Pilot Study for the Efficacy and Tolerability of Senokot-S in the Treatment of Diabetic Gastroparesis
Phase: PHASE2
Conditions: Diabetic Gastroparesis
Sponsor: Wake Forest University Health Sciences

Protocol Version Tracking Date:  29 MAY 2018 
Page 1 of 7 
AURORA HEALTH CARE, INC. 
 
PROTOCOL TITLE:   Pilot study for the efficacy and tolerability of Senokot-S® 
in the treatment of diabetic gastroparesis 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR:  
Bradley Gose, MD 
 
 
 
 
 
 
Hospitalist 
 
 
 
 
 
 
2901 W Kinnickinnic River Parkway 
 
 
 
 
 
 
Suite 315 
 
 
 
 
 
 
Milwaukee, WI 53215 
 
 
 
 
 
 
Phone: (318)344-8668 
 
 
 
 
 
 
 
Fax: (414)385-2591 
 
 
 
 
 
 
 
 
Email: bwgose1@gmail.com 
 
 
 
 
INVESTIGATORS AND KEY PERSONNEL:   Gary Dennison, CIP 
 
 
 
 
 
 
                     Sheldon Garrison, PhD 
 
 
 
 
 
 
                     Maharaj Singh, PhD 
 
 
 
 
 
 
                     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT03342157

Protocol Version Tracking Date:  29 MAY 2018 
Page 2 of 7 
This protocol was designed and developed by Aurora Healthcare, Inc. It is in-
tended to be used only in conjunction with institution-specific IRB approval for 
study entry. 
 
 
I.   
Background and Significance 
Diabetic gastroparesis can be a difficult-to-treat complication of longstanding diabetes that can 
significantly compromise quality of life in those affected. Today there is only one medication 
approved by the FDA for the indication of diabetic gastroparesis and it has received a black 
box warning due to potential for severe neurological side effects. There are other medications 
that have found some success in the treatment of diabetic gastroparesis, but they also have the 
potential for serious side effects, and some are only available through a special use program.1 
 
II.   Specific Aim 
The aim of the study is to evaluate the efficacy of the stimulant laxative Senokot-S® for the 
treatment of diabetic gastroparesis. Senokot-S, and its metabolites, are thought to produce peri-
stalsis, drive intra-luminal fluid and electrolyte shifts, and have an irritant effect on the gut mu-
cosa2,3. These complex physiologic mechanisms appear may sufficiently promote stomach emp-
tying, and thereby reduce or eliminate the severity of gastroparesis symptoms. In this open label 
study, participants will be randomized into high and low dose groups to assess for ideal dosing 
and tolerability. It is the overall goal of this study to select the most promising dose-strength for 
the treatment of mild through severe gastroparesis.  
 
(c) 
Study End Points 
a. Primary Endpoint 
i. 
Modified GCSI-DD: Subjects will complete the modified Gastroparesis 
Cardinal Symptom Index-Daily Diary (mGCSI-DD)4,5. The mGCSI-DD is 
a validated patient reported outcome (PRO) instrument with excellent test-
retest reliability, and will be used as the primary instrument to assess for 
efficacy in this study. 
ii. Questions on the mGCSI-DD are a 6-point Likert scale from 0 (none) to 
very severe (5) that address: nausea, retching, vomiting, stomach fullness, 
ability to finish a normal-sized meal, feeling excessively full after meals, 
loss of appetite, bloating, external assessment of stomach size, upper ab-
dominal pain or discomfort. 
b. Secondary Endpoint 
i. 
Breakthrough medication use: Defined as the change in the frequency of 
use of breakthrough medication, which is the medication that has been 
previously prescribed on an as-needed basis to manage symptoms.  

Protocol Version Tracking Date:  29 MAY 2018 
Page 3 of 7 
Any change in frequency of use of breakthrough medications will be used 
as a secondary endpoint to assess for efficacy in the study. 
ii. 
Bowel habits: Subjects will self report bowel habits during the baseline 
week and through the study period on the same questionnaire form.  Since 
Senokot-S functions primarily as a mild bowel stimulant any significant 
change in bowel habits will help to assess for tolerability in this study. 
IV.      Study Design 
The Phase II study design will be an open label, pre- and post-treatment assessment, prospec-
tive study. Sixty (60) study participants will be recruited over a 5-month period at a single site. 
Participants will be randomized into two treatment groups, a high- and low-dose, and will take 
medication dosed orally, twice daily or once daily at night.  
 
V.       Experimental Design, Methods, and Study Procedures 
a. Initial Identification of Potential Study Subjects Gastroenterologists who have 
agreed to refer their patient with diabetic gastroparesis for this study will make the ini-
tial contact with those patient (study inclusion/exclusion criteria will be provided to 
these physicians for ready reference). If the patient is interested in participating in the 
study the gastroenterologists will secure the patient’s verbal permission to provide their 
name and contact information (phone or e-mail) to Dr. Gose or another member of the 
study team. The study team member will contact the patient and arrange a time to meet 
with them to explain the study and to answer any questions the potential subject may 
have.   
 
b. Screening Visit The screening visit will include reviewing the participants’ complete 
medical history after reviewing and obtaining informed consent. Data from the partici-
pant’s medical history will be abstracted from the electronic medical record (EMR) and 
will be securely stored with other study-related data. Participants will be given the 
mGCSI-DD questionnaire and instructed on its use. At this visit participants will start 
recording their week of baseline scores by filling out a separate mGCSI-DD question-
naire and Breakthrough Medication Use and Bowel Habits documentation form daily. 
 
c. Visit 1 will occur 1 week after the screening visit. Participants will return with their 
mGCSI-DD baseline week of scores. They will be sequentially randomized (1:1) into 
either the high (8.6/50mg of senna/docusate taken by mouth twice daily) or low 
(8.6/50mg of senna/docusate taken by mouth once every night) dose study group. To 
reduce potential subject bias and placebo effect, participants will not be informed as to 
which dose of study medication they are randomized. They will be given their study 
medication and their 28-day mGCSI-DD questionnaire sheets, along with a pre-printed 
return envelope for use after completing their month of treatment in the study. They 
will be instructed to decrease use of any previously prescribed breakthrough medication 
as can safely be tolerated.  Examples of these medication may include prokinetics such 
as Reglan (metoclopramide), erythromycin, or domperidone; anti-emtics such as Zofran 
(ondansetron), or Compazine (prochloperazine); or analgesics such as tramadol, 

Protocol Version Tracking Date:  29 MAY 2018 
Page 4 of 7 
hydrocodone, or oxycodone.  They will also be instructed to resume any breakthrough 
medication use as previously prescribed at the completion of the study and to continue 
routine follow ups with their care providers.   
 
Subjects will be instructed to immediately contact the Principal Investigator if they ex-
perience episodes of significant diarrhea or rectal bleeding.  
 
Participants may be notified by phone at the end of their study period to verify data or 
request missing data. 
 
VI.  Risks 
Senokot-S side effects. Known side effects of Senokot-S include diarrhea, nausea or vomiting, 
stomach pain, rectal bleeding, gas, abdominal bloating, and potential for allergic reaction such 
as skin rash. There have been safety concerns in the past about potential complications from 
long term use of stimulant laxatives like Senokot-S, such as cathartic colon, increased inci-
dence of colorectal cancer, and liver disease.  Several recent studies and reviews refute those 
previous conclusions and suggest long-term use of mild stimulant laxatives is likely safe when 
needed3,6,7. Senokot-S is listed as pregnancy category C by the FDA.   
Women with child bearing potential will be required to use an effective form of birth control 
while participating in this study. 
 
Ineffective treatment of diabetic gastroparesis. Since this medication has not yet been studied 
in the treatment of diabetic gastroparesis it is possible that symptoms of the disorder may 
worsen.  The common symptoms of diabetic gastroparesis include nausea, vomiting, postpran-
dial fullness, early satiety, and abdominal pain.  
 
Loss of confidentiality. It is expected that this risk will be low because of numerous safeguards 
that will be in place, including standard data management procedures with Aurora Health Care. 
 
VII.  Benefits 
A successful outcome in the proposed study will have immediate implications by reducing the 
symptoms of diabetic gastroparesis. Such a result will address the significant unmet need by 
providing a safe, inexpensive pharmacological therapy for a difficult to treat chronic disorder. 
These findings would allow patients to reduce or eliminate intake of the only FDA-approved 
therapeutic medication, Reglan®, which has a black box warning and unfavorable side-effect 
profile. These known potential benefits are highly likely to outweigh the potential risks of the 
intervention in this study.    
 
VIII.  Study Population 
Inclusion Criteria: 
 Age 18-75 years, male and non-pregnant, non-lactating females 
 Diagnosis of type 1 or type 2 diabetes mellitus  
 Clinical diagnosis of diabetic gastroparesis 

Protocol Version Tracking Date:  29 MAY 2018 
Page 5 of 7 
 
Exclusion Criteria: 
 Diagnosed idiopathic gastroparesis 
 A history or inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis 
 A history of bowel obstruction, current unexplained abdominal pain, or undiagnosed 
rectal bleeding 
 Gastrointestinal cancer 
 Any active cancer 
 Prior gastric surgery 
 End-stage heart disease, liver disease, lung disease 
 Known or suspected drug abuse 
 Any condition requiring use of daily narcotics 
 Concurrent usage of mineral oil or products containing mineral oil 
 Current or recent (within the last 3 months) usage of Senokot-S, docusate or senna 
 
IX.  Recruitment and Screening 
Recruitment will occur through care provider referrals. Clinicians will be notified of the study 
through paper advertisement and posters. Initial screening will be done over the phone or 
through e-mail at the time of referral and will include a medical record review. Final screening 
and informed consent will be completed during the formal in person screening visit between 
the participant and research staff and is expected to take about one to two hours. 
 
X.  
Privacy Plan 
Patients will initially be notified of the potential to be in a research study by a current caregiv-
er. If the patient is agreeable to consideration for the study the research team will be contacted 
by phone or through e-mail by the clinician with the patient’s contact information. The patient 
will then be contacted by a member of the research team via an institution-based phone or 
EMR e-mail (based on the patient’s preference) for initial screening and to set up a clinic visit 
for final screening and informed consent.  
XI.     Data Collection 
The data to be collected will include a complete medical history of the participant, mGCSI-DD 
score forms, medication usage and bowel habits forms. Data will not be shared with any out-
side institutions. 
 
This research study plans to store and manage the subject lists, demographic information, vali-
dated questionnaire, study and breakthrough medication use, and bowel habits datasets in 
REDCap Cloud, a secure electronic data capture application that is based on Vanderbilt Uni-
versity’s REDCap application. Flexible for a variety of types of research, REDCap Cloud pro-
vides an intuitive data-entry interface for end users into study-specific data collection forms as-
sociated with study events. The application includes real time validation rules and query man-
agement, audit trails, and the automated export of study data into statistical programs. The 
REDCap Cloud platform is compliant with GCP predicate rule requirements and US FDA 21 

Protocol Version Tracking Date:  29 MAY 2018 
Page 6 of 7 
CFR Part 11 pertaining to the use of electronic records and signatures. Aurora Health Care, 
Inc. has executed an agreement for use of the application with nearly all research studies con-
ducted at Aurora. 
 
Access to data housed in REDCap Cloud and associated with this research study will be lim-
ited to those individuals listed on the IRB approved research study, as well as caregivers from 
Research Analytics for administrative reasons. Study team members access to the system and 
the data itself will be limited in accordance with need (i.e., biostatisticians may be limited to 
simply export the dataset to statistical tools, research coordinators may be limited to entering 
data, etc.). Overall, limiting access to study team members by need should reduce the risk of 
accidental disclosure and breach of confidentiality. However, using a cloud-based application 
may incidentally raise the risk of a breach in confidentiality, and, therefore, Aurora Health 
Care, Inc. has negotiated strong protections with the vendor in the event of a breach of confi-
dentiality. 
 
XII.  Statistical Plan 
All category and continuous variables will be described using appropriate descriptive statistics 
such as frequency, percentage for category variables and mean, standard deviation, median, 
and range for continuous variables. Pre and post outcomes variables for two groups of patients 
in the experimental groups will be compared using appropriate parametric and/or non paramet-
ric statistical tests. For all statistical tests an alpha level of 0.05 will be used and all statistical 
analysis will be carried out using SAS version 9.4, SAS Institute, Cary, NC. 
 
XIII. Monitoring Plan 
Data monitoring, safety monitoring, and statistical analysis will be done through the research 
office and principal investigator.  
Participants can stop the study at any time for any reason and can resume previous treatments 
whenever needed. Stopping points will be at the end of the 5 month study period or if a nega-
tive trend in mGCSI-DD post-treatment scores is observed. 
XIV. Regulatory Requirements 
The investigators and all key personnel agree to abide by the determinations of the Aurora IRB, 
including obtaining documented informed consent prior to inclusion of any individual in this 
research study. The investigators and all key personnel will comply with reporting require-
ments as outlined in the Aurora IRB Standard Operating Procedures (SOPs). In addition, inves-
tigators will permit access for on-site monitoring by representatives of the Aurora IRB, the Au-
rora Research Institute Investigator-Initiated Research unit, and the Aurora Research Institute 
Quality Improvement Program. 
 
 

Protocol Version Tracking Date:  29 MAY 2018 
Page 7 of 7 
 
XV. References 
 
1 
Camilleri, M., Bharucha, A. E. & Farrugia, G. Epidemiology, mechanisms, and manage-
ment of diabetic gastroparesis. Clinical gastroenterology and hepatology : the official 
clinical practice journal of the American Gastroenterological Association 9, 5-12; quiz 
e17, doi:10.1016/j.cgh.2010.09.022 (2011). 
2 
Geboes, K., Spiessens, C., Nijs, G. & de Witte, P. Anthranoids and the mucosal immune 
system of the colon. Pharmacology 47 Suppl 1, 49-57 (1993). 
3 
Morales, M. A., Hernandez, D., Bustamante, S., Bachiller, I. & Rojas, A. Is senna laxa-
tive use associated to cathartic colon, genotoxicity, or carcinogenicity? Journal of toxi-
cology 2009, 287247, doi:10.1155/2009/287247 (2009). 
4 
Revicki, D. A. et al. Development and content validity of a gastroparesis cardinal symp-
tom index daily diary. Alimentary pharmacology & therapeutics 30, 670-680, 
doi:10.1111/j.1365-2036.2009.04078.x (2009). 
5 
Revicki, D. A. et al. Evaluating symptom outcomes in gastroparesis clinical trials: validi-
ty and responsiveness of the Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-
DD). Neurogastroenterology and motility : the official journal of the European Gastroin-
testinal Motility Society 24, 456-463, e215-456, doi:10.1111/j.1365-2982.2012.01879.x 
(2012). 
6 
Muller-Lissner, S. A. Adverse effects of laxatives: fact and fiction. Pharmacology 47 
Suppl 1, 138-145 (1993). 
7 
Wald, A. Is chronic use of stimulant laxatives harmful to the colon? Journal of clinical 
gastroenterology 36, 386-389 (2003).