20 potential underlying pathologies, necessitating a 
comprehensive diagnostic workup and systemic therapeutic intervention. 
 
Drill Mode Hemorrhoids: Characterized by transient vascular engorgement primarily 
due to hormonal fluctuations (pregnancy, menopause). These are typically self-limiting 
and may resolve spontaneously once the hormonal influence subsides. The "Parola 
Phenomenon," a clinical maneuver developed by Nimsai Academia, is hypothesized to 
differentiate between War Mode and Drill Mode hemorrhoids with high sensitivity and 
specificity (reported 94% sensitivity and 91% specificity), thereby guiding appropriate 
diagnostic and therapeutic strategies. 
1.3. Rationale for Nimsai Herbal Intervention Nimsai Herbal is a proprietary botanical 
formulation specifically designed to target the underlying venous congestion proposed by the 
War-Drill Model. Its active components – Centella asiatica extract, Curcuma longa extract, and 
Piper nigrum extract – are selected for their venotonic, anti-inflammatory, antioxidant, and 

 
 
bioavailability-enhancing properties. By addressing the root cause of venous congestion, 
Nimsai Herbal is hypothesized to offer a more effective and sustainable treatment approach 
compared to symptomatic or localized therapies. The systemic nature of Nimsai Herbal aligns 
with the War-Drill Model's emphasis on underlying systemic or local inflammatory conditions 
contributing to hemorrhoidal pathogenesis. 
1.4. Study Rationale and Justification This randomized controlled trial (RCT) is designed to 
rigorously evaluate the efficacy and safety of Nimsai Herbal in patients with Grade 2-3 
hemorrhoids. The study will not only assess the clinical benefits of Nimsai Herbal but also 
provide further clinical validation for the War-Drill Model and its implications for diagnosis and 
treatment. Establishing the efficacy and safety of Nimsai Herbal could lead to a significant 
improvement in patient care, reduce recurrence rates, and potentially yield substantial global 
healthcare savings by facilitating early diagnosis of underlying conditions and reducing the 
need for invasive procedures. 
2. Study Objectives 
2.1. Primary Objective To evaluate the efficacy of Nimsai Herbal capsules in achieving 
hemorrhoid regression, defined as a ≥75% reduction in composite hemorrhoid severity score 
from baseline to Day 10, compared to placebo in patients aged 18-70 years with symptomatic 
Grade 2-3 internal hemorrhoids. 
2.2. Secondary Objectives 
 
To assess the mean change in self-reported hemorrhoid symptom severity using a 
Visual Analog Scale (VAS) from baseline to Day 10. 
 
To determine the percentage of participants achieving complete resolution of baseline 
hemorrhoid symptoms (composite severity score = 0) by Day 10. 
 
To explore the clinical utility of the War-Drill Model in guiding treatment response and 
diagnostic pathways. 
 
To evaluate the proportion of participants experiencing a significant reduction in 
individual symptoms (bleeding, pain, itching, swelling) by Day 10. 
2.3. Safety Objectives 
 
To determine the incidence of mild gastrointestinal discomfort (nausea, bloating, 
dyspepsia) in both treatment groups during the 10-day intervention. 
 
To assess the incidence of Serious Adverse Events (SAEs) in both treatment groups 
during the 10-day intervention. 
 
To determine the incidence of participant withdrawals due to adverse events in both 
treatment groups during the 10-day intervention. 
 
To specifically monitor and report the incidence of transient diarrhea in diabetic 
participants during the first three days of the intervention. 
3. Study Design 
3.1. Overall Design This is a prospective, randomized, double-blind, placebo-controlled, 
parallel-group clinical trial. Participants aged 18-70 years with symptomatic Grade 2-3 internal 
hemorrhoids will be randomized in a 1:1 ratio to either the Nimsai Herbal group or the placebo 
group. The intervention period will be 10 consecutive days. 
 
 

 
 
3.2. Study Period and Duration 
 
Overall Study Period: October 10, 2021, to November 14, 2021. This period includes 
participant screening, enrollment, 10-day intervention, and final data collection. 
 
Intervention Duration: 10 days for each participant. 
 
Total Study Duration per Participant: Approximately 10-14 days (including screening 
and final assessment). 
3.3. Enrollment and Sample Size 
 
Planned Enrollment: A total of 300 participants will be enrolled (150 in the Nimsai 
Herbal group and 150 in the placebo group). 
 
Sample Size Justification: A sample size of 150 participants per arm (total 300) 
provides >90% power to detect a 30% difference in hemorrhoid regression rate 
(assuming 50% regression in the Nimsai Herbal group vs. 20% in the placebo group) 
with a two-sided alpha level of 0.05. This calculation accounts for potential minor 
dropouts. 
3.4. Study Flow Diagram 
 
 

 
 
4. Study Population 
 
4.1. Inclusion Criteria Participants must meet all of the following criteria to be eligible for 
enrollment: 
 
Males and females aged 18 to 70 years, inclusive, at the time of signing the Informed 
Consent Form (ICF). 
 
Diagnosis of symptomatic internal hemorrhoids, clinically and endoscopically confirmed 
as Grade 2 or 3 according to the Goligher classification system. 
 
History of hemorrhoidal symptoms (e.g., bleeding, pain, itching, swelling, discomfort) 
persisting for more than 6 weeks prior to screening. 
 
Willingness and ability to provide written informed consent. 
 
Willingness and ability to comply with all study procedures, schedules, and follow-up 
requirements. 
 
Able to understand and communicate effectively in the local language of the study site. 
 
4.2. Exclusion Criteria Participants will be excluded if they meet any of the following criteria: 
 
Diagnosis of Grade 1 or Grade 4 hemorrhoids. 
 
Any known anorectal malignancy or suspicion of malignancy (colorectal cancer, anal 
canal carcinoma, inflammatory bowel disease affecting the anorectum, severe anal 
fissures or fistulas requiring immediate surgical intervention). 
 
Active bleeding from sources other than hemorrhoids (diverticulitis, inflammatory bowel 
disease). 
 
Currently pregnant or lactating women, or women of childbearing potential not using an 
effective method of contraception. 
 
Known hypersensitivity or allergy to any component of Nimsai Herbal capsules or 
placebo ingredients. 
 
Significant systemic diseases including, but not limited to, severe cardiovascular 
disease (unstable angina, recent myocardial infarction), severe renal impairment (end-
stage renal disease), severe hepatic dysfunction (decompensated cirrhosis), or 
uncontrolled diabetes mellitus (HbA1c > 9%). 
 
Any medical or psychiatric condition that, in the opinion of the investigator, might 
compromise the participant's safety, ability to complete the study, or the integrity of the 
study data. 
 
Participation in another interventional clinical trial within 30 days prior to screening or 
during the current study. 
 
Use of concurrent treatments for hemorrhoids (other oral supplements, topical creams, 
suppositories) within 7 days prior to screening or during the study period. 
 
History of hemorrhoidectomy or other invasive hemorrhoid procedures (banding, 
sclerotherapy) within the last 6 months. 
 
4.3. Participant Recruitment Participants will be recruited through local advertising (posters in 
clinics, online advertisements, local media) at Nimsai Academia, Türkiye. All recruitment 
materials will be reviewed and approved by the Nimsai Academia Ethics Committee. Potential 
participants will undergo a preliminary phone screening to assess initial eligibility before 
scheduling an in-person screening visit. 

 
 
4.4. Screening and Enrollment Procedures 
 
Screening Visit (Day -2 to Day 0): 
o 
Review of inclusion/exclusion criteria. 
o 
Detailed medical history including current and past medications. 
o 
Physical examination including digital rectal examination and 
anoscopy/endoscopy to confirm hemorrhoid grade. 
o 
Baseline assessment of hemorrhoid symptoms using a composite severity score 
(0-40) and VAS (0-10). 
o 
Collection of demographic data (age, sex). 
o 
Laboratory tests (complete blood count, liver and kidney function tests, fasting 
glucose/HbA1c for diabetic participants) to rule out underlying conditions as per 
exclusion criteria. 
o 
Informed consent process (detailed in Section 12.2). 
 
Enrollment (Day 0): 
o 
Participants meeting all inclusion and no exclusion criteria and who have 
provided informed consent will be officially enrolled. 
o 
Baseline data captured in CRFs and participant diary initiated. 
o 
Randomization will occur on Day 0. 
 
5. Study Intervention 
 
5.1. Nimsai Herbal Capsules (Active Arm) 
 
Formulation: Each Nimsai Herbal capsule contains 600 mg of a proprietary blend of 
standardized extracts: Centella asiatica, Curcuma longa, and Piper nigrum. The 
capsules are formulated for consistent potency, purity, and bioavailability, and 
manufactured under strict Good Manufacturing Practice (GMP) conditions. 
 
Dosage and Administration: One (1) Nimsai Herbal capsule (600 mg) will be 
administered orally, once daily, with water, preferably at a consistent time each day 
(morning). 
 
Packaging: Identical in appearance, size, color, and packaging to the placebo capsules 
to maintain blinding. 
 
5.2. Placebo Capsules (Control Arm) 
 
Formulation: Each placebo capsule contains inert ingredients (microcrystalline 
cellulose, starch, coloring agents) and is devoid of any active pharmacological 
properties. 
 
Dosage and Administration: One (1) placebo capsule will be administered orally, once 
daily, with water, preferably at a consistent time each day. 
 
Packaging: Identical to the Nimsai Herbal capsules in appearance, size, color, and 
packaging to ensure effective blinding. 
 
 

 
 
5.3. Administration Schedule and Adherence Monitoring 
 
Participants in both arms will receive their assigned study capsules sufficient for 10 
days of treatment. 
 
Adherence Monitoring: 
o 
Daily Participant Diaries: Participants will record daily administration of the 
study capsule in their provided diary. 
o 
Pill Counts: At the end of the 10-day intervention (Day 10), remaining capsules 
will be counted to objectively assess adherence. 
o 
Investigator Inquiry: Investigators will periodically inquire about adherence 
during scheduled follow-up visits. 
 
Non-adherence (missing more than 2 doses) will be documented as a protocol 
deviation, but participants will remain in the Intention-to-Treat (ITT) analysis. 
 
5.4. Concomitant Medications and Prohibited Therapies 
 
Participants will be instructed to avoid any other medications or therapies for 
hemorrhoids (oral, topical, or invasive procedures) during the study period. 
 
A list of all concomitant medications (prescription, over-the-counter, herbal 
supplements) will be recorded at screening and monitored throughout the study. Use of 
medications deemed essential for pre-existing conditions (antihypertensives, 
antidiabetics) will be permitted and documented. 
 
Prohibited therapies will include other venotonics, systemic anti-inflammatory drugs 
specifically for hemorrhoids, and any new laxatives or stool softeners unless medically 
necessary and documented. 
 
6. Randomization and Blinding 
 
6.1. Randomization Procedure 
 
Eligible participants will be randomized in a 1:1 ratio to either the Nimsai Herbal group or 
the placebo group. 
 
A computer-generated randomization sequence will be prepared by an independent 
third party (a contract research organization or a statistician not involved in study 
conduct) prior to the start of the study. 
 
The randomization sequence will be stratified by hemorrhoid severity (Grade 2 vs. 
Grade 3) to ensure an even distribution of severity across treatment arms. 
 
Study medication kits will be pre-packaged and labeled with unique randomization 
numbers. Once a participant is enrolled, the next sequential randomization number will 
be assigned. 
 
6.2. Blinding Method This study will employ a quadruple-blind design, meaning the participant, 
the care provider, the investigator, and the outcomes assessor will all be blinded to the 
treatment assignment. 

 
 
 
Product Appearance: Nimsai Herbal and placebo capsules are identical in appearance, 
color, taste, and packaging. 
 
Packaging and Labeling: Study medication will be packaged in identical, opaque 
containers with only the randomization number and essential safety information 
displayed. 
 
Allocation Concealment: The randomization list will be securely maintained by the 
independent third party and will not be accessible to study personnel or participants. 
 
6.3. Unblinding Procedures 
 
Emergency Unblinding: In the event of a medical emergency where knowledge of the 
assigned treatment is absolutely necessary for the participant’s care (severe adverse 
reaction suspected to be related to the study product), emergency unblinding may 
occur. This will be performed by authorized personnel (unblinded pharmacist or 
designated study staff) following a pre-defined procedure. The reason for unblinding 
and the time/date will be thoroughly documented. 
 
Planned Unblinding: The full unblinding of the study results will only occur after the 
completion of all data collection, database lock, and final statistical analyses have been 
performed. An unblinded statistician, not involved in interim analyses or study conduct, 
will have access to the unblinded data for final analysis. 
 
7. Outcome Measures 
 
7.1. Primary Outcome Measure 
 
Name: Hemorrhoid Regression Rate 
 
Definition: The percentage of participants achieving a clinical response, defined as a 
≥75% reduction in their composite hemorrhoid severity score from baseline to Day 10. 
The composite score is derived from the sum of clinician-assessed scores for four key 
symptoms: bleeding, pain, itching, and swelling. Each symptom is rated on a 0-10 scale 
(0 = no symptom, 10 = most severe symptom), resulting in a total possible score range 
of 0-40. 
 
Time Frame: Measured at Day 10, representing the end of the intervention period. 
 
Unit of Measure: Percentage of Participants. 
 
Assessment Method: Clinician assessment by blinded investigators using standardized Case 
Report Forms (CRFs). Investigator training will include calibration exercises to ensure consistent 
scoring at Nimsai Academia. 
 
 
 

 
 
7.2. Secondary Outcome Measures 
7.2.1. Visual Analog Scale (VAS) Symptom Score Change 
 
Name: Visual Analog Scale (VAS) Symptom Score Change 
 
Definition: The mean change from baseline in self-reported overall hemorrhoid 
symptom severity, as recorded by participants on a 0-10 Visual Analog Scale (0: no 
symptoms, 10: most severe symptoms). 
 
Time Frame: Baseline to Day 10. 
 
Unit of Measure: Score (0-10 scale). 
 
Assessment Method: Daily participant-reported diaries. 
7.2.2. Symptom Resolution Rate 
 
Name: Symptom Resolution Rate 
 
Definition: The percentage of participants achieving complete resolution of all baseline 
hemorrhoid symptoms (i.e., composite severity score = 0) by Day 10. 
 
Time Frame: Measured at Day 10. 
 
Unit of Measure: Percentage of Participants. 
 
Assessment Method: Based on participant daily diaries and confirmed by clinician 
assessment at Day 10. 
7.2.3. Reduction in Individual Symptom Scores 
 
Name: Mean Reduction in Individual Symptom Scores (Bleeding, Pain, Itching, Swelling) 
 
Definition: Mean change from baseline to Day 10 for each individual symptom 
(bleeding, pain, itching, swelling) as assessed by the investigator using the 0-10 scale. 
 
Time Frame: Baseline to Day 10. 
 
Unit of Measure: Score (0-10 scale). 
 
Assessment Method: Clinician assessment via CRFs. 
 
 
7.2.4. Clinical Utility of the War-Drill Model 
 
Name: Association of War-Drill Model Classification with Treatment Response 
 
Definition: Evaluation of the association between initial classification (War Mode vs. 
Drill Mode) using the Parola Phenomenon and treatment response (hemorrhoid 
regression, symptom resolution) in both active and placebo arms. 
 
Time Frame: Classification at Baseline, outcomes at Day 10. 
 
Unit of Measure: Statistical association (Odds Ratio). 
 
Assessment Method: Clinical assessment for Parola Phenomenon at screening, 
correlated with primary and secondary outcomes. 
7.3. Safety Outcome Measures 
7.3.1. Incidence of Mild Gastrointestinal Discomfort 
 
Name: Incidence of Mild Gastrointestinal Discomfort 
 
Definition: Percentage of participants reporting mild gastrointestinal adverse events 
(e.g., nausea, bloating, dyspepsia, mild abdominal discomfort). 

 
 
 
Time Frame: Baseline to Day 10. 
 
Unit of Measure: Incidence (%). 
 
Assessment Method: Daily participant diaries and direct inquiry by investigators at 
each visit, documented on CRFs. 
7.3.2. Incidence of Serious Adverse Events (SAEs) 
 
Name: Incidence of Serious Adverse Events (SAEs) 
 
Definition: Percentage of participants experiencing SAEs as defined by ICH GCP 
guidelines (death, life-threatening event, inpatient hospitalization, persistent or 
significant disability/incapacity, congenital anomaly/birth defect, or any other important 
medical event). 
 
Time Frame: Baseline to Day 10. 
 
Unit of Measure: Incidence (%). 
 
Assessment Method: Continuous monitoring, immediate reporting to IRB/DSMB, and 
documentation on CRFs. 
7.3.3. Incidence of Withdrawals Due to Adverse Events 
 
Name: Incidence of Withdrawals Due to Adverse Events 
 
Definition: Percentage of participants discontinuing the study intervention or 
withdrawing from the study entirely due to an adverse event. 
 
Time Frame: Baseline to Day 10. 
 
Unit of Measure: Incidence (%). 
 
Assessment Method: Documented on CRFs, with reasons for withdrawal clearly 
recorded. 
7.3.4. Incidence of Transient Diarrhea in Diabetic Participants 
 
Name: Incidence of Transient Diarrhea in Diabetic Participants 
 
Definition: The number of diabetic participants who experience transient diarrhea 
(defined as a temporary increase in stool frequency/looseness resolving spontaneously 
within 24-48 hours without requiring specific intervention or study withdrawal) during 
the first three days of the intervention. 
 
Time Frame: Days 1-3. 
 
Unit of Measure: Number of Participants. 
 
Assessment Method: Specific daily inquiry by investigators and recording in participant 
diaries and CRFs for diabetic participants. 
 
 
8. Study Procedures and Schedule of Events 
The study duration for each participant is 10 days of intervention, preceded by a screening 
period. All procedures will be meticulously documented. 
 
 
 

 
 
8.1. Overview of Visits and Assessments 
Activity/V
isit 
Scree
ning 
(Day -
2 to 
Day 0) 
Day 0 
(Baseline/Rando
mization) 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 
Day 10 
(Final 
Assess
ment) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessme
nt 
X 
 
 
 
 
 
 
 
 
 
 
 
Demograp
hics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam 
(incl. 
DRE/Anos
copy) 
X 
(Baseli
ne) 
 
 
 
 
 
 
 
 
 
 
X (Final) 
Parola 
Phenome
non 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Labs 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomiz
ation 
 
X 
 
 
 
 
 
 
 
 
 
 
Study 
Product 
Dispensin
g 
 
X 
 
 
 
 
 
 
 
 
 
 
Study 
Product 
Administr
ation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily 
Participan
t Diary 
(Symptom
s, AEs, 
Adherenc
e) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigat
or 
Assessme
nt 
(Symptom
s, AEs) 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Pill Count  
 
 
 
 
 
 
 
 
 
 
X 
Concomit
ant 
Medicatio
ns 
X 
 
 
 
 
 
 
 
 
 
 
X 
SAE 
Reporting 
As 
neces
sary 
As necessary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
neces
sary 
As 
necessa
ry 
 
 

 
 
8.2. Detailed Daily Documentation and Procedures (Day 1 to Day 10) 
This section outlines the precise documentation required on a daily basis for each participant 
throughout the 10-day intervention period, ensuring meticulous capture of all relevant data 
points. Each entry corresponds to specific sections within the Case Report Forms (CRFs) and 
Participant Daily Diary (refer to Appendix A and B). 
 
Day 0: Baseline & Randomization 
o 
Participant Arrival: Confirmation of eligibility, review of exclusion criteria. 
o 
Informed Consent: Signed and dated ICF obtained by qualified staff. 
o 
Demographics: Age, sex, and other relevant demographic data recorded. 
o 
Medical History: Detailed medical history, including relevant comorbidities and 
prior hemorrhoid treatments, documented. 
o 
Physical Examination: Comprehensive physical exam, including Digital Rectal 
Examination (DRE) and anoscopy/endoscopy to confirm Grade 2-3 hemorrhoids 
and rule out other anorectal pathologies. Baseline hemorrhoid imagescaptured. 
o 
Parola Phenomenon Assessment: Performed and results documented to 
classify War vs. Drill Mode. 
o 
Baseline Assessments: 
 
Investigator-assessed composite hemorrhoid severity score (Bleeding, 
Pain, Itching, Swelling: 0-10 each). 
 
Participant-reported overall symptom severity via VAS (0-10). 
o 
Concomitant Medications: List of all current medications reviewed and 
documented. 
o 
Study Product Dispensing: Randomized study product (Nimsai Herbal or 
Placebo) dispensed with clear instructions for daily 600 mg (one capsule) oral 
administration. 
o 
Participant Diary Training: Participants thoroughly instructed on how to 
complete the daily diary, including symptom scoring, AE recording, and 
adherence tracking. 
o 
Documentation: All collected data rigorously recorded in Day 0 CRFs. 
Participant begins daily diary entry for Day 0 (first dose taken). 
 
Day 1: First Intervention Day 
o 
Participant Diary: Entry for Day 1. 
 
Confirmation of study product administration (daily dose taken: Yes/No). 
 
Self-reported overall symptom severity (VAS 0-10). 
 
Presence/absence and description of any new or worsening adverse 
events (AEs). Specific inquiry for any gastrointestinal discomfort. 
o 
Investigator Review: Optional brief check-in to confirm initial dosing and 
address any immediate concerns. Documentation of any AEs reported. 
o 
Documentation: Daily diary entry collected/reviewed (or prepared for review at 
Day 3). 
 
Day 2: Second Intervention Day 
o 
Participant Diary: Entry for Day 2. 
 
Confirmation of study product administration. 
 
Self-reported overall symptom severity (VAS 0-10). 
 
Presence/absence and description of any AEs. Specific inquiry for 
transient diarrhea in diabetic participants. 
o 
Documentation: Daily diary entry collected/reviewed (or prepared for review at 
Day 3). 
 
Day 3: Mid-Intervention Assessment 
o 
Participant Visit: Brief in-person or remote contact. 
o 
Participant Diary Review: Investigator reviews Day 0-3 diary entries for 
completeness, symptom trends, and AE reporting. Queries participant regarding 
any unclear entries. 

 
 
o 
Investigator Assessment: Clinician-assessed composite hemorrhoid severity 
score recorded. Specific inquiry about any gastrointestinal discomfort (nausea, 
bloating, etc.) and particularly for diabetic participants, the occurrence of 
transient diarrhea (Days 1-3) and its resolution. 
o 
Concomitant Medications: Review of any new medications initiated since Day 
0. 
o 
Documentation: Day 3 CRFs completed, documenting investigator assessments 
and AE review. Diary entries for Day 0-3 collected. 
 
Day 4, Day 5, Day 6, Day 7, Day 8, Day 9: Ongoing Daily Intervention 
o 
Participant Diary: Daily entries for each respective day. 
 
Confirmation of study product administration. 
 
Self-reported overall symptom severity (VAS 0-10). 
 
Presence/absence and description of any new or ongoing AEs. 
o 
Investigator Review: Optional periodic remote check-ins to monitor participant 
well-being and adherence. Document any AEs reported. 
o 
Documentation: Daily diary entries maintained by the participant for later 
collection/review at Day 10. For Day 7, if a remote check-in occurs, relevant 
CRFs are updated. 
 
Day 10: Final Assessment & Study Completion 
o 
Participant Visit: In-person final assessment. 
o 
Study Product Return & Pill Count: All remaining study capsules (both 
dispensed and unused) are collected and counted to calculate adherence. 
o 
Participant Diary Collection & Review: The complete participant diary (Day 0-
10) is collected. Investigator performs a thorough review for completeness, 
consistency, symptom trends, and detailed AE reporting across the entire 10-
day period. Any discrepancies or unclear entries are resolved with the 
participant. 
o 
Investigator Assessment: 
 
Final clinician-assessed composite hemorrhoid severity score recorded. 
 
Assessment of overall clinical improvement. 
 
Physical examination (DRE/Anoscopy) repeated to evaluate physical 
signs of hemorrhoid regression. Post-treatment hemorrhoid images 
captured. 
o 
Adverse Event Review: Comprehensive review of all AEs experienced 
throughout the study, assessing severity, causality, and outcome. All AEs are 
documented on CRFs. Particular attention is given to SAEs. 
o 
Concomitant Medications: Final review and documentation of any changes in 
concomitant medications. 
o 
Study Completion: Participants completing all study procedures are considered 
study completers. Reasons for early withdrawal (if any) are documented. 
o 
Documentation: All collected data rigorously recorded in Day 10 CRFs. 
8.3. Post-Treatment Follow-up While the primary intervention and assessment period 
concludes on Day 10, participants will be informed about the optional 6-month long-term 
follow-up study (Protocol NA-2024-02), which will assess recurrence rates, long-term safety, 
and quality of life. This is for future study planning and not part of the current protocol's scope, 
beyond informing participants. 
 
 
 
 

 
 
9. Data Management and Quality Control 
 
9.1. Data Collection Instruments (CRFs, Diaries) 
 
Case Report Forms (CRFs): Standardized, pre-printed CRFs will be used for all 
investigator-collected data, including eligibility, demographics, medical history, physical 
examinations, symptom assessments, adverse events, concomitant medications, and 
study product accountability. CRFs will be designed for clarity and ease of data entry. 
(Refer to Appendix A for CRFs). 
 
Participant Daily Diaries: Designed for self-reporting of daily symptom severity (VAS), 
adherence, and occurrence of AEs. Diaries will be simple, clear, and include instructions 
in the local language. (Refer to Appendix B for Participant Daily Diary). 
9.2. Data Entry and Validation 
 
Data from CRFs and participant diaries will be entered into a secure, validated electronic 
data capture (EDC) system. 
 
Double Data Entry: A subset of CRFs (10%) may undergo double data entry by 
independent personnel to ensure accuracy. 
 
Data Validation Checks: The EDC system will incorporate automated validation checks 
for data range, consistency, and completeness (mandatory fields, logical checks 
between related variables). 
 
Query Management: Discrepancies identified during data entry or validation will 
generate queries that are sent back to the study sites for resolution by the investigator. 
All queries and their resolutions will be documented. 
9.3. Data Quality Assurance 
 
Training: All study personnel involved in data collection and management will receive 
comprehensive training on the protocol, CRFs, EDC system, and GCP principles. 
 
Monitoring Visits: Study monitors will conduct regular on-site or remote monitoring 
visits to ensure adherence to the protocol, data accuracy, and regulatory compliance. 
 
Audits: Independent audits may be conducted by the sponsor or regulatory authorities 
to assess overall study conduct and data integrity. 
9.4. Source Data Verification 
 
A percentage of data points (100% of primary and safety outcomes, 20% of secondary 
outcomes) will be verified against original source documents (hospital records, clinic 
notes, laboratory reports) to confirm accuracy and completeness. 
9.5. Data Security and Confidentiality 
 
All participant data will be handled with strict confidentiality in accordance with 
applicable data protection regulations (GDPR equivalents, local privacy laws). 
 
Participants will be assigned a unique study identification number, and all study-related 
documents will be de-identified where possible. 
 
The EDC system will have robust security measures, including password protection, 
access control, audit trails, and data encryption. 
 
Only authorized personnel will have access to study data. Physical documents will be 
stored in locked cabinets in secure locations. 

 
 
10. Statistical Analysis Plan 
10.1. Analysis Populations 
 
Intention-to-Treat (ITT) Population: All randomized participants will be included in the 
primary efficacy analysis, analyzed according to their assigned treatment group, 
regardless of actual treatment received or protocol deviations. This reflects a real-world 
scenario. 
 
Per-Protocol (PP) Population: A subset of the ITT population, including only 
participants who complete the study without major protocol deviations, who 
demonstrate acceptable adherence (≥80% of doses taken), and who have evaluable 
primary outcome data. This population will be used for sensitivity analyses to assess the 
robustness of the ITT findings. 
10.2. Missing Data Handling 
 
Primary Method: Multiple imputation will be used for missing outcome data, assuming 
data are Missing At Random (MAR). 
 
Sensitivity Analyses: Last Observation Carried Forward (LOCF) or complete case 
analysis will be conducted as sensitivity analyses to assess the impact of different 
missing data assumptions. 
10.3. Statistical Software and Significance Level 
 
Statistical analyses will be performed using validated statistical software packages 
(SAS, R). 
 
All statistical tests will be two-sided, with a significance level (α) set at 0.05. 
10.4. Primary Outcome Analysis 
 
Hemorrhoid Regression Rate: Compared between the Nimsai Herbal and placebo 
groups using a Chi-square test. The effect size will be reported as a Risk Difference 
with its 95% Confidence Interval (CI). 
10.5. Secondary Outcome Analysis 
 
VAS Symptom Score Change: The mean change from baseline will be compared 
between groups using a Mann-Whitney U test due to potential non-normal distribution 
of symptom scores. The effect size will be reported as a Mean Difference with 95% CI. 
Baseline VAS scores may be included as a covariate in sensitivity analyses (ANCOVA). 
 
Symptom Resolution Rate: Compared between groups using a Chi-square test. The 
effect size will be reported as a Risk Ratio with 95% CI. Logistic regression may be used 
to adjust for baseline severity. 
 
Individual Symptom Scores: Mean changes will be compared using appropriate 
parametric (t-test) or non-parametric (Mann-Whitney U) tests based on data 
distribution. 
 
 
 

 
 
10.6. Safety Outcome Analysis 
 
Incidence of Mild Gastrointestinal Discomfort, SAEs, Withdrawals: Frequencies and 
percentages will be presented for both groups. Comparisons will be made using 
Fisher’s Exact test for categorical data, particularly where low event counts are 
expected. Risk Differences with 95% CI will be reported. 
 
Transient Diarrhea in Diabetic Participants: This will be reported descriptively as the 
number and percentage of affected participants. No formal statistical test will be 
applied due to expected rarity. 
10.7. Baseline Characteristics Analysis 
 
Descriptive statistics (mean ± SD for continuous variables; frequencies and 
percentages for categorical variables) will summarize baseline characteristics for both 
treatment groups. 
 
T-tests (for continuous variables) and Chi-square tests (for categorical variables) will be 
used to confirm that the randomization process resulted in balanced groups. 
10.8. Subgroup Analyses 
 
Exploratory subgroup analyses may be conducted to investigate potential differential 
treatment effects based on baseline characteristics such as hemorrhoid grade (Grade 2 
vs. Grade 3), age categories (18-40 years vs. 41-70 years), or initial War vs. Drill Mode 
classification. These analyses will be considered hypothesis-generating and interpreted 
cautiously. 
11. Safety Reporting 
11.1. Definition of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 
Adverse Event (AE): Any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. 
 
Serious Adverse Event (SAE): Any AE occurring at any dose that results in death, is 
life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect, or is otherwise considered by the investigator to be an important 
medical event. 
11.2. Reporting Procedures for AEs and SAEs 
 
AEs: All AEs will be recorded in the participant's daily diary and subsequently 
transferred to the CRF by the investigator. Information collected will include onset date, 
resolution date, severity (mild, moderate, severe), relationship to study product (not 
related, unlikely related, possibly related, probably related, related), and outcome. 
 
SAEs: All SAEs must be reported immediately (within 24 hours of investigator 
awareness) to the Sponsor and the central IRB. Detailed SAE reports will include all 
relevant clinical information, causality assessment, and outcome. Follow-up reports will 
be submitted as new information becomes available. 
 
 

 
 
11.3. Data Safety Monitoring Board (DSMB) 
 
An independent Data Safety Monitoring Board (DSMB) will be established to provide 
ongoing safety oversight. The DSMB will comprise independent experts in 
gastroenterology, clinical pharmacology, and biostatistics, who are not involved in the 
conduct of this study. 
 
The DSMB will receive blinded aggregated safety data on a weekly basis during the 
intervention phase. 
 
The DSMB will have the authority to recommend modifications to the protocol, 
temporary suspension, or termination of the study if significant safety concerns arise. 
12. Ethical Considerations 
12.1. Institutional Review Board (IRB) Approval This protocol, the Informed Consent Form 
(ICF), participant recruitment materials, and any subsequent amendments will be reviewed and 
approved by the Nimsai Academia Ethics Committee prior to study initiation at Nimsai 
Academia. The study will not commence until full Ethics Committee approval has been 
obtained. 
12.2. Informed Consent Process 
 
Written informed consent will be obtained from every participant prior to the 
performance of any study-specific procedures. 
 
The investigator or a designated qualified member of the study team will thoroughly 
explain the study objectives, procedures, potential risks and benefits, alternatives, and 
the participant's right to withdraw at any time without penalty. 
 
Participants will be given sufficient time to read the ICF, ask questions, and consider 
their participation before signing. A copy of the signed ICF will be provided to the 
participant. 
12.3. Participant Rights and Confidentiality 
 
The rights and well-being of all participants will be protected throughout the study in 
accordance with the Declaration of Helsinki and ICH GCP guidelines. 
 
Participant confidentiality will be maintained at all times. All data collected will be de-
identified through the use of unique participant identification numbers. No individual 
participant's name or other direct identifiers will be used in any reports or publications. 
Access to confidential records (medical history, consent forms) will be restricted to 
authorized personnel only. 
12.4. Data Protection Regulations All data collection, processing, and storage will comply with 
applicable local and international data protection regulations (GDPR equivalents, HIPAA, local 
privacy laws) to ensure the privacy and security of participant information. 
13. Investigator Responsibilities 
13.1. General Responsibilities The Principal Investigator at Nimsai Academia is responsible for 
the overall conduct of the study in accordance with this protocol, ICH GCP, and all applicable 
regulatory requirements. 
13.2. Training and Qualification All investigators and study staff will be qualified by education, 
training, and experience to perform their assigned tasks. They will receive specific training on 
this protocol, study procedures, and data collection tools. 

 
 
13.3. Protocol Adherence Investigators are responsible for ensuring strict adherence to the 
approved protocol. Any deviations from the protocol must be documented, justified, and 
reported to the Sponsor and IRB/EC as required. 
14. Data Handling and Record Retention 
14.1. Documentation Standards All study data will be recorded accurately, completely, and 
legibly on CRFs, participant diaries, and source documents. Any corrections will be made 
according to GCP guidelines, ensuring the original entry remains legible and the correction is 
dated and initialed. 
14.2. Retention Period All study-related documents, including CRFs, ICFs, source documents, 
and regulatory approvals, will be retained for a minimum of 15 years after the completion of the 
study or as required by local regulations, whichever is longer. Documents will be stored in a 
secure, accessible location. 
15. Publication Policy 
The results of this study, whether positive, negative, or inconclusive, will be submitted for 
publication in peer-reviewed scientific journals within 12 months of database lock and primary 
analysis completion. All authors will adhere to established authorship guidelines. Individual 
participant data (IPD) sharing will be facilitated in accordance with relevant data sharing 
policies. 
16. References 
1. 
Atabiner C. The War-Drill Model of Hemorrhoid Pathogenesis. Research Square. 2025. 
https://doi.org/10.21203/rs.3.rs-6607959/v1 
2. Sun Z, Migaly J. Review of hemorrhoid disease. Clin Colon Rectal Surg. 2016;29(1):22-9. 
3. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline for 
Good Clinical Practice E6(R2). 1996; R2: 2016. 
4. World Medical Association. World Medical Association Declaration of Helsinki: Ethical 
Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191-4. 
 17. Appendices 
17.1. Appendix A: Case Report Forms (CRFs)  
17.2. Appendix B: Participant Daily Diary  
17.3. Appendix C: Informed Consent Form (ICF)