Clinical trial NCT03352414
Conditions: Ileus
Keywords: HIPEC peritoneal carcinomatosis
Sponsor: University of California, San Diego
Start date: 2018-03-08; Completion date: 2020-04-28
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the ability of alvimopan to reduce the time to return of bowel function in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Half of the participants will receive alvimopan or and half will receive placebo immediately before and for up to seven days after surgery.

Detailed description:
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a surgical procedure to treat cancer that has spread to the lining of the abdominal cavity (peritoneal metastases). It is associated with a prolonged time for return of bowel function after surgery.

Alvimopan is a drug used to speed up the time for return of bowel function after surgery. It works by blocking the opioid receptors in the gastrointestinal tract, which normally slow down bowel function in patients receiving postoperative opioid pain medication. It has not previously been tested in patients undergoing CRS/HIPEC.

Arms: arm 1: alvimopan 12 mg PO twice daily, starting POD 1 for the earlier of 7 days or hospital discharge arm 2: Placebo pill PO twice daily, starting POD 1 for the earlier of 7 days or hospital discharge
Interventions: intervention 1: Alvimopan intervention 2: Placebo
Intervention descriptions: intervention 1: alvimopan pill intervention 2: placebo pill

Protocol documents:
Prot_SAP_000.pdf: 
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The ILEUS Study: A Phase 2 Randomized Controlled Trial 
Investigating ALvimopan for Enhanced Gastrointestinal Recovery after 
CytoredUctive 
Surgery 
and 
Hyperthermic 
Intraperitoneal 
Chemotherapy 
 
 
 
 
PRINCIPAL INVESTIGATOR 
Joel M. Baumgartner, MD, MAS 
Assistant Professor of Surgery 
Division of Surgical Oncology 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive # 
La Jolla, CA 92093 
Phone: (858) 534-1301 
Fax: (858) 312-7010 
E-mail: j1baumgartner@ucsd.edu 
 
 
Study Drug: 
Alvimopan (Entereg®) 
 
IND Number:  
IND exempt 
 
IND Holder Name: 
Merck 
 
Initial Version:  
Dated 5.17.17 
Protocol Amendment 1 v2.0: Dated 06.20.2019 
 


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LIST OF INVESTIGATORS 
 
PRINCIPAL INVESTIGATOR 
Joel M. Baumgartner, MD, MAS 
Associate Professor of Surgery 
Division of Surgical Oncology 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
(858) 534-1301 
(858) 312-7010 
j1baumgartner@ucsd.edu 
 
CO-INVESTIGATORS 
Andrew M. Lowy, MD 
Professor of Surgery 
Division of Surgical Oncology 
University of California, San Diego 
alowy@ucsd.edu 
 
Kaitlyn J. Kelly, MD 
Assistant Professor of Surgery 
Division of Surgical Oncology 
University of California, San Diego 
k6kelly@ucsd.edu 
 
Sonia Ramamoorthy, MD 
Professor of Surgery 
Division of Colorectal Surgery 
University of California, San Diego 
sramamoorthy@ucsd.edu 
 
Jula Veerapong, MD 
Associate Professor of Surgery 
Division of Surgical Oncology 
University of California, San Diego 
jveerapong@ucsd.edu 
 
BIOSTATISTICIAN 
 
Ruifeng Chen MS 
Moores UCSD Cancer Center Biostatistics Shared Resource 
ruc075@ucsd.edu 
 
Karen Messer PHD 
Division of Biostatistics and Bioinformatics 
Department of Family Medicine and Public Health 
University of California, San Diego 
kmesser@ucsd.edu 
 


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Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................................................................... 6 
STUDY SCHEMA ......................................................................................................................................................................... 7 
STUDY SUMMARY ..................................................................................................................................................................... 8 
1.0 
BACKGROUND AND RATIONALE ..................................................................................................................... 9 
1.1 
DISEASE BACKGROUND ............................................................................................................................................... 9 
1.2 
STUDY AGENT ............................................................................................................................................................... 9 
1.3 
RATIONALE ................................................................................................................................................................. 12 
2.0 
STUDY OBJECTIVES ............................................................................................................................................ 12 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................................. 12 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................................... 12 
2.3 
ENDPOINTS ................................................................................................................................................................. 13 
3.0 
PATIENT ELIGIBILITY ....................................................................................................................................... 13 
3.1 
INCLUSION CRITERIA ................................................................................................................................................ 13 
3.2 
EXCLUSION CRITERIA ............................................................................................................................................... 13 
4.0 
TREATMENT PLAN ............................................................................................................................................. 14 
4.1 
TREATMENT DOSAGE AND ADMINISTRATION ...................................................................................................... 14 
4.2 
PERMITTED CONCOMITANT THERAPY .................................................................................................................... 15 
4.3 
PROHIBITED CONCOMITANT THERAPY................................................................................................................... 15 
4.4 
OTHER MODALITIES OR PROCEDURES ................................................................................................................... 15 
4.5 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS................................................................................. 15 
4.6 
DURATION OF THERAPY ........................................................................................................................................... 15 
4.7 
DURATION OF FOLLOW UP ...................................................................................................................................... 16 
5.0 
STUDY PROCEDURES ......................................................................................................................................... 16 
5.1 
SCHEDULE OF EVENTS .............................................................................................................................................. 16 
5.2 
SCREENING/BASELINE PROCEDURES .................................................................................................................... 17 
5.3 
PROCEDURES DURING TREATMENT ....................................................................................................................... 18 
5.4 
FOLLOW-UP PROCEDURES ....................................................................................................................................... 18 
5.5 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY ....................................................................... 18 
6.0 
MEASUREMENT OF EFFECT ..................................................................................................................................... 19 
6.1 
EFFECT ON RETURN OF BOWEL FUNCTION .......................................................................................................... 19 
6.2 
SAFETY/TOLERABILITY ............................................................................................................................................ 19 
7.0 
ADVERSE EVENTS ............................................................................................................................................... 19 
7.1 
ADVERSE EVENT MONITORING ............................................................................................................................... 19 
7.2 
SEVERITY .................................................................................................................................................................... 20 
7.3 
SERIOUSNESS .............................................................................................................................................................. 20 
7.4 
RELATIONSHIP ........................................................................................................................................................... 21 
7.5 
PRIOR EXPERIENCE ................................................................................................................................................... 21 
7.6 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS .......................................................................................... 21 
8.0 
AGENT INFORMATION ...................................................................................................................................... 22 
8.1 
AGENT ALVIMOPAN .................................................................................................................................................. 22 
9.0 
STATISTICAL CONSIDERATIONS .................................................................................................................. 23 
9.1 
STUDY DESIGN/STUDY ENDPOINTS ....................................................................................................................... 23 
9.2 
SAMPLE SIZE AND ACCRUAL ................................................................................................................................. 233 
9.3 
PROTOCOL DEVIATIONS, DATA BLIND REVIEW, AND UNBLINDING .................................................................... 24 
9.4 
ANALYSIS POPULATIONS .......................................................................................................................................... 24 
9.5 
ANALYSES OF THE PRIMARY ENDPOINT .............................................................................................................. 255 
9.6 
ANALYSES OF SECONDARY ENDPOINTS .................................................................................................................. 25 
9.7 
EXPLORATORY ANALYSES ......................................................................................................................................... 25 
9.8 
INTERIM ANALYSIS .................................................................................................................................................... 25 
9.9 
SAFETY ANALYSIS................................................................................................................................................... 266 
 
10.0 
STUDY MANAGEMENT ...................................................................................................................................... 26 
10.1 
CONFLICT OF INTEREST ............................................................................................................................................ 26 
10.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ................................................................. 26 


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10.3 
SUBJECT DATA PROTECTION ................................................................................................................................... 26 
10.4 
DATA AND SAFETY MONITORING/AUDITING ....................................................................................................... 27 
10.5 
ADHERENCE TO THE PROTOCOL ............................................................................................................................. 27 
10.6 
AMENDMENTS TO THE PROTOCOL ......................................................................................................................... 28 
10.7 
RECORD RETENTION................................................................................................................................................. 28 
10.8 
OBLIGATIONS OF INVESTIGATORS .......................................................................................................................... 28 
11.0 
REFERENCES ......................................................................................................................................................... 29 
12.0 
APPENDICES ....................................................................................................................................................... 300 
 APPENDIX A. ECOG PERFORMANCE STATUS .................................................................................................................... 300 
 APPENDIX B. POSTOPERATIVE BOWEL FUNCTION DIARY ............................................................................................... 311 
 APPENDIX C. DIVISION OF BIOSTATISTICS AND BIOINFORMATICS REPORT ....... ERROR! BOOKMARK NOT DEFINED.2 
 APPENDIX D. UCSD MOORES CANCER CENTER DATA MONITORING PLAN ...................................................................... 39 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BM 
Bowel Movement 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CRS 
Cytoreductive Surgery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
GI 
Gastrointestinal 
HIPEC 
Hyperthermic Intraperitoneal Chemotherapy  
HRPP 
Human Research Protections Program 
IRB 
Institutional Review Board 
LN 
Lymph Node 
NCI 
National Cancer Institute 
OS 
Overall Survival 
PC 
Peritoneal Carcinomatosis 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
Per Os (By Mouth) 
POD 
Postoperative Day 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event 
UPR 
Unanticipated Problems involving Risk to subjects or 
others 
 
 


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STUDY SCHEMA 
 
NOTE:  Randomized Patients who do not undergo CRS/HIPEC will be considered 
screen failures after randomization. 
 


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STUDY SUMMARY 
Title 
The ILEUS Study: A Phase 2 Randomized Controlled Trial Investigating 
Alvimopan for Enhanced Gastrointestinal Recovery after Cytoreductive 
Surgery and Hyperthermic Intraperitoneal Chemotherapy 
Short Title 
Phase 2 Randomized Controlled Trial of Alvimopan after CRS/HIPEC 
Phase 
II 
Methodology 
Double-blind, randomized, placebo-controlled trial 
Study Duration 
2 years 
Study Center(s) 
Single-center (UCSD) 
Objectives 
Primary Endpoint 
 
Time to recovery of upper and lower GI function (GI-2), as 
measured by the later of the following 2 events: time that the 
patient first tolerates solid food and time that the patient first 
passes bowel movement 
Secondary Endpoints 
 
Proportion of prolonged ileus (> 7 days) 
 
Time to return of bowel function components: time to first flatus, 
time to first bowel movement, time to tolerance of solid food 
 
Time to hospital discharge order written 
 
Adverse events 
 
Subgroup analyses: number of anastomoses, number of visceral 
resections, epidural/no epidural, etc. 
Number of Subjects 
128 
Diagnosis and Main 
Inclusion Criteria 
Eligible participants are those who undergo open cytoreductive surgery 
(CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) 
Study Product(s), Dose, 
Route, Regimen 
Alvimopan 12 mg, by mouth, 30 minutes to 5 hours preoperatively, then 
POD 1 by mouth twice for the earlier of 7 days or hospital discharge 
(maximum 15 doses) 
Duration of administration 
8 days (maximum) 
Reference therapy 
Placebo 
Statistical Methodology 
Based upon a sample size of n=64 patients per group (128 total), this 
study has 82% power to detect a HR of 1.59 which approximately 
corresponds to an improvement in the median primary endpoint (GI-2) 
from 9 days to 5.7 days, with a single-sided alpha of 0.05, and 5% 
withdrawal rate. 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
The peritoneum is a common site of metastasis, with approximately 55,000 new cases of 
peritoneal metastases occurring annually in the US.1 Tumors that commonly metastasize 
to the peritoneum include gastrointestinal (colorectal, small intestine, appendix, gastric, 
pancreatic, gallbladder, liver), gynecologic (ovarian), and primary peritoneal (peritoneal 
mesothelioma, primary peritoneal serous carcinoma) malignancies. Tumor histology and 
extent of disease are the primary determinants of long-term outcome, but patients with 
peritoneal metastases typically have a poor prognosis – 16 months medial survival from 
colorectal cancer.2 Treatment options for peritoneal metastases are limited as systemic 
chemotherapy has poor penetration of the peritoneum and many peritoneal tumors are 
hypovascular and can be surrounded by a viscous layer of mucin.3 The fact that the 
peritoneal cavity may represent the only site of metastatic disease in selected patients has 
prompted the utilization of aggressive surgical resection (cytoreduction) and hyperthermic 
intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases.4 HIPEC 
is a method of delivering high doses of cytotoxic chemotherapy directly the peritoneal 
cavity with limited systemic toxicity, and is typically performed concurrently with surgical 
resection of visible intraperitoneal disease (cytoreductive surgery, CRS).5 The combined 
procedure (CRS/HIPEC) generally is performed through a large midline incision and 
includes extensive lysis of adhesions, resection of all visible peritoneal metastases, often 
with multivisceral resections including bowel resections and possibly multiple 
anastomoses, and requires a mean of eight hours of operative time. Large case series 
have estimated CRS/HIPEC doubles the median survival verses systemic chemotherapy 
alone in certain settings (colorectal cancer, appendiceal cancer and peritoneal 
mesothelioma).6-8 Perioperative complications of this extensive surgery are considerable, 
with a 1-2% risk of mortality and 16% risk of severe morbidity.9 This procedure remains 
highly specialized and is mostly performed in a limited number of high-volume centers in 
the US, which include UCSD. Approximately 60-70 CRS/HIPEC procedures are 
performed annually at UCSD. 
 
The median length of stay after CRS/HIPEC is 10 days at our institution. A majority of the 
hospital stay is comprised of awaiting return of bowel function. The first flatus or bowel 
movement does not typically occur until postoperative day 4-5, and in 13% of patients it 
takes longer than 7 days.9 This is despite the fact that all patients undergo enhanced 
recovery pathways; including early mobilization, foley catheter removal as soon as 
feasible, and early advancement to liquid diet. Although attempts are made to minimize 
narcotic use after CRS/HIPEC - including use of epidural catheters and opioid-sparing 
medications (such as ketorolac and lidocaine patch) – all patients still require 
postoperative narcotics, which likely contributes to the prolonged ileus. 
1.2 
Study Agent 
 
Alvimopan is an oral peripherally-acting mu opioid receptor antagonist, with limited ability 
to cross the blood-brain barrier. There have been eight randomized-controlled trials 
published in English language journals documenting the safety and efficacy of alvimopan 
for postoperative ileus. 
 
From a safety standpoint, a meta-analysis of all randomized controlled trials found the 


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most common adverse events with alvimopan included nausea, vomiting, constipation, 
flatulence, distension, headache, and pruritis (all greater than 10% in incidence).10 Rates 
of all common AEs from this meta-analysis is listed in the table below. 
 
Adverse Event 
Rate (%)1 
Nausea 
56.1 
 Vomiting 
18.3 
Constipation 
15.4 
Flatulance 
14.5 
Distension 
12.2 
Headache 
11.2 
Hypotension 
8.5 
Hypertension 
9.4 
Pyrexia 
9.9 
Pruritis 
11.7 
Tachycardia 
7.1 
1Among patients receiving 12 
mg alvimopan dose 
 
It is worth noting that most of the GI-related adverse events are also symptoms of 
postoperative ileus, making attribution to alvimopan imprecise. Furthermore, many AEs 
were significantly lower in the alvimopan groups than the placebo groups (nausea, 
vomiting, constipation, and pyrexia). The remaining common AEs were no different in the 
alvimopan and placebo groups. 
 
Serious adverse events were reported in 3-25.7% of participants in RCTs, and included 
infection, anastomotic leak, dehiscence, pain, postoperative ileus, dehydration and small 
bowel obstruction.11-16 In all trials reporting SAEs, the rate in the alvimopan group was 
equal to or less than in the placebo group, and no trials reported deaths attributed to 
alvimopan. 
 
One study investigating 0.5 mg twice daily alvimopan for 12 months for the treatment of 
opioid-induced bowel dysfunction found a higher incidence of myocardial infarction in the 
alvimopan group.17 The events occurred 1-4 months after the start of treatment, and the 
increased risk of MI has not been observed in other studies with shorter duration (7 days) 
of alvimopan in postoperative patients.13 A large matched-cohort study using a national 
inpatient database including 7050 patients found a lower risk of cardiovascular morbidity 
in the alvimopan cohort than in the control cohort (19.4% vs. 24.0%, p = 0.0001).18 
 
Alvimopan has been found to decrease the time to return of bowel function and time to 
discharge in multiple randomized controlled trials, as seen in the table below. 
 


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A meta-analysis incorporating the studies listed above has been completed.10 The pooled 
Study 
Year 
Procedures 
Intervention 
N 
Endpoint(s)1 
Taguchi et al.19 
2001 
15 LBR 
63 TAH 
Alv. 1 mg 
26 
Time to flatus: RR 1.2 (p=0.59) 
Time to BM: RR 1.2 (p=0.69) 
Time to D/C: RR 1.2 (p=0.48) 
Alv. 6 mg 
26 
Time to flatus: RR 2.5 (p=0.004) 
Time to BM: RR 2.9 (p=0.01) 
Time to D/C: RR 2.4 (p=0.003) 
Placebo 
26 
 
Wolff et al.16 
2004 
395 LBR  
56 SBR 
18 TAH 
Alv. 6 mg 
155 
Time to GI-3: HR 1.28 (p<0.05) 
Time to GI-2: HR 1.38 (p=0.013) 
Time to D/C: HR 1.25 (p=0.070) 
Alv. 12 mg 
165 
Time to GI-3: HR 1.54 (p<0.001) 
Time to GI-2: HR 1.67 (p<0.001) 
Time to D/C: HR 1.42 (p=0.003) 
Placebo 
149 
 
Delaney et al.20 
2005 
303 LBR 
129 TAH 
Alv. 6 mg 
150 
Time to GI-3: HR 1.45 (p=0.003) 
Time to GI-2: HR 1.46 (p=0.007) 
Time to D/C: HR 1.50 (p<0.001) 
Alv. 12 mg 
146 
Time to GI-3: HR 1.28 (p=0.059) 
Time to GI-2: HR 1.31 (p=0.057) 
Time to D/C: HR 1.18 (p=0.17) 
Placebo 
153 
 
Herzog et al.12 
2006 
519 TAH 
Alv. 12 mg 
413 
Time to GI-3: HR 1.16 (p=0.176) 
Time to GI-2: HR 2.23 (p<0.001) 
Time to D/C: HR 1.13 (p=0.268) 
Placebo 
106 
 
Viscusi et al.15 
2006 
437 LBR/SBR 
200 TAH 
Alv. 6 mg 
220 
Time to GI-3: HR 1.24 (p=0.037)2 
Time to GI-2: HR 1.40 (p=0.005)2 
Time to D/C: HR 1.36 (p=0.002)2 
Alv. 12 mg 
221 
Time to GI-3: HR 1.26 (p=0.028)2 
Time to GI-2: HR 1.36 (p=0.012)2 
Time to D/C: HR 1.30 (p=0.010)2 
Placebo 
224 
 
Buchler et al.11 
2008 
705 LBR/SBR 
Alv. 6 mg 
237 
Time to GI-3: 84.2 hrs (p=0.042) 
Time to GI-2: 95.2 hrs (p<0.001) 
Time to D/C: HR 1.08 (p=0.13) 
Alv. 12 mg 
239 
Time to GI-3: 87.8 hrs (p=0.20) 
Time to GI-2: 98.8 hrs (p=0.008) 
Time to D/C: HR 1.07 (p=0.49) 
Placebo 
229 
Time to GI-3: 92.6 hrs 
Time to GI-2: 109.5 hrs 
Ludwig et al.14 
2008 
654 LBR/SBR 
Alv. 12 mg 
329 
Time to GI-3: HR 1.5 (p<0.001) 
Time to GI-2: HR 1.5 (p<0.001) 
Time to D/C: HR 1.4 (p<0.001) 
Placebo 
325 
 
Lee et al.13 
2014 
280 RC 
Alv. 12 mg 
143 
Time to GI-2: HR 1.8 (p<0.0001) 
Time to D/C: HR 1.7 (p=0.0002) 
Placebo 
137 
 
LBR, large bowel resection (colectomy); SBR, small bowel resection; TAH, total abdominal 
hysterectomy; Alv., alvimopan; GI-3, solid food + BM/flatus; GI-2, solid food + BM; RR, relative risk; 
BM, bowel movement; D/C, discharge; HR, hazard ratio; RC, radical cystectomy 
1Versus Placebo 
2adjusted for sex and surgical duration 


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analysis revealed a significant reduction in time to GI-2 bowel function (6 mg, HR = 1.5, 
p<0.00001; 12 mg, HR = 1.59, p<0.00001), BM (6 mg, HR = 1.54, p<0.00001; 12 mg, HR 
1.74, p=0.0002), and time to discharge order written (6 mg, HR = 1.37, p< 0.00001; 12 
mg, HR = 1.34, p<0.00001) versus placebo. 
 
From a pharmacokinetic standpoint, alvimopan is metabolized by the intestinal flora and 
is primarily excreted in the bile, secondarily in the feces, and 35% in the urine. Its half-life 
is 10-17 hours, although this is longer in patients with mild-moderate hepatic impairment 
(Child’s Pugh Class A and B) and severe renal impairment. P450 drug-interactions… 
 
Alvimopan is FDA-approved for short-term, in-hospital use in patients at risk for 
postoperative ileus, particularly those following bowel resection with primary anastomosis. 
However, due to potential increased cardiovascular risks with long-term use, distribution 
of the drug is restricted to short-term use (maximum 15 doses) under a Risk Evaluation 
and Mitigation Strategy (REMS), which includes only institutions enrolled in the ENTEREG 
Access Support and Education (E.A.S.E.) Program, of which UCSD is one. The current 
FDA-approved dose is 12 mg orally 30 minutes to 5 hours prior to surgery, followed by 12 
mg orally twice daily beginning the day after surgery for up to seven days or until hospital 
discharge, with a maximum of 15 doses.17 
1.3 
Rationale 
 
In an analysis of 50 consecutive CRS/HIPEC procedures performed at UCSD the median 
time to return of bowel function, as defined in prior phase III clinical trials with alvimopan 
(later of time to first bowel movement or tolerance of solid diet, GI-2), was 9 days. No 
studies have been published investigating the use of alvimopan after CRS/HIPEC. The 
current proposal is being performed to investigate the efficacy of alvimopan on the time to 
return of bowel function in patients undergoing CRS/HIPEC.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective   
To determine the efficacy of alvimopan to reduce postoperative ileus in patients 
undergoing CRS/HIPEC, as measured by the composite of time to recovery of upper and 
lower GI function, as defined by the later of the following two events (GI-2): 
 
Time that the patient first tolerates solid food 
 
Time that the patient first passes a bowel movement 
 
2.2 
Secondary Objectives  
1. To determine the proportion of prolonged ileus (> 7 days) in each group 
2. To determine the time to return of bowel function components in each group: time 
to first flatus, time to first bowel movement, time to tolerance of solid food 
3. To determine the time to hospital discharge order written in each group 
4. To measure the adverse event rate in each group 
5. To perform subgroup analyses on each group: 0 vs. 1 or greater anastomoses, 0 
vs. 1 or greater visceral resection, high vs. low amount of postoperative narcotic 
use (above or below the median total postoperative morphine equivalent dose of 
narcotics), epidural vs. no epidural 


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2.3 
Endpoints 
 
Primary Endpoint: 
 
The time to return of upper and lower GI function (GI-2) will be measured as follows: 
 
Time measured in hours from the time leaving the operating room to the later 
of the following two events: 
i. Time that the patient first tolerates solid food 
ii. Time that the patient first passes a bowel movement 
 
If upper and lower GI function have not occurred by the time of discharge, the 
patient will be censored. 
 
Secondary Endpoints: 
 
1. Prolonged ileus will be measured by the proportion of patients who do not pass 
flatus or bowel movement greater than 7 days from the time of surgery 
2. The time to return of bowel function components will be measured in hours 
from the time leaving the operating room until: 
o The time to first flatus 
o The time to first bowel movement 
o The time to tolerance of solid food 
3. The time to hospital discharge order written will be measured in hours from the 
time leaving the operating room 
4. Adverse events will be measured using CTCAEv3 criteria. 
5. Primary and secondary endpoints will be measured in each subgroup 
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
 
1. Ability to understand and the willingness to sign a written informed consent. 
 
2. Scheduled to undergo open (non-minimally invasive) CRS/HIPEC. 
3. Scheduled to receive postoperative pain management with intravenous opioids. 
 
4. Age > 18 years. 
 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2. 
6. Women of child-bearing potential with negative pregnancy test prior to initiating study 
drug dosing. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation.   
 


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1. Greater than 7 days of consecutive opioid use immediately prior to scheduled surgery. 
 
2. Child-Pugh Class C hepatic impairment. 
 
3. End-stage renal disease (GFR < 15 mL/min/1.73 m2 and/or on peritoneal dialysis or 
hemodialysis). 
 
4. Complete mechanical bowel obstruction. 
 
5. Contraindication or inability to tolerate oral medication postoperatively. 
 
6. Presence of gastrointestinal ostomy after CRS/HIPEC. 
 
7. Pancreatic or gastric anastomosis performed during CRS/HIPEC. 
 
8. History of allergic reactions or hypersensitivity attributed to compounds of similar 
chemical or biologic composition as alvimopan at the treating investigators discretion. 
 
9. Severe or uncontrolled medical disorder that would, in the investigator’s opinion, 
impair ability to receive study treatment (i.e. uncontrolled diabetes, chronic renal 
disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric 
illness/social situations that would limit compliance with study requirements). 
 
10. History of myocardial infarction in the 12 months prior to scheduled surgery. 
 
11. Pregnant or nursing. 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
Participants will receive alvimopan (or placebo) preoperatively, then every day after 
surgery until hospital discharge or for a maximum of 7 days.  
 
Twelve (12) mg of alvimopan (or placebo) will be given by mouth in the preoperative 
holding area 30 minutes to 5 hours prior to surgery. The treatment with continue at a dose 
of 12 mg BID by mouth starting on postoperative day (POD) 1 for  the earlier of seven 
days or hospital discharge, as defined by GI-2 (later of time of tolerance of solid diet or 
bowel movement), for a maximum of 15 total doses. In patients with a gastrostomy tube 
in place, this will be clamped for 1 hour after administration of the study drug per standard 
of care for oral medication administration in a patient with a gastrostomy tube. 
Documentation of gastrostomy tube clamping after study drug administration will be made 
in the medical record by nurses according to the standard of care nursing policies and 
usual practices of each nursing unit. The study drug (alvimopan or placebo) will be 
administered in the hospital by the patient’s nurse. 
 
 
 
 
 


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Agent 
 
Dose 
 
Route 
 
Schedule 
Alvimopan 
12 mg 
PO 
30 minutes – 5 hours prior to surgery, 
then twice daily (BID) starting POD 1 
for a maximum of 7 days or until 
hospital discharge 
Placebo 
NA 
PO 
30 minutes – 5 hours prior to surgery, 
then twice daily (BID) starting POD 1 
for a maximum of 7 days or until 
hospital discharge 
 
 
4.2 
Permitted concomitant therapy 
 
Medications used to treat typical postoperative symptoms are permitted, as clinically 
indicated. This includes, but is not limited to, analgesics (local, regional and systemic; 
narcotics, non-steroidals, and local anesthetics), antiemetics, and anti-pruritics. These are 
all given per standard of care, and at the discretion of the treating clinicians.  
4.3 
Prohibited concomitant therapy 
 
Participants with greater than seven days of consecutive opioid use immediately prior to 
the date of surgery (CRS/HIPEC) are ineligible for the study. Any other use of preoperative 
opioids may be used with caution, at the investigator’s discretion. 
4.4 
Other Modalities or Procedures 
 
After CRS/HIPEC, participants will undergo a standardized postoperative care pathway, 
which is the standard of care at our institution. This includes use of epidural analgesia, 
early mobilization and ambulation on POD 1-2, liquid diet on POD 1-3, early removal of 
the foley catheter, and clamping trials of the gastric tube (if present) once bowel function 
returns. 
4.5 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the NCI Common 
Toxicity Criteria for Adverse Events (CTCAE), version 4.03. Dose adjustments are not 
applicable in this study and will not be made. Participants who have emesis within one 
hour after taking the study medication or have visible study medication within the gastric 
tube effluent or who otherwise miss a dose for any other reason, will not be re-dosed, and 
they will resume standard dosing at the next scheduled dose. Participants or providers 
may decide to cease the study medication before all doses have been administered per 
the criteria listed in Section 4.6. 
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for a 
maximum of seven days or less if one of the following occurs: 
 
Participant is discharged home prior to seven days after surgery 


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 
Inter-current illness that prevents further administration of treatment (i.e. 
participant is unable to tolerate oral medication with gastric tube clamped or the 
participant is intubated and cannot take oral medication). Participants may resume 
study drug administration once it can be tolerated without “make-up” doses given 
(i.e. no study drug will be given beyond postoperative day seven). If more than 
50% of the doses are missed, then the participant will be withdrawn from the study 
(see Section 5.5). 
 
Unacceptable adverse event(s) 
 
Participant decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
4.7 
Duration of Follow Up 
 
Participants will be monitored daily during their postoperative stay by nurses and 
physicians, per standard of care after CRS/HIPEC. Typical length of stay after this 
procedure is 10 days. After discharge, participants will be followed (by postoperative visit 
or telephone call) for 30 days from the date of surgery for adverse events. 
 
5.0 
STUDY PROCEDURES 
5.1 
Schedule of Events 
 
 
 
Screening 
(POD -30 to -1) 
Preoperative Day 
(POD -3 to -1) 
Postoperative 
Admission 
(POD 1 – Date 
of Discharge) 
Postoperative Clinic 
Visit ± 5 days 
Follow–up visit 
(POD > 30)1 
Assessment 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
Medical history  
X 
 
 
 
 
Physical exam, 
including vitals2 
X 
 
 
 
 
Demographic 
X 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
ECOG 
X 
 
 
 
 
Adverse events3 
 
 
X 
X 
X 
Concomitant 
medications4 
X 
X 
 
 
 
Confirmation that 
CRS/HIPEC 
performed and 
eligibility criteria 
still met5 
 
 
X 
 
 
Assessment of 
return of bowel 
function6 
 
 
X 
 
 
Alvimopan 
administration7 
 
X 
X 
 
 
Urine Pregnancy 
Test8 
X 
 
 
 
 
1By standard of care clinic visit, or telephone call if no clinic visit at this time (> 30 days 


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after surgery) 
2 Physical exam and vital signs: consist of temperature, heart rate, respiration and blood 
pressure. 
3Adverse events: to be collected once patient signs consent form. See Section 7 for more 
information. 
4Concomitant medications: to be collected for any subject being followed for a Serious 
Adverse Event (SAE) occurring up to 30 days after last dose of study drug until resolution 
of the SAE. (see Section 7). 
5Confirmed on POD 1, prior to administration of first postoperative dose of study 
medication. 
6Includes recording the date and hour of the time of first flatus, bowel movement, and 
tolerance of solid food (per participant diary); as well as the date/hour of leaving the 
operating room  
7Alvimopan administration: see section 8.1 for instructions on administration.  
8Pregnancy test: A serum or urine pregnancy test is required for all females of childbearing 
potential. 
5.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
The screening procedures include: 
5.2.1 Informed Consent 
5.2.2 Medical history 
Complete medical, surgical and oncology history as well as history of infections 
will be obtained at screening. Any changes from Screening (e.g. worsening 
severity or abnormal findings) are considered to be adverse events (AEs). 
5.2.3 Demographics 
 Demographic information to be collected at screening will include date of birth, 
gender, race, and ethnicity. 
5.2.4 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure subject qualification 
for study entry. 
5.2.5 Review previous and concomitant medications 
All prior medication taken by the subject within 4 weeks before starting the study 
is to be recorded. Concomitant medications taken by the subject during the study 
are to be recorded up until 30-days after last study dose. If a reportable adverse 
event (see Section 7) occurs within 30-days after last study dose, recording of 
concomitant medications should continue until resolution of the adverse event. 
5.2.6 Physical exam including vital signs, height and weight 
Physical exam will include collection of vital signs (temperature, pulse, 
respirations, blood pressure), height, weight. 
5.2.7 ECOG performance status 


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ECOG performance status will be evaluated prior to study entry. 
5.2.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See 
Section 7 for Adverse Event monitoring and reporting. 
5.2.9 Pregnancy test (for females of child bearing potential) 
See section 3.1 for definition.  
5.3 
Procedures During Treatment 
Treatment will be administered in the hospital in the postoperative recovery period. There 
are no additional procedures or visits performed during the treatment period. However, 
there are some additional data collected during this period, as follows: 
 
5.3.1 Date and Time of Completion of Operation 
 To be determined from the electronic medical record (Time is the “Out of 
Room” time recorded in the chart). 
5.3.2 Total Opioid Consumption 
 To be measured in morphine equivalents, calculated after discharge.  
5.3.3 Assessment of Bowel Function 
 To be recorded in patient postoperative bowel function diary (Appendix B) 
 An audit of at least 10% of all diaries will be undertaken to compare the patient 
recorded date of first recorded bowel movement with that from the electronic 
medical record. 
5.4 
Follow-up Procedures 
Patients will be followed for at least 30 days after surgery. Follow-up will consist of 
postoperative visit or telephone call (in situations where there is no postoperative visit > 
30 days from surgery). 
5.5 
Removal of Subjects from Study Treatment and Study 
Patients can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
5.5.1 Patient completed study treatment; 
5.5.2 Patient voluntarily withdraws from treatment (follow-up permitted);  
5.5.3 Patient withdraws consent (termination of treatment and follow-up); 
5.5.4 Patient is unable to comply with protocol requirements (i.e. the patient is unable to 
tolerate or misses more than 50% of the study drug doses); 
5.5.5 Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
5.5.7 Patient becomes pregnant (pregnancy to be reported along same timelines as a 


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serious adverse event); 
5.5.8 Lost to follow-up.  
If a research subject cannot be located to document adverse events after a period 
of at 60 days after surgery, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during this period will be documented.  
 
6.0 
Measurement of Effect 
6.1 
Effect on Return of Bowel Function 
Time to first flatus, time to first BM, time to tolerance of solid diet will all be measured as 
endpoints for return of bowel function.  
 
Time to flatus is a more subjective and unreliable endpoint for return of lower bowel 
function versus time to first BM. More recent alvimopan studies have used GI-2 rather 
than GI-3 endpoints, which consider BM rather than flatus as evidence of lower bowel 
function. Thus, the current study will use the GI-2 definition, which is the time, in hours, 
from leaving the operating room to the later of the time of tolerating solid food and having 
a BM. Tolerance of solid food is defined as the time of solid food ingestion without 
significant nausea or vomiting for 4 hours. The precise date and hour of first flatus, first 
BM, and first tolerance of solid diet will be recorded in a participant diary (Appendix B). 
These dates and times will be corroborated and audited by reviewing the inpatient medical 
record (in > 10% of participants). 
 
6.1.1 Prolonged Ileus 
Participants without flatus or BM for more than seven days after surgery, are 
considered to have a prolonged ileus. 
6.1.2 Time to Hospital Discharge 
The time, in hours, from leaving the operating room to when the discharge order 
is signed. 
6.2 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. 
The study will use the CTCAE version 4.03 (http://ctep.cancer.gov/reporting/ctc.html) for 
reporting of adverse events. 
 
7.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
experimental intervention, whether or not related to the intervention.  
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 


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trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. Additionally, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
 
duration (start and end dates) 
 
severity (grade) 
 
seriousness 
 
relationship to study agent 
 
action taken (i.e., none, study agent modification, medical intervention) 
 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
7.2 
Severity 
All adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
7.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
If death results from (progression of) the disease, the disease should be reported 
as event (SAE) itself. 
2. Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe). 


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3. Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
7.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.5 
Prior experience 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in the current known adverse events listed in the agent clinical experience section 
of this protocol  or the current Product Label. 
7.6 
Reporting Requirements for Adverse Events 
7.6.1 Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug.  
 
The UCSD Human Research Protections Program (HRPP) must be notified 
within 10 business days of “any unanticipated problems involving risk to 
subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, 


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updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 
7.6.2 Routine Reporting Requirements 
 
The UCSD HRPP will be notified of any adverse events that are not 
unanticipated problems involving risk to subjects or others (non-UPRs) at the 
time of the annual Continuing Review.  
 
8.0 
AGENT INFORMATION 
8.1 
Agent Alvimopan 
Please refer to Prescribing Information for more comprehensive information. 
 
Other names for the drug: Entereg® 
 
Mechanism of action (or Product description):   
 
Alvimopan is a peripherally acting mu-opioid receptor antagonist, blocking the peripheral 
effects of opioids on gastrointestinal motility and secretion but not the central analgesic 
effects of mu-opioid agonists.  
 
Availability:  
 
Alvimopan (and placebo) will be provided by the sponsor free of charge. 
 
How supplied:  
 
Alvimopan will be supplied as 12 mg oral capsules by the sponsor. Unmatched placebo 
capsules will also be supplied, and alvimopan and placebo will be over-encapsulated by 
UCSD pharmacy to maintain double-blinding. 
 
Storage and stability:  
 
Alvimopan capsules may be stored at controlled room temperature (77˚ F) with excursions 
between 59˚ and 86˚ F. 
 
Preparation:  
 
Alvimopan and placebo will be over-encapsulated by USCD pharmacy prior to 
administration. 
 
 
Route of administration for this study:  
 


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Study drug (alvimopan or placebo) will be administered orally. If a gastric or nasogastric 
tube is present, it will be clamped for one hour after oral administration of the study drug. 
 
Side effects:  
 
The most common adverse events of alvimopan include the following: 
 
Hypokalemia (10%) 
 
Dyspepsia (2-7%) 
 
Anemia (5%) 
 
Urinary retention (3%) 
 
Back pain (3%) 
 
Myocardial infarction (rate unknown, higher rate than placebo in study with 
12 month use of alvimopan) 
 
8.1.1 Return and Retention of Study Drug 
Remaining drug is to be destroyed, according to Moores Cancer Center Investigational 
Drug Services destruction policy. 
 
8.1.2 Subject Compliance 
Subject compliance of study drug will be maintained by directly-observed administration 
in the hospital. 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
 
The proposed study is a double blind prospective, randomized controlled phase 2 trial.  
 
Subjects will be assigned 1:1 to either placebo or alvimopan groups using a permuted 
block randomization of block size 4. The block and package in the R statistics software 
will be used to generate group assignments.  The randomization file will be given to the 
investigational Pharmacy which will carry out the randomization. Patients who do not 
undergo CRS/HIPEC during surgery are considered screen failures after randomization. 
Their randomization IDs will not be discarded and will be passed to the next available 
subjects to keep the 1:1 ratio. 
 
9.2 
Sample Size and Accrual 
 
Our sample size calculation is based on detecting a difference in distributions of times 
until GI-2 between groups. Assuming a similar hazard ratio between the Alvimopan 12 mg 
and placebo groups as Xu et. al. (HR = 1.59, which approximately corresponds to an 
improvement in the median primary endpoint (GI-2) from 9 days to 5.7 days), a log-rank 
test for a difference in distributions of times until GI-2 is met will have 80% power at the 
one sided 0.05 significance level with a total sample size of n = 122. (Note that this does 
not adjust for a reduction in power due to the interim analysis.) Accounting for a 5% drop-
out rate, the total enrolled sample size is 128 participants.  
 


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Approximately 60-70 CRS/HIPEC procedures are performed at UCSD annually. Accrual 
of 128 participants could occur over 2-3 years.  Annual target accrual will be 40 
participants per year. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
8 
5 
13 
Not Hispanic or Latino 
63 
52 
115 
Ethnic Category: Total of all subjects 
71 
57 
 
128 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
8 
5 
13 
Black or African American 
2  
1 
3 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
60 
50 
110 
Racial Category: Total of all subjects 
71 
 
57 
 
128 
 
9.3 
Protocol Deviations, Data Blind Review, and Unblinding 
Classification of deviations from the protocol as minor or major, and decisions regarding 
exclusion of patients and/or patient data from the statistical analyses, will be decided on 
a case-by-case basis without knowledge of the treatment assigned and before the 
database lock (Data Blind Review). After database lock, the responsible statistician will 
request the treatment codes, the study will be unblinded, and the statistical analysis will 
be conducted. 
 
9.4 
Analysis Populations 
Analysis populations are defined as follows: 
 The Safety population will include all randomized patients who took at least 
one dose of the study medication, including screen failures after randomization 
and subjects withdrawn from the study. 
 The modified Intent-to-Treat (mITT) population will include all randomized patients 
who took at least one dose of the study medication and who have at least 
one efficacy evaluation following baseline. 
 The Per Protocol (PP) population will include all mITT patients who: 
- took assigned medication during the treatment period (who received at least 50% 
of the study drug), and 
- did not have any major protocol deviations. 
 
The primary population for all efficacy analyses is the mITT population, without imputation 
for missing values. Sensitivity analyses will also be performed using the PP populations 


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for efficacy endpoints, and using the mITT population with multiple imputation. The safety 
population will be used for analyses of safety endpoints. 
 
 
9.5 
Analyses of the primary endpoint 
 
For our primary endpoint, we will use a log-rank test at 5% level to compare the 
distributions of times until recovery (GI-2) between groups.  
 
9.6 
Analyses of secondary endpoints 
 
Log-rank test will also be used to compare  the time to return of bowel function outcome. 
A Cox proportional hazards model will also be considered for this endpoint, controlling 
for potential confounders such as age and gender. The proportion of patients with 
prolonged ileus will be compared between groups with a Pearson’s chi square test . A 
logistic regression model will be used to assess the association between prolonged ileus 
and treatment, controlling for potential confounders. We will compare the time to 
discharge between groups with a two-sample t-test, and consider a linear regression to 
control for potential confounders, including opioid use (i.e. total morphine equivalents) 
+/- epidural placement, bowel resection, and other complications. 
.    
 
9.7 
Exploratory analyses  
 
For any prespecified subgroup analyses, we will include a binary covariate indicating 
subgroup membership in each of the regression frameworks described. We will also fit 
models with interactions between each subgroup and treatment group. Descriptive 
statistics (mean, standard deviation, counts, and percentages) and plots will be produced 
for all demographic, safety, and outcome variables. All analyses will be conducted using 
the latest version of R (R Foundation for Statistical Computing, Vienna, Austria. 
http://www.R-project.org/). 
 
9.8 
Interim analysis 
 
When the 64th subject has reached the primary endpoint (or been censored because of 
loss to follow-up), a futility analysis will be performed.  
 
The futility analysis will use a stochastic curtailment approach (Crowley and Anhkerst, 
Clinical Trials in Oncology, 2nd ed p 233), as computed in PASS 14.0.6.  If at the interim 
analysis, the conditional power (i.e. the probability that the study will go on to reject the 
null hypothesis, given the observed data at the interim analysis) is below 20%, the study 
will stop. This futility analysis will be carried out by the statisticians at the MCC 
Biostatistics Shared Resource, using a one-sided logrank test at the 5% significance 
level. 


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9.9 
Safety Analysis 
 
Safety will be assessed by summarizing and analyzing AEs during the intervention 
period. Adverse events will be coded according to established Medical Dictionary for 
Regulatory Activities (MedDRA) terms and summarized by MedDRA System Organ Class 
and Preferred Term. Treatment-emergent adverse events (TEAE) will be defined as 
events that first occurred or worsened on or after randomization. 
 
An overview of AEs, including the number and percentage of participants who died, 
suffered SAEs, discontinued due to AEs, and who suffered TEAEs, will be provided. A 
comparison between intervention arms will be performed. Summaries of AEs within 
system organ class will be provided for: (1)   pre-existing conditions, (2) TEAEs, and (3) 
SAEs. Discontinuations due to AEs will also be listed. 
 
 
 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed according to UCSD conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
10.3 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
subjects who have provided written informed consent must also sign a subject 
authorization to release medical information to the study Sponsor and allow a regulatory 


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authority, or Institutional Review Board access to subject’s medical information relevant 
to the study. 
10.4 
Data and Safety Monitoring/Auditing 
Data and Safety reporting will be supported by the study statisticians according to the 
attached monitoring plan (Appendix C and D).  A series of comprehensive safety and 
data monitoring reports will be generated every six months for review by the study team 
in addition to the annual DSMB report described below. 
 
In addition to adverse event monitoring and clinical oversight by the principal investigator 
and co-investigators, quality assurance of the study will be performed by the clinical trials 
office internal monitor. Monitoring intervals will be dependent upon the number of patients 
enrolled and the complexity of the study.  
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring 
Board (DSMB) to provide oversight in the event that this treatment approach leads to 
unforeseen toxicities. Data from this study will be reported annually and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date  
3) 
the date of first and most recent patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution   
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study.  
10.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
10.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form must be 
completed within five (5) business days of making the change.  
10.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned 
variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the value 
of the data collected  
 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research participants. 


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 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, State 
laws, or University policies. 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies. Deviations should be summarized and 
reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one (1) week of the 
investigator becoming aware of the event using the same IRB online mechanism used to 
report Unanticipated Problems.  
10.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. 
10.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 


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the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
11.0 
REFERENCES 
 
1. 
Surveillance Epidemiology and End Results, in Institute NC (ed), 2013 
 
2. 
Franko J, Shi Q, Meyers JP, et al: Prognosis of patients with peritoneal 
metastatic colorectal cancer given systemic therapy: an analysis of individual patient data 
from prospective randomised trials from the Analysis and Research in Cancers of the 
Digestive System (ARCAD) database. Lancet Oncol, 2016 
 
3. 
Hasovits C, Clarke S: Pharmacokinetics and pharmacodynamics of 
intraperitoneal cancer chemotherapeutics. Clin Pharmacokinet 51:203-24, 2012 
 
4. 
Sugarbaker 
PH: 
Patient 
selection 
and 
treatment 
of 
peritoneal 
carcinomatosis from colorectal and appendiceal cancer. World J Surg 19:235-40, 1995 
 
5. 
Glehen O, Mohamed F, Gilly FN: Peritoneal carcinomatosis from digestive 
tract cancer: new management by cytoreductive surgery and intraperitoneal 
chemohyperthermia. Lancet Oncol 5:219-28, 2004 
 
6. 
Chua TC, Moran BJ, Sugarbaker PH, et al: Early- and long-term outcome 
data of patients with pseudomyxoma peritonei from appendiceal origin treated by a 
strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin 
Oncol 30:2449-56, 2012 
 
7. 
Franko J, Ibrahim Z, Gusani NJ, et al: Cytoreductive surgery and 
hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for 
colorectal peritoneal carcinomatosis. Cancer 116:3756-62, 2010 
 
8. 
Yan TD, Deraco M, Baratti D, et al: Cytoreductive surgery and hyperthermic 
intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional 
experience. J Clin Oncol 27:6237-42, 2009 
 
9. 
Baumgartner JM, Kwong TG, Ma GL, et al: A Novel Tool for Predicting 
Major Complications After Cytoreductive Surgery with Hyperthermic Intraperitoneal 
Chemotherapy. Ann Surg Oncol 23:1609-17, 2016 
 
10. 
Xu LL, Zhou XQ, Yi PS, et al: Alvimopan combined with enhanced recovery 
strategy for managing postoperative ileus after open abdominal surgery: a systematic 
review and meta-analysis. J Surg Res 203:211-21, 2016 
 
11. 
Buchler MW, Seiler CM, Monson JR, et al: Clinical trial: alvimopan for the 
management of post-operative ileus after abdominal surgery: results of an international 
randomized, double-blind, multicentre, placebo-controlled clinical study. Aliment 
Pharmacol Ther 28:312-25, 2008 
 
12. 
Herzog TJ, Coleman RL, Guerrieri JP, Jr., et al: A double-blind, 
randomized, placebo-controlled phase III study of the safety of alvimopan in patients who 
undergo simple total abdominal hysterectomy. Am J Obstet Gynecol 195:445-53, 2006 
 
13. 
Lee CT, Chang SS, Kamat AM, et al: Alvimopan accelerates 
gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-
controlled trial. Eur Urol 66:265-72, 2014 
 
14. 
Ludwig K, Enker WE, Delaney CP, et al: Gastrointestinal tract recovery in 
patients undergoing bowel resection: results of a randomized trial of alvimopan and 
placebo with a standardized accelerated postoperative care pathway. Arch Surg 
143:1098-105, 2008 


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15. 
Viscusi ER, Goldstein S, Witkowski T, et al: Alvimopan, a peripherally 
acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after 
major abdominal surgery: results of a randomized, double-blind, controlled study. Surg 
Endosc 20:64-70, 2006 
 
16. 
Wolff BG, Michelassi F, Gerkin TM, et al: Alvimopan, a novel, peripherally 
acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-
controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg 
240:728-34; discussion 734-5, 2004 
 
17. 
Entereg Prescribing Information, Merck & Co., Inc. 
 
18. 
Delaney CP, Craver C, Gibbons MM, et al: Evaluation of clinical outcomes 
with alvimopan in clinical practice: a national matched-cohort study in patients undergoing 
bowel resection. Ann Surg 255:731-8, 2012 
 
19. 
Taguchi A, Sharma N, Saleem RM, et al: Selective postoperative inhibition 
of gastrointestinal opioid receptors. N Engl J Med 345:935-40, 2001 
 
20. 
Delaney CP, Weese JL, Hyman NH, et al: Phase III trial of alvimopan, a 
novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major 
abdominal surgery. Dis Colon Rectum 48:1114-25; discussion 1125-6; author reply 1127-
9, 2005 
 
12.0 
APPENDICES 
Appendix A. ECOG Performance Status 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
1 
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
2 
In bed < 50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair 
5 
Dead. 
 


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Appendix B. Postoperative Bowel Function Diary 
 
 
DIARY INSTRUCTIONS: 
 Note the date and time of day you had each event. 
 In the comment section, please include any any uncertainties regarding date or time. 
 If you have any questions, please contact your nurse to contact the study staff listed in your 
informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EVENT 
DATE 
(MO-DD-YYYY) 
TIME OF DAY 
COMMENTS 
Example. 
03-15-2017 
9:00 AM 
 
First Postoperative Flatus 
 
 
 
First Postoperative Bowel Movement 
 
 
 
First Solid Food  
(without significant nausea or vomiting within 4 hours) 
 
 
 


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Appendix C. Division of Biostatistics and Bioinformatics Report 
 
 
 
 
Report Type 
Trial: The ILEUS Study: A Phase 2 Randomized Controlled Trial Investigating 
ALvimopan for Enhanced Gastrointestinal Recovery after CytoredUctive Surgery and 
Hyperthermic Intraperitoneal Chemotherapy (UCSD IRB 171044) 
Protocol Version V2.0 dated 06/10/2019 
CONFIDENTIAL DOCUMENT 
 
 
 
Date 
Principal Investigator: Joel M. Baumgartner, MD, MAS 
Statistician: Karen Messer, PhD and Ruifeng Chen, MS 
 
 
 


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Contents: 
1. Executive Summary 
2. Protocol Synopsis 
3. Report Overview 
4. Quality Management 
5. Methods 
6. Participants Status 
7. Subjects Consent and Treatment Dates 
8. Screen Failures 
9. Early Discontinuation/Off Treatment 
10. Demographics 
11. Stopping Rules 
12. Deaths 
13. Adverse Events 
14. Serious Adverse Events 
15. Outcomes Data 
16. Software 
17. Appendices 
 
 


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1. Executive Summary 
Report Overview 
This report reviews enrollment and safety data available in the study VELOS database 
as of xxxx. Summary tables are provided in sections 6-15. Additional tables and figures 
referenced in the report are provided in the Appendices. 
  
Study Site Status 
This is a single site trial at UCSD.  It was activated 02/28/2018.  
Enrollment Status 
XXX subjects have been screened for this study. 
XXX subjects have been enrolled. 
Early Discontinuation/Off Treatment Status 
XXX treated subjects have been discontinued (withdrawn) from the study.  XXX 
treated subjects have completed treatment. Details are specified in section Early 
Discontinuation/Off Treatment. 
Stopping/Halting Rules 
At accrual of 64 patients, a futility analysis will be performed. The stopping rule is stated 
in section protocol synopsis. 
 
Safety Summary 
XXXX adverse events have occurred in XXX subjects.  XXX serious adverse events 
have occurred in XXX subjects. 
Of the XX adverse events: XX were mild (grade 1), XX were moderate (grade 2) and 
XX were severe (Grade 3+). 
 
Deaths 
 
Quality Management 
Quality management reviews are performed annually and were last completed on 
xxxx. 
 
 
2. Protocol Synopsis 
 
Planned Accrual: N= 128; approximately 60-70 CRS/HIPEC procedures are 
performed annually at UCSD. 
Study Design: The proposed study is a prospective, randomized controlled phase 2 
trial. Subjects will be assigned to either placebo or alvimopan groups according to a 
block randomization. 
Primary Objective: To determine the efficacy of alvimopan to reduce postoperative 
ileus in patients undergoing CRS/HIPEC, as measured by the composite of time to 
recovery of upper and lower GI function. 
Treatment Description:  Alvimopan (12 mg) or Placebo 30 minutes – 5 hours prior to 
surgery, then twice daily (BID) starting POD 1 for a maximum of 7 days or until 
hospital discharge.  
Primary Endpoint(s): Time to either 1st solid food or 1st bowel movement 
postoperatively, whichever is later. 
Study Stopping Rules:  


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At accrual of 64 patients, a futility analysis will be performed. If the conditional 
power (as computed for log-rank tests) is less than 10% at this halfway point, we 
will suspend the study. The conditional power threshold of 10% was chosen based 
on boundaries set in Jennison and Turnbull, as well as with consideration to the 
probability of stopping early based on a series of effect sizes. If the null hypothesis 
is true (i.e. a hazard ratio of 1), the study will stop early at the interim to fail to reject 
the null hypothesis 69.49% of the time. Under the alternative hypothesis, the study 
will stop early 10.35% of the time while maintaining a type II error rate of 20%. 
 
3. Report Overview 
The purpose of this report is to review cumulative enrollment and safety data for the 
subjects enrolled in the ILEUS study. This report reflects data from the study database 
as of xxx. Within the body of the report are summary tables of enrollment, demographic 
characteristics, and adverse events. Readers of this report are asked to maintain the 
confidentiality of the information provided in this report. 
 
4. Quality Management 
4.1 This study was monitored by the UCSD Moores Cancer Center CTO xxxxx 
Protocol deviations/violations: 
 
4.2 Protocol deviations 
 
5. Methods – Data Set 
This report is based on all data downloaded on xxxx from the VELOS portal 
(https://velos.ucsd.edu). 
 
6. Participant Status 
This section summarizes the participant status and enrollment by study month. 
Enrollment is defined as received at least one treatment. 
Study Month 
Year & Month 
N Subjects Enrolled 
1 
 
 
2 
 
 
3 
 
 
 
XX Subjects have been consented.  This trial is accruing at a rate of X subjects per 
month. 
 
7. Subject Consent and Treatment Dates  
 
Consent and Treatment Dates 
Subject ID 
Consent Date 
Treatment Start Date 
 
 
 
 
 
 
 
 
 
 
 
 


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8. Screen Failures 
This study having two time points where subjects potentiality may fail to initiate (screen 
fails) or continue treatment (surgical fails). Subjects with a surgical failure will be 
followed since they are in both the safety and IIT populations. 
 
8.1 Screen Failures 
Subject ID 
Consent Date 
Screen Failure 
Date 
Reason for 
Screen Failure 
 
 
 
 
 
 
 
 
 
8.2 Surgical Failures 
Surgical Failures are still in the intent to treat and safety populations since they were 
randomized and received at least one dose of medication. 
 
Subject ID 
Consent Date 
Surgical Failure 
Date 
Reason for 
Surgical Failure 
 
 
 
 
 
 
 
 
 
 
9. Early Discontinuation/Off Treatment 
 
9.1 Completed Treatment 
 
Subject ID 
Off Treatment Date 
Off Treatment 
Reason 
 
 
 
 
 
 
 
 
9.2 Early Discontinuation 
Subject ID 
Off Treatment Date 
Off Treatment 
Reason 
 
 
 
 
 
 
 
10. Demographics 
 
This section includes the key demographics for the treated subjects, including 
surgical failures. 
Categorical measures: 
- Gender 
- Race 
- Ethnicity 
Continuous measures: 
- Age (years) 
Continuous variables are summarized with N, mean, standard deviation, median. 
Categorical variables are summarized using frequency tables and percentages 
 
Gender, Race, Ethnicity 


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Frequency 
Proportion 
Gender 
 
 
Female 
 
 
Male 
 
 
Race 
 
 
White 
 
 
Black, African- American 
 
 
Asian 
 
 
Native America 
 
 
Unknown or Not Reported 
 
 
Ethnicity 
 
 
Non-Hispanic 
 
 
Hispanic 
 
 
 
 
Continuous measures: Continuous variables are summarized with N, mean, standard 
deviation, median. 
 
Age (years) 
 
 
N 
Mean 
SD 
Median 
Age 
 
 
 
 
 
Demographic Information for All Consented Subjects 
Subject ID 
Age 
Gender 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
11.  Stopping Rules 
At accrual of 64 patients, a futility analysis will be performed. 
 
12. Deaths 
 
Subject ID 
Date of Death 
Reason for Death 
On Treatment? 
 
 
 
 
 
 
 
 
 
13. Post-Treatment Adverse Events 
 
13.1 Adverse Events Summary 
Severity 
N Adverse Events 
Mild (grade 1) 
 
Moderate (grade 2) 
 
Severe (grade 3) 
 
Life-threatening 
(grade 4) 
 


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Severity 
N Adverse Events 
Fatal (grade 5) 
 
Total 
 
 
 
13.2 AE by Grade 
13.3 AE by relationship 
Note: A list of all adverse events is in Appendix A. These are all AEs; SAEs are also 
reported in next section. 
 
13.4 Serious Adverse Events 
 
Serious Adverse Events 
Patient 
Study ID 
Serious Adverse Event 
Name 
Severity/Grade 
Start 
Date 
Stop 
Date 
Attribution 
  
 
 
  
 
14.  Software 
Statistical software R (version 3.1.3) is used http://www.r-project.org. 
 
 
 
Appendices 
1 Adverse Events 
2 Treatment Assessment 
3 Response Assessment 
4 Issues with data 
BSR data checks include verification of doses, number of appropriate drug and response 
cycles based on treatment start date, redundant and/or missing data, and other data 
elements as needed based on study protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D. UCSD Moores Cancer Center Data Monitoring Plan 
 
 
Introduction 
This data reporting plan outlines the routine monitoring reports that are to be 
generated by the study statistician or the study data manager, based on the 
data that have already been entered into the electronic data capture data base 
(VELOS). 
The purposes of these reports are to monitor the progress of trials and the 
safety of participants, to assure data accuracy, data completeness and protocol 
compliance. 
All the study personnel listed on the VELOS Clinical study information and 
personnel contact information page will receive these reports. (see Appendix A). 
For an outline of the report see Appendix B. 
I. Table of Contents  
II. Executive Summary –  
The Executive Summary will be an overarching description of the data analyzed. 
III. Protocol Synopsis -  
The Protocol will be an overarching description of the study.  
(note: Study coordinator is to obtain this information from the research plan and 
the first page of IRB submission for this report. It may be also available on the 
VELOS study information page.) 
             IV. Study Data Report –  
 
The Study Report will include the following Tables: 
 
Table 1: Overall Enrollment  
 
Table 2: Monthly Enrollment 
 
Table 3: Consent and Treatment Dates  
 
Table 4: Screen Failures  
 
Table 5: Early Discontinuations/Off Treatment 
 
Table 6: Gender, Race, Ethnicity 
 
Table 7: Age (years) 
 
Table 8: Subjects Demographics 
 
Table 9: Deaths 
 
Table 10: Adverse Events Summary 
 
Table 11: Serious Adverse Events  
 
Appendix: Listing of All Adverse Events 
 


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The Principal Investigator will receive additional tables in regards to study 
treatment, response assessment and data completeness as outlined in sections 
5-8 below.  Additional tables related to stopping rules will be added in the interim 
futility report.  These may include unblinded randomization tables, as well as, 
response assessments.   
Only, the Principal Investigator will received reports of outcome data and 
appendices that include treatment assessment, response assessment, baseline 
characteristics and data issues, as determined by study statistician.  
Below has details for each of the tables/reports listed above. The frequencies of 
running the reports was determined by the study protocol. Note: This is a double 
blind study.  All reports, except futility and final, will contain aggregated data. 
 
 
 
1.  Overall Enrollment - Table 1 
 
Purpose 
To monitor enrollment; to ensure that accrual goals are met in a timely manner; 
to notify the team when accrual goal is nearing completion 
 
Components 
Accrual (number of patients and percentages) by month. 
 Frequency: first two week data analysis, futility, semi-annually, annually 
2. Study Status Report – Tables 2-5 
 
Purpose 
To provide a summary of the status of study subjects. 
 
Components 
1) Total number of accrual as of date; number of subjects who are 
on/off study; number of subjects who are still on study treatment 
(s); number of subjects who are still on study but off study 
treatment (s). 
2) Listings of off study/off treatment with subject ID, date, week and 
reason. 


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 
Frequency: first two week data analysis, futility, semi-annually, annually 
  3. Baseline Characteristics Report –Tables 6-8 and Appendix 
 
Purpose 
To provide a summary of subjects' baseline characteristics  
 
Components 
Baseline variables which are crucial to study design and analysis  
For categorical variables frequency tables will be generated. 
For continuous variables, mean (range) will be reported. 
 
Frequency: first two week data analysis, futility, semi-annually, annually 
  4. Toxicity/Adverse Event Report – Tables 9-11 and appendix 
 
Purpose: 
To monitor toxicities; to evaluate unexpected toxicities; to ensure that toxicity 
rates are acceptable. All participants receiving investigational agents will be 
evaluated for safety.    
 Components: adverse events reported to the investigator by participants.   
1) Listing of all deaths. 
2) Frequency tables of all the signs and symptoms or laboratory 
toxicities by grade and across grades 
3) Listing of all adverse events. The list will include patient number, 
toxicity name, severity/grade of reaction, relationship to study drug.  
 
Frequency: first two week data analysis, futility, semi-annually, annually 
5.  Stopping Rules (Tables may vary) 
 Components: adverse events reported to the investigator by participants.  


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 
Tables of response times for either 1st solid food or 1st bowel movement, 
whichever is later. 
 
Frequency: first two week data analysis, futility, semi-annually, annually 
 
NA 
6.  Treatment and Dose Modifications Report (Treatment Form) 
 
Purpose: To monitor treatment and dose adjustment  
 
Components: Listings of study treatment (s) and their corresponding 
dosages,  
 
Frequency: first two week data analysis, semi-annually, annually 
7. Response Assessment report 
 
Purpose: To monitor responses. 
 
Components: Table of responses times.  
 Frequency : first two week data analysis, semi-annually, annually 
8. Issues with Data including Data Completeness Report (various data forms) 
 
Purpose:  
To ensure that clinic visits and other endpoint-related visits are conducted 
according to schedule; that endpoint-related data are collected 
appropriately and in a timely manner; to correct the database; to make sites 
and site principal investigators (PIs) aware of specific problems and to 
ensure that the compliance rate for visits and sample acquisition is high 
enough to satisfy protocol objectives. 
 
Frequency: first two week data analysis, semi-annually, annually 


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Timeline for Reports 
 
 
 
 
 
 
 
*Accrual and Baseline Characteristics Reports may be discontinued following closing the study to accrual 
*** Futility Analysis will be completed when necessary 
 
Date 
Accrual* 
Study 
Status 
Baseline 
Characteristics* 
Study 
Completeness 
Toxicity/Adverse 
Event 
Treatment 
and Dose 
Modifications 
Interim 
Analysis 
Response 
Assessment 
4/17/2018 
X 
X 
X 
X 
X 
X 
 
Xxxxxx *** 
(futility Analysis) 
X 
X 
X 
X 
X 
X 
X 
11/21/2018 
X 
X 
X 
X 
X 
X 
 
5/1/2019 
X 
X 
X 
X 
X 
X 
 
11/1/2019 
X 
X 
X 
X 
X 
X 
 
5/1/2020 
X 
X 
X 
X 
X 
X 
 
11/1/2020 
X 
X 
X 
X 
X 
X 
 
5/1/2021 
X 
X 
X 
X 
X 
X