Caphosol Study: A Randomized Controlled Open-Labeled Trial Investigating Topical Caphosol for Prevention of Oral Mucositis in Children, Adolescents and Young Adults Receiving Chemotherapy
Phase: PHASE3
Conditions: Oral Mucositis
Sponsor: Medical College of Wisconsin

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 1 of 32 
 
 
Caphosol Study 
Version No. 2.0 
 
 
 
 
 
 
Version Date:  02/24/2016  
 
Caphosol Study 
 
A Randomized Controlled Open-Labeled Trial Investigating Topical Caphosol for 
Prevention of Oral Mucositis in Children, Adolescents and Young Adults Receiving 
Chemotherapy 
 
 
PRINCIPAL INVESTIGATOR: 
Michael J. Burke, MD 
 
Medical College of Wisconsin Department of Pediatrics 
 
Division of Hematology/Oncology/BMT 
 
CO-PRINCIPAL  
INVESTIGATORS: 
 
Melissa Acquazzino, MD  
 
 
Medical College of Wisconsin Department of Pediatrics 
 
 
Division of Hematology/Oncology/BMT 
 
 
 
Molly Brickler, NP 
 
 
Medical College of Wisconsin Department of Pediatrics 
 
 
Division of Hematology/Oncology/BMT 
 
 
 
Kristen Tews, PA 
 
 
Medical College of Wisconsin Department of Pediatrics 
 
 
Division of Hematology/Oncology/BMT 
 
 
STATISTICIAN: 
Raymond Hoffmann, PhD  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 2 of 32 
 
 
Caphosol Study 
 
TABLE OF CONTENTS 
 
Section 
Page  
PROTOCOL CONTACT INFORMATION 
4 
PROTOCOL REVISION HISTORY 
6 
SYNOPSIS 
7 
1.0 
BACKGROUND 
10 
2.0 
STUDY OVERVIEW 
11 
 
2.1 
Study Design 
12 
3.0 
SELECTION OF PATIENTS 
12 
 
3.1 
Inclusion Criteria 
12 
 
3.2 
Exclusion Criteria 
13 
4.0 
Registration Procedures 
13 
 
4.1 
Registration 
13 
 
4.2 
Patients Who Do Not Begin Study Treatment 
14 
5.0 
TREATMENT PLAN 
14 
 
5.1 
Treatment Plan Schema 
16 
 
5.2 
Dose Modifications 
16 
 
5.3 
Supportive Care Guidelines 
17 
 
5.4 
Duration of Therapy 
17 
 
5.5 
Follow-Up 
17 
 
5.6 
Criteria for Removal from Protocol Therapy and Off-Study Criteria 
18 
6.0 
STUDY CALENDAR 
19 
7.0 
DRUG FORMULATION AND PROCUREMENT 
19 
 
7.1 
Caphosol 
19 
8.0 
ADVERSE EVENT MONITORING, DOCUMENTATION, AND REPORTING 
21 
 
8.1 
Definitions 
21 
 
8.2 
Adverse Event Documentation 
22 
 
8.3 
Adverse Event Reporting Requirements 
22 
9.0 
STUDY DATA COLLECTION AND MONITORING 
23 
 
9.1 
Data Management 
23 
 
9.2 
Case Report Forms 
24 
 
9.3 
Data and Safety Monitoring Plan (DSMP) 
24 
 
9.4 
Monitoring 
25 
 
9.5 
Record Retention 
25 
10.0 STATISTICAL CONSIDERATIONS 
25 
 
10.1 Statistic Endpoints 
25 
 
10.2 Statistical Analysis 
25 
 
10.3 Sample Size Justification 
26 
11.0 CONDUCT OF THE STUDY 
26 
 
11.1 Good Clinical Practice 
26 
 
11.2 Ethical Considerations 
26 
 
11.3 Informed Consent 
27 
References 
27 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 3 of 32 
 
 
Caphosol Study 
Section 
Page  
Appendix 1 
Eligibility Checklist 
30 
Appendix 2 
Performance Status Criteria 
31 
Appendix 3 
Pain Assessment Scales 
32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 4 of 32 
 
 
Caphosol Study 
 
PROTOCOL CONTACT INFORMATION 
 
Principal Investigator 
Michael J Burke, MD 
Associate Professor of Pediatrics 
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: 414-955-4198 
Fax:  414-955-6543 
Email:  mmburke@mcw.edu 
C0-Principal Investigator 
Molly Brickler, NP 
Nurse Practitioner  
Department of Pediatrics 
Division of 
Hematology/Oncology/BMT  
Children’s Hospital of Wisconsin 
Phone:  414-266-3675 
Email:  mbrickler@chw.org 
 
Medical Emergency Contact 
Children’s Hospital Switchboard:   
414-266-2000  
Ask for Pediatric Oncologist On-Call 
 
CO-PRINCIPAL INVESTIGATORS 
Melissa A. Acquazzino, MD 
Division of Pediatric 
Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: 414-266-3082 
Fax:  414-955-6543 
Email:  macquazzi@mcw.edu 
Molly Brickler, NP 
Nurse Practitioner  
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Children’s Hospital of Wisconsin 
Phone:  414-266-3675 
Email:  mbrickler@chw.org 
Kristen Tews, PA 
Physician’s Assistant 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Children’s Hospital of Wisconsin 
Phone: 414-266-3050 
Email:  ktews@chw.org  
 
 
SUB-INVESTIGATORS 
Meghen Browning, MD 
Assistant Professor 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4628 
Email:  mbrownin@mcw.edu 
Bruce Camitta, MD 
Professor 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone:  414-955-4106 
Email:  bcamitta@mcw.edu 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 5 of 32 
 
 
Caphosol Study 
SUB-INVESTIGATORS 
Paul Harker-Murray, MD, PhD  
Assistant Professor  
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4047 
Email:  pharker@mcw.edu 
Sachin Jogal, MD 
Assistant Professor 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-5772 
Email:  sjogal@mcw.edu 
Michael Kelly, MD, PhD 
Associate Professor  
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4993 
Email:  mekelly@mcw.edu 
Julie-An Talano, MD 
Associate Professor  
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4185 
Email:  jtalano@mcw.edu 
Richard Tower, MD 
Assistant Professor  
Department of Pediatrics 
Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-5653 
Email:  rtower@mcw.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 6 of 32 
 
 
Caphosol Study 
 
PROTOCOL REVISION HISTORY 
 
Version 
No. 
Revision 
Date 
Summary of Changes 
Consent Revised 
Yes/No 
2 
02/24/2016 
Added updated DSMC language as requested by the 
MCW DSMC on 1/22/15: 
 
 This study will be reviewed by the Medical 
College of Wisconsin Cancer Center Data and 
Safety Monitoring Committee (MCWCC DSMC). 
A summary of the MCWCC DSMC activities are 
as follows:  
• Review the clinical trial for data integrity and 
safety.  
• Review all unexpected grade 3, and all grade 4, 
and 5 adverse events, as well as any others 
requiring expedited reporting as defined in this 
protocol. (Grades 4 & 5 events must be reported to 
the DSMC within 5 calendar days of study staff’s 
knowledge.)  
• Review all DSM reports.  
• Submit a summary of any recommendations 
related to study conduct.  
• Terminate the study if deemed unsafe for 
patients.  
 
A copy of the MCWCC Data and Safety 
Monitoring Plan and membership roster will be 
maintained in the study research file and updated 
as membership changes. The committee will 
review reports from the study PI twice annually (or 
more frequently if needed) and provide 
recommendations on trial continuation, suspension 
or termination as necessary.  
Any available DSMC letters will be submitted to the 
IRB of record as required. 
YES 
– 
Footers/Headers 
only– 
updated 
to 
protocol v2 Dated 
2/24/2016 
 
Consent 
 
Assent 
 
Consent 
Spanish 
Short Form 
 
HIPPA 
Adult 
 
HIPAA 
Adult 
Spanish 
 
HIPAA 
Child 
 
HIPAA 
Child 
Spanish 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 7 of 32 
 
 
Caphosol Study 
SYNOPSIS 
 
Study Title: A Randomized Controlled Trial Investigating Topical Caphosol for Prevention of 
Oral Mucositis in Children, Adolescents and Young Adults (AYA) Receiving Chemotherapy  
 
Randomized Controlled Trial 
 
Number of Patients: A total of 96 patients will enroll to this study with 48 patients in the Caphosol 
group and 48 patients in the control group. 
 
Study Objectives 
 
 Primary Objectives 
o To determine if topically administered Caphosol at the initiation of chemotherapy 
prevents the development of oral mucositis (Grade > 2) in children, adolescents and 
young adults. 
o To determine the tolerability of four times daily Caphosol therapy. 
 
 Secondary Objectives 
o To determine if topically administered Caphosol reduces the severity of oral 
mucositis, as measured by incidence of severe mucositis (CTCAE v4.0 Grades 3 
or 4), age-appropriate pain scores (FACES and Likert), use of narcotic pain 
medicine, number of hospital days and duration of total parenteral nutrition 
(TPN). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 8 of 32 
 
 
Caphosol Study 
Treatment Plan Schema 
 
 
 
Caphosol Administration:   
 Take 30 mL QID (can increase frequency up to 6 times daily with symptoms of mucositis). 
 Each dose consists of 2, 15 mL syringes, to be mixed at time of administration.  Caphosol 
must be used within 15 minutes of mixing. 
 Rinse and gargle (if patient is able) approximately half of the solution (15 mL) for one 
minute and then spit.  Repeat. 
 For younger patients (≤ 6 years of age), volume may be reduced to 10-20 mL (5-10 mL x 
2). 
 For patients unable to successfully rinse and spit, caregivers may paint their mouth (using 
medical sponge swabs) with the solution x 2. Prior to swabbing the patient’s mouth, mix 
half of the 2, 15 mL syringes into a cup and dip swab prior to coating the inside of the 
patient’s mouth. Repeat  
 Patients are to avoid other oral medications, other mouth cares and food or drink for 15 
minutes after using Caphosol. 
 Take Biotene (5-10 mL) QID swish and spit 
 
Control Arm: 
 Take Biotene (5-10 mL) QID swish and spit  
 For patients unable to successfully rinse and spit, caregivers may paint their mouth 
(using medical sponge swabs) with the solution x 2. Prior to swabbing the patient’s 
mouth, mix 5-10 mL into a cup and dip swab prior to coating the inside of the 
patient’s mouth. Repeat  
 
 
 
Enrollment on study and 
Randomization
Day 1 of scheduled therapy:
Start Caphosol, 30 mL QID
Start Biotene 5-10mL QID
Start study diary
Completion of therapy:
Continue Caphosol, Biotene and 
study diary for 7 days AND until 
ANC > 500 after nadir or mucositis 
resolves (whichever occurs later)
Day 1 of scheduled therapy:
Start Biotene 5-10mL QID
Start study diary
Completion of therapy:
Continue study diary and Biotene 
for 7 days AND until ANC > 500 
after nadir or time of mucositis 
resolution (whichever occurs later)
CONTROL ARM 
CAPHOSOL ARM 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 9 of 32 
 
 
Caphosol Study 
Study Population: 
 Oncology patients at any point during their oncology therapy who are at risk of developing 
oral mucositis defined as: 
Patients receiving one or more of the following chemotherapy agents associated 
with high incidence of oral mucositis: 
 Actinomycin D 
 Carboplatin 
 Cisplatin 
 Cytarabine at doses > 1 gram/m2 
 Daunorubicin 
 Doxorubicin 
 Methotrexate at doses > 1 gram/m2 
 Mitoxantrone 
 
 Age 0 to 25 years. 
 Voluntary written consent before performance of any study-related procedure not part of 
normal medical care, with the understanding that consent may be withdrawn by the subject 
at any time without prejudice to future medical care. 
 
Exclusion Criteria: 
 Patients receiving glutamine therapy for mucositis. 
 Patients receiving concurrent Head & Neck radiation therapy or within 6 weeks of 
completion of radiation therapy. 
 Patients receiving autologous or allogeneic hematopoietic cell transplantation 
 Pregnant or lactating patients. The agent used in this study is not known to be teratogenic 
to a fetus, but has not been studied, and there is no information on the excretion of the agent 
into breast milk. All females of childbearing potential must have a blood test or urine study 
within 2 weeks prior to registration to rule out pregnancy. 
 Known allergy to Caphosol. 
 
Duration of Study: 6-8 months  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 10 of 32 
 
 
Caphosol Study 
1.0 
BACKGROUND 
 
Mucositis in Children, Adolescents and Young Adults Undergoing Chemotherapy 
 
Oral mucositis, a common and debilitating complication of cancer therapy, is an inflammatory 
injury to the epithelial and sub-epithelial cells of the oral mucosa.  Oral mucositis is thought to 
develop according to a five-stage model: 1) initiation; 2) up-regulation with generation of 
messengers; 3) signaling and amplification 4) ulceration with inflammation; and 5) healing, and 
typically develops 7-14 days into a chemotherapy course (1). 
 
The incidence and severity of oral mucositis depends on many factors including the age and 
diagnosis of the patient, the specific treatment regimen, underlying oral hygiene and genetic factors 
(2-4).  The incidence of oral mucositis in patients receiving chemotherapy ranges from around 40% 
of patients receiving myelosuppressive chemotherapy for solid tumors to 70-90% of patients 
receiving myeloablative therapy prior to stem cell transplant (1, 5, 6).   A commonly used grading 
scale for mucositis is the Common Terminology Criteria for Adverse Events (CTCAE version 4.0) 
grading scale, where grading is based on both subjective and objective assessments on a 5 point 
scale (Grade 1 to Grade 5).  
 
Adverse 
Event 
1 
2 
3 
4 
5 
Mucositis 
Oral 
 
Definition:  
A disorder 
characterized 
by 
inflammation 
of the oral 
mucosal. 
Asymptomatic 
or mild 
symptoms; 
intervention 
not indicated 
Moderate 
pain; not 
interfering 
with oral 
intake; 
modified diet 
indicated 
Severe pain; 
interfering 
with oral 
intake 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
From the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: 
June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health 
National Cancer Institute, p. 19 
 
 Oral mucositis causes significant pain, interferes with eating, talking and swallowing, significantly 
diminishes enteral nutritional intake and has a substantial negative impact on quality of life (1, 6-
10).  Patients may require hospitalization for management of the complications of mucositis, 
including poor nutrition, dehydration and pain (1, 6-10).  This becomes a significant burden on the 
patients, their families and the healthcare system alike.  As well injury to the oral mucosa increases 
the risk of systemic infections (11, 12).  Finally, the development of oral mucositis may require 
delays or dose reductions in future chemotherapy courses, potentially jeopardizing disease cure 
rates (6, 10). 
 
Despite all that is known about the mechanism, course and complications of oral mucositis, there 
are no consensus guidelines on prevention or treatment of chemotherapy-induced oral mucositis 
and there is significant variation on approach to mucositis across treatment centers. 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 11 of 32 
 
 
Caphosol Study 
 
Caphosol (Jazz Pharmaceuticals, Inc. Palo Alto, CA) is a supersaturated aqueous electrolyte 
solution comprised of sodium phosphate, calcium chloride and sodium chloride, resembling 
human saliva that was designed in part to replace the normal ionic and pH balance of the oral 
cavity and  been used to prevent and/or treat oral mucositis. Caphosol is hypothesized to diffuse 
into epithelial intracellular spaces and permeate mucosal lesions in oral mucositis.  In addition, 
calcium may modulate the inflammatory response and tissue repair processes and phosphate may 
be involved in repairing damage to the mucosal surface. In a 2013 review article by Quinn et al., 
24 of the 30 studies reviewed found Caphosol to be beneficial for the prevention and treatment of 
oral mucositis in patients receiving high-dose chemotherapy and/or radiotherapy (13). The author 
concluded that despite the heterogeneous nature of the reviewed studies, with many involving 
small patient numbers, involving single-centers and including historical controls, the data 
supported strong consideration for the addition of Caphosol to oral mucositis prevention and 
treatment plans.  The largest, randomized study of Caphosol for the prevention and treatment of 
oral mucositis was a double blind adult study comparing Caphosol to fluoride therapy in 95 
allogeneic and autologous hematopoietic stem cell transplant recipients (14). This 2003 study by 
Papas and colleagues, they reported that 40% of patients in the Caphosol arm had no mucositis 
compared with 19% in the control arm.  Also, patients in the Caphosol arm had significantly fewer 
mean days of mucositis (3.72 vs. 7.22; p=0.001), duration of pain (2.86 vs. 7.67; p=0.0001), days 
receiving morphine (1.26 vs. 4.02; p=0.0001), dose of morphine (34.54 mg vs. 122.78 mg; 
p=0.0001) and days to the onset of neutrophil recovery >200 mm3 (11.12 vs. 12.56; p=0.00173) 
(14).  
 
Although a 2014 randomized, controlled trial in 33 pediatric patients receiving high-dose 
chemotherapy failed to show any therapeutic benefit of Caphosol when initiated at development 
of mucositis, it did demonstrate safety of Caphosol therapy with no reported side effects (15).  This 
study did not evaluate Caphosol for the prevention of oral mucositis which is the intention of our 
study. A prevention strategy for development of mucositis was chosen for this study objective as 
it would potentially allow for less analgesic to be used, less parenteral nutrition and shorter hospital 
stays compared to a treatment strategy when mucositis has already developed as attempts to 
enhance recovery of mucositis, particularly in the setting of profound neutropenia, would be more 
difficult given Caphosol’s mechanism of action. 
 
2.0 
STUDY OVERVIEW 
 
Eligible patients will be identified in the oncology clinic and/or the oncology ward and 
consented/enrolled on study. Study patients randomized to the Caphosol arm will begin Caphosol 
therapy prior to administration of systemic chemotherapy on Day 1 according to protocol. 
Caphosol administration will continue through the planned chemotherapy administration and until 
stopping criteria are met.  Chemotherapy will be administered either in the MACC Fund Center or 
the inpatient service.  Once the chemotherapy is complete the patient will be discharged to home 
and followed in the MACC Fund Center at regular intervals as dictated by standards of care. 
Caphosol treatment will continue at home as outlined in the protocol for 7 days following 
completion of chemotherapy and adequate neutrophil recovery, or until oral mucositis symptoms 
resolve,  whichever occurs later. In the event the patient requires hospital admission, Caphosol 
treatment will continue according to protocol. The patient/family will keep a daily drug diary of 
administration of Caphosol throughout each cycle which will be reviewed by the study team at 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 12 of 32 
 
 
Caphosol Study 
each study visit. As well patients in each cohort will record in their diary other oral topical agents 
they are using and any narcotic and non-narcotic medications used for treatment of pain/mucositis. 
 
 
2.1 
Study Design  
 
This is a randomized controlled trial designed for the purpose of evaluating the efficacy 
and tolerability of Caphosol therapy for the prevention of oral mucositis (Grade ≥ 2) in 
children, adolescents and young adults at risk for developing oral mucositis due to their 
cancer therapy.  
 
Our hypothesis is that by initiating Caphosol at the initiation of chemotherapy 
administration, we will decrease the incidence and/or severity of oral mucositis (Grade 3 
or 4) as well as limit the number of days requiring narcotic analgesics, days of 
hospitalization and need/duration of total parental nutrition in patients randomized to the 
treatment group compared to the control group. 
 
 
Primary Objectives  
 
 To determine if topically administered Caphosol at the initiation of chemotherapy 
prevents the development of oral mucositis (Grade > 2) in children, adolescents and 
young adults. 
 
 To determine the tolerability of four times daily Caphosol therapy. 
 
 
Secondary Objectives 
 
To determine if topically administered Caphosol reduces the severity of oral mucositis, 
as measured by incidence of severe mucositis (CTCAE v4.0 Grades 3 or 4), age-
appropriate pain scores, use of narcotic pain medicine, number of hospital days and 
number of days on TPN. 
 
3.0 
SELECTION OF PATIENTS 
 
Study patients will be recruited from the MACC Fund Center and the oncology inpatient service.  
Study entry is open to patients regardless of gender or ethnic background.  While there will be 
every effort to seek out and include females and minority patients, the patient population is 
expected to be no different than that of other oncology studies at the Medical College of 
Wisconsin. 
 
3.1  
Inclusion Criteria 
 
Oncology patients, at initiation of their oncology therapy, who are at risk of developing 
oral mucositis during their scheduled cancer therapy, defined by meeting one or more of 
the following criteria: 
 
a. Patients receiving one or more of the following chemotherapy agents: 
 Actinomycin D 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 13 of 32 
 
 
Caphosol Study 
 Carboplatin 
 Cisplatin 
 Cytarabine at doses > 1 gram/m2 
 Daunorubicin 
 Doxorubicin 
 Methotrexate at doses > 1 gram/m2 
 Mitoxantrone 
 
b. Age 0 to 25 years  
c. Voluntary written consent before performance of any study-related procedure 
not part of normal medical care, with the understanding that consent may 
be withdrawn by the subject at any time without prejudice to future medical 
care 
 
3.2  
Exclusion Criteria 
 
a. Patients receiving glutamine treatment for oral mucositis.  
b. Patients undergoing autologous or allogeneic hematopoietic cell transplantation 
are excluded from this study. 
c. Patients receiving concurrent Head & Neck radiation therapy or within 6 weeks 
of completion of radiation therapy. 
d. Pregnant or lactating patients. The agent used in this study is not known to be 
teratogenic to a fetus, but has not been studies, and there is no information on 
the excretion of the agent into breast milk. All females of childbearing 
potential must have a blood test or urine study within 2 weeks prior to 
registration to rule out pregnancy. 
e. Known allergy to Caphosol  
 
4.0 
REGISTRATION PROCEDURES 
 
Registration will occur after eligibility is confirmed and the patient/parent has signed the 
subject consent, but before any treatment has been administered. 
 
The eligibility checklist will be completed at the time of study enrollment. 
 
4.1 
Registration 
 
Upon completion of the screening evaluation, eligibility confirmation and obtaining 
written consent, the patient will be registered in the study file by the Department of 
Pediatrics Division of Hematology/Oncology/BMT MACC Fund Center Clinical Trials 
Office (CTO).  When the OnCore™ Clinical Trials Management System (CTMS) is fully 
functioning for this study, the MACC Fund Center CTO will use this program for patient 
registration. 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 14 of 32 
 
 
Caphosol Study 
4.2 
Patients Who Do Not Begin Study Treatment 
 
If a patient is registered on the study, and is later found not able to begin the planned 
study treatment, for whatever reason, the patient will be removed from study and treated 
at the physician’s discretion.  Study data will be collected until the time of study removal. 
The reason for removal from study will be clearly indicated on the case report forms. 
 
If a patient begins treatment, and then decides to come off of study for whatever reason, 
the patient must be followed per Section 6.1. 
 
4.3   RANDOMIZATION PLAN 
 
The randomization procedure will be based on creating a block for every 4 subjects with 2 
subjects of each treatment randomly positioned in the block. Withdrawal is covered in 
section 5.5.  This should provide balance among the two arms for rates of mucositis by 
disease.  If imbalance exists after randomization, covariates will be used for adjustment of 
the results.  
 
5.0 
TREATMENT PLAN 
 
This study is a randomized, controlled trial evaluating the use of topical Caphosol therapy to 
prevent oral mucositis (Grade ≥ 2) in children, adolescents and young adults undergoing 
chemotherapy.  At the time of enrollment, patients will be randomized to either the control arm or 
the Caphosol arm.  The treatment period will extend from the start of chemotherapy and continue 
for 7 days after completion of chemotherapy AND until the ANC is > 500 after nadir (count 
recovery) or until the symptoms of oral mucositis resolve; whichever occurs last. 
 
Treatment 
 
Caphosol Arm:  Subjects randomized to the Caphosol Arm will use Caphosol 4 times per day as 
follows: 
 
 Each dose consists of two 15 mL syringes, to be mixed at time of administration.  Caphosol 
must be used within 15 minutes of mixing.  
o Subjects may increase the use to 6 times per day if they  have symptoms of 
mucositis. 
 Using one of the syringes, rinse and gargle (if patient is able) for one minute and then spit. 
Repeat using the remaining syringe.  
o For younger patients (less than or equal to 6 years of age), volume may be reduced 
to two syringes containing 5-10 mL each.  
o For patients unable to successfully rinse and spit, caregivers may paint their mouth 
(using medical sponge swabs) with the solution two times. Prior to swabbing the 
patient’s mouth, squirt one of the syringes into a cup and using the medical sponge, 
soak up the solution and use the swab to coat the inside of the patient’s mouth. 
Repeat using the second syringe. 
 Patients are to avoid other oral medications, other mouth cares and food or drink for 15 
minutes after using Caphosol.  

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 15 of 32 
 
 
Caphosol Study 
 Patients will also use Biotene (5-10 mL) to swish and spit after the 15 minutes has passed. 
Biotene is part of our standard of care to prevent oral infections in oncology patients.  
 
Control Arm:  Subjects randomized to the Control Arm will use Biotene only 4 times per 
day as follows: 
 
 Use 5 to 10 mL of Biotene to swish and spit  
o For patients unable to successfully rinse and spit, caregivers may paint their mouth 
(using medical sponge swabs) with the solution two times. Prior to swabbing the 
patient’s mouth, pour Biotene into a cup and using the medical sponge, soak up the 
solution and use the swab to coat the inside of the patient’s mouth. Repeat with a 
second swab. 
 
 
The following will be observed: 
 
 Incidence of oral mucositis. Oral mucositis will be defined and characterized by the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 as Grade 1-4. 
 Severity of oral mucositis, according to: 
o Age-appropriate pain scales (LIKERT and FACES) 
o CTCAE V 4.0 grading 
o Total narcotic usage (both the total amounts in milligrams and the number of days 
the patient required intravenous narcotic therapy as well as any increase of dose 
above baseline for patients who are on scheduled chronic use of narcotics)  
o Number of hospital days with oral mucositis present  
o TPN use and duration 
 
The following will be observed on all patients on the Caphosol arm, via the study diary: 
 
 Missed doses of Caphosol and reason 
 Side effects attributed to Caphosol therapy 
 Use of any other oral topical agents for oral mucositis (dose, schedule, number of doses 
taken) such as biotene/ chlorhexidine rinses and/or magic mouthwash.  
 Use of any non-narcotic pain medications for oral mucositis (dose, schedule, number of 
doses taken) 
 Use of any narcotics for oral mucositis (dose, schedule, number of doses taken) 
 
The following will be observed on all patients on the Biotene arm, via the study diary: 
 
 Use of any other oral topical agents for oral mucositis (dose, schedule, number of doses 
taken) such as chlorhexidine rinses and/or magic mouthwash.  
 Use of any non-narcotic pain medications for oral mucositis (dose, schedule, number of 
doses taken) 
 Use of any narcotics for oral mucositis (dose, schedule, number of doses taken) 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 16 of 32 
 
 
Caphosol Study 
5.1 
Treatment Plan Schema 
 
 
 
Table 1:  Treatment Plan 
 
Day 
Agent/Procedure 
Enrollment 
Randomization to control arm or Caphosol arm 
Day 1 of 
Chemotherapy 
Start study diary 
IF on Caphosol Arm: Start Caphosol, 30 mL QID 
Completion of 
Chemotherapy 
 
Control Arm: Continue study diary and Biotene for 7 days after therapy 
completed AND until ANC > 500 after nadir or until mucositis resolution, 
whichever occurs later. 
Caphosol Arm: Continue Caphosol, Biotene, and study diary for 7 days after 
therapy completed AND until ANC > 500 after nadir or until resolution of 
oral mucositis; whichever occurs latest. 
 
5.2 
Dose Modifications 
 
The dosing frequency may be increased up to 6 times daily for patients with signs or 
symptoms of oral mucositis. An increase in frequency of Caphosol administration up to 
the 6 times daily will not be considered a treatment failure. 
 
If younger patients (< 5 years of age) are unable to tolerate the full volume, the volume 
may be reduced to a total of 10-20 mL per dose (5-10 mL x 2), as tolerated.  For patients 
unable to swish and spit, caregivers may paint the Caphosol solution (using medical 
sponge swabs) on the oral mucosa x 2 for each dose. 
 
 
Enrollment on study and 
Randomization
Day 1 of scheduled therapy:
Start Caphosol, 30 mL QID
Start Biotene 5-10mL QID
Start study diary
Completion of therapy:
Continue Caphosol, Biotene and 
study diary for 7 days AND until 
ANC > 500 after nadir or mucositis 
resolves (whichever occurs later)
Day 1 of scheduled therapy:
Start Biotene 5-10mL QID
Start study diary
Completion of therapy:
Continue study diary and Biotene 
for 7 days AND until ANC > 500 
after nadir or time of mucositis 
resolution (whichever occurs later)
CAPHOSOL ARM 
CONTROL ARM 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 17 of 32 
 
 
Caphosol Study 
5.3 
Supportive Care Guidelines 
 
Patients on study will receive the standard, recommended supportive cares based on the 
therapy received.   
 
Allowed oral topical medications on study:  
 Standard oral cares, such as scheduled biotene or chlorhexidine rinses   
 If needed for symptom management, patients may receive topical viscous 
lidocaine or topical “magic mouthwash” containing lidocaine, diphenhydramine 
and Maalox.  
 
5.4 
Duration of Therapy 
 
Caphosol will be initiated on Day 1 of scheduled cancer therapy and will continue for:  
 
 7 days after therapy completion  
AND 
o ANC > 500 after nadir (count recovery)* 
OR 
o Resolution of oral mucositis symptom* 
*(whichever occurs last) 
 
 
 
Caphosol will be continued each time the patient receives chemotherapy where eligibility 
criteria are met for patients randomized to Caphosol arm. 
 
Caphosol will be discontinued for allergy or patient intolerance.  Please see Section 5.6 
for criteria for removal from protocol therapy and off study criteria. 
 
5.5 
Follow-Up 
 
Study patients will be followed through their first clinic appointment after treatment 
completion with the appropriate evaluations. Data collection will continue through 
completion of planned therapy, or until subject meets criteria for removal from protocol 
therapy or off –study criteria are met as outlined below.  Patients who are removed from 
study per the protocol criteria below, or who withdraw from the study, will not be replaced 
but will be treated as part of the analysis using either an “intention to treat”, “last 
observation carried forward” or “by imputation of the missing values”.  
 
Study evaluations will occur each time chemotherapy is received where Caphosol is 
administered.  
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 18 of 32 
 
 
Caphosol Study 
5.6 
Criteria for Removal from Protocol Therapy and Off-Study Criteria 
 
5.6.1  Criteria for Removal from Protocol Therapy 
 Completion of planned Caphosol therapy (all eligible chemotherapy 
cycles have been completed)  
 Physician determines it is in the patient’s best interest 
 Adverse Event/Side Effects/Complications which based on the treating 
physician or patient/family opinion warrant coming off protocol 
therapy 
 Inevaluable 
 Patient Intolerance/Refusal 
 
5.6.2  Off-Study Criteria 
 Death 
 Lost to follow-up 
 Withdrawal of consent for any further data submission 
 
6.0 
STUDY CALENDAR 
 
Table 2:  Required Evaluations* 
Evaluations 
Pre-
Study 
Treatment 
Period 
Clinical history 
X 
Weekly 
Physical exam 
X 
Weekly 
Vital exam 
X 
Weekly 
Weight 
X 
 
Height 
X 
 
Performance status 
X 
Weekly 
Oral mucositis grading 
X 
X 
Study diary 
 
Daily 
At Each Clinic Visit 
 
 
- Oral mucositis grading 
 
X 
- Age-appropriate pain scale 
 
X 
- Assessment of narcotic use 
 
X 
For Patients Requiring Admission 
 
 
- Oral mucositis grading 
 
Daily 
- Age-appropriate pain scale 
 
Daily 
- Assessment of narcotic use 
 
Daily 
- Nutrition assessment 
 
Daily 
*Patient evaluations (inpatient and outpatient) will occur at least weekly and be collected by the 
study nurses and entered into the patient’s medical record (EPIC) under a separate progress note 
as well as recorded in the protocol specific electronic case report forms (eCRF) in Oncore. 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 19 of 32 
 
 
Caphosol Study 
7.0 
DRUG FORMULATION AND PROCUREMENT 
 
7.1 
Caphosol 
 
7.1.1     Other Names 
 
Supersaturated calcium phosphate rinse 
 
7.1.2     Classification 
 
Topical oral agent 
 
7.1.3     Mode of Action 
 
Caphosol is a supersaturated aqueous solution of calcium phosphate and high 
concentrations of calcium and phosphate ions are hypothesized to diffuse into 
epithelial intracellular spaces and permeate mucosal lesions in oral mucositis.  
Caphosol resembles human saliva and is designed to restore the normal ionic and 
pH balance in the oral cavity.  In addition, calcium may modulate the inflammatory 
response and tissue repair processes and phosphate may be involved in repairing 
damage to the mucosal surface.  There are no known interactions between Caphosol 
and other drugs.  No systemic toxicities have been described when using Caphosol 
as a mouth rinse. 
 
7.1.4     Storage and Stability 
 
Although commercially available, Caphosol will be considered an investigational 
product for purposes of this clinical trial. Investigational products are required to 
be stored in the Investigational Drug service area by central pharmacy in the lower 
level of the West Tower. 
 
Caphosol is supplied as two separately packaged aqueous solutions; a 15 mL 
phosphate solution and a 15 mL calcium solution.  When mixed, Caphosol solution 
contains dibasic sodium phosphate 0.032%, monobasic sodium phosphate 0.009%, 
calcium chloride 0.052% and sodium chloride 0.569% in purified water.  Caphosol 
is stored at room temperature conditions for the duration of its shelf life. It should 
not be refrigerated. 
 
7.1.5     Dose Specifics 
 
For the purposes of this study, Caphosol will be administered topically at the dose 
of 30 mL QID.  Dose frequency may be increased up to 6 times daily for symptoms 
of oral mucositis. 
 
If younger patients (age ≤ 6 years) are unable to tolerate the full volume, the 
volume may be reduced to a total of 10-20 mL per dose (5-10 mL x 2), as 
tolerated.  For patients unable to successfully swish and spit, caregivers may paint 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 20 of 32 
 
 
Caphosol Study 
the Caphosol solution using medical sponge swabs on the oral mucosa x 2 for 
each dose. 
 
7.1.6     Administration 
 
Investigational Pharmacy will dispense the agent for this clinical trial and place the 
unit of use, (oral syringe A & B) in a baggie with label for each dose. Unit dosing 
the oral syringe A&B in a baggie with med label and date/time due should ensure 
both A&B being administered. 
 
This process means that the product will be in the patient’s med drawer with other 
meds. If the dosing schedule is 6 doses per day (not 4), then Investigational 
pharmacy would send the evening and overnight doses with regular meds and bring 
the AM doses up each morning. Patients who receive Caphosol in the outpatient 
setting will receive a home supply for 2 weeks with appropriate drug labeling and 
instructions for use and will be evaluated in clinic for compliance and proper 
administration of the agent. 
 
Caphosol will be supplied in two 15 mL syringes per dose.  These are to be mixed 
together within 15 minutes of dose administration.  Patients are to swish and gargle 
(if able) one half of the mixture (approximately 15 mL) for one minute, and then 
spit.  Immediately repeat with second half of mixture. 
 
For patients unable to successfully rinse and spit, caregivers may paint their mouth 
(using medical sponge swabs) with the solution x 2. Prior to swabbing the patient’s 
mouth, mix half of the 2, 15 mL syringes into a cup and dip swab prior to coating 
the inside of the patient’s mouth. Repeat  
 
7.1.7     Side Effects 
 
No side effects are expected.  Previous studies have shown Caphosol to be safe and 
well-tolerated with no known side effects, even when inadvertently swallowed. 
 
Pregnancy:  It is not known if Caphosol is teratogenic or passes through breast milk; 
therefore, pregnant and lactating patients will not be eligible for enrollment on study. 
Patients who become pregnant while on study receiving Caphosol will become 
ineligible and removed from protocol therapy. 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 21 of 32 
 
 
Caphosol Study 
8.0 
ADVERSE EVENT MONITORING, DOCUMENTATION AND REPORTING 
 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria 
for Adverse Events V 4.0 (CTCAE) and reported on the schedule below.  A copy of the CTCAE 
can 
be 
downloaded 
from 
the 
CTEP 
home 
page:http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
 
 
8.1 
Definitions 
 
The following definitions are based on the Code of Federal Regulations Title 21 Part 
312.32 (21 CFR 312.32(a)). 
 
Adverse Event:  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected Adverse Reaction:  Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. 
 
Life-Threatening  Adverse  Event Or  Life-Threatening  Suspected  Adverse 
Reaction: An  adverse event  or  suspected  adverse  reaction  is  considered  “life-
threatening”  if,  in  the  view  of  either  the investigator or sponsor, its occurrence places 
the patient or subject at immediate risk of death. 
 
Event Attribution Categories:  CTCAE does not define an AE as necessarily ‘caused by 
a therapeutic intervention.’ The clinical investigator must assign attribution for an adverse 
event after naming and grading of the event. 
 
Attribution 
Description 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
Unanticipated (unexpected) adverse event or unexpected suspected adverse reaction 
as defined by the Children’s Hospital Wisconsin (CHW) IRB are those that are not already 
described as potential risks in the consent form, not listed in the Investigator’s Brochure 
or not part of an underlying disease. 
 
Expedited (Rapid) Reporting: Certain events may require rapid notification to entities 
providing patient safety oversight (e.g. IRB) as detailed in Section 8.3. 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 22 of 32 
 
 
Caphosol Study 
 
 
8.2 
Adverse Event Documentation 
 
Adverse events occurring after the initiation of any study treatment must be documented. 
There are no expected toxicities from the addition of Caphosol therapy. 
 
Adverse event documentation requirements will be determined based on grade, 
expectedness and relationship to study therapy as follows: 
 
Stopping Rule Events: The following events count toward a study stopping rule per 
Section 10.3 and must be reported to the MCW Study Coordinator. 
 
 Any Grade 4 non-hematologic treatment related event 
 Any death, regardless of cause during the reporting period for this study 
from initiation of study treatment to end of study. 
 
Events that count toward an early stopping rule do not necessarily constitute a 
serious adverse event requiring expedited reporting and should be reported as such 
only if they meet the criteria for expedited reporting to the IRB as defined in section 
8.3. 
 
All patients will be monitored through the treatment period, as it is expected that 
most treatment related adverse events will occur during this period. 
 
8.3 
Adverse Event Reporting Requirements 
 
The reporting period for this study is from initiation of study treatment through 
completion of Caphosol therapy; however after this time point, the investigator must 
report upon knowledge any study treatment related event meeting the expedited reporting 
criteria in the following table. 
 
 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4     
and 5 
 
Expected or 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
Not 
Required 
Required 
Required 
Possible 
Probable 
Definite 
Not required 
Not 
required 
Not Required Not 
Required 
Required 
(Non 
hematologic 
only) 
Required 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 23 of 32 
 
 
Caphosol Study 
Regulatory 
Reports To 
Criteria for Reporting 
Timeframe 
Form to 
Use 
Copy AE 
To: 
CHW IRB 
UPIRSO: Any event which is 
unanticipated, involved new or increased 
risk to subjects, and was at least possibly 
related to study procedures through Day 60 
or the start of a new treatment whichever is 
earlier 
5 calendar 
days 
SAE 
MCW SAE 
Coordinator 
Other problems or events meeting the 
definition of UPIRSO 
MCW 
DSMC 
Any event that counts toward a study 
stopping rule. 
 
 
All unexpected grade 3, and all grade 4, 
and 5 adverse events, as well as any others 
requiring expedited reporting as defined in 
this protocol.  
Within 24 
hours of PI 
notification 
 
Grades 4 & 
5 events 
must be 
reported to 
the DSMC 
within 5 
calendar 
days of 
study 
staff’s 
knowledge 
SAE 
 
 
 
SAE 
MCW SAE 
Coordinator 
 
 
MCW SAE 
Coordinator 
 
 
If the SAE meets CHW IRB criteria for expedited reporting, then an official signed report 
is submitted to the IRB within 5 days. Adverse events which did not meet the CHW Prompt 
Reporting Criteria as outlined in the CHW IRB policy and procedure should be reported 
to the IRB at time of continuing review. All deaths, regardless of the cause, need to be 
reported to the PI within 48 hours and then reported to the IRB. 
 
The Study Coordinator will provide the MCW’s Data and Safety Monitoring Committee 
(DSMC) and CHW IRB with the SAE in an appropriate format depending on the 
individual SAE (as reported or in a summary format). 
 
9.0 
STUDY DATA COLLECTION AND MONITORING 
 
9.1 
Data Management 
 
Data management will be performed utilizing an electronic clinical trials management 
system called OnCore. OnCore is a secure, web-based application designed exclusively to 
support research protocols  
 
Once an institution consents a patient, they will enter the patient demographics into the 
OnCore system and assign a study ID. Any paper data (i.e. safety reports, reports generated 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 24 of 32 
 
 
Caphosol Study 
from OnCore) will be kept in a locked and secure location within the MACC Fund Center 
Clinical Trials Office of the Pediatric Hematology/Oncology and Bone Marrow Transplant 
Program.  The Clinical Trials Office has secure, electronic employee badge access only. 
Any paper data that is generated will be kept for at least 10 years.  
 
9.2 
Case Report Forms 
 
Participant data will be collected using protocol specific electronic case report forms (e-
CRFs) developed within OnCore based on its library of standardized forms.  The e-CRF 
will be approved by the study Principal Investigator and the Biostatistician prior to release 
for use.  The Study Coordinator or designee will be responsible for registering the patient 
into OnCore at time of study entry, completing e-CRFs based on the patient specific 
calendar, and updating the patient record until the end of required study participation. 
 
9.3 
Data and Safety Monitoring Plan (DSMP) 
 
The study’s Data and Safety Monitoring Plan will be in compliance with the Medical 
College of Wisconsin Cancer Center's Data & Safety Monitoring Plan (DSMP). 
 
 This study will be reviewed by the Medical College of Wisconsin Cancer Center Data 
and Safety Monitoring Committee (MCWCC DSMC). A summary of the MCWCC 
DSMC activities are as follows:  
• Review the clinical trial for data integrity and safety.  
• Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events 
must be reported to the DSMC within 5 calendar days of study staff’s knowledge.)  
• Review all DSM reports.  
• Submit a summary of any recommendations related to study conduct.  
• Terminate the study if deemed unsafe for patients.  
 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee 
will review reports from the study PI twice annually (or more frequently if needed) and 
provide recommendations on trial continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
For the purposes of data and safety monitoring, this study is classified as moderate risk. 
Therefore the following requirements will be fulfilled: 
 
 The PI will complete and submit a semi-annual Study Progress Report to the MCW 
Cancer Center Data and Safety Monitoring Committee (DSMC) with the 
understanding the MCW DSMC may require more frequent reporting. 
 This protocol will be monitored by an individual or group of individuals from the 
MCW Cancer Center who are not directly or indirectly responsible for the supervision 
of this trial. Monitoring will occur at a minimum of once per year to ensure all 
regulatory aspects of this study are in compliance with the FDA and any other 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 25 of 32 
 
 
Caphosol Study 
applicable regulatory boards/bodies. 
 The PI will oversee the submission of all reportable events per the definition of 
reportable in Section 8.3 to the MCW Cancer Center’s DSMC and the CHW IRB. 
 
9.4       Monitoring 
 
The investigator will permit study-related monitoring, audits, and inspections by the 
MCW compliance groups. The investigator will make available all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, 
study data, etc.).  The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.) will be available for 
trial related monitoring, audits, or regulatory inspections. 
 
9.5       Record Retention 
 
The investigator will retain study records including source data, copies of case report 
forms, consent forms, HIPAA authorizations, and all study correspondence in a secured 
facility for at least 10 years after the study file is closed with the IRB. 
 
 
 
In addition, the MACC Fund Center Clinical Trials Office (CTO) will keep a master log 
of all patients participating in the study with sufficient information to allow retrieval of 
the medical records for that patient.  Please contact the CTO before destroying any study 
related records. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1     Statistic Endpoints 
 
The study will not stratify based on diagnosis. The effectiveness of the study will be based 
on comparing incidence and severity of oral mucositis. Safety and tolerance will be based 
on the differential incidence of severe adverse events.  A continuous sequential boundary 
will be used to terminate the study if the difference in adverse events occurs at a rate of 
10% or greater at the interim analysis performed at the end of study month 3.  A continuous 
sequential boundary will also be constructed for a differential rate of 5%.   
      An interim analysis will be conducted half way through using the O’Brien-Fleming 
rule for early stopping because of success.  
 
10.2    Statistical Analysis 
 
Comparisons of binary outcomes such as prevention of oral mucositis will use logistic 
analysis or Fisher’s exact test if the numbers are small. Comparisons of the severity of oral 
mucositis (an ordinal scale) will use the Wilcoxon rank sum test since the data is on a 5 
point Likert scale, although there are really only two levels of values.  Similarly for the 
secondary outcome an ordinal pain scale can be treated as an ordinal scale.  Length of stay 
and duration of TPN will use a t-test plus  a log transform, if necessary to reduce the 
skewness of the data.  Otherwise the Wilcoxon test will be used. 
Although there may be loss to follow-up, we don’t expect it because continued 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 26 of 32 
 
 
Caphosol Study 
chemotherapy depends on the clearing of the mucositis. 
 
The primary analysis for mucositis will be based on a binary scale (Grade 1 versus Grade 
>2 mucositis) because the mucositis essentially has only two clinically pieces to the scale.  
It also represents common clinical practice. 
 
10.3 
Sample Size Justification 
 
For an alpha of 0.05 and a power of 80%, 48 subjects per group allow detection of a 30% 
difference in the incidence of oral mucositis (range of oral mucositis is 25% to 50%). 
Efficacy assessment will occur at study completion. 
 
Twenty subjects per group can detect a 0.6 unit difference in the toxicity scale. This is 
based on an effect size of 0.90 and a SD of 0.66 units. This is a medium sized clinical 
difference using Cohen’s criteria. This study will serve as a pilot for a larger study. For 
toxicity, which can only be estimated in the treatment group, 48 subjects in the Caphosol 
group will allow estimation of a 95% confidence interval of the toxicity of about + 15%. 
Assessment of toxicity will occur once the study enrolls 20 patients to each arm to obtain 
a preliminary estimate (95% CI) for toxicity and again at study completion (to obtain a 
more precise estimate). While the study is stopped if it passes the sequential boundary, 
to obtain an estimate of the toxicity and its 95% Confidence interval (95% CI) both an 
interim analysis and an analysis at the end of the study will be used to estimate the 95% 
CI – most precisely at the end of the study. 
 
11.0 
CONDUCT OF THE STUDY 
 
11.1 
Good Clinical Practice 
 
`The   study   will   be   conducted   in   accordance   with   the   appropriate   regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of 
the drug as described in the protocol.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files 
should be established at the beginning of the study, maintained for the duration of the 
study and retained according to the appropriate regulations. 
 
11.2 
Ethical Considerations 
 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients.  The study will only 
be conducted at sites where IRB approval has been obtained.  The protocol, informed 
consent, written information given to the patients, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the investigator. 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 27 of 32 
 
 
Caphosol Study 
11.3 
Informed Consent 
 
All potential study participants will be given a copy of the CHW IRB-approved consent 
to review. The investigator or designee will explain all aspects of the study in lay language 
and answer all questions regarding the study. If the participant (or parents/guardians for a 
minor) decides to participate in the study, he/she will be asked to sign and date the 
consent document. Patients who refuse to participate or who withdraw from the study 
will be treated without prejudice. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 28 of 32 
 
 
Caphosol Study 
REFERENCES 
 
1. Sonis ST. The pathobiology of mucositis. Nature Reviews Cancer. 2004;4(4):277-84. 
2. Dodd MJ, Miaskowski C, Shiba GH, Dibble SL, Greenspan D, Macphail L, et al. Risk factors 
for chemotherapy-induced oral mucositis: Dental appliances, oral hygiene, previous oral lesions, 
and history of smoking. Cancer Invest. 1999;17(4):278-84. 
3. Sonis ST, Fey EG. Oral complications of cancer therapy. Oncology (Williston Park). 2002 
May;16(5):680,6; discussion 686, 691-2, 695. 
4. Barasch A, Peterson DE. Risk factors for ulcerative oral mucositis in cancer patients: 
Unanswered questions. Oral Oncol. 2003;39(2):91-100. 
5. Filicko J, Lazarus H, Flomenberg N. Mucosal injury in patients undergoing hematopoietic 
progenitor cell transplantation: New approaches to prophylaxis and treatment. Bone Marrow 
Transplant. 2003;31(1):1-10. 
6. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of 
cancer therapy. Cancer. 2003;98(7):1531-9. 
7. Avritscher EB, Cooksley CD, Elting LS. Scope and epidemiology of cancer therapy-induced 
oral and gastrointestinal mucositis. Seminars in oncology nursing; Elsevier; 2004. 
8. Dodd MJ, Dibble S, Miaskowski C, Paul S, Cho M, MacPhail L, et al. A comparison of the 
affective state and quality of life of chemotherapy patients who do and do not develop 
chemotherapy-induced oral mucositis. J Pain Symptom Manage. 2001;21(6):498-505. 
9. Pico JL, Avila-Garavito A, Naccache P. Mucositis: Its occurrence, consequences, and treatment 
in the oncology setting. Oncologist. 1998;3(6):446-51. 
10. Saunders DP, Epstein JB, Elad S, Allemano J, Bossi P, van de Wetering, Marianne D, et al. 
Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the 
management of oral mucositis in cancer patients. Supportive Care in Cancer. 2013;21(11):3191-
207. 
11. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, et al. Oral mucositis and the 
clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol. 2001 
Apr 15;19(8):2201-5. 
12. Spijkervet FK, Sonis ST. New frontiers in the management of chemotherapy-induced 
mucositis. Curr Opin Oncol. 1998 Aug;10 Suppl 1:S23-7. 
13. Quinn B. Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and 
treatment of oral mucositis in patients receiving high‐dose cancer therapy: A review of current 
data. European journal of cancer care. 2013;22(5):564-79. 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 29 of 32 
 
 
Caphosol Study 
14. Papas A, Clark R, Martuscelli G, O'loughlin K, Johansen E, Miller K. A prospective, 
randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell 
transplantation. Bone Marrow Transplant. 2003;31(8):705-12. 
15. Raphael M, den Boer A, Kollen W, Mekelenkamp H, Abbink F, Kaspers G, et al. Caphosol, a 
therapeutic option in case of cancer therapy-induced oral mucositis in children? Supportive Care 
in Cancer. 2014;22(1):3-6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 30 of 32 
 
 
Caphosol Study 
APPENDIX 1 
Eligibility Checklist 
 
INCLUSION CRITERIA 
 
#1 -3 of the following Inclusion Criteria must be marked “Yes” for the patient to enroll on study. 
 
1. Yes ☐   No ☐  Risk of developing oral mucositis during cancer therapy. 
Patients receiving one or more of the following chemotherapy agents associated with high 
incidence of oral mucositis (Must check at least one of the following): 
☐ Actinomycin D 
☐ Carboplatin 
☐ Cisplatin 
☐ Cytarabine at doses ≥ 1 gram/m2 
☐ Daunorubicin 
☐ Doxorubicin 
☐ Methotrexate at doses > 1 gram/m2 
☐ Mitoxantrone 
 
2. Yes ☐   No ☐  Patient Age: Patient is 0 to 25 years of age 
 
3. Yes ☐   No ☐  Informed Consent: Voluntary written consent obtained before performance 
of any study-related procedure not part of normal medical care. 
 
EXCLUSION CRITERIA 
Each of the following questions must be marked “No” Or “N/A” for the patient to enroll on 
study 
 
1. Yes ☐   No ☐  N/A ☐ Patient is receiving glutamine therapy for mucositis. 
 
2. Yes ☐   No ☐  N/A ☐ Patient is receiving concurrent Head & Neck radiation therapy or 
within 6 weeks of completing radiation therapy 
 
3. Yes ☐   No ☐  N/A ☐ Patient is receiving autologous or allogeneic hematopoietic cell 
transplantation 
 
4. Yes ☐   No ☐  N/A ☐ Female patient who is pregnant or lactating.  
 
5. Yes ☐   No ☐  N/A ☐ Patient has known allergy to Caphosol. 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 31 of 32 
 
 
Caphosol Study 
APPENDIX 2 
Performance Status Criteria 
 
For patients 16 years of age and older: 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 
 
For patients less than 16 years of age: 
 
Lansky Performance Scale 
Lansky 
Score 
Play Score 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play but able to participate 
in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Caphosol Study  
 
 
 
Confidential   
 
 
 
 
Page 32 of 32 
 
 
Caphosol Study 
APPENDIX 3 
Pain Assessment Scales 
 
 Wong-Baker FACES Pain Rating Scale 
 
  
 
0 = Very Happy, No Hurt 
1 = Hurts Just a Little Bit 
2 = Hurts a Little More 
3 = Hurts Even More 
4 = Hurts a Whole Lot 
5 = Hurts as Much as You Can Imagine (Don’t have to be crying to feel this much pain) 
 
Explain to the person that each face is for a person who feels happy because he has no pain (no 
hurt) or sad because he has some or a lot of pain. Face 0 is very happy because he doesn’t hurt at 
all. Face 1 hurts just a little bit. Face 2 hurts a little more. Face 3 hurts even more. Face 4 hurts a 
whole lot. Face 5 hurts as much as you can imagine, although you don’t have to be crying to feel 
this bad. Ask the person to choose the face that best describes how he is feeling. 
 
Pain Rating scale is recommended for subject’s age 3 years and older. 
 
Brief Word Instructions: Point to each face using the words to describe the pain intensity. Ask 
the child to choose face that best describes own pain and record the appropriate number. 
 
Likert 0–10 Numeric Pain Rating Scale