A Randomized, Single Center, Double-blind, Parallel-group, Placebo-controlled Study Assessing the Effect of CSP01 on Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation
Phase: NA
Conditions: Constipation, Chronic Idiopathic Constipation, Irritable Bowel Syndrome With Constipation
Sponsor: Massachusetts General Hospital

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A randomized, single center, double-blind, parallel-
group, placebo-controlled study assessing the effect of 
CSP01 on chronic idiopathic constipation and irritable 
bowel syndrome with constipation 
 
Principal/Overall Investigator: 
Kyle Staller, MD, MPH 
 
Funding: 
Gelesis Inc.  
 
Version Date: 
October 30th, 2017 
 
 
I. Background and Significance 
 
a.) Historical background 
Constipation remains one of the most common clinical conditions encountered by physicians 
with an estimated general population prevalence ranging from 2% to 28%1 generating 2.5 million 
physician visits per year with an annual direct medical cost of more than $230 million in the U.S. 
alone.2 Constipation is a symptom described as infrequent stool passage often associated with 
straining or the sensation of incomplete evacuation.3 In addition to gastroenterological pathology 
such as poor bowel motility or outlet obstruction, there are many other etiologies of constipation 
such as secondary to a medical condition or medication. Chronic constipation without a 
demonstrable physiologic abnormality is classified by Rome III Criteria as chronic idiopathic 
constipation (CIC), a functional gastrointestinal disorder that exists on a spectrum with irritable 
bowel syndrome with constipation (IBS-C).4 The prevalence of CIC worldwide is 14%, and it is 
more common in women, elderly people, and those of lower socioeconomic status. Additionally, 
patients with chronic constipation report impaired quality of life comparable to other chronic 
conditions, and consequently tend to contribute considerably to physician visits and other 
healthcare costs.5 Therefore, there is a need for more effective and well-tolerated devices, as 50% 
of patients with constipation are not satisfied with available therapies.6 
 
 
b.) Previous studies supporting the proposed research 
Although CIC and IBS-C are common problems, the treatment of constipation symptoms 
is often provider-specific, and there is weak evidence to support many of the drugs that are 
commonly used in the treatment of this disorder.7 Lifestyle measures such as hydration, exercise, 
and increased fiber intake are an important component of the multi-faceted approach to treating 
chronic constipation prior to initiation of medical therapy.8 Notably, fiber supplementation 
significantly alleviates symptoms in patients without slow transit constipation9, the majority of 
patients with constipation.3 
CSP01 is a non-systemic, orally administered capsule that contains thousands of 

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proprietary, biocompatible hydrogel particles synthesized with starting materials that are 
Generally Recognized as Safe by the U.S. Food and Drug Administration (FDA).10 CSP01 is 
similar to Gelesis100 and Gelesis200, both of which have been tested in humans and show 
excellent safety profiles, and differs from Gelesis200 only by the addition of the excipient 
sodium stearyl fumarate, which allows for the packing of more hydrogel particles into the 
capsule. CSP01 capsules are taken prior to a meal with water, after which the small particles 
within the capsules hydrate and expand in the stomach and small intestine. Gelesis100, a similar 
product, has undergone multiple early phase clinical trials.11 The First Loss Of Weight (FLOW) 
study demonstrated the safety of the Gelesis100 medical device with 12 weeks of use in 
overweight and obese subjects. Currently, Gelesis Inc. is conducting the Gelesis Loss Of Weight 
(GLOW) study, a pivotal, randomized, double-blind, placebo-controlled, parallel-group study 
designed to assess the effect of repeated administration of Gelesis100 over six months on body 
weight and glycemic control parameters in overweight and obese subjects.12 
 
c.) Rationale behind the proposed research 

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By acting as a bulking agent and possibly reducing colonic transit time through increase 
of colonic water content, CSP01 may contribute to constipation relief. In contrast to traditional 
fiber that retains water without influencing colonic water content, CSP01 absorbs water solutions 
up to 85 times its original weight while in the stomach, acts as a bulking agent as it moves 
through the small intestine, and partially degrades in the large intestine through loss of its three- 
dimensional matrix structure and most of its hydration capacity. By losing its water absorption 
capacity in the colon, colonic water content is thus increased in a mechanism of action similar to 
current therapies treating constipation, and CSP01 is expelled in the feces. 
Given the in vitro performance of this novel, fiber-like hydrogel, it is therefore 
hypothesized that the device may be of benefit in patients with CIC and IBS-C, however, 
analysis of how it affects whole gut motility has not been conducted. This will be observed using 
wireless motility capsule (WMC) testing, a non-invasive diagnostic tool capable of measuring 
intraluminal pressure and pH through the whole GI tract, assessing both transit and contractility. 
WMC has been demonstrated as a safe, convenient, and reliable method of assessing whole gut 
transit after a dietary intervention in a more physiologic setting than traditional manometry or 
scintigraphy. 
 
II. Specific Aims 
 
This is a single center, randomized, double-blind, parallel-group, placebo-controlled pilot 
study. The purpose of the study is to evaluate the efficacy of the hydrogel capsule CSP01 vs 
active control (carboxymethylcellulose) vs placebo in accelerating colonic motility among 
patients with chronic idiopathic constipation. Patients who meet the Rome IV criteria for CIC or 
IBS-C and who meet the inclusion criteria will be offered participation in this study. 
 
III. Subject Selection 
 
This study aims to recruit 53 total subjects to be enrolled at one site, Massachussetts 
General Hospital. The 53 subjects that this study aims to recruit factors in a dropout rate of 15%, 
with a final sample size of 45 subjects. 
 
 
INCLUSION/EXCLUSION CRITERIA: 
 
Inclusion 
1. Age 22-70 years old 
2.   BMI >18.5 and <35 kg/m2 
3. Rome IV criteria for functional constipation or IBS-C 
4. Continued IBS-C or CIC throughout Run-in period 
5. Compliant with reporting during Run-in (confirm the presence of constipation during the 
7-day Run-in baseline period; patients are required to report an average of <3 continuous 
spontaneous bowel movements [CSBMs] and ≤6 spontaneous bowel movements [SBMs] 
per week via the interactive web response system).

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6. Ability to follow verbal and written instructions 
7. Ability to record daily bowel habits, including frequency, stool consistency (BSFS), 
straining (EoPS), completeness of evacuation, and Patient Reported Outcomes (PROs) 
(abdominal discomfort, severity of constipation, bloating, overall relief) 
8. Informed consent form signed by the subjects 
 
Exclusion 
1. History of loose stools 
2. History of irritable bowel syndrome with diarrhea (IBS-D) or mixed irritable bowel 
syndrome (IBS-M) 
3. Non-compliance with reporting during Run-in 
4. Patients reporting laxative, enema, and/or suppository usage for >2 days or any usage of a 
prohibited medication during the Run-in period 
5. Patients reporting watery stools for any SBM (Type 7 on the Bristol Stool Form Scale 
[BSFS]) or loose (mushy) stools for >1 SBM (Type 6 on the BSFS) in the absence of 
laxatives during Run-in 
6. GI motility obstruction or GI tract structural abnormality 
7. Current use of prescribed or illicit opioids 
8. History of pelvic floor dysfunction 
9. Need for manual maneuvers in order to achieve a BM 
10. History of GI lumen surgery at any time or other GI or abdominal operations within 60 
days prior to entry into the study 
11. History of high-dose stimulative or cathartic laxative abuse as judged by investigator 
team 
12. Neurological disorders, metabolic disorders, or other significant disease that would 
impair their ability to participate in the study 
13. Cardiovascular disease, diabetes, cancer, Crohn’s disease, ulcerative colitis 
14. BMI of <18.5 or >35 kg/m2 
15. Pregnancy (or positive serum or urine pregnancy test(s) in females of childbearing 
potential) or lactation 
16. Absence of contraception in females of childbearing potential 
17. History of allergic reaction to carboxymethylcellulose, citric acid, sodium stearyl 
fumarate, raw cane sugar, gelatin, or titanium dioxide 
18. Administration of investigational products within 1 month prior to Screening Visit 
19. Exclusion of colonic inertia with symptoms of < 1 BM per 2 weeks 
20. Subjects anticipating surgical intervention during the study 
21. Known history of diabetes (type 1 or 2) 
22. History of eating disorders including binge eating (except mild binge eater) 
23. Supine SBP > 160 mm Hg and/or supine DBP > 95 mm Hg (mean of two consecutive 
readings) 
24. Angina, coronary bypass, or myocardial infarction within 6 months prior to Screening 
Visit 
25. History of swallowing disorders 
26. Esophageal anatomic abnormalities (e.g., webs, diverticuli, rings) 
27. History of gastric bypass or any other gastric surgery 

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28. History of small bowel resection (except if related to appendectomy) 
29. History of gastric or duodenal ulcer 
30. History of gastroparesis 
31. History of abdominal radiation treatment 
32. History of pancreatitis 
33. History of intestinal stricture (e.g., Crohn’s disease) 
34. History of intestinal obstruction or subjects at high risk of intestinal obstruction including 
suspected small bowel adhesions 
35. History of malabsorption 
36. History of sucrose intolerance 
37. History of hepatitis B or C 
38. History of human immunodeficiency virus 
39. History of cancer within the past 5 years (except adequately-treated localized basal cell 
skin cancer or in situ uterine cervical cancer) 
40. Any other clinically significant disease interfering with the assessments of Gelesis100, 
according to the Investigator (e.g., disease requiring corrective treatment, potentially 
leading to study discontinuation) 
41. HbA1c > 8.5% (> 69 mmol/mol) 
42. Positive test for drugs in the urine 
43. Any relevant biochemical abnormality interfering with the assessments of Gelesis100, 
according to the Investigator 
44. Antidiabetic medications within 1 month prior to Screening Visit (except stable dose of 
metformin, ≤ 1500 mg/day, for at least 1 month in subjects with type 2 diabetes) 
45. Medications requiring mandatory administration with meal at lunch or dinner 
46. Anticipated requirement for use of prohibited concomitant medications 
47. Implanted or externally worn medical device such as, but not limited to, a pacemaker, 
infusion pump, or insulin pump 
 
 
c.) Source of subjects and recruitment process 
 
Subjects will be recruited from the MGH Center for Neurointestinal Health based on the 
following enrollment criteria. Other GI physicians at MGH will be informed of the study and 
can refer patients to the clinic if they are deemed appropriate for the study. Study staff will 
review subject’s electronic medical records to confirm inclusion and exclusion criteria. Subjects 
may also be identified using the Research Patient Data Registry (RPDR) system. Electronic 
medical records of potential subjects will be reviewed to confirm inclusion and exclusion 
criteria. The patient’s provider will be contacted to confirm the patient’s eligibility as well as to 
gain permission to contact the patient. The recruitment letter by the PI and the patient’s provider 
will be sent. Patients who agreed to direct contact (RODY YES) will receive a recruitment letter 
from the PI. If the patient does not contact the study coordinator within 1 week, they will be 
contacted by phone and/or email by the study coordinator. All subjects will undergo telephone 
prescreening by the study staff. 
In addition to patients of MGH, subjects from the general greater Boston population will 
also be recruited. Subjects from the general population will be recruited through online 
advertisements run using the Galen Recruitment Service. Through this service, respondents will 
be filtered by qualifying questions. Contact information for qualified respondents will be 
provided to research study staff. 

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IV. Subject Enrollment 
 
a.) Methods of enrollment 
1. Patients may be approached by a research coordinator in the Neurointestinal Health 
clinic if they have a history of chronic constipation and agree to hear more about the 
trial 
2. Patients may be called by the research coordinator prior to their appointment and 
asked if they would like to hear more about the trial 
3. Any patients agreeing to hear more about the trial will learn more before beginning 
the informed consent process should they agree to participate as well as determining 
whether they meet all of the inclusion criteria 
4. Patients may be contacted about the research study by their MGH physician on 
behalf of the research team. Afterward, patients may then be contacted by the 
research team directly. 
5. Subjects who have provided their contact information through internet advertising 
may be contacted by the research team directly. 
 
b.) Procedures for obtaining informed consent 
 
 
1.  Patients agreeing to participate will sign an informed consent with the study doctor at 
the time of enrollment, after proper informed consent has been provided by the site.

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c.) Treatment assignment and randomization 
 
1. Patients who have been enrolled and consented in the trial will be randomized with a 
ratio of 1:1:1 with 15 subjects per arm: 15 subjects on 3 capsules BID of CSP01, 15 
subjects on 3 capsules BID (morning, evening) of carboxymethylcellulose (CMC), 
and 15 subjects on 3 capsules BID of placebo (sucrose). 
2. We will stratify by Rome IV diagnosis of CIC vs. IBS-C to avoid clustering of IBS-
C patients in one group. 
3. The study personnel and patients will be blinded to treatment allocation. 
4. Patients who fulfill study admission criteria and have a signed consent form will be 
assigned a 3-digit sequential patient number. The number will be used throughout the 
study. 
5. Randomization will be conducted via an interactive web-based response system 
(IWRS). Based on the randomized treatment assignment, an unblinded pharmacist at 
MGH will prepare the study treatment in a manner that ensures maintenance of the 
blind utilizing study-specific labels and completing details pertinent to the individual 
patient. 
6. This is a double-blind study. The individual treatment assignment will not be revealed 
to patients or their representatives, study staff (except for the unblinded pharmacist), 
or the sponsor or the sponsor’s representatives, until all patients complete the study 
and the database is locked. The unblinded pharmacist will maintain the treatment 
assignment for each patient. 
 
V. Study Procedures 
 
a.) Study visits and parameters to be measured 
 
1. Eligibility Screen (Day -28 to -15) 
a. Vital signs, height, weight, and physical exam will be performed. 
b. Rome IV questionnaire to screen for CIC and IBS-C 
c. Blood sample collection (CBC, Chem 7, LFTs, Thyroid Hormone, ESR, and if 
applicable, serum pregnancy test) 
d. Urine sample for toxicity screening 
 
2. Run-In Period (Day -14 to 0) 
 
Day -14: After a screening visit in which patient eligibility will be determined 
through use of Rome IV constipation module along with other inclusion and 
exclusion criteria as above, there will be a two-week run-in period. 
 
During this time no use of contraindicated medication per exclusion criteria or 
medications that may affect the bowel mobility will be allowed unless the subject has 
been on a stable dose for the last 3 months: 

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a. Laxatives 
b. Prokinetic medications 
c. Anti-Depressant medications 
d. Medications for treatment of Parkinson disease 
e. Opiates 
f. Calcium-channel Blockers 
g. Aluminium/Magnesium 
h. Hydroxides 
i. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) as defined by 
a frequency of at least 3 times a week for at least 6 months. Subjects on 
cardiac doses of aspirin may be enrolled in the study. 
 
Day -7: Seven days into the run-in period, patients will undergo wireless motility 
capsule (WMC) testing to assess baseline motility. To allow for complete passing of 
the capsule, there will be a 7-day period following WMC ingestion prior to initiation 
of treatment to coincide with the end of the two-week run-in period. 
 
If there is an issue with capsule transit, will be monitored by investigator team and 
depending on location may exclude patient (i.e. if capsule transit delayed in stomach, 
would exclude patient based on exclusion criteria of gastroparesis). Patients with no 
bowel movement for 5 consecutive days, who are in need of a rescue treatment, will 
be instructed to contact the investigator. The following treatment is recommended, as 
applicable, in the following order: 
1. Glycerin suppository 
2. Enema 
3. Laxadin/Bisacodyl tablets (3x5mg) 
 
Administration of rescue treatment is at the discretion of the investigator based on an 
assessment of the subject; administration of rescue should be monitored and recorded. 
 
3. Treatment Period (Day 0 to 22) 
 
a. Day 0: On the visit to initiate treatment, patients will return to the clinic to 
return their WMC monitor and be treated in a parallel-group design for 3 
weeks.  At this visit, the patient will return the SmartPill receiver and the 
study diary. Questions or concerns about the study will be discussed, 
including any changes in concomitant medications and new or worsening 
adverse events. If available, results of the SmartPill test will be reviewed by 
the patient’s physician. If it is unclear that the capsule has passed, based on 
the subject’s history or on the study results, erythromycin may be prescribed if 
the capsule is still in the stomach as a promotility medication or obtain an 
abdominal x-ray for verification to determine if the capsule is still in the 
colon. If the subject is female, then a urine pregnancy test will be performed 
before any abdominal xray. Issues with capsule transit will be addressed as 
above.

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b. Following the two-week run-in period, subjects will again complete the Rome 
IV Constipation module confirming that inclusion and exclusion criteria 
continue to be satisfied, and the patient will be randomized using the IWRS. 
The IWRS will notify the pharmacy to prepare the study drug (randomization 
output must only be seen by unblinded pharmacist). 
 
c. During 3-week treatment period, patients will ingest three capsules, twice 
daily, before breakfast and dinner (with 16 oz water). 
 
d. Patients will be asked to refrain from making any major lifestyle changes 
(e.g., starting a new diet or changing their exercise pattern) during the study. 
 
e. Patients will be instructed to complete a simple, web-based daily diary using 
the Redcap system throughout the duration of the study which includes daily 
recording of number and time of bowel movements, complete/incomplete 
evacuation, and straining, abdominal discomfort, bloating, constipation 
severity, and overall relief using a nominal rating scale. 
 
f. Day 1: Subjects will begin taking study device. Patients will complete the 
Patient Assessment of Constipation Symptoms (PAC-SYM) and Quality of 
Life (PAC-QOL) to determine the severity of their constipation. 
 
g. Day 15: Following 14 days of treatment, patients will return to the clinic to 
undergo WMC testing to establish their motility profile on treatment and 
complete PAC-SYM, PAC-QOL questionnaires. 
 
h. Day 22: Following 21 days of treatment, patients will return to the clinic to 
return the WMC monitor and complete PAC-SYM, PAC-QOL questionnaires. 
 
i. Day 31 (+3 days): There will be a post-treatment period of 7 days during 
which time patients will continue to complete their daily diary. The clinical 
coordinator will call patients at the end of this follow-up period to ensure 
no adverse events occurred. After completion of the study, patients will be 
mailed the results of their SmartPill baseline test. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. Schedule of Events 
 
Study 
 
Run-in period 
Treatment period 
Post- 
treatment 
period 
Time Point 
Day -28 to -15 
Day -14 
Day -7 
Day 0 
Day 1
Day 15 
Day 22 
Day 31 
Eligibility screen 
X 
 
 
Informed consent 
X 
 
Allocation 
X 
CSP01 group 
CMC group 
 
 
 
Placebo group 
Rome IV 
questionnair
X 
 
X 
Daily diary 
 
X 
X 
X 
X 
X 
X 
X 
PAC-SYM 
X 
X 
X 
X 
X 
PAC-QOL 
 
X 
X 
X 
X 
X 
WMC testing 
X 
X 
Adverse events 
X 
X 
X 
X 

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5. There will be no routine monitoring of labs or imaging for the purposes of the study 
outside of usual care. Other study monitoring activities will be conducted as per 
Section IX of this protocol. 
6. Patients enrolled in the study will not be allowed to be given standing laxative 
medications for prophylactic purposes, but rescue medications will be allowed on an 
as-needed (PRN) basis 
 
b.) Investigational Product (IP) to be used 
 
1. The IP will be supplied by the Sponsor and stored in the MGH inpatient pharmacy 
a. CSP01 is supplied in capsule form (0.79 g per capsule, 2.37 g per dose) 
b. CMC dose is supplied in capsule form (0.70 g per capsule, 2.1 g per dose) 
c. Matching placebo consists of an inert mixture supplied by the Sponsor in 
identical-appearing capsules 
2. Rescue medications (in case of emergency) 
a. If a subject experiences inadequate prevention of constipation while on the 
study treatment or placebo, the patient may be administered a rescue 
medication (laxative) at the discretion of the patient conferring with the Study 
physician or research NP consistent with “prn” orders or new orders from the 
medical team. Drugs that are available to treat constipation include: Colace 
(Docusate), Polyethylene glycol (Miralax), Senna (Senokot), magnesium 
citrate, and lactulose. Because constipation is not a side effect of the 
medication, all patients will be able to receive laxative doses as needed at their 
request throughout the study consistent with nurse’s or physician’s discretion 
without restriction. 
b. Patients with no bowel movement for 5 consecutive days, who are in need of a 
rescue treatment, will be instructed to contact the investigator. The following 
treatment is recommended, as applicable, in the following order: 
i. 1. Glycerin suppository 
ii. 2. Enema 
iii. 3. Laxadin/Bisacodyl tablets (3x5mg) 
c. Administration of rescue treatment is at the discretion of the investigator 
based on an assessment of the subject; administration of rescue should be 
monitored and recorded. 
 
c.) Data to be collected and timeline for collection 

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1. Primary endpoints 
a. Colonic Transit Time (CTT) 
2. Secondary endpoints 
a. Spontaneous Bowel Movement (SBM) frequency rate 
b. Complete Spontaneous Bowel Movement (CSBM) frequency rate 
c. Stool consistency (Bristol Stool Form Scale) 
d. Straining (Ease-of-Passage Scale) 
e. Abdominal discomfort (Self Assessment on 0–10-point numerical rating 
scale) 
f. Bloating (Self Assessment on 0–10-point numerical rating scale) 
g. Constipation severity (Self Assessment on 0–10-point numerical rating scale) 
h. Overall relief (Self Assessment on 0–10-point numerical rating scale) 
i. Balloon Expulsion Time (BET) before and after 
j. PAC-SYM change 
k. PAC-QOL change 
l. Need for rescue laxatives  
 
c.) Adverse events 
 
1. Definition of adverse events 
a. An adverse event (AE) is any untoward medical occurrence (sign, symptom, 
illness, abnormal laboratory value, or other medical event) in a subject, whether 
or not related to the investigational medical device. This includes events related 
to the procedures involved (any procedure in the Clinical Investigation Plan). 
 
2. A serious adverse event (SAE) is any AE that: 
a. led to death 
b. resulted-in a life-threatening condition 
c. resulted-in a permanent impairment of a body structure or a body function 
d. required inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 h (elective hospitalizations and/or hospitalizations for treatment of pre-
existing conditions that did not worsen from baseline are not considered AEs 
and should not be reported as SAEs) 
e. resulted-in a medical or surgical intervention to prevent permanent 
impairment to a body structure or a body function 
f. led to fetal distress, fetal death or a congenital abnormality, or birth defect 
 
3. A device deficiency is an inadequacy of the medical device with respect to its identity, 
quality, durability, and safety (e.g., use errors and inadequate labeling). Medical device 
deficiency can lead to an adverse device effect (ADE) or a serious ADE (SADE) (see 
below). 
a. For the purpose of this study and for reporting purposes, all device  deficiencies 
that could have led to SAEs, if suitable action had not been taken or intervention 
had not been made, or if circumstances had been less fortunate, will also be 
considered as SAE.

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4. Adverse device event definitions: 
a. An adverse device event (ADE) is an AE with a reasonable causal relationship 
to the use of the investigational medical device (i.e., an AE assessed as either 
“most probably related” or “possibly related” to the use of medical device) (see 
Section 13.1.3). 
b. An unanticipated ADE (UADE) is an ADE not previously reported or an ADE 
that occurs with specificity, severity, frequency, or outcome that is not 
consistent with the current Investigator’s Brochure (8). 
c. A SADE is a SAE with a reasonable causal relationship to the use of the 
investigational medical device (i.e., a SAE assessed as either “most probably 
related” or “possibly related” to the use of medical device). 
d. An unanticipated SADE (USADE) is a SADE not previously reported or an 
SADE that occurs with specificity, severity, frequency, or outcome that is not 
consistent with the current Investigator’s Brochure. In US, this definition is 
equivalent to the definition of an UADE in Medical Device Reporting 
regulation at Title 21. 
 
5. Adverse Event and Device Deficiency Recording, Assessment, and Reporting 
Procedure 
a. All AEs regardless of seriousness or relationship to the investigational  medical 
device including those occurring during the screening period (after  the 
signature of the Informed Consent Form) are to be recorded in the appropriate 
electronic CRF. 
b. AEs reported by subject will be discussed in details and recorded by the 
Investigator at each visit. AEs will be collected until 28 days after the last 
administration of the investigational medical device (i.e., until subject 
terminates his/her participation in the study). 
c. The Investigator should specify the date of onset, severity, action taken with 
respect to the investigational medical device, corrective treatment, outcome, 
and whether or not there is a reasonable possibility that the AE may have been 
caused by the use of the investigational medical device. 
d. AEs are graded as follows: 
i. Mild: sign or symptom, usually transient, requiring no special  
treatment and generally not interfering with usual activities. 
ii. Moderate: sign or symptom, which may be ameliorated by simple 
therapeutic measures, may interfere with usual activity. 
iii. Severe: sign or symptom intense or debilitating and interfering with 
usual activities without being immediately life-threatening. Recovery  is 
usually aided by therapeutic measures. 
iv. Very severe: sign or symptom life-threatening. Urgent intervention 
indicated. 
e. The assessment of the relationship of an AE to the use of the medical device is 
a clinical decision based on all available information at the time of the 
completion of the electronic CRF: 

Page 11 of 20 
 
i. Most probably related: follows a reasonable temporal sequence from 
medical device use, and cannot be reasonably explained by known 
characteristics of the subject’s clinical data. 
ii. Possibly related: follows a reasonable temporal sequence from medical 
device use, but could have been produced by the subject’s clinical state 
regardless of the medical device. 
iii. Probably not related: temporal association is such that the medical 
device use is not likely to have had any reasonable association with the 
observed event. 
iv. Not related: no relationship to the use of the medical device is perceived. 
f. Abnormalities of vital signs and laboratory results are to be recorded as AEs 
only if they are considered by the Investigator as clinically significant 
(symptomatic, requiring corrective treatment, leading to discontinuation, or 
fulfilling a seriousness criteria). 
g. Any pre-existing conditions or signs and/or symptoms present in a subject prior 
to the Screening Visit should be recorded as medical/surgical history. 
h. In this study, the following events will be reported to the authorities on 
expedited basis: 
i. All SAEs (including SADEs) will be expeditiously reported to the 
relevant European Regulatory Authorities and the Ethics Committees. 
ii. All suspected USADEs will be expeditiously reported to the Food and 
Drug Administration (FDA) and Institutional Review Board. 
i. 
All device deficiencies are to be recorded in the appropriate electronic CRF. 
 
6. Anticipated Adverse Device Effects 
a. The ADEs anticipated with the administration of Gelesis100 in overweight or 
obese subjects include nausea, dyspepsia (heartburn), abdominal distension 
(bloating), flatulence, abdominal pain, diarrhea, defecation urgency, and 
constipation. These AEs were observed in the FLOW study. A comprehensive 
list of anticipated ADEs is provided in the Investigator’s Brochure (8).\ 
 
7. Risk Analysis 
a. The Sponsor has established and maintains a process for identifying hazards 
associated with the use of its products, estimating, evaluating, controlling these 
risks and monitoring the effectiveness of the control. Detailed information 
regarding risk analysis is available in the Investigator’s Brochure (8). 
 
8. Precautions to Minimize Risk 
a. To minimize technical and medical complications, the investigational medical 
device should be used only as instructed in the Clinical Investigation Plan. This 
includes: 
i. administering the prescribed amount of medical device before breakfast 
and dinner (3 capsules at each) 

Page 12 of 20 
 
ii. drinking the prescribed volume of water (approximately 100 mL + 500 
mL) at the prescribed timing before meal 
iii. consuming food at the prescribed timing (20 to 30 min after medical 
device administration) 
9. Pregnancy 
a. In case of pregnancy, the investigational medical device use must be 
discontinued and the Sponsor informed. Every effort should be made to follow 
up the pregnancy until its outcome is available. 
b. The Contract Research Organization (CRO) Clinical Safety will provide the 
Investigator with the Pregnancy Reporting Form for completion. If the 
pregnancy is to be terminated, the anticipated date of termination should be 
provided. 
 
10. Responsibilities of the Investigator 
a. to inform the Sponsor about all AEs 
b. to inform the Sponsor about all SAEs, newly discovered pregnancies or 
pregnancy outcomes, within 24 h of awareness of the events, by: 
i. entering the information about the event into the electronic CRF 
ii. in case the Investigator does not receive an automatic notification from 
the electronic CRF system of successful SAE submission or electronic 
CRF data entering is not possible: 
1. printing the completed section of the electronic CRF (or in case 
completion of electronic CRF is not possible, completion of 
paper SAE form) 
2. signing the completed SAE form 
3. sending the scanned SAE form by e-mail to the CRO Clinical 
Safety at pharmacovigilance@easthorn.eu (or in case sending a 
scan is not possible, faxing it to the CRO Clinical Safety at 
+420 244 462 271) 
c. to inform the Sponsor about all device deficiencies 
d. to make every effort to follow up the subject to a satisfactory resolution of the 
safety event or until the end of the study 
e. to respond to follow-up requests from the Sponsor/CRO Clinical Safety 
 
11. Responsibilities of the Sponsor 
a. to ensure that: 
i. all AEs are recorded and reviewed with the Investigators 
ii. all SAEs are reported to the relevant European Regulatory 
Authorities/Ethics Committees as required by local regulations 
iii. all suspected USADEs are reported to the FDA/Institutional Review 
Board as required by the US regulations 
iv. all device deficiencies are recorded and reviewed with the Investigators 
b. during the course of the study, inform in writing all Investigators about all SAEs 
occurring at any of the participating sites 

Page 13 of 20 
 
c. to collect and maintain records of all AEs, device deficiencies, and 
pregnancies 
 
VI. Biostatistical Analysis 
1. Specific data variables to be collected from WMC 
a. Colonic Transit Time (CTT), Whole gut transit time (WGTT), Gastric 
emptying time (GET), Small bowel transit time (SBTT) 
2. Specific data to be collected through patient-reported questionnaires 
a. Spontaneous Bowel Movement (SBM) frequency rate 
b. Complete Spontaneous Bowel Movement (CSBM) frequency rate 
c. Stool consistency (Bristol Stool Form Scale) 
d. Straining (Ease-of-Passage Scale) 
e. Abdominal discomfort (Self Assessment on 0–10-point numerical rating 
scale) 
f. Bloating (Self Assessment on 0–10-point numerical rating scale) 
g. Constipation severity (Self Assessment on 0–10-point numerical rating scale) 
h. Overall relief (Self Assessment on 0–10-point numerical rating scale) 
i. Balloon Expulsion Time (BET) before and after 
j. Constipation symptom severity (PAC-SYM) 
k. Constipation quality of life (PAC-QOL) 
l. Need for rescue laxatives 
3. Study endpoints – As above 
4. Statistical methods 
a. Analysis populations 
i. Intent-to-treat (ITT) population: all patients who are randomized will 
be included in the ITT population. This will be the primary population 
for all analyses of demographics, patient characteristics and 
disposition, and efficacy data. 
ii. Safety population: All patients who are randomized and receive any 
study treatment will be included in the safety population. This will be 
the primary population for all analyses of safety data 
iii. Per-Protocol (PP) population: All patients who are randomized and 
receive the study medication on each day of their hospitalization. 
Major protocol violations include the following: 
1. Prohibited concomitant medication usage (specifically standing 
laxatives during hospitalization) 
The PP population may be used for supplementary analysis of selected 
efficacy and safety data, as appropriate. 
b. Endpoint analyses 
i. Primary endpoint: Colonic transit times will be compared in a paired 
fashion for individual patients before and after the intervention by 
means of a repeated measures ANOVA using a 3x2 design to 
distinguish between the outcomes of the three different groups. We 
will also use multivariable linear regression to compare change in 
transit time after adjusting for confounders, specifically: presence of 
IBS-C, abnormal balloon expulsion testing indicating dyssynergic 
defecation (BET ≥ 2 minutes), age, and sex.

Page 14 of 20 
 
ii. Secondary endpoints: The secondary endpoints will be compared in a 
similar fashion, with logistic regression adjusting for confounders. 
c.   Power analysis 
This is a randomized, double-blind, single-center clinical exploratory pilot 
comparing treatment with CSP01 to standard control (CMC) to placebo 
(sucrose) for prevention of constipation in patients with chronic idiopathic 
constipation. Notably, there is no data either from the wireless motility 
capsule or from radio-opaque marker transit studies establishing a clinically-
meaningful threshold for change in transit time in response to any colonic 
motility agent, and our hope is that transit data combined with patient-
reported outcomes (our secondary endpoints) from this pilot study would 
provide a meaningful transit improvement threshold that may be used in 
future research as well.  There is some data demonstrating the effect of 
dietary fiber on colonic transit time.7 If we extrapolate data from the trial of 
dietary fiber on colonic transit time, which demonstrated a 10-hour 
difference in colonic transit time with a standard deviation of 12 hours, we 
would assume the same effect for our standard fiber (CMC) group.  
Assuming that CSP01 would give an additional 3-hour decrease in colonic 
transit over conventional fiber, our current sample size would have 94% 
(with ≥90% considered excellent) power to detect a difference.  Even with 
30 total subjects, we would still have 80% power (see graph below which 
varies the sample size). 
   
 
If we are more conservative with the effect of CSP01 over standard fiber and 
decrease the additional effect to 1 hour decreased colonic transit time (1/3 of what 

Page 15 of 20 
 
we would expect), we would still have 88% power with our current sample size. 
 
VII. Risks and discomforts 
 
 
1. Device side effects and adverse events 
a. The CSP01 device is constructed out of carboxymethyl cellulose cross-linked 
with citric acid. The device as a powder is mixed with sodium stearyl fumarate 
and then placed in a gelatin capsule. Construction risks, such as contaminations 
either from the supplier or during production, allergic reaction to the component 
of the device, were in most cases broadly acceptable; except two risks that were 
found to be intolerable (interaction with nutrients and/or drugs or mechanical 
crush of capsules), but after implementation of risk mitigation, these risks have 
been reduced to the acceptable level. The remaining risks have been found to be 
broadly acceptable and the benefit outweighs the risk of the device. 
 
b. CSP01 may contribute to constipation relief by acting as a bulking agent and 
possibly reducing colonic transit time through increase of colonic water content. 
In contrast to traditional fiber that retains water without influencing colonic water 
content, CSP01 absorbs water solutions up to 85 times its original weight while in 
the stomach, acts as a bulking agent as it moves through the small intestine, and 
partially degrades in the large intestine through loss of its three-dimensional 
matrix structure and most of its hydration capacity. Thus, CSP01 releases water in 
the colon increasing the colonic water content, and the CSP01 particles are 
expelled in the feces. 
 
The following adverse device effects are anticipated based on the product 
composition (CMC), the form and route of administration (capsule taken orally), 
and the AEs reported in the STAGE and the FLOW studies: 
 
- decreased appetite (lost appetite) 
- dysgeusia 
- nausea 
- dysphagia 
- dyspepsia (heartburn, pyrosis) 
- reflux 
- eructation (burping) 
- vomiting 
- abdominal distension (fullness, bloating) 

Page 16 of 20 
 
- flatulence 
- abdominal pain, abdominal pain upper, abdominal pain lower 
- gallstone 
- diarrhea (loose stools) 
- defecation urgency (urgency, urge to defecation, fecal urgency) 
- fecal color change 
- fecal incontinence 
- infrequent bowel movements (less frequent stools) 
- constipation 
- feces hard (hard stools) 
- feces soft (soft stools) 
- anorectal discomfort (anal irritation) 
 
Because CSP01 non-invasive and does not achieve its primary intended purpose 
through chemical action within or on the body, and is not dependent upon being 
metabolized for the achievement of its primary intended purposes, it meets the 
definition of a medical device. CSP01 is a non-significant risk device in the US, 
because it does not meet the definition of a significant risk device under § 
812.3(m) of the investigational device exemptions regulation (21CFR812) 
 
c. TSE/BSE risk from gelatin capsules found to be broadly acceptable as the 
Scientific Steering Committee (SSC) of the European Union (EU) in 2003 stated 
that the risk associated with bovine bone gelatin is very low or zero.14,15 In 2006, 
the European Food Safety Authority (EFSA) stated that the SSC opinion was 
confirmed, that the BSE risk of bone-derived gelatin was very small, and removed 
support for the 2003 request of excluding the skull and vertebrae of bovine origin 
older than 12 months from the material used in gelatin manufacturing.16 
 
VIII. Potential benefits 
 
1. It is hypothesized that it may be of benefit in patients with chronic idiopathic 
constipation. Potential benefits may include improved colonic transit, a decrease in 
self- reported abdominal discomfort, straining, bloating, and constipation severity, as 
well as improved quality of life and symptom severity. 
 
IX. Monitoring and Quality Assurance 
 
1. Good clinical practice 
The investigator will ensure that this study is conducted in accordance with the principles 
of “Good Clinical Practice”, as outlined in Title 21 of Code of Federal Regulations 
(CFR), Part 312, subpart D, “Responsibilities of Sponsors and Investigators”; 21 CFR, 

Page 17 of 20 
 
part 50, “Protection of Human Subjects”; 21 CFR, part 54, “Financial Disclosure by 
Clinical Investigators”; 21 CFR, part 56, “Institutional Review Boards”; and 21 CFR, 
Part 11,“Electronic Records, Electronic Signature”, are adhered to. 
2. Institutional review board (IRB) approval 
The protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to the MGH IRB. Approval 
from the IRB must be obtained before starting the study and should be documented in a 
letter to the investigator specifying the protocol number, protocol version, protocol date, 
documents reviewed, and date on which the committee met and granted approval. Any 
modifications made to the protocol after receipt of IRB approval must also be submitted 
to the IRB for approval before implementation. 
3. Informed consent 
Written informed consent, in accordance with 21 CFR Part 50, must be obtained prior to 
participation in the study. Within the context of the inclusion criteria, a proportion of 
eligible patients may be exhibiting significant cognitive impairment and the lack of 
capacity to provide consent. As such, all patients will require surrogate consent by a 
legally authorized representative. The investigator or staff will determine the appropriate 
family member-person to contact regarding the study, based on the standard operating 
procedures of MGH and local and state laws. The signed consent form must remain in the 
patient’s medical chart and must be available for verification at any time. 
4. Liability and insurance 
The civil liability of the investigator, the persons instructed by the investigator and the 
hospital, practice, or institute in which they are employed, and the liability of the 
financial loss due to personal injury and other damage which may arise as a result of the 
carrying out of this study are governed by the terms and conditions set forth in the 
Clinical Trial Agreement and applicable law. 
5. Documentation of study findings 
Required information will be entered into the appropriate CRFs. All CRFs are to be 
completed accurately and promptly, and should be updated as needed so they reflect the 
latest information on the patient’s file. All records are to be kept in conformance with 
applicable guidelines and SOPs. When the study is completed, the investigator must 
retain the essential documents for as long as needed to comply with regulatory authority, 
local regulations and sponsor requirements further detailed in Section 10.2.5. The 
investigator shall notify the sponsor prior to moving or destroying any of the study 
documents. 
6. Study monitoring 
a. For Investigator-Initiated Research Studies, Investigators are responsible for 
ensuring proper monitoring of the investigation. The Investigator’s assigned 
clinical monitors are responsible for inspecting the CRFs throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of data; 
and adherence to GCPs. The monitors should have access to patient medical 
records and other study-related records needed to verify entries on the CRFs. In 
accordance to ICH Good Clinical Practice (ICH/GCP) guidelines, the 
Investigator’s assigned clinical monitors must have direct access to the 

Page 18 of 20 
 
investigator’s source documentation in order to verify the data recorded in the 
CRFs for consistency. 
b. The monitor is responsible for routine review of the eCRFs at regular interval 
throughout the study to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them. The monitor should 
have access to any patient records needed to verify the entries on the CRFs. The 
investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
 
The Sponsor may monitor Investigators’ compliance and adherence to their contractual 
obligations related to disclosure of the Investigator’s findings, agreed upon milestones, and 
safety information reporting. 
7. Access to Information for Auditing or Inspections 
Representatives of regulatory authorities, IRB, or of the Sponsor may conduct inspections 
or audits of this clinical study. If the investigator is notified of an inspection by a 
regulatory authority the investigator agrees to notify the Sponsor immediately. The 
investigator agrees to provide to representatives of a regulatory agency, IRB or IEC, or 
Sponsor access to source documents/records, facilities, and personnel for the effective 
conduct of any inspection or audit. 
8. Data quality assurance 
Data will be entered into a secure and validated database using eCRFs. Data entered may 
be checked at the point of entry and through external validation checks for accuracy. 
After resolution of any discrepancies and automated data-review procedures, the final 
data sets will be subject to a quality assurance audit. When the database is declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can 
only be made by written notice. The investigator will be responsible for ensuring the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs 
and in all required reports. Data reported on the CRFs, which are derived from source 
documents, should be consistent with source documents or the discrepancies should be 
explained. To ensure the quality of the clinical data across all participants and sites, a 
clinical data management review will be performed on all patient data. During this 
review, patient data will be checked for consistency, omissions, and any apparent 
discrepancies. In addition, the data will be reviewed for adherence to protocol and GCPs. 
To resolve any questions arising from the clinical data-review process, data queries will 
be sent for the site to complete. The principal investigator will electronically sign and 
date the indicated places on the CRF. This signature will indicate that the principal 
investigator inspected or reviewed the data on the CRF and the data queries, and that the 
investigator agreed with the content. 
9. Study Files and Retention of Records 
a. The investigator must maintain adequate and accurate records to fully document 
the conduct of the study and to ensure that study data is subsequently verified. 
These documents should be classified into two separate categories: (1) 
investigator’s study file, and (2) patient clinical source documents. The 
investigator’s study file will contain the protocol/amendments, printed (or 
electronically archived) copies of the patient CRFs, IRB, and governmental 
approval with correspondence, informed consent, drug accountability 

Page 19 of 20 
 
(receipt/dispensing) records, staff curriculum vitae and authorization forms, 
information regarding monitoring activities, sponsor/investigator correspondence, 
and other appropriate documents and correspondence. 
b. Patient clinical source documents for this study would include, but are not limited 
to, the following: 
i. Patient identification (name, date of birth, gender) 
ii. Documentation that patient meets eligibility criteria, i.e., relevant medical 
history, physical examination, and confirmation of diagnosis 
iii. Dated notes of the day of entry into the study including study number, 
patient identification number, verification that the trial was discussed and 
written informed consent was obtained 
iv. Dated notes for each protocol assessment and documentation that protocol 
specific procedures were performed 
v. Study drug accountability (investigator must keep blinded records of 
volume of study drug given and timing of each daily dose based on the 
hospital chart; this will not entail review of the unblinded pharmacy 
records for the sake of maintaining the blind) 
vi. Documentation of all adverse events, including any action taken with 
regard to study drug and outcome 
vii. Concomitant medications (including start and end date, dose if relevant) 
viii. Date of trial completion and reason for early discontinuation, if applicable 
10. Confidentiality 
a. The investigator must ensure that all participants’ confidentiality will be strictly 
maintained and that their identities are protected from unauthorized parties. Only 
patient initials, date of birth, and an identification code (i.e., not names) should be 
recorded on any form or biological sample submitted to the sponsor, IRB, or 
laboratory. The investigator must keep a screening log showing codes, names and 
addresses for all patients screened and for all patients enrolled in the trial. On 
CRFs or other documents that are submitted to the sponsor, participants should be 
identified by an identification code and not by their names. 
b. The investigator agrees that all information received from the Sponsor, including 
but not limited to the Investigator Brochure, the investigational product, and any 
other study information, remain the sole and exclusive property of the Sponsor 
during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from the 
Sponsor. The investigator further agrees to take all reasonable precautions to 
prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
11. Publication 
a. After the completion of the study and the analysis of all data, the Sponsor will 
support efforts by all Study Investigators to jointly publish the primary study 
results. 
12. Protocol and Protocol Amendments 
a. The investigator is responsible for ensuring the study is conducted in accordance 
with the procedures and evaluations described in this protocol. No amendments 

Page 20 of 20 
 
will be permitted to this protocol or to the conduct of the study without approval 
from the Sponsor and if applicable, the IRB. These communications will be 
documented in writing. 
b. All protocol amendments must be submitted to the IRB in accordance with local 
requirements. Approval must be obtained before changes are implemented. 
 
 
 
 
X. References 
1. 
Higgins, P. D. R. & Johanson, J. F. Epidemiology of constipation in North America: a 
systematic review. Am. J. Gastroenterol. 99, 750–9 (2004). 
2. 
Sonnenberg, A. & Koch, T. R. Physician visits in the United States for constipation: 1958 
to 1986. Dig. Dis. Sci. 34, 606–11 (1989). 
3. 
Bharucha, A. E., Pemberton, J. H. & Locke, G. R. American Gastroenterological 
Association technical review on constipation. Gastroenterology 144, 218–38 (2013). 
4. 
Jung, H. K. Rome III Criteria for Functional Gastrointestinal Disorders: Is There a Need 
for a Better Definition? J Neurogastroenterol Motil 17, 211–212 (2011). 
5. 
Paré, P. et al. Health-related quality of life, work productivity, and health care resource 
utilization of subjects with irritable bowel syndrome: baseline results from LOGIC 
(Longitudinal Outcomes Study of Gastrointestinal Symptoms in Canada), a naturalistic 
study. Clin. Ther. 28, 1726–35; discussion 1710–1 (2006). 
6. 
Mozaffari, S., Didari, T., Nikfar, S. & Abdollahi, M. Phase II drugs under clinical 
investigation for the treatment of chronic constipation. Expert Opin. Investig. Drugs 1–13 
(2014). doi:10.1517/13543784.2014.932770 
7. 
Jones, M. P., Talley, N. J., Nuyts, G. & Dubois, D. Lack of objective evidence of efficacy 
of laxatives in chronic constipation. Dig. Dis. Sci. 47, 2222–30 (2002). 
8. 
Ramkumar, D. & Rao, S. S. C. Efficacy and safety of traditional medical therapies for 
chronic constipation: systematic review. Am. J. Gastroenterol. 100, 936–71 (2005). 
9. 
Voderholzer, W. A. et al. Clinical response to dietary fiber treatment of chronic 
constipation. Am. J. Gastroenterol. 92, 95–8 (1997). 
10. 
Oral Administration of Gelesis100, a Novel Hydrogel, Significantly Decreases Body 
Weight in Overweight and Obese Subjects : Human Obesity: Targets and Therapies. 
ENDO Meet. at <http://press.endocrine.org/doi/abs/10.1210/endo- 
meetings.2014.OABA.12.SUN-0897> 
11. 
Completed and ongoing trials involving Gelesis100. Search of: gelesis - List Results - 
ClinicalTrials.gov at <https://clinicaltrials.gov/ct2/results?term=gelesis&Search=Search> 
12. 
Proposed Clinical Trials, Gelesis100 and Gelesis200 Pipeline. Gelesis Inc. at 
<http://www.gelesis.com/clinical-trials.php> 

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13. 
Completed and ongoing trials involving Gelesis200. Search of: gelesis - List Results - 
ClinicalTrials.gov at <https://clinicaltrials.gov/ct2/results?term=gelesis&Search=Search> 
14. 
UPDATED OPINION ON THE SAFETY WITH REGARD TO TSE RISKS OF 
GELATINE DERIVED FROM RUMINANT BONES OR HIDES ADOPTED BY THE 
SCIENTIFIC STEERING COMMITTEE AT ITS MEETING OF 6-7 MARCH 2003 
http://ec.europa.eu/food/fs/sc/ssc/out321_en.pdf 
15. 
The Removal and Inactivation of Potential TSE Infectivity by the Different Gelatin 
Manufacturing Processes A Summary of the Results of different Parts of the 
comprehensive GME Study Prepared by the Gelatin Manufacturers of Europe (GME), 
June 2003 http://www.fda.gov/OHRMS/DOCKETS/AC/03/briefing/3969B1_1d.pdf 
16. 
Opinion of the Scientific Panel on Biological Hazards of the European Food Safety 
Authority on the “Quantitative assessment of the human BSE risk posed by gelatine with 
respect to residual BSE risk” Adopted on 18 January 2006 
http://www.efsa.europa.eu/en/efsajournal/doc/312.pdf 
17. 
Timm, D., Willis, H., Thomas, W., Sanders, L., Boileau, T. and Slavin, J., 2011. The use 
of a wireless motility device (SmartPill®) for the measurement of gastrointestinal transit 
time after a dietary fibre intervention. British journal of nutrition, 105(09), pp.1337-
1342.