Conditions: Oral Mucositis
Keywords: Oral Mucositis Cancer Chemotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if the administration of Caphosol rinse, at the start of chemotherapy, will prevent the development of mucositis (greater than or equal to grade 2 in children, adolescents and young adults. This is a randomized, controlled trial.

Detailed description:
Oral mucositis, is a common and debilitating complication of cancer therapy. It is an inflammatory injury to the epithelial and sub-epithelial cells of the oral mucosa. 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. This ranges from around 40% of patients getting chemotherapy for solid tumors to 70-90% of patients getting chemotherapy for before stem cell transplant.

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. Patients may require hospitalization for management of the complications of mucositis, including poor nutrition, dehydration and pain. Injury to the oral mucosa also increases the risk of systemic infections. Finally, the development of oral mucositis may require delays or dose reductions in future chemotherapy courses, potentially jeopardizing disease cure rates.

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 (Jazz Pharmaceuticals, Inc. Palo Alto, CA) 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.

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.

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.

Arms:
arm 1: Caphosol Arm: Subjects randomized to the Caphosol Arm will use Caphosol 4 times per day from the start of chemotherapy until 7 days after the completion of chemotherapy AND until the ANC is \>500 after count recovery OR until the the symptoms or oral mucositis resolve, whichever occurs last. Patients will also complete a study diary to record symptoms of oral mucositis. arm 2: Control Arm: Subjects randomized to the Control Arm will use Biotene 4 times per day. They will also complete a study diary to record doses and any symptoms of oral mucositis. This will begin at the start of chemotherapy until for 7 days AND until ANC \>500 after nadir or oral mucositis resolves (whichever occurs later)

Interventions: intervention 1: Caphosol intervention 2: Biotene
Intervention descriptions: intervention 1: 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 Participants may increase the use to 6 times per day if you 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.

  * For younger patients (less than or equal to 6 years of age), volume may be reduced to two syringes containing 5-10 mL each.
  * For patients unable to successfully rinse and spit, caregivers may paint their mouth (using medical sponge swabs) with the solution two times. 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.
* Patients may use Biotene (5-10 mL) to swish and spit after the 15 minutes has passed intervention 2: • 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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 


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


 
 
 
 
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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 


 
 
 
 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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 


 
 
 
 
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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. 


 
 
 
 
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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 


 
 
 
 
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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 


 
 
 
 
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 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. 
 
 
 
 


 
 
 
 
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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.  


 
 
 
 
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 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) 
 
 


 
 
 
 
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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 


 
 
 
 
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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.  
 
 
 
 
 
 
 


 
 
 
 
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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. 
 
 
 


 
 
 
 
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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 


 
 
 
 
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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. 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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. 
 
 


 
 
 
 
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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 


 
 
 
 
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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 


 
 
 
 
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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 
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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. 
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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. 
 
 
 
 


 
 
 
 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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. 


 
 
 
 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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. 
 
 
 
 
 
 


 
 
 
 
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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 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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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 
 
 

ICF_001.pdf: 
 
 
 
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CHILDREN’S HOSPITAL OF WISCONSIN INSTITUTIONAL REVIEW BOARD 
STATEMENT OF VOLUNTEER CONSENT FOR RESEARCH STUDY 
 
TITLE OF STUDY:  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 Burke, MD    PHONE:  414-955-4170 
 
CO-PRINCIPAL INVESTIGATORS:   Melissa Acquazzino, MD     PHONE:  414-955-4170 
        Molly Brickler, NP 
      PHONE:  414-266-3675 
        Kristen Tews, PA 
      PHONE:  414-266-3050 
 
STREET ADDRESS:  8701 Watertown Plank Road, MFRC 3018, Milwaukee, WI  53226 
 
E-MAIL ADDRESS:   
mmburke@mcw.edu FAX NUMBER:  414-955-6543 
 
 
 
   
macquazzi@mcw.edu  
 
 
 
 
mbrickler@chw.org 
 
 
 
   
ktews@chw.org  
 
SUB-INVESTIGATORS:   Meghen Browning, MD                 
414-955-4170 
Bruce Camitta, MD      
 
414-955-4170 
 
 
 
 
Sarah Dobrozsi, MD  
 
414-955-4170 
Paul Harker-Murray, MD, PhD 
414-955-4170 
Michael Kelly, MD, PhD 
 
414-955-4170 
Jeffrey Knipstein, MD 
 
414-955-4170 
 
 
 
 
Julie-An Talano, MD  
 
414-955-4170 
Richard Tower, MD  
 
414-955-4170 
 
Name of Subject _________________________________ Medical Record No. ___________ 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you and the assent (agreement) of your child may be required.  When the word “you” appears in 
this consent form, it refers to you or your son or daughter; “we” means the doctors and other 
staff. 
 
We invite you to take part in this research study.  Taking part in this research study is your 
decision.  You do not have to participate.  You may stop or decide to leave the study at any 
time.  If you stop or leave the study, you will not be penalized.  You will still receive any 
treatments, help, or benefits coming to you.  The information in this Consent form is 
supposed to help you understand what the research team thinks is hurting your health, and 
what they think can be done to treat your condition.   
Subject Label 


 
 
 
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This form explains what will happen in the research study.  The researchers may be 
reviewing this form with you and can answer any questions you may have.  This form also 
tells you about the risks, discomforts, and other information about the study.  
 
Medical language is hard to understand for most people.  If there is anything that you do 
not understand or are unsure about, please ask questions.  You should only agree to take 
part in this research study and sign the Consent form if you understand what will happen 
to you, what the risks are, and that your questions have been answered. 
 
A.  WHAT IS THE PROBLEM? 
 
This study is a clinical trial (a protocol, or research study involving patients) of an experimental 
new treatment for children and young adults who will be receiving chemotherapy. Clinical trials 
only include patients who choose to take part.  
 
This study is being carried out by the Pediatric Clinical Trials Office (CTO) for the Medical 
College of Wisconsin.  Treatment will take place at Children’s Hospital of Wisconsin.  
 
You are being asked to take part in this research study because you are about to receive 
chemotherapy.  Patients receiving chemotherapy are at risk of getting a painful inflammation 
(swelling) of the mucous membranes (the skin inside your mouth) called mucositis. 
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between other treatments for mucositis and this clinical trial.  
 
Please take your time to make your decision. Discuss it with your friends and family. We 
encourage you to include your child in the discussion and decision to the extent that she or he is 
able to understand and take part. 
 
B.  WHAT IS THE PURPOSE OF THIS RESEARCH STUDY? 
 
In this study, researchers want to find out if there is a difference in development of oral mucositis 
using Biotene mouth rinse compared to Caphosol mouth rinse.  
 
Caphosol , manufactured by EUSA Pharma,  is a mouth rinse designed to moisten, lubricate and 
clean the mouth, including the mucosa of the mouth, tongue and oropharynx. Studies with adults 
have shown that Caphosol is beneficial in the prevention and treatment of oral mucositis in 
patients receiving high-dose chemotherapy and/or radiation therapy. This data supported adding 
caphosol to treatment plans designed to prevent treat oral mucositis.  
 
The use of Caphosol to prevent oral mucositis in children receiving chemotherapy is 
experimental. 
 


 
 
 
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The overall goal of this study is to: 
 
 To determine if topically administered Caphosol at the start of chemotherapy is a 
viable option to prevent the development of oral mucositis in children, adolescents 
and young adults. 
 To determine the tolerability of four times daily Caphosol therapy. 
 
 
What is the Current Standard Treatment for This Disease? 
 
There is no standard of treatment to prevent oral mucositis in children, adolescents, and young 
adults. Treatments that have been used in the past to try to reduce mucositis or make patients 
more comfortable include ice chips, mouthwashes, and a variety of different drugs. Many 
different treatments are used and work to some extent, but none have prevented mucositis from 
occurring in the first place or have been shown to make it heal faster.   
 
How Many People Will Take Part In This Study? 
 
About 96 subjects from infant to 25 years of age will take part in this study.  48 subjects will 
receive Caphosol and Biotene and 48 subjects will receive Biotene only as a comparison group.  
All 96 subjects will be from Children’s Hospital of Wisconsin. 
 
C.  WHAT IS INVOLVED IN THIS STUDY? 
 
What Will Happen on This Study That is Research? 
 
The study involves the use of Caphosol and/or Biotene* used as an oral rinse. Subjects (people 
participating in the study) will receive 1 of 2 different arms which are explained below. The 
study arms use either the Caphosol along with the Biotene as an oral rinse (the experimental 
arm), or the Biotene only as an oral rinse (the control/ comparison arm) starting on the first day 
of chemotherapy. You will use the oral rinse 4 times each day. However, if you develop severe 
mucositis, you have the choice to use the study rinse up to 6 times each day.  
 
Treatment with Caphosol and Biotene), or the Biotene rinse only,  will continue for 7 days after 
completion of chemotherapy AND until the Absolute Neutrophil Count (ANC)** is greater than 
500 after white blood cell count recovery or until the symptoms of oral mucositis resolve; 
whichever occurs last. If you do not have mucositis at all, you will stop treatment on Day 7 but 
study doctors will continue to examine your mouth until your white blood cell count recovers. 
 
*Biotene is a soothing rinse that gently cleans and helps relieve dry mouth symptoms. This is 
used as standard of care for oncology patients getting chemotherapy to help prevent mouth 
infections.  
** Absolute Neutrophil Count is a measure of the number of Neutrophils, a type of white blood 
cell that fights infection 
 


 
 
 
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Each participant will use a Study Diary to document any incidence of oral mucositis beginning 
after the start of chemotherapy.  You will also record the severity of oral mucositis.  This study 
will compare the results of the two arms and evaluate the effect and tolerability of using 
Caphosol as a preventative for oral mucositis.      
 
Caphosol Arm:  Subjects in the Caphosol Arm will begin using Caphosol the same day they 
begin chemotherapy, at least 4 times per day, and will continue to use Caphosol for 7 days after 
completion of chemotherapy AND until the Absolute Neutrophil Count (ANC) is greater than 
500 after white blood cell count recovery OR until the symptoms of oral mucositis resolve; 
whichever occurs last.  You will also keep a diary to write down your symptoms while using 
Caphosol. Your study team will explain what kinds of things to write down in this diary.  
 
Subjects in the Caphosol arm will also use Biotene, the standard of care,  as a rinse but must wait 
for 15 minutes after using the Caphosol rinse. 
 
Control Arm:  Subjects in the Control Arm will not receive Caphosol as a preventative, but will 
use Biotene only to rinse and spit.  Biotene is standard of care for our oncology patients getting 
chemotherapy to help prevent mouth infections. You will also keep a diary to write down your 
symptoms while using Biotene.  Your study team will explain what kinds of things to write down 
in this diary..  If you develop oral mucositis and your care team thinks it’s in your best interest to 
add Caphosol as a treatment, you will be removed from study and you will then receive 
Caphosol as prescribed by your care team. 
 
Random Assignment 
 
Subjects (people participating in the study) will receive 1 of 2 different arms. The arm they 
receive is decided by a process called randomization. Randomization means that the treatment is 
assigned based on chance. It is a lot like flipping a coin, except that it is done by computer to 
make sure that there are about the same number of people on each treatment arm of the study. 
You will have an equal chance of being placed in either of the arms. The randomization process 
is described in the COG Family Handbook for Children with Cancer. 
 
Treatment 
 
Caphosol Arm:  Subjects randomized to the Caphosol Arm will use Caphosol and Biotene 4 
times per day as follows: 
 
 
Each dose consists of one blue and one clear ampule.   
 
Mix the contents of 1 blue ampule (Caphasol A) and 1 clear ampule (Caphasol B), in a 
clean glass.   
 
Note: Caphosol must be used within 15 minutes of mixing. 
 
Using 1/2 of the solution, swish thoroughtly and gargle (if you are able) for one minute 
and then spit. Repeat using the remaining ½ of the solution.  


 
 
 
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o For subjects who are 6 years old or younger and are not able to swish the 
full 15ml (half of the solution), you may reduce the amount of solution used to 5-
10 mL for each rinse.  
o If you are unable to rinse and spit, caregivers may paint your mouth (using 
medical sponge swabs) with the solution two times.  
 
Mix the blue ampule with the clear ampule as above. Soak up ½ the 
solution and use the swab to coat the inside of the patient’s mouth. Repeat 
using the remaining solution. 
 
You are to avoid other oral medications, other mouth cares and food or drink for 15 
minutes after using Caphosol.  
 
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.  
 
You may increase the use of Caphasol from 4 times per day  to 6 times per day if you 
have symptoms of mucositis. 
 
Control Arm:  Subjects randomized to the Control Arm will use Biotene 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. 
 
 
Research Study Procedures 
 
You will have tests and procedures as defined by the chemotherapy treatment you are receiving.  
At each clinic visit your care providers will assess your pain level and the need for further oral 
pain relief based on your responses. 
  
Research Measurements 
 
The only test that will be done because you are part of this study is the careful measurement of 
mouth sores. There should be no extra visits because of this study. The time to discharge home 
or the number of visits after discharge home will not be increased due to participating in this 
study. 
 
Oral Mucositis Measurements:  Subjects that participate in this clinical trial will have oral 
mucositis measured daily throughout treatment starting on Day 1 of scheduled chemotherapy. 
This will involve recording details such as your ability to eat, and the amount of pain you have. 
Each mucositis measurement will take about 5 minutes. A healthcare provider will ask you 
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These are the measurements that will be completed by a trained healthcare professional: 
 
1. Pain Rating Scale 
 
Measurements will be done before treatment starts, and then daily until one of the following 
occurs: 
 
1. 7 days have passed since the scheduled chemotherapy; and 
2. You have adequate white blood cell recovery; and 
3. You are discharged from the hospital to go home 
4. You no longer agree to participate in daily mucositis measurements 
 
How Long Will You Be in the Study?     
 
Subjects in this clinical trial may participate for each of their scheduled chemotherapy cycles.  
Depending on your chemotherapy schedule, your participation may last up to 6 or 8 months.   
 
Your doctor or study doctor may decide to take you off this study for the following reasons:  
 
 If he/she believes that it is in your best interest 
 If you experience side effects from the treatment that are considered too severe 
 If new information becomes available that shows that another treatment would be better 
for you  
 If the study is stopped 
 If you do not follow study directions 
 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the researcher and your regular doctor first.  They will help you stop 
safely. 
 
D.  WHAT ARE THE RISKS TO YOU IN THIS RESEARCH STUDY? 
  
Risks for Subjects Who Receive Caphosol (Study Risk) 
 
The use of a Caphosol rinse may cause complications in children. However, there are no known 
risks or side effects when Caphosol is used as a mouth rinse in adults. If Caphosol is swallowed 
accidentally, no side effects are expected. There is a risk of salty or unpleasant taste. There are 
no known interactions with other medicines. 
 
Risks for Subjects Who Receive Biotene Rinse (Study Risk) 
 
The risk of receiving any side effects from using the Biotene rinse is very small.  Biotene 
products have been found not to cause any significant side effects.  Biotene products are made of 


 
 
 
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natural ingredients, and are free of alcohol, sugar, and gluten, which are common causes of 
allergies and product sensitivities.  However, there is still a risk of allergic reaction or sensitivity 
to Biotene. The use of natural ingredients and low-foaming formulas that restore moisture to the 
mouth minimize the risk of encountering any side effects. 
 
In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
 
Reproductive Risks 
 
Women should not become pregnant and men should not father a baby while on this study 
because it is not known if the Caphosol used in this study can be bad for an unborn baby. If you 
or your partner can get pregnant, it is important for you to use birth control or not have sex while 
on this study. Check with your study doctor about what kind of birth control methods to use and 
how long to use them. Some birth control methods might not be approved for use in this study. 
Women should not breastfeed a baby while on this study. Also check with your doctor about 
how long you should not breastfeed after you stop the study treatment(s). 
 
E.  WHAT IF PROBLEMS OCCUR DURING THE STUDY OR WITH TREATMENT? 
 
Your health is more important than following the research plan. If any changes are needed to 
protect your health, we will talk with you about them before they are made.  We will also tell 
you if a better treatment is discovered somewhere else.  If you want, this treatment will be given 
to you in place of or in addition to the current plan.  A Data Safety and Monitoring Committee, 
an independent group of experts, will be reviewing the data from this research throughout the 
study. We will tell you about the new information from this or other studies that may affect your 
health, welfare, or willingness to stay in this study. 
 
If you think you have been injured as a result of the experimental parts of this research study, 
you should immediately contact Michael Burke, MD at 414-955-4170.  You may also call the 
Chairperson of the Children’s Hospital of Wisconsin Institutional Review Board that reviewed 
this research study at 414-266-2986.   
 
In the event that this research activity results in an injury, care for such injuries will be billed in 
the ordinary manner to you or your insurance company.  Insurance companies may refuse to pay 
for injuries sustained while participating in a research study or while receiving a treatment that is 
considered experimental.   If you think that you have suffered a research-related injury, let the 
study physician(s) know right away. 
 
By signing this form, you do not waive your legal right to seek other compensation for study 
related injuries.   
 
 
 
 


 
 
 
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F.  WHAT ARE THE POSSIBLE BENEFITS TO YOU IN THIS RESEARCH STUDY? 
 
We hope that you will get personal medical benefit from participation in this clinical trial, but we 
cannot be certain.  
 
Taking part in this study may or may not make your health better.  While doctors hope Caphosol 
will be useful to prevent oral mucositis, there is no proof of this yet.  We expect that the 
information learned from this study will benefit other patients in the future. 
 
G.  WHAT ARE THE FINANCIAL RISKS TO YOU IN THIS RESEARCH STUDY? 
 
If you take part in this study, the Caphosol will be billed to your insurance company, so there 
will be added costs to you or your insurance company. Caphosol is more expensive than Biotene.  
Some third party payers (insurance companies, HMOs, etc.) may not pay for hospitalization, 
treatments or procedures which are determined to be experimental or research related.  The study 
has no plans to pay for medical treatment.  All costs not paid by your insurance will be your 
financial responsibility.  Please ask about any expected added costs or insurance problems.  
Financial Counselors are available to discuss insurance, costs and other issues.   
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury.   
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout.    You can print a 
copy of the Clinical Trials and Insurance Coverage information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy of Clinical Trials and Insurance Coverage. 
 
H.  WILL YOU BE PAID FOR TAKING PART IN THIS RESEARCH STUDY? 
 
There are no plans to pay you for taking part in this study.  
 
I.  DO YOU HAVE TO TAKE PART IN THIS RESEARCH STUDY? 
 
You do not have to participate in this study.  You may choose not to be in this study. If you 
decide not to be in this study, you will not be penalized and you will not lose any benefits to 
which you are entitled.  You will still receive the best medical care this hospital can provide. 
 
If you choose to participate, you are free to withdraw at any time.  Your decision to withdraw 
will not change the quality of care that you receive from the Medical Staff.  However, if you 


 
 
 
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decide to stop participating in the study, we encourage you to talk to the researcher and your 
regular doctor first so any risks from the treatment can be evaluated by your doctor and he or she 
will tell you how to stop safely.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
You also have the right to know about new information that may affect your health, welfare, or 
your willingness to participate in the study. You will be provided with this information as soon 
as it becomes available.  A committee closely monitors study reports and notifies the Principal 
Investigator if changes must be made to the study.  Members of the Data Safety Monitoring 
Committee meet twice a year to discuss results of treatment. 
 
What Other Options Are There?  
 
Instead of being in this study, you have these options: 
 
 Current standard therapy even if you do not take part in the study. Standard therapy is to 
receive Caphosol after mucositis is diagnosed  
 Taking part in another study 
 
Please talk to your doctor about these and other options. 
 
J.  WHAT IF YOU HAVE MORE QUESTIONS? 
 
For questions about the study or a research-related injury, contact the researcher, Michael Burke, 
MD at 414-955-4170.  Dr. Burke or a member of the Investigation team will be available 24-
hours a day, 7 days a week at 414-266-3050.  If additional questions arise, you can ask your 
doctor.  Also, the research study has been reviewed and approved by the Children’s Hospital of 
Wisconsin Institutional Review Board, whose purpose is to see that the rights and welfare of 
research participants are adequately protected, and that risks are balanced by potential benefits.  
A member of this committee is available to speak to you if you have any questions or complaints 
at 414-266-2986. 
 
Where Can You Get More Information? 
 
Resources for additional information on clinical trials and cancer care include: 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor 
can 
get 
you 
this 
Handbook, 
or 
you 
can 
get 
it 
at 
http://www.childrensoncologygroup.org/familyhandbook 
 
If you are in the United States, you may call the NCI’s Cancer Information Service at: 
1–800–4–CANCER (1–800–422–6237)  
 
You may also visit the NCI Web site at http://www.cancer.gov/ 


 
 
 
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 For NCI’s clinical trials information, go to: http://www.cancer.gov/clinicaltrials/ 
 
Visit the COG Web site at http://www.childrensoncologygroup.org 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/ 
 
You will get a copy of this form.  You may also ask for a copy of the protocol (full study plan).  
A copy of the signed consent, assent (if applicable), and HIPAA Authorization will be kept in 
your medical record. 
 
K.  WILL INFORMATION BE CONFIDENTIAL? 
 
Children's Hospital of Wisconsin/Children's Health System, its researchers and their designees 
will maintain the privacy and confidentiality of your personal and health information to the 
extent permitted by law.  Efforts will be made to keep your personal information confidential. 
We cannot guarantee absolute confidentiality. Your personal information may be disclosed if 
required by law.  Also, scientific data from this study, without identifiable information, may be 
presented at meetings and published so that it may be useful to others, as long as it is not 
identifiable with you.  You may read your medical record. 
 
Organizations that may look at and/or copy your research or medical records for quality 
assurance and data analysis include: 
 
 Representatives of the National Cancer Institute (NCI) and other US and International 
governmental regulatory agencies involved in overseeing research  
 Children’s Hospital of Wisconsin Institutional Review Board (CHW IRB) 
 The Food and Drug Administration (FDA) may inspect study records 
 
L.  PERMISSION TO PROCEED 
 
The signing of this consent does not release your doctors from their responsibility for your 
proper medical care at all times. 
 
The proposed research study and consent has been explained to you by: 
 
___________________________________    __________________________      ________ 
Name of Principal Investigator or Designee 
   Signature of Principal or Designee        Date 
 
When you sign this form, you agree that you have read the above description of this research.  
You also agree that you have had a chance to discuss the research study with a member of the 
research team; that your questions have been answered, and that you want to take part in this 
research. 
 
__________________________________________________ 
 
____________ 
Signature of Subject or Authorized Representative  
 
 
Date 


 
 
 
APPROVED 05/09/16 CHW IRB 
 
11 of 12 
Protocol Version 2.0 Dated 02/24/2016 
 
__________________________________________________ 
 
____________ 
Signature of Subject or Authorized Representative  
 
 
Date 
 
AGE OF MAJORITY SIGNATURE: (To be signed when the subject reaches age of 
majority (18 years of age) 
 
Now that you have reached the age of majority (18 years old), we are asking for your consent for 
continued participation in this research study.  The age of majority means you are considered an 
adult and are able to sign legal contracts and consents for yourself. 
 
When you sign this form, you confirm that the purpose of the research, the study procedures, and 
the possible risks and discomforts as well as potential benefits that you may experience with 
your continued participation have been explained to you.  Alternatives to your continued 
participation in the study also have been discussed.  You have read the informed consent and/or 
it has been explained to you.  You were given the opportunity to ask questions about the 
information, all of your questions have been answered, and you want to take part in this research.   
A copy of this signed informed consent form will be given to you. 
 
By signing below, you agree to continue your participation in this research study. 
 
Participant ___________________________________ 
Date ____________________ 
 
PI or Designee ________________________________ 
Date ____________________ 
 
CONSENT OF NON-ENGLISH SPEAKING SUBJECTS: 
 
A witness signature is required for all consent conferences involving an interpreter.  Witness 
cannot be the Interpreter. 
 
An oral translation of this document was administered to the subject in ____________________ 
(state language) by an individual proficient in English and ____________________ (state 
language).  See the attached short form (as applicable) for documentation. 
 
________________________________________ 
Name of Interpreter 
 
 
___________________________________      __________________________      ________ 
Name of Witness                                                Signature of Witness                       Date 
 
ASSENT OF MINOR: 
 
“The above has been explained to me and I agree to participate.” 
 
__________________________________________________ 
 
____________ 


 
 
 
APPROVED 05/09/16 CHW IRB 
 
12 of 12 
Protocol Version 2.0 Dated 02/24/2016 
Signature of Minor 
 
 
 
 
 
 
 
Date  
 
 
 
WAIVER OF MINOR'S ASSENT: 
 
In my opinion, this child is not capable of assent because _______________________________ 
 
_____________________________________________________________________________ 
 
__________________________________________________ 
 
____________ 
Signature of Principal Investigator or Research Team Designee 
 
Date