Conditions: Internal Hemorrhoids
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
A randomized, double-blind, placebo-controlled, multicenter, parallel group study of the safety and efficacy of Hydrocortisone Acetate Suppositories, 25 mg compared to placebo suppositories in the treatment of symptomatic internal hemorrhoids.

Detailed description:
STUDY DESIGN:

25 mg hydrocortisone suppositories administered twice daily compared to a vehicle placebo in approximately 100 subjects with symptomatic internal hemorrhoids. Subjects will be randomized in a 1:1 ratio (Test product: placebo).

The study will consist of 2 periods:

1. Treatment Period (2 weeks/ Days 1-14)
2. Follow-up Period (2 weeks/ Days 15-28)

The visits are as follows:

Visit 1 (Day 1 Baseline/Randomization) Visit 2 (Day 8±1, Interim Visit) Visit 3 (Day 15±2, End of Treatment Visit) Visit 4 (Day 29±3, End of Study Visit)

ENDPOINTS:

1. Clinician Reported Outcome (ClinRO) - Anoscopy (Visits 1, 3). Anoscopy - Visual assessment of hemorrhoids. Video of the procedure will be recorded for blinded central reading and assessment
2. Patient Reported Outcome: Subjects will use Daily Diaries to record the time and date of each medication application, concomitant medication and adverse events. The subjects will complete the Subject Questionnaire at Visits 1, 2, 3 and 4 (or early termination) and daily between visits.

Arms:
arm 1: One (1) Hydrocortisone Acetate Suppository, 25 mg is inserted into the anal canal twice daily (morning and evening) for 2 weeks (14 days). arm 2: One (1) Placebo (Vehicle) Suppository is inserted into the anal canal twice daily (morning and evening) for 2 weeks (14 days).

Interventions: intervention 1: Hydrocortisone Acetate Suppository, 25 mg (Nivagen) intervention 2: Placebo (Vehicle) Suppository (Nivagen)
Intervention descriptions: intervention 1: One (1) Hydrocortisone Acetate Suppository, 25 mg is inserted into the anal canal twice daily (morning and evening) for 2 weeks (14 days). intervention 2: One (1) Placebo (Vehicle) Suppository is inserted into the anal canal twice daily (morning and evening) for 2 weeks (14 days).

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 1 of 67 
Version 4.0 
 
A RANDOMIZED DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER, PARALLEL GROUP 
PILOT 
STUDY 
OF 
THE 
SAFETY 
AND 
EFFICACY 
OF 
HYDROCORTISONE 
ACETATE 
SUPPOSITORIES, 25 MG COMPARED TO PLACEBO SUPPOSITORIES IN THE TREATMENT OF 
SYMPTOMATIC INTERNAL HEMORRHOIDS 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Number:  HDCS 1701 (formerly 1-2017) 
Protocol Version Number:  4.0 
Protocol Version Date:  26Apr2019 
Study Sponsor:  Nivagen Pharmaceuticals, Inc. 
IND:  129039 
 
PROTOCOL APPROVAL: 
 
I am aware of, and agree to comply with, all of the procedures contained within this protocol and requirements of 
applicable regulatory agencies: 
 
Sponsor Representative 
Anand Shukla, MS, MBA 
Vice President, Research & Development 
Nivagen Pharmaceuticals Inc  
Signature: 
Date: 
Sponsor Representative 
Jay Shukla, RPh, MBA 
President and CEO 
Nivagen Pharmaceuticals Inc 
Signature: 
Date: 
Medical Monitor 
Allison M. Harper, PharmD 
President 
Harper Clinical Research Services, LLC  
Signature: 
Date: 
Statistical Consultant  
Charles Bon 
President 
Biostudy Solutions, LLC 
Signature: 
Date: 
CRO Representative 
Allan Shepard, PhD 
Project Manager  
Catawba Research, LLC 
Signature: 
Date: 
 
 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential. This information may not be used, published or 
disclosed without prior written approval from Nivagen Pharmaceuticals, Inc. and Catawba Research, LLC 
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 2 of 67 
Version 4.0 
 
CONTACT LIST 
 
Sponsor: 
Anand Shulka 
Vice President, R&D 
Nivagen Pharmaceuticals, Inc. 
3050 Fite Circle, Suite 100 
Sacramento,CA 95827 
Office:  916-364-1662 
Cell: 720-469-0635 
Fax:  844-270-3131 
Email:  ashukla@nivagen.com 
 
Contract Research Organization: 
Allan Shepard, PhD 
Project Manager 
Catawba Research, LLC 
5200 77 Center Drive, Suite 160 
Charlotte, NC 28217 
Office: (740) 469-4341 
Fax: (980) 422-0783 
Email: allan@catawbaresearch.com 
 
Statistics and Data Management: 
Soumitra Chowdhury 
Vice-President, Operations 
Quartesian, LLC 
3 Independence Way, Suite 106 
Princeton, NJ  08540 
Phone: (609) 454-3312 Ext.103 
Cell: (609) 902-9060 
Email: soumitra.chowdhury@quartesian.com 
 
Institutional Review Board (IRB): 
IntegReview  IRB 
3815 S. Capital of Texas Hwy, Suite 320 
Austin, TX 78704 
Phone: (512) 326-3001 
Fax: (512) 697-0085 
 
Central Laboratory:  
ACM Global Laboratory 
160 Elmgrove Park 
Rochester, NY 14624, USA 
Phone: (800) 525-5227 
 
Medical Monitor: 
Allison M. Harper, PharmD,  
President 
Harper Clinical Research Services, LLC 
53 Stono Drive 
Greenville, SC 29609 
Office/Mobile: (704) 996-6579 
Email: allison@harpercrs.com 
 
Drug Labeling, Packaging and Shipping 
Facility: 
Karl Adcock, CCRC 
Operations Manager 
ASKE Solutions, LLC  
4007 N Highway 183,  
Lockhart, Texas 78644 
Phone: (512) 481-2753  
Email: Karl.Adcock@askesolutions.com 
 
Retention Samples Storage Facility: 
Glenn Bullett 
BioRepository Resources, LLC 
755 Central Avenue, Unit 3 
New Providence, NJ 07974 
Phone: (908) 790-8890 
Fax: (908) 790-8899 
swww.brr.us.com 
 
Statistical Consultant: 
Charles Bon 
President 
Biostudy Solutions, LLC 
4008 Caesar Court 
Wilmington, NC 28405-6444 
Phone:  (910)  352-5648 
Fax: (866) 830-3720 
Email: chuck@biostudysolutions.com 
www.biostudysolutions.com 
 
Gwaltney Consulting: 
Chad Gwaltney, PhD 
Gwaltney Consulting 
1 Bucks Trail, Westerly, RI 02891 
Phone:  (412) 370-3378 
Email:  cgwaltney@gwaltneyconsulting.com 
www.gwaltneyconsulting.com 
 
 
 
Corporate Information 
 
Corporate Information 
 
Personal Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 3 of 67 
Version 4.0 
 
PRINCIPAL INVESTIGATOR AGREEMENT 
 
I have carefully read and understand the foregoing protocol HDCS 1701 “A Randomized, 
Double-blind, Placebo-controlled, Multicenter, Parallel Group Pilot Study of the Safety and 
Efficacy of Hydrocortisone Acetate Suppositories, 25 mg Compared to Placebo Suppositories in 
the Treatment of Symptomatic Internal Hemorrhoids” and agree that it contains all the necessary 
information for conducting this study safely. I will conduct this study in strict accordance with 
this protocol, ICH guidelines for Good Clinical Practice, the Code of Federal Regulations, the 
Health Insurance Portability and Accountability Act (HIPAA) and local regulatory guidelines. I 
will attempt to complete the study within the time designated. 
 
I will ensure that the rights, safety and welfare, of Subjects under my care are protected. I will 
ensure control of the drugs under investigation in this study. 
 
I will provide copies of the protocol and all other study-related information supplied by the 
Sponsor to all personnel responsible to me who participate in the study. I will discuss this 
information with them to assure that they are adequately informed regarding the drug and 
conduct of the study. 
 
I agree to keep records on all Subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) and drug disposition in accordance 
with FDA regulations. 
 
I will not enroll any Subjects into this protocol until IRB approval and Sponsor approval are 
obtained. 
 
 
 
____________________________ ___________________________ ________________ 
 
Principal Investigator 
 
Signature 
 
Date 
 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 4 of 67 
Version 4.0 
 
TABLE OF CONTENTS: 
PRINCIPAL INVESTIGATOR AGREEMENT ............................................................................ 3 
TABLE OF CONTENTS:............................................................................................................... 4 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
1. 
TITLE: ................................................................................................................................. 6 
2. 
INTRODUCTION: .............................................................................................................. 6 
3. 
OBJECTIVE: ....................................................................................................................... 7 
4. 
PHASE:….. .......................................................................................................................... 7 
5. 
STUDY DESIGN: ............................................................................................................... 7 
6. 
STUDY POPULATION: ..................................................................................................... 7 
7. 
PRODUCT DESCRIPTION: ............................................................................................... 7 
8. 
GROUPS: ............................................................................................................................. 7 
9. 
STUDY SCHEDULE: ......................................................................................................... 7 
10. 
STUDY OUTLINE: ............................................................................................................. 8 
11. 
RANDOMIZATION: .......................................................................................................... 9 
12. 
INCLUSION CRITERIA: ................................................................................................... 9 
13. 
EXCLUSION CRITERIA: ................................................................................................ 10 
14. 
TREATMENTS: ................................................................................................................ 10 
15. 
LABORATORY STUDIES: .............................................................................................. 11 
16. 
DIAGNOSTIC TESTS: ..................................................................................................... 12 
17. 
RETENTION SAMPLES: ................................................................................................. 12 
18. 
ADMINISTRATIVE MATTERS:..................................................................................... 12 
19. 
STUDY DISCONTINUATION: ....................................................................................... 12 
20. 
SUBJECT POPULATIONS: ............................................................................................. 13 
21. 
ENDPOINTS: .................................................................................................................... 13 
22. 
SUBJECT SAFETY: ......................................................................................................... 14 
23. 
STATISTICAL METHODS: ............................................................................................. 15 
24. 
ADVERSE EVENTS: ........................................................................................................ 15 
25. 
ETHICS.............................................................................................................................. 18 
26. 
DOCUMENTATION: ....................................................................................................... 19 
27. 
SUBJECT INTERVIEWS: ................................................................................................ 23 
28. 
STUDY VISITS: ................................................................................................................ 25 
29. 
REFERENCES: ................................................................................................................. 29 
I. 
APPENDIX 1: IHSSA Training Materials, Post-Bowel Movement Assessment, and End 
of Day Assessment ............................................................................................................. 30 
II. 
APPENDIX 2: PROMIS Global Health Questionnaire Version 1.2 ................................. 35 
III. 
APPENDIX 3: Patient Global Impression of Change (PGIC) and Patient Global 
Impression of Severity (PGIS) Items ................................................................................. 37 
IV. 
APPENDIX 4: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
(NCI, 2009) ........................................................................................................................ 40 
V. 
APPENDIX 5: Cognitive Interview Guide ........................................................................ 41 
VI. 
APPENDIX 6: Exit Interview Guide ................................................................................. 61 
VII. 
APPENDIX 7: Revision History ....................................................................................... 67 
 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 5 of 67 
Version 4.0 
 
LIST OF ABBREVIATIONS 
 
ADR 
AE 
Adverse Drug Reaction 
Adverse Event 
CFR 
Code of Federal Regulations 
eCRF 
CBC 
ClinRO 
CMP 
Electronic Case Report Form 
Complete Blood Count 
Clinician Reported Outcome 
Complete Metabolic Panel 
CRO 
Contract Research Organization 
DCF 
Data Clarification Forms 
EC 
Ethics Committee 
ED 
Early Discontinuation 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IGA 
Investigator Global Assessment 
ICH 
International Conference on Harmonization 
ID 
Identification 
IHSSA 
Internal Hemorrhoid Sign and Symptom Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
LOCF  
Last Observation Carried Forward 
mITT 
Modified Intent To Treat 
OTC 
Over the Counter 
PGIS 
Patient Global Impression of Severity 
PGIC 
Patient Global Impression of Change 
PP 
Per Protocol 
PRO 
RLD 
Patient Reported Outcome 
Reference Listed Drug 
SAE 
Serious Adverse Event 
US 
United States 
UV 
Unscheduled Visit 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 6 of 67 
Version 4.0 
 
1. TITLE:  
A randomized, double-blind, placebo-controlled, multicenter, parallel group pilot study of the 
safety and efficacy of Hydrocortisone Acetate Suppositories, 25 mg compared to placebo 
suppositories in the treatment of symptomatic internal hemorrhoids. 
 
2. INTRODUCTION:  
Hemorrhoidal disease is common in the United States with at least 15 million people comprising 
nearly 5% of the population suffering from this condition. Hemorrhoids begin with the 
enlargement of normal vascular cushions which are present in the anal canal at birth and are 
themselves a normal part of the human anatomy. However, hemorrhoids may be diagnosed only 
if symptoms of bleeding, prolapse or thrombosis exist in addition to the presence of enlarged 
vascular cushions. Hemorrhoids may be internal and/or external. Internal hemorrhoids occur 
above the dentate line and are covered with colonic mucosa whereas external hemorrhoids occur 
below the dentate line and are covered with squamous epithelium. The incidence of hemorrhoids 
peaks in the 65-74-year-old age group with lesser rates for both younger and older age groups.  
 
Current theory attributes the development of hemorrhoids to the dilation of the vascular cushions 
due to increased anal sphincter pressure which interferes with the drainage of blood from the rich 
plexus of arterial and venous vessels in these cushions but does not interfere with the in-flow of 
blood through the arteries. This results in dilation and progressive development of hemorrhoids. 
A major factor contributing to hemorrhoidal development is the gradual degeneration of the 
connective tissue in the vascular cushions which leads to further enlargement of the vessels and 
to their eventual prolapse. This combination of decreased outflow and gradual connective tissue 
degeneration results in the progressive development of the condition. 
 
Early hemorrhoids are frequently treated with a fiber diet and with lifestyle modifications such as 
increased exercise and the avoidance of obesity and sedentary occupation which appear to be 
significant risk factors for the disease. Also, control of diarrhea appears to be a useful option in 
the prevention of the development of hemorrhoids. However, in more advanced cases acute 
hemorrhoidal attacks are present with bleeding, inflammation and often thrombosis of the 
hemorrhoidal veins. Conservative therapy consists of local treatment. Several types of drugs 
have been used for this purpose. These include local anesthetics, chiefly pramoxine. This is a 
rapidly acting, local anesthetic which is applied topically as needed up to five times a day. It 
provides local relief particularly of itching through its anesthetic action. Local application of 
phenylephrine is also used in the treatment of hemorrhoids to reduce blood flow through the 
hemorrhoids by utilizing the drug’s vasoconstricting action. This produces temporary relief of 
burning and itching. 5-amino salicylic acid (Mesalamine) is also used off-label as a local anti-
inflammatory agent to treat hemorrhoids. It appears to reduce the pain and bleeding of 
hemorrhoids during acute attacks. Hydrocortisone in various types of vehicles is also a 
prominent modality of treatment for hemorrhoids as well as other anorectal conditions. Foams, 
suppositories and locally applied creams have been used as vehicles for the application of 
hydrocortisone, although none are FDA-approved products for the treatment of hemorrhoids. 
Hydrocortisone’s potent anti-inflammatory action is thought to reduce the inflammation 
associated with the hemorrhoids and thus improve bleeding, itching and other symptoms of 
hemorrhoids. Products using these ingredients have a long history of use in the United States and 
are commonly relied upon for the non-surgical, conservative treatment of hemorrhoids. 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 7 of 67 
Version 4.0 
 
 
3. OBJECTIVE:  
a. 
To determine the effectiveness of Nivagen’s Hydrocortisone Acetate Suppositories 25 mg 
for the relief of symptoms associated with internal hemorrhoids. 
b. To determine the safety and tolerability of Nivagen’s Hydrocortisone Acetate 
Suppositories 25 mg. 
 
4. PHASE:  2 
 
5. STUDY DESIGN: 
This study will be a randomized, double-blind, placebo-controlled, multicenter, parallel group 
pilot study of 25 mg hydrocortisone suppositories administered twice daily compared to a 
vehicle placebo in subjects with symptomatic internal hemorrhoids. Approximately 100 subjects 
will be randomized in a 1:1 ratio (Test product: placebo). 
 
The study will consist of 3 periods:  
a. 
Screening Period (2 weeks/Days -14 to -1) 
b. Treatment Period (2 weeks/ Days 1-14) 
c. 
Follow-up Period (2 weeks/ Days 15-29) 
 
Subjects will use daily paper diaries to record the time and date of each medication application, 
concomitant medication and adverse events (AEs). The subjects will use electronic diaries to 
complete the Internal Hemorrhoids Sign and Symptom Assessment (IHSSA) daily for the 
duration of the study and the Patient Global Impression of Severity (PGIS) and Change (PGIC) 
at visits.  
 
6. STUDY POPULATION:  
Male and female subjects, at least 18 years of age, with a diagnosis of symptomatic internal 
hemorrhoids will be selected to participate in the study.  
 
7. PRODUCT DESCRIPTION: 
Test Product: Hydrocortisone Acetate Suppository, 25 mg (Nivagen Pharmaceuticals Inc.) 
Placebo: Vehicle Suppository (Nivagen Pharmaceuticals Inc.) 
 
8. GROUPS:  
Two Groups (1:1) 
Total Subjects: Approximately 100 (50:50) 
 
9. STUDY SCHEDULE: 
Visit 1 (Days -14±2; Initiation of Screening) 
Visit 2 (Day 1; Start of Treatment) 
Visit 3 (Day 8±1, Interim) 
Visit 4 (Day 15±2, End of Treatment) 
Visit 5 (Day 29±3, Follow-Up/End of Study; UV/ED) 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 8 of 67 
Version 4.0 
 
10. STUDY OUTLINE: 
 
 
Visit Title 
Initiation of 
Screening 
Start of 
Treatment 
Interim 
End of 
Treatment  
Follow-up/End 
of Study 
UV/ED8 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Study Day 
Day -14±2 
Day 1 
Day 8±1 
Day 15±2 
Day 29±3 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
Physical Exam including 
Vital Signs 
X 
 
 
 
 
Clinical Laboratory Tests 
X1 
 
X2 
X3 
 
Urine Pregnancy Test4 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
Breath Alcohol Test 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Adverse Events Assessment 
 
X 
X 
X 
X 
Anoscopy 
 
X 
 
X 
 
Assessment of Disease 
Grade/ Diagnosis 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Cognitive Interview5 
X 
 
 
 
 
Exit Interview6 
 
 
 
X 
 
PROMIS Global Health 
Questionnaire 
 
X 
 
X 
 
IHSSA daily diary7 (ePRO) 
X 
X 
X 
X 
X 
Patient Global Impression of 
Severity (PGIS) (ePRO) 
 
X 
 
X 
 
Patient Global Impression of 
Change (PGIC) (ePRO) 
 
 
 
X 
 
Dispense IP Supplies 
 
X 
 
 
IP Accountability 
Drug will be returned 
 
 
 
X 
X as needed 
Dispense Diary/Instructions 
X 
X 
 
X 
 
Subject Compliance/Diary 
Review and Collection 
 
X 
 
X 
X as needed 
Schedule Next Visit 
X 
X 
X 
 
X as needed 
1Complete blood count (CBC), comprehensive metabolic panel (CMP), urinalysis, HIV, Hepatitis B, Hepatitis C 
2Comprehensive metabolic panel (CMP) 
3Complete blood count (CBC), comprehensive metabolic panel (CMP) 
4The urine pregnancy test is to be conducted for women of child-bearing potential. Tubal ligation is not considered equivalent to female 
sterilization. Women with a history of tubal ligation are still considered females able to become pregnant and must complete a urine pregnancy 
test. 
5First 5 enrolled subjects at a sponsor selected site 
6First 25 enrolled subjects who reach Visit 4 and agree to participate in the interview  
7Internal Hemorrhoids Sign and Symptom Assessment. To be completed daily throughout the study via electronic diary (ePRO).  
8UV, Unscheduled Visit; ED, Early Discontinuation Visit 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 9 of 67 
Version 4.0 
 
11. RANDOMIZATION: 
a. 
Two groups. 
b. This is a double-blind study. 
c. 
An independent third party will generate and hold the randomization code throughout the 
conduct of the study. The Nivagen product and placebo will be similar in appearance and 
will also be labelled and packaged to be similar in appearance. The Subject and Investigator 
will be blinded as to the treatment.  
 
12. INCLUSION CRITERIA: 
a. 
Subject reports an average score of 1.5 or greater (on 0-4 scale) on either the IHSSA itch 
severity or itch frequency items (Section 21.b) during the 2-week screening period  
b. Subject reports hemorrhoidal bleeding associated with their bowel movements at least 50% 
of the days where a bowel movement occurs, as indicated by responses to the IHSSA 
(Section 21.b) during the 2-week screening period. 
c. Have a diagnosis of symptomatic Grade I, II or III internal hemorrhoids (Banov et al. 1985) 
by history; confirmed by anoscopy.  
d. Is a male or female aged 18 years and older. 
e. Give voluntary consent to participate in the study following a full explanation of the nature 
and purpose of the study, by signing the IRB-approved Informed Consent document prior to 
any study specific evaluations. 
f. 
Is willing to forego the use of non-prescription (OTC) and prescription medication or 
procedures for the treatment of hemorrhoidal disease and/or pain for the duration of the 
study. 
g. 
Female Subjects of childbearing potential (excluding women who are or premenarchal, 
surgically sterilized (by hysterectomy) or postmenopausal for at least 1 year), in addition to 
having a negative urine pregnancy test, must be willing to use an acceptable form of birth 
control during the study from the day of the first dose administration to 30 days after the last 
administration of study drug. For this study, the following are considered acceptable 
methods of birth control: oral or injectable contraceptives, contraceptive patches, Depo-
Provera® (stabilized for at least 3 months), NuvaRing® (vaginal contraceptive), 
Implanon™ (contraceptive implant), double barrier methods (e.g. condom and spermicide), 
IUD, tubal ligation, Essure or abstinence with a 2nd acceptable method of birth control 
should the Subject become sexually active. Subjects on hormonal contraception must be 
stabilized on the same type for at least three months prior to enrollment in the study and 
must not change the method during the study. A sterile sexual partner is NOT considered an 
adequate form of birth control. 
h. 
All male Subjects must agree to use accepted methods of birth control with their partners, 
from the day of the first dose administration to 30 days after the last administration of study 
drug. Abstinence is an acceptable method of birth control. Female partners should use an 
acceptable method of birth control as described in the above Item g. 
i. 
Subjects agree to not appreciably change their diet during the study.  
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 10 of 67 
Version 4.0 
 
13. EXCLUSION CRITERIA:  
a. Has a fissure or a fistula-in-ano, abscess, polyps or colorectal adenoma or colorectal cancer, 
arteriovenous malformations, or any other pathological condition of the anus other than 
symptomatic internal hemorrhoids which might be a potential cause of hematochezia. 
b. Has inflammatory bowel disease. 
c. Has Grade IV hemorrhoidal disease (Banov et al. 1985).  
d. Has external hemorrhoids.  
e. Has had or is receiving pelvic radiation. 
f. 
Is using other OTC, prescription or narcotic medications for treatment of hemorrhoidal 
disease and/or pain. Washout of 7 days required if medicated treatment used. 
g. Has had a sphincterotomy, anal stretch or other procedure that may reduce the resting anal 
pressure. 
h. Endoscopic or surgical treatment of internal hemorrhoids in the past such as IRC, rubber 
band ligation or injection therapy. 
i. 
Is immunocompromised (e.g. receiving cancer chemotherapy, steroids, HIV positive). 
j. 
Is a pregnant or nursing female. 
k. Is known to be allergic to latex, lanolin, white petrolatum, paraffin wax, sorbitan 
sesquioleate, propylene glycol, hydrocortisone or psyllium. 
l. 
Is not willing to use a finger to insert the suppository even with a finger cot. 
m. Has received glucocorticoids (any form) within the last 2 months prior to starting study. 
n. Subjects who have unstable medical disorders that are clinically significant or have life-
threatening diseases. 
o. Subjects who consume excessive amounts of alcohol (greater than two drinks per day) or 
use drugs of abuse (including, but not limited to, cannabinoids, cocaine and barbiturates). 
p. Positive urine screening for drugs of abuse or positive alcohol breath test.  
q. Subjects who have participated in an investigational drug study (i.e., Subjects have been 
treated with an investigational drug) within 30 days prior to baseline will be excluded from 
study participation. Subjects who are participating in non-treatment studies such as 
observational studies or registry studies can be considered for inclusion. 
r. 
Subjects who have been previously enrolled in this study. 
s. 
A subject who has a history of being unresponsive to anal hydrocortisone therapy. 
t. 
Lacks suitability for participation in this study for any reason in the opinion of the 
Investigator. 
u. Clinically significant complete blood count (CBC), comprehensive metabolic panel (CMP), 
urinalysis or positive HIV, Hepatitis B, Hepatitis C.  
v. Female subjects with Abnormal Uterine Bleeding (menorrhagia).  
 
14. TREATMENTS:  
Suppositories should be stored at room temperature away from moisture and heat. One (1) 
Hydrocortisone Acetate Suppository, 25 mg or Placebo (Vehicle) Suppository is inserted into the 
anal canal twice daily (morning and evening) for 2 weeks (14 days).  Subjects are to be 
instructed to wash their hands before and after handling the suppository and to try to empty their 
bowel and bladder just before inserting suppository.  Subjects should clean their rectum with a 
moist cloth or wipe before using the suppository and gently dry the area by blotting with toilet 
tissue.  The outer wrapper is to be removed from the suppository before inserting and handling of 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 11 of 67 
Version 4.0 
 
the suppository too long is to be avoided or it will melt in their hands.  To insert the suppository, 
the subject is to lie on their side with their lower leg straight out and their upper leg bent forward 
toward their stomach and then lift their upper buttock to expose their rectal area. No more than 
the specified amount of suppository is to be used and is not to be applied more than twice daily 
as this will not produce faster results and may increase irritation.  To insert one suppository, 
pointed end first, subject is to use their finger until it passes the muscular sphincter of the rectum, 
about 1 inch in adults. (If not inserted past the sphincter, the suppository may pop out.).  Subject 
is to hold their buttocks together for five seconds and for best results, to remain lying down for 
five minutes to avoid having the suppository come out.  The suppository will melt quickly once 
inserted and there should be little or no discomfort while holding it in.  Subject is to avoid having 
a bowel movement for one to three hours after inserting the suppository. 
 
Note that the medication from the suppository may stain fabric. Subjects may experience 
irritation such as burning, itching, dryness, skin/hair follicle irritation, or changes in skin color 
around the rectal area. Subjects are to report to the study staff any reactions that make continued 
application of the study medication difficult. The PI may recommend that the study medication 
be used less frequently on the irritated areas until the irritation goes away.  If subject sees a 
doctor for any medical problems, they are to be advised to inform the study staff at their next 
visit.  Subject is to record any illness or unwell feelings such as headaches, cold, cramps, etc., on 
the last page of their diary.  Subjects are to record any change in medications since the previous 
visit (other than study medication) on the last page of the diary. All unused study medication 
must be returned to the study site at the end of treatment. 
 
15. LABORATORY STUDIES:  
Complete 
blood 
count 
(CBC), 
comprehensive 
metabolic 
panel 
(CMP), 
blood 
HIV/Hepatitis B/Hepatitis C testing, urinalysis, urine pregnancy, urine drug screen, breath 
alcohol tests.  
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 12 of 67 
Version 4.0 
 
16. DIAGNOSTIC TESTS:  
Anoscopy - Classification of Internal Hemorrhoids (Banov et al. 1985).  
Video of the procedure will be recorded and sent to the CRO for central reading.  
 
Grade Description 
I 
Hemorrhoids are visualized on anoscopy and may bulge into the lumen but do not 
prolapse below the dentate line 
II 
Hemorrhoids prolapse out of the anal canal with defecation or with straining but 
reduce spontaneously 
III 
Hemorrhoids prolapse out of the anal canal with defecation or straining, and require 
manual reduction 
IV 
Hemorrhoids are irreducible and may strangulate 
 
17. RETENTION SAMPLES:  
Retention samples will be randomly selected at the study sites from the clinical drug supplies 
received prior to dispensing to subjects and sent to BRR for long-term storage. Retention 
samples will not be returned to the sponsor at any time.  
 
18. ADMINISTRATIVE MATTERS:  
In addition to recording the time and date of each medication application, the Daily Personal 
Diaries will be used to record concomitant medication taken and all adverse events experienced.  
Paper copies of the IHSSA daily electronic diaries will be provided to subjects for use as a 
backup for missed ePRO questionnaires.  
 
19. STUDY DISCONTINUATION:  
Subjects could be discontinued from the study for the following reasons: 
a. 
Pregnancy. 
b. Acute illness or clinically significant laboratory result. 
c. 
Significant protocol deviation. 
d. Serious adverse experience. 
e. 
Decision by the Subject to leave for any reason. 
f. 
If the Subject’s condition has worsened to the degree that the Principal Investigator feels it is 
unsafe for the Subject to continue in the study. 
g. If the Subject’s drug code is unblinded. 
i. 
If the Subject is lost to follow-up. 
j. 
If the Subject becomes pregnant. 
k. If the Subject becomes a prisoner or become involuntarily incarcerated. 
l. 
Any other reason that may affect the outcome of the study or the safety of Subjects. 
m. Termination of the study by the Sponsor. 
 
A significant protocol violation is defined as any Subject or Investigator activity that could have 
possibly interfered with the therapeutic administration of the treatment or the precise evaluation 
of treatment efficacy. 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 13 of 67 
Version 4.0 
 
The reasons for a Subject discontinuation will be documented. If a Subject is discontinued from 
the study for any reason, the procedures scheduled for Visit 5 will be completed and any 
outstanding data and study drug should be collected if possible. Data, in addition to the reason 
for discontinuation and the date of removal, will be documented on the End of Study eCRF. 
 
Before a Subject is considered lost to follow-up, the Principal Investigator will document all 
attempts to reach the Subject twice by telephone and will send a certified follow-up letter. 
 
If a Subject discontinues from the study at any time due to an adverse event, the reason for 
discontinuation, the nature of the event and its clinical course must be fully documented. For 
such a Subject, the Principal Investigator must strive to follow the Subject until the adverse event 
has resolved, becomes clinically insignificant, is stabilized or the Subject is lost to follow-up. 
Should a serious adverse event (SAE) be noted, procedures stated in Section 24.d. must be 
followed.  
 
20. SUBJECT POPULATIONS:  
a. 
The per-protocol (PP) population includes all subjects who meet all inclusion and no 
exclusion criteria, completed the evaluations for Visit 4 within the designated visit window 
(+/- 2 days) with no protocol violations that would affect the treatment evaluation. Subjects 
must take at least 80% but no more than 120% of the required doses. Compliance will be 
verified using subject diaries.  
b. The modified intent-to-treat (mITT) population includes all subjects who meet all 
inclusion/exclusion criteria, apply at least one (1) dose and return for at least one (1) post-
baseline evaluation visit. 
c. The safety population (intent-to-treat (ITT)) includes all subjects who meet all 
inclusion/exclusion criteria and apply at least one (1) dose.  
 
21. ENDPOINTS:  
a. 
Clinician Reported Outcome (ClinRO) - Anoscopy (Visits 2, 4).  
 
Anoscopy – Visual assessment of hemorrhoids (Fukuda et al. 2005; Lunniss and Mann 2004). 
Video of the procedure will be recorded for blinded central reading and assessment according to 
the following scale: 
 
Swelling % Lumen Score 
0 
None 
0 
≤25 
Mild 
1 
≤50 
Moderate 
2 
≤75 
Severe 
3 
>75 
Very severe 4 
 
b. Patient Reported Outcome (PRO) – Internal Hemorrhoid Sign and Symptom Assessment 
(IHSSA) (Daily between Visits 1 and 5). 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 14 of 67 
Version 4.0 
 
The IHSSA is completed by patients immediately following each bowel movement each day and 
at the end of each day. The IHSSA post-bowel movement items address signs and symptoms 
during bowel movements. The end of day items assess signs, symptoms, functional limitations, 
and emotional impacts over the course of a day. Patients are asked to rate their most severe signs 
and symptoms using 5-point verbal rating scales that have verbal anchors for each response. 
Frequency of hemorrhoid-related pruritus is also addressed through a 5-point verbal response 
scale. The Bristol Stool Scale, a measure of stool consistency, is administered during episodic, 
post-bowel movement assessments. The IHSSA is administered via a web browser-based portal 
system on the patient’s own smartphone or personal computer. The IHSSA training materials, 
post-bowel movement assessment, and end of day assessment are included in Appendix 1. 
 
c. 
Patient Reported Outcome (PRO) – Patient Reported Outcome Measurement Information 
System (PROMIS) Global Health Questionnaire Version 1.2 (Visits 2 and 4). 
 
The PROMIS Global Health Questionnaire is completed by patients during Visits 2 and 4.  It 
will be completed before any clinical or laboratory tests are administered.  The PROMIS Global 
Health Questionnaire assesses an individual’s physical, mental, and social health using 10 items. 
The measure is generic, rather than disease-specific, and often uses an “In General” item context 
as it is intended to globally reflect individuals’ assessment of their health. The questionnaire 
produces two scores: Physical Health and Mental Health. Raw scores for both scales are 
converted to T-scores with a mean of 50 and standard deviation of 10. The items of the PROMIS 
Global Health Questionnaire are included in Appendix 2. 
 
d. Patient Reported Outcome (PRO) – Patient Global Impression of Severity (Visits 2 and 4) 
and Patient Global Impression of Change (Visit 4) Items 
 
The Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change 
(PGIC) items are designed to capture the patient’s overall perspective on sign and symptom 
severity. The 8-item PGIS asks patients to rate the severity of their hemorrhoid-related signs and 
symptoms over the past week. The 9-item PGIC asks patients to rate the direction and magnitude 
of the change in their signs and symptoms since starting the study medication. The PGIS and 
PGIC are included in the study to help establish the threshold for clinically relevant change on 
the IHSSA. Although they address signs and symptoms of internal hemorrhoids, the IHSSA is 
considered the primary measure of these constructs. The PGIS and PGIC items are included in 
Appendix 3. 
 
Based on the results of the pilot study, primary and secondary endpoints will be selected for 
future studies.  
 
22. SUBJECT SAFETY: 
a. 
Safety assessment will be conducted on all subjects administered at least one suppository. 
Adverse drug reactions may include burning and local irritation upon application. Systemic 
absorption of topical corticosteroids has produced reversible suppression of the HPA axis. 
Adverse medical events experienced by the subjects will be tabulated. The relationship of 
adverse events, if any, to the study drug will be assessed by the Investigator (see Section 
24).  
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 15 of 67 
Version 4.0 
 
 
b. Physical Examination 
The investigator, sub-investigator or appropriately delegated designee, (Physician’s 
Assistant, Advanced Registered Nurse Practitioner, and Registered Nurse as per local 
regulations) will perform a brief physical examination, prior to the Subject starting study 
drug.   
The physical examination will include, at a minimum, examination of the Subject’s general 
appearance, skin, HEENT (head, eyes, ears, nose and throat), heart, lungs, musculoskeletal 
system, neurological system, lymph nodes, abdomen and extremities.  
Vital signs, including blood pressure, pulse rate, respiratory rate and oral body temperature 
will be documented at Visit 1. Vital signs will be measured after the Subject has rested in a 
seated position for at least 5 minutes. 
The Subject’s body weight will also be measured while the Subject is lightly clothed (e.g., no 
coat or shoes). Height will be measured without shoes. 
c. Concomitant medications 
Concomitant medications, including the use of non-drug treatments/therapies, in addition to 
the reason for the medication use, will be assessed at baseline and at each subsequent study 
visit. The start and stop date of concomitant medication use during the study should be 
provided in the data set in addition to the reason for the medication use. 
d. A record of concomitant medications taken by the Subject is to be obtained using generic 
name, if known, with the corresponding indication. The medications to be recorded will 
include prescription and over-the-counter (OTC) medications and dietary supplements.  All 
medications taken on a regular basis, including acetaminophen, should be recorded.  
e. Individual subject stopping criteria 
Subjects will be withdrawn if they are hypersensitive to the drug product or develop a 
CTCAE v4.0 (NCI 2009) Grade 3 or higher adverse event (Appendix 4). Subjects will be 
monitored for drug-induced liver injury (DILI) (FDA 2009). Subjects will be withdrawn if:  
i. 
Alanine or aspartate aminotransferase (ALT or AST) >8x upper limit of normal 
(ULN).  
ii. 
ALT or AST >3x ULN and (total bilirubin (TBL) >2x ULN).  
iii. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).  
Subjects will be re-tested (CMP) within 48-72 hours if ALT or AST >3x ULN and/or 
TBL >2x ULN. If repeat testing shows ALT or AST >3x ULN, close observation will 
be initiated to determine whether the abnormalities are improving or worsening.   
Close observation includes:  
iv. 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
the trial drug has been discontinued and the subject is asymptomatic. 
v. 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
vi. 
Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 16 of 67 
Version 4.0 
 
vii. 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract disease. 
viii. 
Obtaining a history of exposure to environmental chemical agents. 
ix. 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
x. 
Considering gastroenterology or hepatology consultations. 
 
f. Pilot study stopping criteria 
The pilot study may be stopped if ≥2 patients on drug develop the same CTCAE v4.0 
Grade 3 adverse event or if 1 patient develops a CTCAE v4.0 Grade 4 or higher adverse 
event (Appendix 4).  
 
23. STATISTICAL METHODS: 
a. 
Endpoints 
Anoscopy results at Day 15 will be compared to responses at baseline (Day 1). IHSSA 
scores from Days 1-15 (treatment period) and 16-29 (follow-up period) will be compared to 
responses from Days -14 to -1 (baseline period). The 95% confidence intervals for the 
differences between the change from baseline for the hydrocortisone acetate suppository and 
that for the placebo will be calculated. 
 
b. Safety 
The incidence of all AEs reported during the study will be classified based on Medical 
Dictionary for Regulatory Activities (MedDRA) version 21.0 terminology (system organ 
classes and preferred terms) and summarized for each treatment group. Incidence of adverse 
events will be tabulated by system organ class, preferred term, and severity, and by system 
organ class, preferred term, and relationship to study drug. 
 
24. ADVERSE EVENTS: 
a. 
Definitions 
i. 
Any untoward events occurring during the study will be documented and summarized upon 
completion of the study.  
ii. 
The term Adverse Event (AE) will cover any untoward medical occurrence in a clinical 
investigation where a volunteer was administered an investigational product, which does 
not necessarily have to have causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
use of a medicinal product, whether considered related to the medicinal product. This 
includes all events both expected and unexpected (the nature or severity of which is not 
consistent with information in the relevant source document(s)).  
iii. 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established, an Adverse Drug Reaction 
(ADR) is defined as follows: all noxious and unintended responses to a medicinal product 
related to any dose. The phrase "responses to a medicinal product" means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal 
products, an adverse drug reaction is defined as a response to a drug which is noxious and 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 17 of 67 
Version 4.0 
 
unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for modification of physiological function.  
iv. 
A medical event is defined as any unintended sign, symptom, or disease that occurs 
between the pre-trial evaluation and the first investigational product administration of the 
clinical study. As no investigational product has been administered yet, those events are 
not to be considered as adverse events.  
v. 
Worsening of a sign or symptom of the condition under treatment will normally be 
measured by efficacy parameters. However, if the outcome fulfills the definition of 
“serious adverse event”, it must be recorded as such (see below).  
b. An adverse event may be:  
i. 
A new illness.  
ii. 
Worsening of a concomitant illness.  
iii. 
An effect of the study medication including comparator; it could be an abnormal laboratory 
value as well as a significant shift from baseline within normal range which the qualified 
investigator or medical qualified designate considers to be clinically important.  
iv. 
A combination of two or more of these factors.  
v. 
Abnormalities in laboratory tests, in the measurements of vital signs, or in other 
measurements performed after the drug administration or at the end of the study are to be 
recorded as adverse events only if they are medically relevant: symptomatic, requiring 
corrective treatment, leading to study discontinuation and/or fulfilling a seriousness 
criterion. If asymptomatic, but with a suspected underlying process, the qualified 
investigator or the qualified medical designate may consider the abnormalities to be 
medically relevant.  
c. 
Surgical procedures themselves are not adverse events. They are therapeutic measures for 
conditions that required surgery. The condition for which the surgery is required is an 
adverse event, if it occurs or is detected during the study period. Planned surgical measures 
permitted by the clinical study protocol and the conditions(s) leading to these measures are 
not adverse events, if the condition(s) was (were) known before the start of study treatment. 
In the latter case, the condition should be reported as medical history.  
d. A serious adverse event is one that occurs at any dose (including overdose) and that:  
i. 
Results in death. 
ii. 
Is life-threatening.  
iii. 
Requires in-patient hospitalization or prolongation of existing hospitalization.  
iv. 
Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions).  
v. 
Is a congenital anomaly or birth defect.  
vi. 
Is an important medical event (including development of drug dependence or drug abuse) 
that may jeopardize the volunteer or may require intervention to prevent one or the other 
outcomes listed above (according to medical judgment of the qualified investigator).  
e. 
Classification of Adverse Events 
All adverse events will be recorded on an adverse event information sheet and graded as 
mild, moderate, or severe according to the following definitions:  
i. 
Mild: Causing no limitation of usual activities; the volunteer may experience slight 
discomfort.  
ii. 
Moderate: Causing some limitation of usual activities; the volunteer may experience 
annoying discomfort.  


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 18 of 67 
Version 4.0 
 
iii. 
Severe: Causing inability to carry out usual activities; the volunteer may experience 
intolerable discomfort or pain.  
f. Relationship to Study Medication 
The relationship is characterized as:  
i. 
Not Related: This applies to any AE that is clearly not related to use of the study 
drug.  
ii. 
Possible: This means the association of the AE with the study drug is unknown; 
however, a relationship between drug and event cannot be ruled out.  
iii. 
Probable: There is a reasonable temporal relationship between the use of the study 
drug and the AE. Based upon the Principal Investigator’s clinical experience, the 
association of the event with the study drug seems likely.  
iv. 
Definite: The AE occurs following the application of the study drug and it cannot be 
reasonably explained by any known characteristics of the Subject’s clinical state, 
environmental or toxic factors or other modes of therapy administered to the Subject. 
It disappears or decreases upon discontinuation of the study drug and reappears on a 
re-challenge of the investigational product.  
g. Documentation and Reporting of Adverse Events 
i. 
For the purposes of this study, the period of observation of adverse events extends from the 
start of treatment with the investigational product until the final study visit. During this 
period, all adverse events spontaneously reported by the volunteer, observed by the 
Qualified Investigator (or delegates) or elicited by general questioning will be documented 
in the CRF and will be reported in the final report.  
ii. 
If necessary, every effort will be made to obtain an adequate follow-up of the volunteers. 
Should any volunteers choose to withdraw early from the study, they will be advised of the 
safety precautions to be taken.  
iii. 
The volunteers will be questioned on their health status at the beginning of the study and 
before their departure from the clinical site. An open-ended question will be asked.  
iv. 
It is the qualified investigator’s responsibility to record and report all adverse events that 
occur during the study regardless of their relationship to the study medication. If judged 
necessary by the qualified investigator, an adverse event will be reported in accordance 
with the applicable regulatory requirements.  
h. Pregnancy in a female volunteer on the study shall be reported to the sponsor or their 
authorized representative within 24 hours of the knowledge of its occurrence by the 
qualified investigator that such pregnancy occurs during the Study or right after. Because of 
the possibility that the fetus/embryo could have been exposed to the study drug through the 
parent and for the volunteer’s safety, the pregnancy will be followed up to determine 
outcome as, including spontaneous or voluntary termination, details of birth, presence or 
absence of any birth defects, congenital anomalies, or maternal and/or newborn 
complications.  
i. 
As for an adverse event, the pregnancy will be recorded on a Clinical Trial Pregnancy Form 
and reported by the qualified investigator to the sponsor. Pregnancy follow-up will also be 
properly recorded to ensure quality and completeness of the data belonging to the study drug 
and will include an assessment of the possible causal relation between the study drug and 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 19 of 67 
Version 4.0 
 
any pregnancy outcome. Any SAE experienced during pregnancy will be reported on a SAE 
Report Form.  
j. 
Any adverse event that is considered serious will be reported to the Institutional Review 
Board (IRB) and to the Sponsor representative promptly by telephone and in writing within 
three working days. Any unexpected fatal or life-threatening serious event will be reported 
to the IRB and to the Sponsor representative promptly by telephone and in writing within 
one working day. This report will contain a detailed description of the observed symptoms 
and the contra-active therapy. The qualified investigator will judge the possible causal 
relationship between the event and the study drug.  
25.  ETHICS 
This study will be conducted in accordance with the ethical principles that have their 
origin in the current Declaration of Helsinki and will be consistent with International 
Conference on Harmonization Good Clinical Practice (ICH GCP) and applicable 
regulatory requirements. The study will be conducted in compliance with the protocol. 
The rights, safety and well-being of the study Subjects are the most important 
considerations and should prevail over interests of society and science.   
i. 
Informed Consent 
The Principal Investigator must ensure that Subjects are clearly and fully informed about 
the purpose, potential risks and other critical issues regarding clinical studies in which 
they volunteer to participate. The principles of Informed Consent, according to FDA 
Regulations and ICH GCP will be followed.  A copy of the proposed consent/assent form 
must be submitted to the IRB, together with the protocol, for approval. Prior to beginning 
of the study, the Principal Investigator must have the IRB’s written approval of the 
written informed consent/assent form and any other information to be provided to 
Subjects. 
Subjects 18 years of age or older must provide Institutional Review Board (IRB) 
approved written informed consent. Subjects under the age of 18 years must have parent 
or legal guardian provide IRB approved written informed consent. In addition, an assent 
form for minors must be completed for subjects under the legal age of consent, if 
applicable, depending on the age range required by state laws. 
Each Subject’s signed informed consent/assent must be kept on file by the Principal 
Investigator. A copy of the signed consent/assent form will be given to the Subject or legal 
guardian. A notation will be made in the Subject’s medical record indicating the date the 
informed consent/assent was obtained. In addition, the Principal Investigator or the Principal 
Investigator’s Designee will provide a HIPAA authorization form (if applicable) for the 
Subject to review and sign. Both the consent/assent form and the HIPAA authorization form 
(if applicable) must be signed by the Subject or legal guardian before any protocol 
assessments can be undertaken. 
ii. 
Institutional Review Board  
Before study initiation, the Principal Investigator must have written and dated approval 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 20 of 67 
Version 4.0 
 
from the IRB for the protocol, consent form, Subject recruitment materials and any other 
written information to be provided to Subjects.  
Any changes to the protocol as well as a change of the Principal Investigator, which is 
approved by the Sponsor, must also be approved by the site’s IRB and documentation of 
this approval provided to the Sponsor/designee. Records of the IRB review and approval 
of all documents pertaining to this study must be kept on file by the Principal Investigator 
and are subject to inspection during or after completion of the study.  All SAEs must also 
be reported to the IRB. 
Periodic status reports must be submitted to the IRB at least annually, as well as 
notification of completion of the study and a final report within one (1) month of study 
completion or discontinuation. A copy of all reports submitted to the IRB must be sent to 
the Sponsor/designee. 
The Principal Investigator will ensure that an IRB that complies with the regulatory 
requirements will be responsible for the initial and continuing review and approval of the 
proposed clinical study. 
iii. 
Subject Confidentiality  
The monitor(s), the auditor(s), IRB/IEC, and the regulatory authority(ies), will be granted 
direct access to the Subject’s original medical records for verification of the clinical trial 
procedures and/or data, without violating the confidentiality, to the extent permitted by 
the applicable laws and regulations and that by signing a written informed consent form, 
the Subject or the Subject’s legally acceptable representative is authorizing such access. 
The identity of the Subject will be kept confidential and, to the extent permitted by the 
applicable laws and regulations, will not be made publicly available. If the results of the 
trial are published, the Subject’s identity will remain confidential. 
 
26. DOCUMENTATION: 
 
a. Site Regulatory Documents Required for Initiation  
The following documents will be received by the CRO prior to the initiation of the study: 
i. 
Current curricula vitae, signed and dated for the Principal Investigator and each 
Sub-Investigator (current within 2 years) 
ii. 
Current medical licenses of the Principal Investigator and Sub-Investigators 
iii. 
Documentation of IRB approval of this study protocol, Principal Investigator and 
informed consent form 
iv. 
Current IRB membership list or roster  
v. 
A copy of the protocol agreement page signed by the Principal Investigator  
vi. 
Non-disclosure Agreements for the Principal Investigator and Sub-Investigators  
vii. 
Completed and signed FDA Form 1572 
viii. 
Statement of Non-Debarment 
ix. 
Fully executed Clinical Trial Agreement (CTA) 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 21 of 67 
Version 4.0 
 
b. Maintenance and Retention of Records 
It is the responsibility of the Principal Investigator to maintain a comprehensive and 
centralized filing system of all relevant documentation. 
Copies of all pertinent records will be retained by the Principal Investigator for at least two 
years following final approval of the drug and/or notification from the Sponsor. These 
regulatory documents should be retained for a longer period if required by local regulatory 
authorities. These records include documents pertaining to the receipt and return of drug 
supplies, IRB, informed consent/assent, source documents, as well as eCRFs (paper or 
electronic files). No documents shall be transferred from the site or destroyed without first 
notifying the Sponsor. If the Principal Investigator withdraws from the study, the records 
shall be transferred to a mutually agreed upon designee. Notice of such transfer will be given 
in writing to the Sponsor. 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories designed to document all observations and other data pertinent to the 
investigation on each individual treated with the Investigational Product or entered as a 
control in the investigation. Data reported on the CRF, which are derived from source 
documents, must be consistent with the source documents.  
 
c. Data Collection and Reporting 
Data for individual Subjects will be collected on eCRF designed by the Contract Research 
Organization. The data management system will be Electronic Data Capture (EDC). The 
Investigator and his/her study site personnel will be responsible for completing the eCRFs. 
The Investigator is required to verify that all of the requested information is accurately 
recorded in the eCRFs. All information requested in the eCRFs needs to be supplied, 
including subject identification, date(s), assessment values, etc., and any omission or 
discrepancy will require explanation. All information on eCRFs must be traceable to source 
documents.  
Source documents such as the clinic chart are to be maintained separately from the eCRF 
in order to allow data verification. Because of the potential for errors, inaccuracies and 
illegibility in transcribing data into eCRFs, originals of laboratory and other test results 
must be kept on file. Source documents and copies of test results must be available at all 
times for inspection by the study monitor. The following should also be available for 
review:   
1. Subject Screening Log – reflecting the reason any Subject screened for the study was 
found to be ineligible 
2. Delegation of Authority / Study Personnel Signature Log – all site personnel will be 
listed along with their responsibilities and signatures; to be maintained at the site 
throughout the study 
3. Monitoring Log – the date and purpose of all monitoring visits by the 
Sponsor/Designee will be documented 
4. Enrollment Log – documenting Subject initials and start and end dates for all 
Subjects enrolled 
5. Drug Inventory/Packing Slip – reflecting the total amount of drug shipped to the site 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 22 of 67 
Version 4.0 
 
and received and signed for by the Principal Investigator 
6. Drug Accountability Log – reflecting the total amount of Investigational Product 
dispensed to and returned by each Subject 
7. Informed Consent Form – which must be available for each Subject and be verified 
for proper documentation 
The study monitor will be responsible for reviewing and verifying the data recorded in 
the eCRFs, utilizing the original source documentation and will query discrepant 
findings. The Investigator and study site personnel will be responsible for answering all 
queries. All queries issued by the CRO’s data management personnel will be answered 
by site personnel and verified by the monitor. 
 
d. Primary Source Documents 
The Principal Investigator must maintain primary source documents supporting significant 
data for each Subject’s medical notes. These documents, which are considered “source data”, 
should include documentation of:  
 Demographic information  
 Evidence supporting the diagnosis/condition for which the Subject is being studied  
 General information supporting the Subject’s participation in the study  
 General history and physical findings  
 Hospitalization or Emergency Room records (if applicable)  
 Each study visit by date, including any evaluations, relevant findings/notes by the 
Principal Investigator(s), occurrence (or lack) of adverse events and changes in 
medication usage, including the date the study drug commenced and completed.  
 Any additional visits during the study  
 Any relevant telephone conversations with the Subject regarding the study or possible 
adverse events  
 An original, signed informed consent form for study participation  
The Principal Investigator must also retain all Subject specific printouts/reports of 
tests/procedures performed as a requirement of the study. During monitoring visits, the 
monitor will need to validate data in the CRFs against these sources of data.  
 
e. 
Quality Assurance 
Designated personnel from Nivagen Pharmaceuticals Inc. will be responsible to ensure that 
the trial is conducted, and data are generated, documented and reported in compliance with 
the protocol, GCP, GLP, and the applicable regulatory requirements. 
 
f. 
Study Monitoring 
The study will be monitored by a representative of the Contract Research Organization to 
assess compliance with the protocol, ICH-GCP and applicable regulations. The Principal 
Investigator will be visited by a monitor prior to the study and at regular intervals during 
the course of the study. These visits are for the purposes of verifying adherence to the 
protocol. 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 23 of 67 
Version 4.0 
 
The study monitor will review the informed consent forms and verify eCRF entries by 
comparing them with the source documents (hospital/clinic/office records) that will be 
made available for this purpose. The monitor will review the maintenance of regulatory 
documentation and drug accountability. The monitor will review on a regular basis the 
progress of the study with the Principal Investigator and other site personnel.  
eCRF sections may be monitored during these visits. At the end of the study, a closeout 
monitoring visit will be performed. Monitoring visits will be arranged in advance at a 
mutually acceptable time with site personnel. Sufficient time must be allowed by the site 
personnel for the monitoring of eCRFs and relevant source documents. The Study 
Coordinator and/or Principal Investigator should be available to answer questions or 
resolve data clarifications. Adequate time and space for these visits should be made 
available by the Principal Investigator. 
g. Audits and Inspections 
During the course of the study and/or after it has been completed, one or more site visits 
may be undertaken by auditors as authorized representatives of the Sponsor. The purpose 
of the audit is to determine whether or not the study is being conducted and monitored in 
compliance with the protocol, recognized GCP guidelines and all applicable regulations. 
Additionally, the study may be inspected by regulatory agencies. These inspections may 
take place at any time during the course of the study and/or after it has been completed.  
THE 
INVESTIGATOR 
MUST 
NOTIFY 
THE 
CONTRACT 
RESEARCH 
ORGANIZATION 
and 
SPONSOR 
PROMPTLY 
OF 
ANY 
INSPECTIONS 
SCHEDULED BY REGULATORY AUTHORITIES, AND PROMPTLY FORWARD 
COPIES OF INSPECTION REPORTS TO THE SPONSOR. 
h. Modifications to the Protocol 
The procedures defined in the protocol and in the eCRF will be carefully reviewed to 
ensure that all parties involved with the study fully understand the protocol. In order to 
ensure the validity of the data, no violations from the protocol, with minimal exceptions, 
may be made unless the issue is broad enough to warrant revision of the protocol. Such 
revisions must be submitted to and have documented approval from the Sponsor and the 
IRB prior to implementation. All amendments to the protocol, which involve substantial 
changes in study design, procedure or analyses, may be submitted to FDA IND for prior 
approval (if required).  
The only circumstance in which an amendment may be initiated without prior IRB 
approval is to eliminate apparent immediate hazards to a Subject or Subjects. However, 
the Principal Investigator must notify the Sponsor immediately and the IRB within 5 
working days after implementation.  
All protocol violations will be reported on the protocol violation log and included in the 
study reports. A protocol violation is defined as any change, deviation, or departure from 
the study design or procedures of research project that is NOT approved by the IRB prior 
to its initiation or implementation, OR deviation from standard operating procedures, 
Good Clinical Practices (GCPs), federal, state or local regulations. 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 24 of 67 
Version 4.0 
 
i. Completion of Study 
The Principal Investigator is required to sign the eCRFs and forward all other relevant 
data and records to the Contract Research Organization.  
The Principal Investigator is expected to submit a final report to the IRB and the Sponsor 
within one (1) month of study completion or discontinuation.  CRO must submit a final 
report as agreed in the Study Agreement for this study between Sponsor and CRO. 
 
j. 
Premature Termination or Suspension of a Study 
Nivagen Pharmaceuticals Inc. may terminate the study at any time for scientific or corporate 
reasons. If the trial is prematurely terminated or suspended for any reason, the Qualified 
Investigator should promptly inform the trial volunteers, should assure appropriate therapy 
and follow-up for the volunteers and, where required by the applicable regulatory 
requirement(s), should inform the regulatory authority(ies).  
 
k. Adherence to Protocol 
Excluding an emergency in which proper treatment is required for the protection, safety and 
well-being of the study volunteers, the study will be conducted as described in the approved 
protocol and performed according to ICH/GCP guidelines. Any deviation from the protocol 
will be recorded and explained. If amendments to the protocol and/or amendments or 
revisions to the ICF are required, the modifications will be documented and submitted to an 
IRB for approval. 
 
27. SUBJECT INTERVIEWS: 
 
Interviews will be conducted with selected patients, in order to (a) ensure comprehension of the 
IHSSA items, (b) describe the internal hemorrhoid signs and symptoms that are most bothersome 
to patients, and (c) explore the threshold for meaningful within-patient change on the IHSSA 
items.  
 
Cognitive interviews will be completed with the first 5 enrolled patients at a sponsor-selected site 
who agree to participate in the interview. The cognitive interview will involve administering the 
IHSSA to subjects and then asking them about their interpretation of the meaning of the 
instructions, items, and response scale. The cognitive interviews will be completed in-person 
during Visit 1 or during a separate visit that will occur within 2 weeks of Visit 1. A cognitive 
interview guide that includes a listing of questions that will be asked during the interview is 
included in Appendix 5. 
 
Exit interviews will be completed with the first 25 enrolled subjects who reach Visit 4 and agree 
to participate in the interview. The exit interview will involve asking the subjects questions 
regarding their experience in the clinical trial and the signs and symptoms that are most relevant 
for them. Subjects will be asked to discuss the importance of the changes in their internal 
hemorrhoids while using the study medication. The exit interviews will be completed during or 
within 1 week following Visit 4. An exit interview guide that includes a listing of questions that 
will be asked during the interview is included in Appendix 6. 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 25 of 67 
Version 4.0 
 
The cognitive and exit interviews will be conducted by a third-party. The interview coordinator 
with the third-party vendor will be in communication with each site to work with each site 
coordinator to identify subjects coming due for their interview. The site coordinator will identify 
those who signed a consent form that allows them to be approached for the interview and who 
have already signed consent for their contact information to be provided to the interview team. 
The subject’s name and telephone number will be provided to the interview coordinator via 
phone or posting on a secure FTP site. Contact information and identifying information will not 
be transmitted across unsecure email. The subject will be telephoned by the interviewer and a 
time convenient to the subject will be scheduled for the exit interview session. The exit interview 
will be conducted by phone and audio recorded. The deidentified voice files will be sent by 
secure FTP site to a professional transcription company and returned to the third party vendor for 
analysis. 
 
The consent form will include a description of the qualitative interviews being included in the 
study activities, and it will include a form that asks the subject to consent to their information 
being provided to the interview coordinator so they can be phoned to schedule the exit interview. 
Participation in the interviews is voluntary. The clinic coordinator will be provided with an 
overview of the importance and value of the interviews so they can relay this information to the 
subject when the time for scheduling arrives. The interview coordinator will provide the subject 
with a description of the purpose of the interview and an opportunity to ask any questions before 
the interview begins. A subject may refuse to move forward with the interview at the time of 
their visit, and they may refuse during the scheduling process or at any time during the interview. 
If a subject participates in the cognitive or exit interview, all personal contact information will be 
destroyed immediately following the interview. Reports generated from the interview data will 
be in aggregate form only and no subject will be able to be individually identified from any 
report materials. 
 
28. STUDY VISITS: 
 
1. Visit 1: Initiation of Screening (Day -14±2) 
The following procedures will be performed at Visit 1: 
1. Written informed consent will be obtained.  Subjects must have provided IRB approved 
written informed consent. Prior to initiating screening for the study, Subjects will be 
given the approved ICF describing the study and any risks associated with participation. 
The Subject will be allowed as much time as needed to read and understand the 
information presented in the consent form. Appropriate study personnel will be available 
to answer any questions the Subject might have regarding the study or study-related 
procedures. If the Subject chooses to participate in the study, he or she will be asked to 
sign and date the consent form and will be provided with a copy for his or her records. 
In addition, the Principal Investigator or the Principal Investigator’s Designee will 
provide a HIPAA authorization form (if applicable) for the Subject to review and sign. 
Both the ICF and the HIPAA authorization form (if applicable) must be signed by the 
Subject before any protocol assessments can be undertaken. 
2. A complete medical history will be obtained for the Subject’s current and past medical 
conditions. Significant medical history should include, but not be limited to, evidence of 
hypertension, lipid disorders, obesity*, heart attack, stroke, congestive heart failure, 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 26 of 67 
Version 4.0 
 
kidney disease, and auto immune disease and gestational diabetes. Significant surgical 
history should include, but not be limited to, removal of blockage from an artery and 
gallbladder removal. 
* Obesity = BMI ≥30 (as defined by Metropolitan Life Insurance Company Chart) 
3. Demographics and vital signs (blood pressure, temperature, heart and breathing rates) 
will be documented. Subjects must remain in a seated position for 5 minutes before vital 
signs are obtained. 
4. A brief physical examination, including height (measured in inches) and weight 
(measured in pounds), will be performed. At a minimum, the physical examination will 
include the following: assessment of general appearance, skin, HEENT, heart, lungs, 
musculoskeletal system, lymph nodes, neurological systems, abdomen, extremities as 
well as a visual rectal exam (to exclude external hemorrhoids). 
5. A complete list of current and past (within the previous 30 days) concomitant 
medications will be obtained and reviewed for each Subject. (See Section 22. Subject 
Safety) 
6. A urine pregnancy test will be conducted for all female Subjects of childbearing 
potential. 
7. Blood and urine samples will be collected for clinical laboratory tests including 
complete blood count (CBC), comprehensive metabolic panel (CMP), urinalysis, HIV, 
Hepatitis B, and Hepatitis C, and drug screening (drugs of abuse, prescription). 
8. A breath alcohol test will be conducted. 
9. When the Subject has completed all screening procedures, compliance with the inclusion 
and exclusion criteria will be reviewed. (See Sections 12 & 13 Inclusion & Exclusion 
Criteria) 
10. The following will be dispensed during Visit 1: 
 A diary card to record Adverse Events and Concomitant Medications along 
with instructions on how to complete. 
 Backup diary cards to record missed ePRO questionnaires (as needed) 
11. Appropriate study personnel will provide training to the Subjects on Internal 
Hemorrhoids Sign and Symptom Assessment (IHSSA) and ePRO, which will be 
recorded by the Subjects daily during the study. (See Appendix 1) 
12. Cognitive interviews will be conducted with selected Subjects via a third party to 
discuss IHSSA and internal hemorrhoid signs and symptoms of the Subjects. (See 
Section 27. Subject Interviews)  
13. Visit 2 (Day 1, 14±2 days from Visit 1) will be scheduled and the Subject will be 
instructed to bring the Subject diary and backup ePRO diary (if applicable) with him or 
her to this visit. 
2. Visit 2: Start of Treatment (Day 1) 
The following procedures will be performed at Visit 2: 
1. The overall status of the Subject’s internal hemorrhoids will be assessed using the PGIS  
(ePRO). (See Appendix 3)  
2. The Subject’s symptomatic internal hemorrhoid will be assessed by an anoscopic 
examination (Grade I, II or III (Banov et al. 1985)). (See Section 16 Diagnostic Tests) To 
be included in the study, subjects must have a diagnosis of symptomatic Grade I, II or III 
internal hemorrhoids. Video of the procedure will be recorded for blinded central reading 
and assessment of swelling as the Clinician Reported Outcome (ClinRO). 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 27 of 67 
Version 4.0 
 
3. Appropriate study personnel will review the use of IHSSA with the Subject. (See 
Appendix 1) 
4. The use of concomitant medications since the previous study visit will be documented 
and assessed for each Subject. (See Section 22. Subject Safety) 
5. The occurrence of all AEs will be assessed and documented following procedures in 
Section 24 Adverse Events.  
6. A urine pregnancy test will be conducted for all female Subjects of childbearing 
potential. 
7. When the Subject has completed all screening procedures, compliance with the inclusion 
and exclusion criteria will be reviewed. (See Sections 12 & 13 Inclusion & Exclusion 
Criteria) After the inclusion and exclusion criteria have been confirmed, the Subject will 
be randomized to a treatment group. The Subject will be assigned a randomization 
number (See Section 11. Randomization). 
8. The following will be dispensed during Visit 2: 
 The Investigational Product (28 suppositories)  
 A diary card to record IP Use, Adverse Events and Concomitant Medications 
along with instructions on how to complete. 
 Backup diary cards to record missed ePRO questionnaires (as needed) 
9. Randomized Subjects will be instructed on the correct method for the application of the 
Investigational Product. The first application of the Investigational Product will be 
performed by the Subject at home. The study restrictions will also be reviewed with the 
Subject and an instruction sheet will be issued to the Subject. (See Section 14. 
Treatments)  
10. Randomized Subjects will be instructed how and when to complete the diary for Study 
Medication use. They will be told that they are to document all treatments administered, 
including the date and all treatments missed. In addition, Subjects will be reminded to 
document all AEs. Subjects will also be instructed to call the study site if they experience 
any severe intolerability to Investigational Product. 
11. PROMIS Global Health questionnaire will be performed. 
12. Study instructions will be reviewed with the Subject, including the procedure for 
application of the Investigational Product. (See Section 14. Treatments)  
13. Visit 3 (Day 8 ± 1 days from the date of Visit 2) will be scheduled and the Subject will be 
instructed to bring the Subject’s diary and backup ePRO diary (if applicable) with him or 
her to this visit. 
3. Visit 3: Interim Visit (Day 8±1) 
The following procedures will be performed at Visit 3: 
1. Appropriate study personnel will review the use of IHSSA with the Subject. (See 
Appendix 1) 
2. The use of concomitant medications since the previous study visit will be documented 
and assessed for each Subject. (See Section 22. Subject Safety) 
3. A urine pregnancy test will be conducted for all female Subjects of childbearing 
potential. 
4. Blood sample will be collected from the Subject for clinical laboratory tests:  
comprehensive metabolic panel (CMP). 
5. The occurrence of all AEs will be assessed and documented following procedures in 
Section 24 Adverse Events.  


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 28 of 67 
Version 4.0 
 
6. Study instructions will be reviewed with the Subject, including the procedure for 
application of the Investigational Product. (See Section 14. Treatments) 
7. Visit 4 (Day 15 ± 2 days from the date of Visit 2) will be scheduled and the Subject will 
be instructed to bring all unused Investigational Product (if applicable) and the Subject 
diary and backup ePRO diary (if applicable) with him or her to this visit. 
4. Visit 4: End of Treatment Visit (Day 15±2) 
The following procedures will be performed at Visit 4: 
1. The Subject’s symptomatic internal hemorrhoid will be assessed by an anoscopic 
examination. Video of the procedure will be recorded for blinded central reading and 
assessment of swelling as the Clinician Reported Outcome (ClinRO). 
2. Appropriate study personnel will review the use of IHSSA with the Subject.  (See 
Appendix 1) 
3. The overall status of the Subject’s internal hemorrhoids will be assessed using the PGIS 
and PGIC  (ePRO). (See Appendix 3) 
4. The use of concomitant medications since the previous study visit will be documented 
and assessed for each Subject. (See Section 22. Subject Safety) 
5. A urine pregnancy test will be conducted for all female Subjects of childbearing 
potential. 
6. Blood sample will be collected from the Subject for clinical laboratory tests: complete 
blood count (CBC), and comprehensive metabolic panel (CMP). 
7. The occurrence of all AEs will be assessed and documented following procedures in 
Section 24 Adverse Events.  
8. The Subject’s compliance with the study protocol, including use and application of 
Investigational Product, will be assessed. The Subject’s diary and backup ePRO diary (if 
applicable) will be collected and reviewed for completion.  
9. The following will be dispensed during Visit 4: 
 A diary card to record AE/CM from Visit 4 to Visit 5 
 Backup diary cards to record missed ePRO questionnaire (if applicable) 
10. Visit 5 (Day 29 ± 3 days from the date of Visit 2) will be scheduled and the Subject will 
be instructed to bring the Subject diary and backup ePRO diary (if applicable) with him 
or her to this visit. 
11. PROMIS Global Health questionnaire will be performed. 
12. The Subject’s unused Investigational Product will be returned to the site. (See Section 
14. Treatments) 
13. Exit interviews will be conducted with the first 25 enrolled Subjects who reach Visit 4 
and agree to participate in the interview. (See Section 27. Subject Interviews)   
5. Visit 5: Follow-Up/End of Study Visit (Day 29±3) 
The following procedures will be performed at Visit 5: 
1. Appropriate study personnel will review the use of IHSSA with the Subject. (See 
Appendix 1) 
2. The use of concomitant medications since the previous study visit will be documented 
and assessed for each Subject. (See Section 22. Subject Safety) 
3. A urine pregnancy test will be conducted for all female Subjects of childbearing 
potential. 
4. The occurrence of all AEs will be assessed and documented following procedures in 
Section 24 Adverse Events.  


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 29 of 67 
Version 4.0 
 
5. The Subject’s compliance with the study protocol, including use and application of 
Investigational Product, will be assessed. The Subject diary and backup ePRO diary (if 
applicable) will be collected and reviewed for completion. 
6. Unscheduled Visits (UV) and Early Discontinuation (ED) Visit 
An Unscheduled Visit is allowed at any time, for any reason, if in the Principal Investigator’s 
opinion, it is warranted. If the Unscheduled Visit is due to an AE, the Principal Investigator will 
determine whether additional visits are needed. If a Subject is discontinued from the study during 
an Unscheduled Visit, the Unscheduled Visit will be referred to as an Early Discontinuation Visit 
and all procedures scheduled for Visit 5 will be performed. If the Unscheduled Visit is not an 
Early Discontinuation Visit (i.e., the Subject will continue to take part in the study), then all 
procedures scheduled for that interim visit will be performed, with the exception of the collection 
of Investigational Product and Subject diaries from Subjects.  If the Subject’s condition has 
worsened to the degree that it is unsafe for the Subject to continue in the study, the Subject may 
be discontinued from the study as treatment failure and a standard of care treatment may be 
advised at the Principal Investigator’s discretion. 
 
29. REFERENCES: 
 
Banov, L, L F Knoepp, L H Erdman, and R T Alia. 1985. “Management of Hemorrhoidal 
Disease.” Journal of the South Carolina Medical Association (1975) 81 (7). United States: 
398–401. 
Bleday, R, and E Breen. 2017. “Hemorrhoids: Clinical Manifestations and Diagnosis.” 
UpToDate. Waltham, MA 
Ebrahimi, Neda, Sabina Vohra-Miller, and Gideon Koren. 2011. “Anorectal Symptom 
Management in Pregnancy: Development of a Severity Scale.” Journal of Population 
Therapeutics and Clinical Pharmacology18: e99--e105.  
FDA. 2009. “Guidance for Industry, Drug-Induced Liver Injury:, Premarketing Clinical 
Evaluation.” https://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf. 
FDA 2016. “Ulcerative Colitis: Clinical Trial Endpoints; Guidance for Industry.” 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM515143.pdf. 
Fukuda, Akihisa, Toru Kajiyama, Hiroyuki Kishimoto, Hiroaki Arakawa, Hitoshi Someda, 
Masahiko Sakai, Hiroshi Seno, and Tsutomu Chiba. 2005. “Colonoscopic Classification of 
Internal 
Hemorrhoids: 
Usefulness 
in 
Endoscopic 
Band 
Ligation.” 
Journal 
of 
Gastroenterology and Hepatology 20 (1). Australia: 46–50. doi:10.1111/j.1440-
1746.2004.03536.x. 
Lunniss, P J, and C V Mann. 2004. “Classification of Internal Haemorrhoids: A Discussion 
Paper.” Colorectal Disease : The Official Journal of the Association of Coloproctology of 
Great Britain and Ireland 6 (4). England: 226–32. doi:10.1111/j.1463-1318.2004.00590.x. 
NCI/NIH 2009. “Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.” US 
Department of Health and Human Services 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 30 of 67 
Version 4.0 
 
I. 
APPENDIX 1: IHSSA Training Materials, Post-Bowel Movement Assessment, and End of 
Day Assessment 
 
Internal Hemorrhoid Sign and Symptom Assessment – Training Script 
 
Patient Training (to be completed in clinic upon enrollment) 
During the study, you will be asked to complete a questionnaire about your hemorrhoid-related symptoms each 
day. You will use an electronic device – what we call an electronic diary – to complete the daily questionnaires. 
Some of the questions will be completed following a bowel movement.  
Bowel movement means when you “poop” or “defecate” in the toilet.   
Immediately after every bowel movement during the study, you will make an entry in the electronic diary. This 
procedure will be reviewed with you when you hear more about how to use the electronic diary.  The questions 
following each bowel movement will ask you about the amount of blood in the toilet and on the toilet paper.  
 
When we ask about blood in the toilet, we mean blood that you can see in or on the bowel movement or 
poop in the toilet AND blood that you can see mixed in with the water in the toilet.  
 
When we ask about blood on the toilet paper, we mean blood that you can see on the toilet paper after 
you wipe yourself. 
There will also be questions following each bowel movement that ask you about hemorrhoid-related pain, 
swelling, pressure, burning, and discomfort in your anus or rectum during the bowel movement. When we say 
“anus,” we mean the area where your bowel movement leaves your body. When we say “rectum,” we mean the 
area inside of your body just before the anus. The anus and rectum are where your hemorrhoids are located. You 
would answer these questions by rating how bad the pain, swelling, pressure, burning, and discomfort were in this 
area during the bowel movement. 
Following each bowel movement, you will also answer a question about the shape of the bowel movement or 
poop. You will use the following scale to answer this question. You should use your own judgment about which 
picture most closely matches your bowel movement. 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 31 of 67 
Version 4.0 
 
  
 
In addition to answering some questions following each bowel movement, you will answer some questions at the 
end of the day before you go to bed. These questions will ask you about the past 24 hours. If you complete the 
questions at about the same time each day, the 24 hours will be approximately equal to the time since your last 
end of day questionnaire. In these questions, you will be asked to enter any bowel movements that you did not 
enter during the day when they occurred. You will also be asked about bleeding and pain that you may have 
experienced at times other than during bowel movements. For example, you may see blood on your clothes or 
underwear due to hemorrhoids or you might experience pain when sitting.  
You will also answer two questions about itching in your anus and rectum. For these questions about itching, you 
will be asked to rate the “worst” itching that you experienced in the past 24 hours and how often you felt itchy. 
You will also be asked a question about how often you experienced hemorrhoid-related pain.  
<For females only> You will also be asked if you experienced any bleeding due to menstruation in the past 24 
hours. We ask this question so we can try to tell the difference between bleeding due to hemorrhoids and bleeding 
that you may experience due to menstruation. 
Finally, there will also be questions asking you about how worried and embarrassed you were about your internal 
hemorrhoids and how they have impacted your daily activities and ability to sit down. 
I will now show you the questions and response options. Before I do, do you have any questions about what you 
will be asked to do? 
 
 
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 32 of 67 
Version 4.0 
 
Internal Hemorrhoid Sign and Symptom Assessment – Post-Bowel Movement Assessment 
Episodic IHSSA Assessment (to be completed following each bowel movement) 
Item Text 
Response Scale 
Instructions: The following questions ask about your bowel movement and symptoms that you may experience as 
a result of your internal hemorrhoids. Please read through and complete the questions on the following screens. 
There are no right or wrong answers. Please select the answer that best applies to you as a result of your internal 
hemorrhoids. 
How long ago did the bowel movement occur? 
____ hours, ____ minutes 
How much blood did you see in the toilet (including 
blood on or around the stool and blood in the toilet and 
toilet water) when you had your bowel movement? 
No blood 
Small amount of blood 
Moderate amount of blood 
Large amount of blood 
Very large amount of blood 
(same response scale for both bleeding items) 
How much blood did you see on the toilet paper when 
you had your bowel movement? 
How bad was your worst hemorrhoid-related pain 
(pain in your rectum or anus) during your bowel 
movement? 
No pain 
A little pain 
Moderate pain 
A lot of pain  
Worst pain that you could imagine  
How bad was your worst hemorrhoid-related swelling 
(swelling in your rectum or anus) during your bowel 
movement? 
No swelling 
A little swelling 
Moderate swelling 
A lot of swelling 
Worst imaginable swelling 
How bad was your worst hemorrhoid-related pressure 
(pressure or feeling of fullness in your rectum or anus) 
during your bowel movement? 
No pressure 
A little pressure 
Moderate pressure 
A lot of pressure 
Worst imaginable pressure 
How bad was your worst hemorrhoid-related burning 
(burning feeling in your rectum or anus) during your 
bowel movement? 
No burning 
A little burning 
Moderate burning 
A lot of burning  
Worst imaginable burning 
How bad was your worst hemorrhoid-related 
discomfort (uncomfortable feeling in your rectum or 
anus) during your bowel movement? 
No discomfort 
A little discomfort 
Moderate discomfort 
A lot of discomfort 
Worst imaginable discomfort 
Read the description and look at the pictures to see 
which one best matches your bowel movement. 
Separate hard lumps, like nuts (hard to pass) 
Sausage-shaped but lumpy 
Like a sausage but with cracks on the surface 
Like a sausage or snake, smooth and soft 
Soft blobs with clear-cut edges 
Fluffy pieces with ragged edges, a mushy stool 
Watery, no solid pieces.  Entirely Liquid 
(to be presented with standard images from Bristol 
Stool Scale) 
Internal Hemorrhoid Sign and Symptom Assessment – End of Day Assessment 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 33 of 67 
Version 4.0 
 
Daily IHSA Assessment (to be completed at the end of each day) 
Item Text 
Response Scale 
Instructions: The following questions ask about your bowel movements and symptoms that you may experience 
as a result of your internal hemorrhoids. Please read through and complete the questions on the following screens. 
There are no right or wrong answers. Please select the answer that best applies to you as a result of your internal 
hemorrhoids. 
These are the bowel movements that you have told us 
about in the past 24 hours. 
<Electronic device displays bowel movements entered 
by user in previous 24 hour period.> 
Did you have any bowel movements in the past 24 
hours that you did NOT enter when they occurred? 
No/Yes 
<If yes, skip to next row. If no, skip to question 
regarding blood observed outside of bowel 
movements.> 
How many bowel movements were NOT entered in the 
past 24 hours? 
01-99 
<Electronic device will ask episodic post-bowel 
movement assessment items for each missed bowel 
movement. After all questions have been asked for 
previous bowel movements, go to next question.> 
In the past 24 hours, did you experience bleeding due 
to menstruation? 
No/Yes 
<Item to be administered to females only> 
Please think about times in the past 24 hours when you 
were NOT having a bowel movement.  
 
In the past 24 hours, how much hemorrhoid-related 
blood did you see at times other than during bowel 
movements (for example, on your clothes when you 
were undressing)? 
No blood 
Small amount of blood 
Moderate amount of blood 
Large amount of blood 
Very large amount of blood 
Please think about times in the past 24 hours when you 
were NOT having a bowel movement. 
 
In the past 24 hours, how bad was your worst 
hemorrhoid-related pain at times other than during 
bowel movements (for example, when you were sitting 
down)? 
No pain 
A little pain 
Moderate pain 
A lot of pain 
Worst pain that you could imagine 
In the past 24 hours, how severe was your worst 
hemorrhoid-related itching (itching in your rectum or 
anus)? 
No itching 
A little itching 
Moderate itching 
A lot of itching 
Worst itching that you could imagine 
In the past 24 hours, how often did you have 
hemorrhoid-related itching (itching in your rectum or 
anus)? 
Never 
Rarely 
Sometimes 
Often 
Always 
In the past 24 hours, how often did you have 
hemorrhoid-related pain (pain in your rectum or anus) 
Never 
Rarely 
Sometimes 
Often 
Always 
In the past 24 hours, how much clear liquid discharge 
did you notice (see or feel) around your anus? 
No clear liquid discharge 
Small amount of clear liquid discharge 
Moderate amount of clear liquid discharge 
Large amount of clear liquid discharge 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 34 of 67 
Version 4.0 
 
Very large amount of clear liquid discharge 
In the past 24 hours, how worried were you about your 
internal hemorrhoids? 
 
Not worried at all 
A little worried 
Somewhat worried 
Very worried 
Extremely worried 
 
In the past 24 hours, how embarrassed were you about 
your internal hemorrhoids? 
 
Not embarrassed at all 
A little embarrassed 
Somewhat embarrassed 
Very embarrassed 
Extremely embarrassed 
 
In the past 24 hours, how much did you limit your daily 
activities (for example, at work or during leisure or 
home activities) due to your internal hemorrhoids? 
 
Not limited at all 
A little limited 
Somewhat limited 
Very limited 
Extremely limited 
 
In the past 24 hours, how difficult was it to sit down 
due to your internal hemorrhoids? 
Not difficult at all 
A little difficult 
Somewhat difficult 
Very difficult 
Extremely difficult 
 
 
 
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 35 of 67 
Version 4.0 
 
II. 
APPENDIX 2: PROMIS Global Health Questionnaire Version 1.2 
 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 36 of 67 
Version 4.0 
 
 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 37 of 67 
Version 4.0 
 
 
III. 
APPENDIX 3: Patient Global Impression of Change (PGIC) and Patient Global Impression 
of Severity (PGIS) Items 
 
Item Text 
Response Scale 
Patient Global Impression of Change Items 
(To be administered at the End of Treatment visit) 
Instructions: The following questions ask you about the overall change in your hemorrhoid-related symptoms 
since you started taking the study medication. Please choose the response that best describes your experience. 
There are no right or wrong answers. Please answer all of the questions. 
Since I started taking the study medication, my 
hemorrhoid-related bleeding is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoid-related itching is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoid-related pain is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoid-related swelling is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoid-related pressure (pressure or feeling of 
fullness in your rectum or anus) is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoid-related burning is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 38 of 67 
Version 4.0 
 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoid-related discomfort is: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my ability to 
complete daily activities (for example, work or leisure 
or home activities) is:  
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Since I started taking the study medication, my 
hemorrhoids are: 
Very Much Better 
Much Better 
A Little Better 
The same (no change) 
A Little Worse 
Much Worse 
Very Much Worse 
Patient Global Impression of Severity Items 
(To be administered at the Randomization and End of Treatment Visits) 
Instructions: The following questions ask you about your hemorrhoid-related symptoms over the past week. 
Please choose the response that best describes your experience. There are no right or wrong answers. Please answer 
all of the questions. 
Please choose the response that best describes your 
hemorrhoid-related bleeding in the past week. 
No bleeding 
Mild bleeding 
Moderate bleeding 
Severe bleeding 
Very severe bleeding 
Please choose the response that best describes your 
hemorrhoid-related itching in the past week. 
No itching 
Mild itching 
Moderate itching 
Severe itching 
Very severe itching 
Please choose the response that best describes your 
hemorrhoid-related pain in the past week. 
No pain 
Mild pain 
Moderate pain 
Severe pain 
Very severe pain 
Please choose the response that best describes your 
hemorrhoid-related swelling in the past week. 
No swelling 
Mild swelling 
Moderate swelling 
Severe swelling 
Very severe swelling 
Please choose the response that best describes your 
hemorrhoid-related pressure (pressure or feeling of 
No pressure 
Mild pressure 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 39 of 67 
Version 4.0 
 
fullness in your rectum or anus) in the past week. 
Moderate pressure 
Severe pressure 
Very severe pressure 
Please choose the response that best describes your 
hemorrhoid-related burning in the past week. 
No burning 
Mild burning 
Moderate burning 
Severe burning 
Very severe burning 
Please choose the response that best describes your 
hemorrhoid-related discomfort in the past week. 
No discomfort 
Mild discomfort 
Moderate discomfort 
Severe discomfort 
Very severe discomfort 
Please choose the response that best describes your 
ability to complete daily activities (for example, work 
or leisure or home activities) in the past week. 
I am not able to complete any daily activities 
I am able to complete some daily activities 
I am able to complete many daily activities 
I am able to complete most daily activities 
I am able to complete all daily activities 
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 40 of 67 
Version 4.0 
 
IV. 
APPENDIX 4: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
(NCI, 2009) 
 
Grades 
 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline. A Semi-colon 
indicates ‘or’ within the description of the grade. A single dash (-) indicates a grade is not 
available. 
 
Grade Clinical description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
 
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for Grade 
selection. Grade 5 Grade 5 (Death) is not appropriate for some AEs and therefore is not an option.  
 
Activities of Daily Living (ADL): 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden  
 
 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 41 of 67 
Version 4.0 
 
V. 
 APPENDIX 5: Cognitive Interview Guide 
INTERVIEW GUIDE 
Cognitive Interviews for Internal Hemorrhoids 
 
TO BEGIN:    
1. Introduce yourself and your association with the study 
2. Explain purpose of the interview 
3. Thank him/her for willingness to participate 
4. Assure him/her of confidentiality 
5. Let him/her know the general process of how it will proceed 
 
 
 
The Primary Objective of this Interview: 
This interview will take approximately 60 minutes. First I will have you fill out a short questionnaire and then we 
will spend some time looking at how relevant or understandable each of those questions are to your experience with 
internal hemorrhoids.  
 
 
To begin the interview, I want to remind you that it is being recorded. I will try to not use your name from the point 
that I turn on the recorder, and I will ask you to try and not use your name or the names of friends or family in any 
of your responses. This will help keep the interview anonymous.   
 
I will be using the recording only to remind me of the important things you said so we can represent everything 
more accurately at the end of the study. The recordings will be transcribed, and then put together with transcripts 
from everyone else taking part in these interviews. You won’t be able to be individually identified in any of the 
reports that result from these interviews. This study information will be used to help make better decisions about 
how to measure these important issues in future studies to treat issues related to people’s experience with internal 
hemorrhoids.    
 
Do you have any questions before we start? 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 42 of 67 
Version 4.0 
 
 
COGNITIVE INTERVIEW  
 
The Primary Objective of this Interview: 
Determine relevance and comprehension of survey items and instructions as they relate to participants diagnosed 
with internal hemorrhoids.   
First, you will complete a draft version of the questionnaire. Then we will discuss the instructions and each of 
the questions to see what they mean to you and how you came to your answer for each item. 
Please take a few minutes to complete the survey.  This survey is designed to be used by patients in a study of 
internal hemorrhoids to tell us about their experience on a daily basis by answering questions on a handheld 
electronic device. We developed the questions to be completed every day. So, when you read the materials, imagine 
that you were completing them each day outside of the clinic. Be sure to read the instructions in each section, and 
complete each item as best as you can.  
 
[Interviewer: Note start time, finish time for the instrument as indicated below.].  
DO NOT ANSWER QUESTIONS during this time but make note of any that are asked]  
 
Time started: ________ Time completed: _________ 
 
Total time needed: ___________(min) 
 
 
[Interviewer: Once Patient has completed the questionnaire and you have the timing recorded, please continue.] 
 
For the next part of the interview, I would like to ask you about the individual items on this questionnaire so we can 
understand specifically what each item means to you (what they make you think about as you formulate your 
answer). 
 
I will be asking you to tell me what thoughts you had about each of these questions and what examples you thought 
about from your own life to help you come to the response you selected in each case.  We also want your impression 
about how clear each item is, how easy or difficult each item is to complete, and to what degree the items are 
meaningful to you. 
 
 
[Interviewer: Have the patient look at Instructions for Patient Training] 
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 43 of 67 
Version 4.0 
 
INSTRUCTIONS: 
Let’s start with the instructions across the top of the page. 
Actual Instruction Text:  
During the study, you will be asked to complete a questionnaire about your hemorrhoid-related symptoms 
each day. You will use an electronic device – what we call an electronic diary – to complete the daily 
questionnaires. Some of the questions will be completed following a bowel movement.  
 
Bowel movement means when you “poop” or “defecate” in the toilet.   
 
Immediately after every bowel movement during the study, you will make an entry in the electronic diary. 
This procedure will be reviewed with you when you hear more about how to use the electronic diary.  The 
questions following each bowel movement will ask you about the amount of blood in the toilet and on the 
toilet paper. 
  
• 
When we ask about blood in the toilet, we mean blood that you can see in  
 
or on the 
bowel movement or poop in the toilet AND blood that you can  
see  
mixed in with the water in 
the toilet.  
 
• 
When we ask about blood on the toilet paper, we mean blood that you can  
see on the toilet 
paper after you wipe yourself. 
 
There will also be questions following each bowel movement that ask you about hemorrhoid-related pain, 
swelling, pressure, burning, and discomfort in your anus or rectum during the bowel movement. When 
we say “anus,” we mean the area where your bowel movement leaves your body. When we say “rectum,” 
we mean the area inside of your body just before the anus. The anus and rectum are where your 
hemorrhoids are located. You would answer these questions by rating how bad the pain, swelling, pressure, 
burning, and discomfort were in this area during the bowel movement. 
 
Following each bowel movement, you will also answer a question about the shape of the bowel movement 
or poop. You will use the following scale to answer this question. You should use your own judgment 
about which picture most closely matches your bowel movement. 
  
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 44 of 67 
Version 4.0 
 
 
In addition to answering some questions following each bowel movement, you will answer some questions 
at the end of the day before you go to bed. These questions will ask you about the past 24 hours. If you 
complete the questions at about the same time each day, the 24 hours will be approximately equal to the 
time since your last end of day questionnaire. In the these questions, you will be asked to enter any bowel 
movements that you did not enter during the day when they occurred. You will also be asked about 
bleeding and pain that you may have experienced at times other than during bowel movements. For 
example, you may see blood on your clothes or underwear due to hemorrhoids or you might experience 
pain when sitting.  
 
You will also answer two questions about itching in your anus and rectum. For these questions about 
itching, you will be asked to rate the “worst” itching that you experienced in the past 24 hours and how 
often you felt itchy. You will also be asked a question about how often you experienced hemorrhoid-related 
pain.  
 
<For females only> You will also be asked if you experienced any bleeding due to menstruation in the 
past 24 hours. We ask this question so we can try to tell the difference between bleeding due to 
hemorrhoids and bleeding that you may experience due to menstruation. 
 
Finally, there will also be questions asking you about how worried and embarrassed you were about your 
internal hemorrhoids and how they have impacted your daily activities and ability to sit down. 
 
I will now show you the questions and response options. Before I do, do you have any questions about what 
you will be asked to do? 
 
 
To be sure these instructions are understandable; please give me a short description back, in your own words, 
what it is these instructions are asking you to do. 
 
Did you have any difficulty understanding these instructions?  (if so, please describe)  
 
What time period did you think we were asking you about?  
 
 
INSTRUCTIONS FOR EPISODIC DIARY:  
Let’s look at the instructions for after each bowel movement. 
Actual Instruction Text:  
 
 
 
 
 
 
 
Please give me a short description back, in your own words, what it is these instructions are asking you to do. 
 
Did you have any difficulty understanding these instructions?  (if so, please describe)  
 
 
 
Episodic Post-Bowel Movement Assessment (User-Initiated): The following questions ask about 
your bowel movement and symptoms that you may experience as a result of your internal 
hemorrhoids. Please read through and complete the questions on the following screens. There are 
no right or wrong answers. Please select the answer that best applies to you as a result of your 
internal hemorrhoids.  
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 45 of 67 
Version 4.0 
 
DISCUSSION ITEM #1:  Episodic Assessment of Internal Hemorrhoids  
# 1:  Episodic Assessment of Internal Hemorrhoid Symptoms 
Please look at this first question. [Interviewer: Have the patient look at item 1] 
Actual Questionnaire Text:  
 
1. How long ago did your bowel movement occur?  
 
____ hours, ____ minutes 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in indicating the answer that reflects 
your experience.  
 
 
DISCUSSION ITEM #2:  Episodic Assessment of Internal Hemorrhoids  
# 2:  Episodic Assessment of Internal Hemorrhoid Symptoms 
Please look at this question.  [Interviewer: Have the patient look at item 2] Actual Questionnaire Text:  
2. How much blood did you see in the toilet (including blood on or around the stool and blood in the 
toilet and toilet water) when you had your bowel movement?  
 
  NO BLOOD  
  SMALL AMOUNT OF BLOOD  
  MODERATE AMOUNT OF BLOOD  
  LARGE AMOUNT OF BLOOD  
  VERY LARGE AMOUNT OF BLOOD  
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does bleeding at that level mean to you? What would you expect to see in the toilet? 
 
Can you give me a description of how much blood you would expect to see in the toilet for each of the 
response options?  For example, how much blood would you be looking at to make you mark   VERY 
LARGE AMOUNT OF BLOOD as your answer?    [Interviewer: get description for amount of blood that 
goes with each response option (reference the last time they had this symptom if they did not have it in past 
24 hours) - skip the one they already picked as their answer and addressed above] 
How about for:   LARGE AMOUNT OF BLOOD (describe amount of blood) 
How about for:   MODERATE AMOUNT OF BLOOD (describe amount of blood) 
How about for:   SMALL AMOUNT OF BLOOD (describe amount of blood) 
Then what would you think of:   NO BLOOD  
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 46 of 67 
Version 4.0 
 
Going back now to the answer you selected  ( __ )   What amount of improvement in bleeding would be 
meaningful to you? 
 
DISCUSSION ITEM # 3:  Episodic Assessment of Internal Hemorrhoid Symptoms 
Please look at this question.  [Interviewer: Have the patient look at item 3]  
Actual Questionnaire Text:  
3. How much blood did you see on the toilet paper when you had your bowel movement? 
 
  NO BLOOD  
  SMALL AMOUNT OF BLOOD  
  MODERATE AMOUNT OF BLOOD  
  LARGE AMOUNT OF BLOOD  
  VERY LARGE AMOUNT OF BLOOD  
 
Please tell me in your own words what this item is asking you about. 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does bleeding at that level mean to you? What would you expect to see on the toilet paper? 
 
 Can you give me a description of how much blood you would expect to see on the toilet paper for each of the 
response options?  For example, how much blood would you be looking at to make you mark   VERY 
LARGE AMOUNT OF BLOOD as your answer?    [Interviewer: get description for amount of blood that 
goes with each response option -- (reference the last time they had this symptom if they did not have it in 
past 24 hours) --skip the one they already picked as their answer and addressed above] 
How about for:   LARGE AMOUNT OF BLOOD (describe amount of blood) 
How about for:   MODERATE AMOUNT OF BLOOD (describe amount of blood) 
How about for:   SMALL AMOUNT OF BLOOD (describe amount of blood) 
Then what would you think of:   NO BLOOD  
Going back now to the answer you selected  ( __ )   What amount of improvement in bleeding would be 
meaningful to you?  
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 47 of 67 
Version 4.0 
 
DISCUSSION ITEM # 4:  Episodic Assessment of Internal Hemorrhoid Symptoms 
Please look at this question.  [Interviewer: Have the patient look at item 4]  
Actual Questionnaire Text:  
4. How bad was your worst hemorrhoid-related pain (pain in your rectum or anus) during your bowel 
movement? 
 
  NO PAIN  
  A LITTLE PAIN  
  MODERATE PAIN  
  A LOT OF PAIN  
  WORST PAIN THAT YOU COULD IMAGINE  
 
Please tell me in your own words what this item is asking you about. 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does pain at that level mean to you? Can you describe the amount of pain that goes with your 
answer? 
 
 Can you give me a description of how much pain you would expect to have for each of the response options?  
For example, how much pain would you be having to make you mark   WORST PAIN YOU COULD 
IMAGINE as your answer?    [Interviewer: get description for amount of pain that goes with each response 
option -- (reference the last time they had this symptom if they did not have it in past 24 hours) --skip the one 
they already picked as their answer and addressed above] 
How about for:   A LOT OF PAIN (describe) 
How about for:   MODERATE PAIN (describe) 
How about for:   A LITTLE PAIN (describe) 
Then what would you think of:   NO PAIN  
Going back now to the answer you selected  ( __ )   What amount of improvement in pain would be 
meaningful to you? 
 
 
DISCUSSION ITEM # 5:  Assessment of Internal Hemorrhoid Symptoms 
Please look at this next question.  [Interviewer: Have patient look at item 5]  
Actual Questionnaire Text:  
5. How bad was your worst hemorrhoid-related swelling (swelling inside your rectum or anus) during 
your bowel movement? 
  NO SWELLING  
Corporate Information 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 48 of 67 
Version 4.0 
 
  A LITTLE SWELLING  
  MODERATE  SWELLING  
  A LOT OF SWELLING  
  WORST IMAGINABLE SWELLING  
 
Please tell me in your own words what this item is asking you about. 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does swelling at that level mean to you? Can you describe the amount of pain that goes with 
your answer? 
 
 Can you give me a description of how much swelling you would expect to have for each of the response 
options?  For example, how much swelling would you be having to make you mark  ____as your answer?     
 
 What amount of improvement in swelling would be meaningful to you? 
 
 
DISCUSSION ITEM # 6:  Assessment of Internal Hemorrhoid Symptoms 
Please look at this next question.  [Interviewer: Have patient look at item 6]  
Actual Questionnaire Text:  
6. How bad was your worst hemorrhoid-related pressure (pressure or feeling of fullness in your rectum 
or anus) during your bowel movement? 
  NO PRESSURE  
  A LITTLE PRESSURE  
  MODERATE PRESSURE  
  A LOT OF PRESSURE  
  WORST IMAGINABLE PRESSURE  
 
Please tell me in your own words what this item is asking you about. 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience. 
  
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does pressure at that level mean to you? Can you describe the amount of pressure that goes 
with your answer? 
 
 Can you give me a description of how much pressure you would expect to have for each of the response 
options?  For example, how much pressure would you be having to make you mark____ as your answer?  
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 49 of 67 
Version 4.0 
 
 
 What amount of improvement in pressure would be meaningful to you? 
DISCUSSION ITEM # 7:  Assessment of Internal Hemorrhoid Symptoms 
Please look at this next question.  [Interviewer: Have patient look at item 7]  
Actual Questionnaire Text:  
7. How bad was your worst hemorrhoid-related burning (burning inside your rectum or anus) during 
your bowel movement? 
  NO BURNING  
  A LITTLE BURNING  
  MODERATE  BURNING  
  A LOT OF BURNING  
  WORST IMAGINABLE BURNING  
 
Please tell me in your own words what this item is asking you about. 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience. 
  
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does burning at that level mean to you? Can you describe the amount of burning that goes 
with your answer? 
 
 Can you give me a description of how much burning you would expect to have for each of the response 
options?  For example, how much burning would you be having to make you mark ___  as your answer?   
 
 What amount of improvement in burning would be meaningful to you? 
 
 
DISCUSSION ITEM # 8:   Assessment of Internal Hemorrhoid Symptoms 
Please look at this next question.  [Interviewer: Have patient look at item 8]  
Actual Questionnaire Text: 
8. How bad was your worst hemorrhoid-related discomfort (uncomfortable feeling in your rectum or 
anus) during your bowel movement? 
  NO DISCOMFORT  
  A LITTLE DISCOMFORT  
  MODERATE  DISCOMFORT  
  A LOT OF DISCOMFORT  
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 50 of 67 
Version 4.0 
 
  WORST IMAGINABLE DISCOMFORT  
 
Please tell me in your own words what this item is asking you about. 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience. 
  
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does discomfort at that level mean to you? Can you describe the amount of discomfort that 
goes with your answer? 
 
 Can you give me a description of how much discomfort you would expect to have for each of the response 
options?  For example, how much discomfort would you be having to make you mark___  as your answer?   
 
    What amount of improvement in discomfort would be meaningful to you? 
 
 
DISCUSSION ITEM #9:  Assessment of Internal Hemorrhoid Symptoms 
Please look at this next question.  [Interviewer: Have patient look at item 9]  
Actual Questionnaire Text:  
9. Bristol Stool Scale – Read the description and look at the pictures to see which one best matches your 
bowel movement 
 
  Type 1: Separate hard lumps, like nuts (hard to pass) 
  Type 2: Sausage shaped but lumpy 
  Type 3: Like a sausage but with cracks on surface 
  Type 4: Like a sausage or snake, smooth and soft 
  Type 5: Soft blobs with clear-cut edges  
  Type 6: Fluffy pieces with ragged edges, a mushy stool 
  Type 7: Watery, no solid pieces. Entirely liquid.  
 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects 
your experience.  
 
 
You answered ____ for this item.  Can you describe what the stool looks like at that level? 
 
 
(For responses of moderate or higher, ask the following) What amount of improvement in stool 
consistency would be meaningful to you? 
 
 
What would be different about your assessment of the stool if you had answered ___? What about ___?  
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 51 of 67 
Version 4.0 
 
DISCUSSION ITEM # 10:  Instructions for End of Day: 
[Interviewer: Have the patient look at Instructions for End of Day] 
Actual Instruction Text:  
 
In addition to answering some questions following each bowel movement, you will answer some questions 
at the end of the day before you go to bed. These questions will ask you about the past 24 hours. If you 
complete the questions at about the same time each day, the 24 hours will be approximately equal to the 
time since your last end of day questionnaire. These questions will ask you about bleeding that you may 
have observed at times other than during bowel movements, such as blood that you saw on your clothes or 
underwear. You will also answer two questions about itching in your anus and rectum. For these questions 
about itching, you will be asked to rate the “worst” itching that you experienced in the past 24 hours and 
how often you felt itchy. There will also be questions asking you about how worried and embarrassed you 
were about your internal hemorrhoids and how they have impacted your daily activities and ability to sit 
down. 
 
I will now show you the questions and response options. Before I do, do you have any questions about what 
you will be asked to do? 
 
To be sure these instructions are understandable; please give me a short description back, in your own words, 
what it is these instructions are asking you to do. 
 
Did you have any difficulty understanding these instructions?  (if so, please describe)  
 
Actual Instruction Text:  
 
 
 
 
 
 
 
 
 
 
 
To be sure these instructions are understandable; please give me a short description back, in your own words, 
what it is these instructions are asking you to do. 
 
Did you have any difficulty understanding these instructions?  (if so, please describe)  
 
 
DISCUSSION ITEM # 11: End of Day Assessment [FOR FEMALES ONLY] 
Please look at this next question.  [Interviewer: Have patient look at item 1]  
Actual Questionnaire Text:  
1. In the past 24 hours, did you experience bleeding due to menstruation? 
  No 
End of Day Assessment (User-Initiated or Device Prompted): The following questions ask about 
your bowel movements and symptoms that you may experience as a result of your internal 
hemorrhoids. Please read through and complete the questions on the following screens. There are 
no right or wrong answers. Please select the answer that best applies to you as a result of your 
internal hemorrhoids. 
Corporate Information 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 52 of 67 
Version 4.0 
 
  Yes 
 
Please tell me in your own words what this item is asking you about. 
 
What time period did you think we were asking you about?  
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects 
your experience.  
 
 
DISCUSSION ITEM # 12:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 2] 
Actual Questionnaire Text:  
2. Please think about times in the past 24 hours when you were NOT having a bowel movement. In 
the past 24 hours, how much hemorrhoid-related blood did you see at times other than during 
bowel movements (for example, on your clothes when you were undressing)? 
  NO BLOOD 
  SMALL AMOUNT OF BLOOD 
  MODERATE AMOUNT OF BLOOD 
  LARGE AMOUNT OF BLOOD 
  VERY LARGE AMOUNT OF BLOOD 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
 
You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does bleeding at that level mean to you? How much blood would you expect to see? 
 
 
Can you give me a description of how much blood you would expect to see for each of the response options?  
For example, how much blood would you be looking at to make you mark   VERY LARGE AMOUNT 
OF BLOOD as your answer?   [Interviewer: get description for amount of blood that goes with each 
response option -- (reference the last time they had this symptom if they did not have it in past 24 hours) --
skip the one they already picked as their answer and addressed above] 
How about for:   LARGE AMOUNT OF BLOOD (describe amount of blood) 
How about for:   MODERATE AMOUNT OF BLOOD (describe amount of blood) 
How about for:   SMALL AMOUNT OF BLOOD (describe amount of blood) 
Then what would you think of:   NO BLOOD  
Going back now to the answer you selected  ( __ )   What amount of improvement in bleeding would be 
meaningful to you? 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 53 of 67 
Version 4.0 
 
DISCUSSION ITEM # 13:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 3]  
Actual Questionnaire Text:  
3. Please think about times in the past 24 hours when you were NOT having a bowel movement. In 
the past 24 hours, how bad was your worst hemorrhoid-related pain at times other than during 
bowel movements (for example, when you were sitting down)? 
  NO PAIN 
  A LITTLE PAIN 
  MODERATE PAIN 
  A LOT OF PAIN 
  WORST PAIN THAT YOU COULD IMAGINE 
 
Please tell me in your own words what this item is asking you about. 
 
What time period did you think we were asking you about?  
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does pain at that level mean to you? How much pain would you have? 
 
Can you give me a description of how much pain you would expect to have for each of the response 
options?  For example, how much pain would you be having to make you mark   VERY LARGE 
AMOUNT OF PAIN as your answer?  [Interviewer: get description for amount of pain that goes with each 
response option -- (reference the last time they had this symptom if they did not have it in past 24 hours) --
skip the one they already picked as their answer and addressed above] 
How about for:   LARGE AMOUNT OF PAIN (describe) 
How about for:   MODERATE AMOUNT OF PAIN (describe) 
How about for:   SMALL AMOUNT OF PAIN (describe) 
Then what would you think of:   NO PAIN (describe) 
Going back now to the answer you selected  ( __ )   What amount of improvement in pain would be 
meaningful to you? 
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 54 of 67 
Version 4.0 
 
DISCUSSION ITEM # 14:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 4]  
Actual Questionnaire Text:  
4. In the past 24 hours, how severe was your worst hemorrhoid-related itching (itching in your 
rectum or anus)? 
 
  NO ITCHING 
  A LITTLE ITCHING 
  MODERATE  ITCHING 
  A LOT OF ITCHING 
  WORST ITCHING THAT YOU COULD IMAGINE 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does itching at that level mean to you? How much itching would you have? 
 
Can you give me a description of how much itching you would expect to have for each of the response 
options?  For example, how much itching would you be having to make you mark   VERY LARGE 
AMOUNT OF ITCHING as your answer?   [Interviewer: get description for amount of itching that goes 
with each response option -- (reference the last time they had this symptom if they did not have it in past 24 
hours) --skip the one they already picked as their answer and addressed above] 
How about for:   LARGE AMOUNT OF ITCHING (describe) 
How about for:   MODERATE AMOUNT OF ITCHING (describe) 
How about for:   SMALL AMOUNT OF ITCHING (describe) 
Then what would you think of:   NO ITCHING  
Going back now to the answer you selected  ( __ )   What amount of improvement in itching would be 
meaningful to you? 
 
 
DISCUSSION ITEM # 15:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 5]  
Actual Questionnaire Text:  
5. In the past 24 hours, how often did you have hemorrhoid-related itching (itching in your rectum 
or anus)? 
 
  NEVER 
  RARELY 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 55 of 67 
Version 4.0 
 
  SOMETIMES 
  OFTEN 
  ALWAYS 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What is itching like at that frequency?  
 
Can you give me a description of how often you would expect to have itching for each of the response 
options?  For example, how often would you be having itching to make you mark   ALWAYS ITCHING 
as your answer?    [Interviewer: get description for the frequency of itching that goes with each response 
option -- (reference the last time they had this symptom if they did not have it in past 24 hours) --skip the 
one they already picked as their answer and addressed above] 
How about for:   OFTEN ITCHING (describe) 
How about for:   SOMETIMES ITCHING (describe) 
How about for:   RARELY ITCHING (describe) 
Then what would you think of:   NEVER ITCHING  
Going back now to the answer you selected  ( __ )   What amount of improvement in of often you had 
itching would be meaningful to you? 
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 56 of 67 
Version 4.0 
 
DISCUSSION ITEM # 16:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 6]  
Actual Questionnaire Text:  
6. In the past 24 hours, how often did you have hemorrhoid-related pain (pain in your rectum or 
anus)? 
 
  NEVER 
  RARELY 
  SOMETIMES 
  OFTEN 
  ALWAYS 
 
Please tell me in your own words what this item is asking you about. 
 
What time period did you think we were asking you about?  
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What is pain like at that frequency?  
 
Can you give me a description of how often you would expect to have pain for each of the response options?  
For example, how often would you be having pain to make you mark   ALWAYS ITCHING as your 
answer?  [Interviewer: get description for frequency of pain that goes with each response option -- 
(reference the last time they had this symptom if they did not have it in past 24 hours) --skip the one they 
already picked as their answer and addressed above] 
How about for:   OFTEN had pain (describe) 
How about for:   SOMETIMES had pain (describe) 
How about for:   RARELY had pain (describe) 
Then what would you think of:   NEVER had pain  
Going back now to the answer you selected  ( __ )   What amount of improvement in the frequency of your 
pain would be meaningful to you? 
 
Which is the more difficult issue for you? The amount of time that you experience hemorrhoid-related pain 
or the severity of the pain? Or are both equal?  
 
DISCUSSION ITEM # 17:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 7]  
Actual Questionnaire Text:  
7. In the past 24 hours, how much clear liquid discharge did you notice (see or feel) around your 
anus? 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 57 of 67 
Version 4.0 
 
  NO CLEAR LIQUID OR DISCHARGE 
  SMALL AMOUNT OF CLEAR LIQUID DISCHARGE 
  MODERATE AMOUNT OF CLEAR LIQUID DISCHARGE 
  LARGE AMOUNT OF CLEAR LIQUID DISCHARGE 
  VERY LARGE AMOUNT OF CLEAR LIQUID DISCHARGE 
 
Please tell me in your own words what this item is asking you about. 
 
 Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
 You answered ____ for this item.  Can you describe what you were thinking about when you chose that 
response? What does that amount of discharge look like? Can you describe the amount that goes with your 
answer? 
 
 Can you give me a description of how much discharge you would expect to have for each of the response 
options?  For example, how much discharge would you be having to make you mark ___  as your answer?   
 
 What amount of improvement in discharge would be meaningful to you? 
 
 
DISCUSSION ITEM # 18:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 8]  
Actual Questionnaire Text:  
8. In the past 24 hours, how worried were you about your internal hemorrhoids? 
 
 NOT WORRIED AT ALL 
 A LITTLE WORRIED 
 SOMEWHAT WORRIED 
 VERY WORRIED 
 EXTREMELY WORRIED 
 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects 
your experience.  
 
 
You answered ____ for this item.  Can you describe what worry at that level is like for you?  
 
 
What amount of improvement in worry would be meaningful to you? 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 58 of 67 
Version 4.0 
 
 
DISCUSSION ITEM # 19:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 9]  
Actual Questionnaire Text:  
9. In the past 24 hours, how embarrassed were you about your internal hemorrhoids? 
 
 NOT EMBARRASSED AT ALL 
 A LITTLE EMBARRASSED 
 SOMEWHAT EMBARRASSED 
 VERY EMBARRASSED 
 EXTREMELY EMBARRASSED 
 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects 
your experience.  
 
 
What time period did you consider when you answered this question? 
 
 
You answered ____ for this item.  Can you describe what embarrassment at that level is like for you? 
 
 
What amount of improvement in embarrassment would be meaningful to you? 
 
 
DISCUSSION ITEM # 20:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 10]  
Actual Questionnaire Text:  
10. In the past 24 hours, how much did you limit your daily activities (for example, at work or during 
leisure or home activities) due to your internal hemorrhoids? 
 
  NOT LIMITED AT ALL 
  A LITTLE LIMITED 
  SOMEWHAT LIMITED 
  VERY LIMITED 
  EXTREMELY LIMITED 
 
 
Please tell me in your own words what this item is asking you about. 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 59 of 67 
Version 4.0 
 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects your 
experience.  
 
 
What time period did you consider when you answered this question? 
 
 
Can you give me a description of the level of limitation that goes with each of the response options?  For 
example, what level of activity limitation would you be experiencing to to make you mark   
EXTREMELY LIMITED as your answer?    [Interviewer: get description for the activity limitation that goes 
with each response option -- (reference the last time they had this symptom if they did not have it in past 24 
hours) --skip the one they already picked as their answer and addressed above] 
How about for:   VERY LIMITED (describe) 
How about for:   SOMEWHAT LMITED (describe) 
How about for:   A LITTLE LIMITED (describe) 
Then what would you think of:   NOT LMITED AT ALL  
Going back now to the answer you selected  ( __ )   What amount of improvement in the limitation you 
experience would be meaningful to you? 
 
 
DISCUSSION ITEM # 21:  End of Day Assessment  
Please look at this next question.  [Interviewer: Have patient look at item 11]  
Actual Questionnaire Text:  
11. In the past the past 24 hours, how difficult was it to sit down due to your internal hemorrhoids? 
 
  NOT DIFFICULT AT ALL 
  A LITTLE DIFFICULT 
  SOMEWHAT DIFFICULT 
  VERY DIFFICULT 
  EXTREMELY DIFFICULT  
 
 
Please tell me in your own words what this item is asking you about. 
 
Describe any difficulty that you had with understanding the item, or in selecting the answer that reflects 
your experience.  
 
 
What time period did you consider when you answered this question?  
 
 
You answered ____ for this item.  Can you describe what difficulty sitting down at that level is like for 
you?  
 
OVERALL IMPRESSION of QUESTIONNAIRE: 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 60 of 67 
Version 4.0 
 
Do you feel like the questionnaire asked you about issues that are relevant to your experience with internal 
hemorrhoids?   
 
Could you describe anything that is important to your experience that you thought was missing from the 
questionnaire? 
 
Were there any items on the questionnaire that you felt were not related to your experience?  
 
Could you describe any questions that you felt were so much alike that you would always answer them 
the same way?   
 
[Interviewer: List item numbers of any questions that were too similar and comment on them (one per line)] 
_________________________________________________ 
_________________________________________________ 
 
 
Could you describe any problems that you may have had with the language used for the questions or the 
instructions?    
 
Are there any other comments you would like to make about the questionnaire?  How well do you think 
it would be able to reflect how you are doing regarding your experience with internal hemorrhoids?   
 
We are at the end of the interview now.  Before we finish, do you have anything to add about the 
questionnaire that I have not asked you about?  
 
Thank you for participating in this interview today! 
 
 
 
 
Corporate Information 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 61 of 67 
Version 4.0 
 
V. 
APPENDIX 6: Exit Interview Guide 
 
INTERVIEW GUIDE  
Exit Interviews for Internal Hemorrhoids 
 
TO BEGIN:    
6. Introduce yourself and your association with the study 
7. Explain purpose of the interview 
8. Thank him/her for willingness to participate 
9. Assure him/her of confidentiality 
10. Let him/her know the general process of how it will proceed 
11. Ask the patient if he/she accepts that the interview will be recorded 
 
 
 
The Primary Objective of this Interview: 
This interview will take approximately 45-60 minutes. We are interested in learning about your experience 
participating in the clinical trial you just finished for internal hemorrhoids.  
 
 
To begin the interview, I want to remind you that it is being recorded. I will try to not use your name from the point 
that I turn on the recorder, and I will ask you to try and not use your name or the names of friends or family in any 
of your responses. This will help keep the interview anonymous.   
 
I will be using the recording only to remind me of the important things you said so we can represent everything 
more accurately at the end of the study. The recordings will be transcribed, and then put together with transcripts 
from everyone else taking part in these interviews. You won’t be able to be individually identified in any of the 
reports that result from these interviews. This study information will be used to help make better decisions about 
how to measure these important issues in future studies to treat issues related to people’s experience with internal 
hemorrhoids.    
 
 
Do you have any questions before we start? 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 62 of 67 
Version 4.0 
 
EXIT INTERVIEW  
 
DISCUSSION ITEM #1: Questionnaire  
  
Please take a few minutes to review the diary training materials and complete the questionnaires that you have been 
completing following every bowel movement and at the end of each day.  These are the same questions that you 
completed during the trial.   
 
[Interviewer: Note start time, finish time for the instrument as indicated below. Do not include time spent reviewing 
the training materials. Present the training material for the post-bowel movement assessment first, then the post-
bowel movement assessment, then the end of day assessment training materials, and then the end of day 
assessment.]  
DO NOT ANSWER QUESTIONS during this time but make note of any that are asked]  
 
Episodic Assessment: 
 
Time started: ________ Time completed: _________ 
 
Total time needed: ___________(min) 
 
 
End of Day Assessment: 
 
Time started: ________ Time completed: _________ 
 
Total time needed: ___________(min) 
 
 
[Interviewer: Once Patient has completed the questionnaires and you have the timing recorded, please continue.] 
 
 
Thank you for completing the questionnaires. Did you have any trouble understanding any of the questions? 
 
If yes – what was the difficulty for you?  
 
Were there any questions or words that you didn’t understand?  
 
Did you have any difficulty using the response options for each question? 
 
Is there anything you would like to add about the instructions or the questions or the response choices 
that were on these two questionnaires?  
 
 
 
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 63 of 67 
Version 4.0 
 
DISCUSSION ITEM #2:  – Ease of Use for Electronic Device 
 
During the clinical trial you were asked to respond to questions using an electronic diary.  Please describe 
how easy or difficult it was for you to use the diary. 
 
Did you have any trouble using the electronic diary to complete the assessments following each bowel 
movement during the study? How about with the end of day assessments that you completed before 
bedtime? 
 
How would you describe using the diary –  
o 
Very difficult to use 
o 
Somewhat difficult to use 
o 
Neither difficult nor easy to use 
o 
Somewhat easy to use 
o 
Very easy to use 
 
 
Is there anything about the diary or the questions that we have not asked you that you think we should 
know?  
 
 (Interviewer- if subject responds with any difficulty, ask whether this happened early in the study or whether it 
changed with experience using the diary) 
 
 
 
DISCUSSION ITEM #3:  Study Treatment - Bleeding 
 
To start, can you tell me about the hemorrhoid related bleeding that you experienced before you started 
taking the study medication? 
 
Did your hemorrhoid related bleeding change at all during the study?  
 
 
How did it change – did it get better or worse?  
 
[If there was a change] Can you give me examples of how the bleeding was different? 
 
[If there was a change] How important was this change in the amount of bleeding for you?  
o 
Not at all important 
o 
Somewhat important 
o 
Very important 
 
Tell me more about why this was <not at all, somewhat, very> important for you.  
 
 
 
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 64 of 67 
Version 4.0 
 
DISCUSSION ITEM #4:  Study Treatment - Itching 
 
Did you experience any hemorrhoid related itching before you started taking the study medication?  Please 
describe the hemorrhoid related itching you experienced.  
[If subject did not experience itching, go to Discussion Item #5] 
 
Did your hemorrhoid related itching change at all during the study?  
 
 
How did it change – did it get better or worse?  
 
[If there was a change] Can you give me examples of how the itching was different? 
 
[If there was a change] How important was this change in the amount of itching for you?  
o 
Not at all important 
o 
Somewhat important 
o 
Very important 
 
Tell me more about why this was <not at all, somewhat, very> important for you  
 
 
DISCUSSION ITEM #5:  Study Treatment - Pain 
 
Did you experience any hemorrhoid related pain before you started taking the study medication?  Please 
describe the pain you experienced. 
[If subject did not experience pain, go to Discussion Item #6] 
 
Did your hemorrhoid related pain change at all during the study?  
 
 
How did it change – did it get better or worse?  
 
[If there was a change] Can you give me examples of how the pain was different? 
 
[If there was a change] How important was this change in the amount of pain for you?  
o 
Not at all important 
o 
Somewhat important 
o 
Very important 
 
Tell me more about why this was <not at all, somewhat, very> important for you  
 
  
 
 
 
 
 
 
[If patient reports experiencing pain either before or during the trial, ask the following:] 
People with internal hemorrhoids may experience pain at different times during the day. For example, people 
may have pain during bowel movements and they may have pain at other times during the day, such as when 
sitting down. What type of pain is most bothersome for you? What type of pain would you most like for a 
medication to improve? 
 
 
 
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 65 of 67 
Version 4.0 
 
DISCUSSION ITEM #6:  Study Treatment – Activities of Daily Living 
 
Did you experience any limitations in your daily activities – for example, limitations at work or in social 
activities - because of your internal hemorrhoids before you started taking the study medication?  Please 
describe the limitations you experienced. 
[If subject did not experience limitations in daily activities, go to Discussion Item #7] 
 
Did your hemorrhoid related limitations in daily activities change at all during the study? (Work, social 
activities, exercise) 
 
 
How did it change – did it get better or worse?  
 
[If there was a change] Can you give me examples of how the limitations were different? 
 
[If there was a change] How important was this change for you?  
o 
Not at all important 
o 
Somewhat important 
o 
Very important 
 
Tell me more about why this was <not at all, somewhat, very> important for you  
 
 
 
DISCUSSION ITEM #7:  Study Treatment – Self View 
 
Did you experience any embarrassment or worry due to your internal hemorrhoids before you started taking 
the study medication? Please tell me about what this was like for you?  
[If subject did not experience any negative emotions or self-perceptions, go to Discussion Item #8] 
 
Did you feel any different after you started the medication during the trial?  
 
 
How did it change – did it get better or worse?  
 
[If there was a change] Can you give me examples of the difference in how you thought about yourself? 
 
[If there was a change] How important was this change for you?  
o 
Not at all important 
o 
Somewhat important 
o 
Very important 
 
Tell me more about why this was <not at all, somewhat, very> important for you  
 
 
 
 
DISCUSSION ITEM #8:  Study Treatment – Other Changes 
 
Were there any other hemorrhoid-related changes that you noticed after you started taking the study 
medication? If so, tell me about what the changes were like for you.   
[If subject did not experience additional changes, go to Discussion Item #9] 
 
 
How did it change – did it get better or worse?   
 
[If there was a change] How important was this change for you?  
o 
Not at all important 
o 
Somewhat important 
o 
Very important 
 
Tell me more about why this was <not at all, somewhat, very> important for you  
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 66 of 67 
Version 4.0 
 
DISCUSSION ITEM #9:  Study Treatment – Importance  
 
Out of all of the changes that you experienced after starting the study medication, which one was the most 
important to you? Why was that the most important?  
 
Thinking about all of your experiences with the study medication, would you want to continue taking it in the 
future?  Why or why not?  
 
Is there anything about the effect of the study medication that we have not asked you about that you think we 
should know?  
 
 
We are at the end of the interview now.  Before we finish, do you have anything to add about the 
questionnaire or about your experience in the clinical trial that I have not asked you about?  
 
 
Thank you for participating in this interview today! 
 
 
 
Corporate Information 
 


 
 
 
 
 
CONFIDENTIAL 
 
 
26Apr2019 
Protocol:  HDCS 1701 
 Page 67 of 67 
Version 4.0 
 
 
VI. 
APPENDIX 7: Revision History 
 
Version # 
Affected Sections 
Final 1.0 (12Sep2017) 
N/A (new) 
Final 2.0 (04Nov2018) 
 
 
 
 
 
 
 
 
 
Protocol version number and date updated 
 
Title Page and Contacts List updated 
 
Principal Investigator Agreement signature page added 
 
Vital Signs in Physical Exam added 
 
IHSSA added 
 
Multiple and various wording changes/additions/edits made to 
comply with CRO SOPs 
 
Updated and added Appendices 
Final 3.0 (15Mar2019) 
 
Protocol version number and date updated 
 
Inclusion criteria a & b revised 
Final 4.0 (26Apr2019) 
 
Protocol version number and date updated 
 
Inclusion criteria a & b revised 
 
Visual rectal exam added to Visit 1 Physical Exam