Evaluation of an Exercise Intervention for Vincristine Induced Peripheral Neuropathy in Pediatric Cancer Patients
Phase: NA
Conditions: Peripheral Neuropathy
Sponsor: Indiana University

  
 
Evaluation of an Exercise intervention for Vincristine induced peripheral neuropathy in pediatric 
cancer patients 
 
 
INDIANA UNIVERSITY PROTOCOL IUSCC-0607 
 
 
Coordinating Center: Indiana University Melvin and Bren Simon Cancer Center 
 
 
Principal Investigator: 
Jamie L. Renbarger, MD, MS 
705 Riley Hospital Drive, ROC 4340 
Indianapolis, IN 46202 
Email: jarenbar@iu.edu 
Phone: 317-274-7309 
 
 
Co-Investigators: 
 
Kamnesh Pradhan, MD 
Tammy J. Sajdyk, PhD, MS 
Stephanie Hullmann, PhD 
Kelly Naugle, PhD 
Jane Marshall, MS 
 
 
Study Statisticians: 
 
 
 
 
 
Joanne Daggy, PhD 
 
 
  Funder:                            
Indiana Clinical and Translational Sciences Institute (CTSI): IU Grant Linking 
University-Wide Expertise (GLUE) 
 
 
 
 
Protocol Version: 
 
May 10, 2019 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
A. FLOW DIAGRAM _____________________________________________________________ 4 
B. SPECIFIC AIMS ______________________________________________________________ 4 
C. BACKGROUND & RATIONALE __________________________________________________ 5 
D. INNOVATION ________________________________________________________________ 7 
E. CONCEPTUAL MODEL ________________________________________________________ 8 
F.  ELIGIBILITY CRITERIA ________________________________________________________ 11 
F.1 
Inclusion criteria ................................................................................................................................... 11 
F.2 
Exclusion Criteria ................................................................................................................................. 11 
G. PATIENT RECRUITMENT _____________________________________________________ 11 
G.1 
Potential enrollment problems and alternative approaches ................. Error! Bookmark not defined. 
H. RESEARCH DESIGN _________________________________________________________ 11 
H.1 
Sample size justification ....................................................................................................................... 12 
H.2 
Fitbit tracker justification....................................................................................................................... 12 
I. 
PROCEDURES ______________________________________________________________ 12 
I.1 
Overview ............................................................................................................................................... 12 
I.2 
Intervention timeline ............................................................................................................................. 13 
I.3 
Exercise (EX) Intervention ................................................................................................................... 13 
I.4 
Demographic and Clinical Data Collection/Measures ......................................................................... 15 
I.5 
Blood Sample Collection ...................................................................................................................... 20 
I.6 
Data Processing and Storage .............................................................................................................. 20 
I. 7 
Treatment fidelity .................................................................................................................................. 21 
I.8  
Compensation for Participation ............................................................................................................ 21 
J. 
DATA ANALYSIS ____________________________________________________________ 22 
J.1 
Baseline Analysis ................................................................................................................................. 22 
J.2 
Aim 1 & 2 Analysis ............................................................................................................................... 22 
J.3 
Missing Data ......................................................................................................................................... 23 
K. RISKS OF PARTICIPATION AND PROTECTION OF HUMAN SUBJECTS ________________ 23 
K.1 
Risks ..................................................................................................................................................... 23 
K.2 
Protection ............................................................................................................................................. 23 
K.3 
Reporting to the IRB ............................................................................................................................. 24 
K.4 
Reporting to the IUSCC Data Safety Monitoring Committee .............................................................. 24 
L. STUDY WITHDRAWAL/DISCONTINUATION ______________________________________ 25 

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M. PATIENT CONSENT AND PEER JUDGEMENT ____________________________________ 25 
N. REFERENCES ______________________________________________________________ 25 
O. APPENDICES _______________________________________________________________ 31 
APPENDIX I – Exercise Schedule .................................................................................................................. 31 
APPENDIX II – Exercise Video Outline .......................................................................................................... 31 
APPENDIX III – Daily Exercise Log ................................................................................................................ 31 
APPENDIX IV – Neuropathy: Total Neuropathy Score (TNS-PV) ................................................................. 31 
APPENDIX V – Clinical Total Neuropathy Score (TNSc) ................................................................................... 
APPENDIX VI - Pediatric Chemotherapy-Induced Neuropathy Patient (P-CIN) Survey v4 .......................... 31 
APPENDIX VII – Pediatric Neuropathic Pain Scale Five ............................................................................... 31 
APPENDIX VIII – Pain: FACES Pain Rating Scale ........................................................................................ 31 
APPENDIX IX – Adverse Events: NCI CTCAE V4.02 .................................................................................... 31 
APPENDIX X – Quality of Life: Pediatric Quality of Life Inventory: Peds QL Scale 4.0 ................................ 31 
APPENDIX XI – Ferrans and Powers Quality of Life Cancer v3 
APPENDIX XII - Self-efficacy, Support and Outcome Expectations Questionnaire ...................................... 31 
APPENDIX XIII – Standardized Fitness Assessment .................................................................................... 31 
APPENDIX XIV – Patient Satisfaction Survey ............................................................................................... 31 
   APPENDIX XV - Parent/Care Giver Satisfaction Survey 
  
 
 
 
 
 

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A. FLOW DIAGRAM 
 
 
B. 
SPECIFIC AIMS  
Although there are only a few studies examining the long-term sequelae of cancer treatment in the pediatric 
population, the overarching conclusion is, during adulthood, these survivors will have a significant increase 
in chronic health issues, such as obesity, type 2 diabetes, metabolic syndrome and cardiovascular 
disease1-4. These health issues have a high cost for individuals and society. Researchers hypothesize 
that the development of these conditions is due to survivors having a higher risk of motor impairment because 

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of exposure to vincristine. Vincristine is a chemotherapeutic agent used in a multi-drug regimen to treat 
pediatric, adolescent and young adult (AYA) cancers, particularly acute lymphoblastic leukemia (ALL) and 
Lymphoblastic lymphoma (LL).  
Exposure to vincristine during the first four weeks of treatment induces clinically significant neuropathy in 78% 
of children5. The trajectory for children with intermediate to severe neuropathy peaks around week 14 5. All 
forms of neuropathy, sensory, motor, and autonomic can arise in children and adolescents; however, motor 
deficits are the most frequent and can persist into adulthood6. With the increase in use of multi-drug 
chemotherapy, survival of children with ALL and LL has reached between 80% - 90%7,8. Thus, the health 
impact of VIPN in adult survivors of pediatric cancer is now becoming apparent. 
Despite the 80% - 90% survival rate, there are no effective treatments or interventions for vincristine-
induced peripheral neuropathy (VIPN) and one is urgently needed. Our long-term goal is to develop and 
implement interventions to minimize the persistent effects of VIPN. The proposed study will assess the 
feasibility of exercise (EX) as a therapeutic intervention for pediatric patients with ALL and LL who have 
clinically significant VIPN. The EX component will be a mix of aerobic, dynamic resistance and isometric 
exercises. Emerging data support the notion that exercise protects against chemotherapy-induced peripheral 
neuropathy (CIPN)9 and may help repair damaged nerves after CIPN develops10. Specifically, exercise 
increases many molecular signals, such as nerve growth factor (NGF), growth associated protein 43 (GAP 43) 
and synapsin (SNAP1), which induce axonal repair in peripheral nerves11. Exercise also decreases levels of 
serum chemerin12, a pro-inflammatory protein and genetic marker associated with VIPN in children. The 
primary objective of this study is to assess the feasibility as well as determine preliminary effect size estimates 
of EX in preparation for a fully powered efficacy trial. Forty children and AYA (ages 5-25 years) who are on 
treatment for ALL or LL and exhibit a total neuropathy score of 3 or greater, will be recruited. The impact of EX 
on the subject’s total neuropathy and quality of life, will be measured at baseline (T1) and following the 8-week 
study (T2). Our study will address the following specific aims: 
Aim 1: Evaluate the feasibility and acceptability of EX as an intervention for VIPN in pediatric patients with 
ALL and LL   
Hypothesis 1: Subjects will complete > 50% of the EX sessions during the 8-week intervention. 
Hypothesis 2: Children, AYA and parents will report satisfaction with the intervention and its components. 
 
Aim 2: Estimate preliminary effect sizes of the EX intervention.  
Hypothesis 1: The EX intervention will lead to improved VIPN (lower TNS-PV scores) at the end of the 
intervention T2 (14 weeks: primary endpoint) compared to baseline T1 (6 weeks) 
Hypothesis 2: The EX intervention will lead to improved secondary outcomes of VIPN (lower P-CIN scores), 
Neuropathic pain (lower NPS and CTCAE scores), Quality of Life (higher Peds QL V4 scores), and Physical 
activity (higher total activity time, more time with higher heart rate throughout the day, more exercises 
completed, and higher oxygen consumption) for patients at the end of the intervention (T2) compared to 
baseline (T1). 
Hypothesis 3:  The EX intervention will lead to increases in Biomarkers  of NGF, SNAP1, GAP 43, and PDGF-
BB and Chemerin at the end of the intervention (T2) compared to baseline (T1). 
Hypothesis 4:  Changes in key predictor variables (e.g. self-efficacy, outcome expectations, support) will be 
associated with changes in outcomes (e.g. neuropathy, pain, and quality of life). 
 
C. 
BACKGROUND & RATIONALE 
Vincristine-induced peripheral neuropathy (VIPN) 

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The most diagnosed pediatric cancer (ages 0-19) is leukemia (26%) with acute lymphoblastic leukemia (ALL) 
being the most common (75%) 7, while lymphoblastic lymphoma (LL) is a fast-growing type of Non-Hodgkins 
Lymphoma ( NHL) accounting for 2% of  all NHLs13. Patients with both ALL and LL receive Vincristine as part 
of their standard treatment plan utilizing the same treatment and dosing schedule13. 
Due to improved multidrug treatment regimens over the past 40 years, the 5-year survival rate for these 
children has increased from 57% to 80% - 90% 7,14. However, due to vincristine exposure, we know that 
approximately 78% of the children with ALL will develop severe peripheral neuropathy (Vincristine-
induced peripheral neuropathy: VIPN)5. To date there is no study on children with LL. VIPN is observed very 
early in treatment, usually within the first four weeks 15. The development of VIPN is characterized by 
progressive motor, sensory and autonomic loss of function and usually results in dose reductions of vincristine 
during treatment and thus an overall loss of therapeutic efficacy 16-18. While we know that methotrexate, 
another chemotherapeutic agent used in the treatment of ALL, can also have toxic effects, severe neuropathy 
induced by this drug is very rare (<1%) and manifests as a reversible optic neuropathy not a peripheral 
neuropathy19,20 
Long-term health outcomes in survivors of childhood cancers 
The development of VIPN not only jeopardizes therapy, but also negatively affects the function and 
quality of life for children long after the completion of treatment 21-24. Due to the increase in survival rate 
of children with cancer, researchers are able to more accurately assess the increased risk of severe diseases 
in adulthood as a result of chemotherapy exposure. A study of 531 adult survivors of pediatric cancer, who 
were on average 32 years post diagnosis, produced evidence that exposure to cumulative doses of vinca-
alkaloids significantly increases the risk of motor impairment, but not sensory impairment, in adulthood22. 
Additional studies have also shown significant increases in obesity, type 2 diabetes, metabolic syndrome and 
cardiovascular disease1-4. Unfortunately, evidence indicates that these survivors will not only experience at 
least one chronic condition (70%), but also at least one severe or life-threatening condition (>40%) in 
adulthood25,26.  To have increased risk to anyone of these conditions in adulthood is a major medical burden to 
the individual as well as society.  
Metabolism of vincristine and association with neuropathy 
Dr. Renbarger’s laboratory has been conducting research focused on VIPN in the pediatric population for more 
than a decade, and she is considered one of the leading experts in this field. Her research team has 
significantly moved this field forward by determining that vincristine is metabolized more efficiently by CYP3A5 
enzyme as compared to CYP3A4 27,28 and that the CYP3A5*1 allele, which is responsible for the fully 
functioning enzyme, is more prevalent in the African American population as compared to Caucasians 29,30. 
Furthermore, they revealed severity of VIPN is significantly worse in the Caucasian children without CYP3A5*1 
allele 30. These findings strongly impact the dosing strategy of children and AYA receiving vincristine as part of 
their chemotherapy regimen.  
Measurement of neuropathy in children, adolescent and young adults  
In addition to understanding the clinical pharmacology of vincristine, Dr. Renbarger and her collaborators have 
validated a modified version of the Total Neuropathy Score specifically for pediatric patients receiving 
vincristine TNS-PV5. The benefit of this version is its sensitivity to change over time (15 weeks) and feasible for 
use in children > 6 years of age.  
Potential biomarkers associated with VIPN 
A recent genome wide association study conducted in our laboratory revealed two significant single nucleotide 
polymorphisms (SNP) in a large cohort of pediatric patients with ALL. One SNP, rs10454966 is part of the 
COCH gene and is associated with progressive hearing loss and vestibular imbalance 31,32. Two studies of 
pediatric cancer survivors found hearing loss to be more prevalent in survivors as compared to controls 26,33, 

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suggesting the COCH gene SNP as a potential indicator of future hearing loss. The second SNP, rs7963521 is 
associated with plasma/serum levels of Chemerin 34. Chemerin, a protein, is processed from its 
preprochemerin form and can be involved in angiogenesis 35, adipogenesis 36, osteoblastogenesis 37 or 
inflammatory processes 38-40 pathways affected by chemotherapy. Recently, one study identified chemerin 
levels as an independent predictor for 5-year mortality in patients with gastric cancer 41. Given our preliminary 
findings it is important to investigate further into Chemerin as a novel target for understanding neuropathy, a 
potential biomarker for dosing vincristine during treatment and as an indicator of long-term consequences of 
treatment.  
Our research team has discovered two other potential biomarkers, Platelet Derived Growth Factor BB (PDGF-
BB) and Interleukin 13 (IL-13)42. Utilizing blood samples from pediatric ALL patients, Dr. Renbarger discovered 
PDGF-BB levels were negatively associated with worse peripheral neuropathy, while IL-13 was positively 
associated with it. The study proposed in this application is going to verify the preliminary data found for these 
biomarkers. 
Following peripheral nerve injury many neurotrophins and proteins are expressed to aid in the nerve repair 
process. In addition to the biomarkers found in our research study, PDGF-BB and IL-13, we will also measure 
three markers of neuronal repair: nerve growth factor (NGF), synapsin 1 (SNAP1), and growth associated 
protein 43 (GAP43). Molteni and colleagues (2004) demonstrated in a rodent model of nerve crush injury that 
rodents which exercised also displayed enhanced regrowth of axons that were associated with increased 
levels of NGF, GAP43, and SNAP111. There is also extensive evidence on the positive effects of exercise on 
sensory nerves and neuropathic pain. Cooper et al (2016) recently published a review on this topic discussing 
the mechanisms underlying exercise and explaining the role of the NGF, SNAP1, and GAP43 in the repair 
process10. 
Exercise for pediatric neuropathy 
Currently, there are only a few prevention and treatment studies in children and AYA with chemotherapy 
induced peripheral neuropathy (CIPN) and they all utilize pharmacotherapies as their interventions. These 
clinical trials have used carbamazepine – showing a small effect 43, oral glutamic acid – mixed results 44,45, and 
pyridoxine and pyridostigmine – beneficial in isolated cases 46. Even when searching extensive journal 
databases with broad terms such as, physical therapy interventions in pediatric patients with CIPN, no results 
are found 47. Although there is no evidence in the pediatric population, there is some data in the adult 
population to support exercise as an intervention for CIPN. In a randomized trial with 314 adults experiencing 
CIPN, – 6 weeks of walking and resistance training – induced a significant decrease in neuropathy as 
compared to usual care 48. A second smaller study examined 31 adults with lymphoma during chemotherapy 
treatment and found that 36 weeks of twice a week exercise significantly improved peripheral neuropathy 
symptoms9. Two key pre-clinical studies modeling nerve transection, demonstrated the impact of exercise in 
their model by showing animals assigned to running on a treadmill following injury had significantly greater 
axonal growth and when combined with Schwann cell grafts exercise could significantly increase myelin in the 
regenerated fibers of the animals49,50.  Currently, the benefits of exercise on neuropathy have not been studied 
at all in the pediatric population, even though the National Comprehensive Cancer Network set forth clinical 
practice guidelines in oncology for survivors regarding healthy lifestyle habits in 201451, with a major 
emphasis on exercise.  
 
D. 
INNOVATION 
Our trial has several innovative features including: (1) The only pediatric trial to develop a non-
pharmacological VIPN intervention; (2) Estimating effect sizes for a subsequent fully-powered efficacy trial of a 
non-pharmacological approach for VIPN; and (3) Including biomarkers as a secondary outcome measure to 
predict severity of VIPN. 

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E. 
CONCEPTUAL MODEL 
 
 
Social Learning Theory (SLT) developed by Bandura 52 is the framework for the interventions and approach in 
this proposed study. SLT proposes that learning is an interaction between cognitive processes, observation, 
and reinforcement in a social context, emphasizing both internal and external factors in the learning process53. 
Previous EX studies in children have demonstrated the importance of SLT constructs. Although there are 
several individual constructs within SLT that are important to increasing EX in children, it is important to note 
that these constructs also have a strong influence on each other and that it is the interaction of these 
constructs that underlie the model. 
The key constructs of SLT relevant to this study are described below: 
Self-efficacy: Self-efficacy is the belief an individual possesses regarding their ability to influence the events of 
their lives54. A person with high self-efficacy is more likely to complete a challenge or try again should they not 
succeed. Studies have consistently shown an increase in EX participation as self-efficacy increases55,56, as 
well as increases in self-efficacy as EX participation increases57. Two of the main sources of self-efficacy are 
mastery (performance) experiences and vicarious experiences.  When a person successfully carries out a task, 
he or she will believe that they have the capabilities necessary to repeat the behavior (i.e., mastery 
experiences).  
Support: Social support is the perception one is cared for and has the necessary assistance from others in 
his/her social network. Support can arise from any person in the individual’s social network, such as parent, 
sibling, physician, or peers. There is evidence showing the total physical activity metabolic equivalents (PA 
Mets) of pediatric cancer survivors are positively correlated with mother, father, and sibling total PA Mets58. 

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Gilliam and colleagues also found a positive effect on PA as a result of family and peer interactions; however, 
they also demonstrated an indirect effect of support: an increase in self-efficacy59. We are also including 
physicians and therapists in our analysis as evidence indicates they have an influence on adult patient PA. 
Calfas and colleagues found that physicians who add just 3–5 min of EX counseling during their patient 
meetings and enlist a health educator to call for a few minute “booster” 2 weeks later were able to increase 
sedentary patient’s PA by 37 min per week in patients compared to a control group with no intervention60.   
Outcome expectations: Outcome expectations are the underlying beliefs an individual has about the likelihood 
and value of the consequences of their behavior61. These expectations motivate individuals to engage in 
behaviors in order to achieve the desired outcome. Individuals who expect exercise to improve their health are 
more likely to engage in exercise and to endorse positive health outcomes as a result. 
 
Theory of the Exercise Intervention 
Education: Education involves increasing health-related knowledge and teaching participants about the 
benefits of exercise.  Education is expected to motivate patients to engage in exercise and increase 
expectations that their VIPN, health, and quality of life will improve as a result of their engagement in exercise.  
Cancer survivors report that they are more willing to participate in physical activity if their Healthcare Providers 
recommend it62. Education may help to diminish the overly cautious approach of caregivers, which has been 
acknowledged as one of the limiting factors of physical activity participation63.  
Self-Monitoring: Self-monitoring is being aware of and tracking one’s own behavior.  Self-monitoring improves 
engagement in physical activity and enhances self-efficacy for physical activity.  Wearing an activity tracker 
and keeping logs of exercise are forms of self-monitoring that have frequently been used in previous exercise 
research.  There is an exercise study which shows that children wearing Fitbits use them to self-regulate and 
as a result increase their activity levels as shown by an increase in their overall steps64. It also allows patients 
to determine if they are reaching their health-related goals.   
Goal Setting: Goal setting motivates individuals to improve their health and quality of life.  Better performance 
is observed when individuals set goals that are specific and challenging and when individuals were provided 
feedback support regarding their progress to their goal65. In our study, the exercise therapist will assist patients 
in setting exercise goals and will provide support and providing feedback.  We expect that setting goals will 
help patients to remain motivated and increase self-efficacy for exercise. 
Planning: Planning requires the individual to develop an action plan to reach their goals. This involves 
identifying times and locations for exercise, identifying potential barriers to exercise participation, and problem-
solving with the exercise therapist about how to overcome barriers to exercise.  Planning improves the 
likelihood that patients will reach the exercise goals that they set and, in turn, will enhance self-efficacy66.  
Reinforcement: Reinforcement is a process that encourages a specific behavior to reoccur over time. We will 
use one-on-one meetings with therapists, Fitbit trackers, and parents/family to reinforce participants to engage 
in exercise. This will provide multiple opportunities for encouragement and positive feedback. Reinforcement is 
expected to enhance self-efficacy, which, in turn, will motivate participants to engage in exercise. There is 
evidence to suggest that in addition to parental support, peer support can be reinforcing 67, thus we will use the 
exercise videos with the age appropriate peers as a form of reinforcement.  
Observational learning: Observational learning is a change in one’s behavior as a result of that individual being 
exposed, either through interpersonal interaction or media, to a specific behavior, particularly by peer 
modeling61. Observing someone similar to you achieve success on a similar task can increase self-efficacy. 
Thus, we will use similar-aged children and AYA to demonstrate the EXs on each video in order to support 
observational learning and enhance self-efficacy for exercise.   
 

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Biological Theory of VIPN 
Exercise:  EX increases oxygen to all organ systems, including the nervous system 10. Emerging data support 
the notion that EX protects against chemotherapy-induced peripheral neuropathy (CIPN) and may help repair 
damaged nerves after CIPN develops. Exact EX prescriptions have not yet been developed, but the more 
hours spent in moderate-to-vigorous activity, the less peripheral neuropathy experienced68.  
Oxygenation: The increase in oxygen which occurs during exercise (both aerobic and resistance) has been 
shown to increase NGF69, SNAP170, and GAP 4311 in rodent models of exercise. In addition, oxygenation 
enhances the pathway that increases Myelin Basic Protein (MBP), thus helping maintain myelin homeostasis71. 
Myelin is important for nerve conduction and is targeted during chemotherapy72, thus maintaining healthy 
myelin sheaths around the axons is necessary to minimize neuropathy. 
Biomarkers: We have selected three key factors, NGF, SNAP1 and GAP 43 known to have a role in neuronal 
repair10 and one involved in myelination disease, PDGF-BB73 to investigate in the current study. These factors 
should increase to compensate for any neuronal damage inflicted by the chemotherapy. In addition, we have 
data suggesting that the cytokine, IL-13 is also associated with VIPN42. In this instance, the higher the IL-13 
plasma levels the worse the neuropathy, therefore we expect exercise to decrease this cytokine. 
Quality of Life: Childhood and AYA cancer has a considerable negative effect on a child’s physical wellbeing 
due to chemotherapy, radiation and the resultant side effects of each.  Improving the symptoms that result from 
cancer treatment (e.g., VIPN) and decreasing symptom burden is related to improved quality of life in this 
population. Further, exercise has been shown to improve both muscle weakness and low cardiorespiratory 
fitness74 for childhood and AYA cancer survivors, which may also improve their quality of life.  
 

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F. 
ELIGIBILITY CRITERIA  
F.1 
Inclusion criteria  
Participants will be eligible for this study if they are:  
(1) age ≥ 5 and ≤ 25 years, (Riley Hematology/Oncology division accepts patients through age 25) 
(2) have been initially diagnosed with acute lymphoblastic leukemia (ALL), or lymphoblastic lymphoma (LL) 
and may also be a relapsed diagnosis,  
(3) will undergo the standard of care treatment for ALL or LL with vincristine. 
(4) will have a TNS-PV score of 3 or greater at week 6 
 
F.2 
Exclusion Criteria 
Participants will be ineligible for this study if they have: 
(1) baseline peripheral neuropathy greater than grade 1 (prior to receiving any doses of vincristine), 
(2) evidence of significant liver dysfunction, 
(3) Down’s Syndrome, 
(4) pregnancy, 
(5) severe illness or infection,  
(6) current active treatment with erythropoietin, 
(7) administration of vitamin supplements above 100% of the recommended daily allowance 
 
 
G. 
PATIENT RECRUITMENT 
Potential subjects will be recruited from the Riley Hospital for Children (Riley) and IU North Hospital. Riley 
medicine doctors are dedicated to the care of pediatric, adolescent and young adults ages 1-25. Study 
personnel will work with the clinicians in the Riley Department of Hematology Oncology to obtain the names of 
patients who have diagnoses of acute lymphoblastic leukemia (ALL) or Non- Hodgkin’s Lymphoma- 
lymphoblastic lymphoma (LL) and are planning to undergo vincristine treatment. Patients will be recruited 
during their first 4 weeks of vincristine treatment.  
Potential minor subjects and their parents/legal guardians may be approached by their physician and/or study 
personnel with information about this study.  Patients and their parents/legal guardians who are interested in 
participating in the study will undergo the informed consent process. Informed consent will be only obtained by 
trained and authorized study personnel or investigators. Patients and their parents/legal guardians may be 
given a study flyer with contact information at the time of consent.   
After consent, eligibility will be verified by a member of the study team and the patient will be registered (i.e., 
enrolled) to this study. The original, signed, IRB-approved Informed Consent Document and all regulatory files 
will be maintained by the Pediatric Clinical Trials Office (PCTO). Applicable regulatory documents must be 
completed and on file prior to registration of any subjects.  
H. 
RESEARCH DESIGN 
This is a multi-center study to test the feasibility of pediatric and AYA patient adherence to a single intervention 
(exercise: EX) during the consolidation phase of vincristine treatment for Acute Lymphoblastic Leukemia or 

12 
 
 
 
Lymphoblastic Leukemia. Fitbit activity tracker data and questionnaires will be used for assessing adherence 
and feasibility. We will use a pre and post intent-to-treat design. Forty subjects will be recruited and enrollment 
is expected to last 24 months. 
 
H.1 
Sample size justification  
We plan to enroll 40 children and AYA who develop VIPN so that we will have at least 34 children and AYA 
who will complete the 14 week time point (assuming a 15% attrition rate based on this population).  This study 
is sufficiently powered to detect a .5 SD difference in TNS-PV at the 14 week time point with 80% power based 
on a paired t-test with type I error set at .05. In a previous study of TPN-VS (Smith et al.) assessments from 
children with high severity VIPN resulted in TNS-PV of (n = 165 assessments from 14 children, mean = 8.02, 
SD = 5.22), for middle severity (n = 559 assessments from 70 children, mean = 4.22, SD = 3.01), and for low 
severity TNS-PV (n = 342 assessments from 25 children, mean = 1.94, SD = 1.86).  Based on a pooled SD = 
3.17 from these three groups, there is approximately a 1.9 SD difference in mean TNS-PV between the high 
and low severity groups, a 1.2 SD difference between the high and middle severity groups and a .7 SD 
difference between the middle and low severity groups.  Thus if our children and AYA mimic the middle 
severity group prior to treatment we should be adequately powered to detect if our intervention is able to move 
them to low severity.  Additionally, in pilot data (unpublished) TNS-PV at baseline (1 month) was 3.36 with SD 
= 3.66.  With 34 children and AYA, we will have 80% power to detect a 2 point change in TNS-PV (which is 
considered clinically meaningful) assuming a SD = 3.66 at both time points and .4 correlation between time 
points with a paired t-test with type I error set at .05.  For FACES (range 0 to 5), based on Smith et al, we 
estimate the pooled SD =.7 for high, middle, and low severity groups.  With a sample size of 34, we are 
powered to detect a .35 mean difference in FACES, based on a paired t-test with type I error set at .05.   
For other outcomes, which we do not have pilot data, we will still be able to detect a .5 SD difference in the 
mean based on a two-sided paired t-test with type I error set at .05.  Even if we do not detect statistically 
significant differences in these outcomes in the proposed study, estimated means and SDs can be used for 
planning larger studies in the future.   
  
H.2 
Fitbit tracker justification  
The Fitbit activity tracker was chosen for this feasibility study due to its versatility and effectiveness within 
younger populations of children. The FitBit’s ease of use, comfort, design and feedback features were important 
factors for all age groups (children and AYA). Researchers in some studies utilized the Fitbit activity tracker to 
assess adherence to home-based activity programs75.  
I. 
PROCEDURES 
I.1 
Overview 
For this feasibility study, 40 pediatric patients with a diagnosis of ALL or LL who have a TNS of >3 at the end of 
four weeks of vincristine treatment will be enrolled from Riley Hospital for Children, Indiana University Health 
North Hospital, . Children and AYA will be recruited during their first four weeks after diagnosis and if they have 
a TNS >3 at the time of baseline (week 4-6 T1) they will be enrolled into the study. During T1 patients will 
complete all questionnaires, neuropathy exams, and provide blood samples and then again at week 14 (T2).  
Neuropathy exam may be performed during weeks 4 through 6 to accommodate regimented clinical visits. 
Exercise assessments will be performed on week 7.Subjects will check-in with the exercise therapist during 
weeks 9, 11, and 13 at a minimum, or once a week during the study if they choose (weeks 7-15). These in-

13 
 
 
 
person sessions will take approximately 15 minutes, and the therapist will provide education, evaluate the 
subject’s exercise plan, review exercises, set goals, and make plans to optimize adherence to the exercise 
program.  
All study visits will take place before or after routine clinic visits so that patients and their families do not have to 
make additional trips to the four hospital sites. EX sessions will be completed by patients at home using 
instructional videos that will be given to participants during their study orientation. 
I.2 
Intervention timeline 
 
 
 
I.3 
Exercise (EX) Intervention 
The EX intervention will include both an in-person exercise schedule and at-home video EX sessions (See 
Appendix I and II).  The EX intervention will be designed and led by an AFAA (Athletics and Fitness 
Association of America) certified physical fitness trainer with fifteen years’ experience and a professional with a 
PhD in an Exercise Science related field.  

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In-Person Exercise Sessions: 
The first session will be completed at one of the four hospital sites with the EX intervention specialist during the 
baseline visit.  Patients will check-in with their intervention specialist during routine visits to one of the sites or 
phone on weeks 8, 10, and 12 at a minimum throughout consolidation treatment, or once per week if they 
choose (weeks 7-15). In-person sessions will last approximately 15 minutes each during which time the 
therapist will provide education on the importance of exercise for VIPN, review the exercises, reassess 
difficulty level, set exercise goals for the following week, and plan to reach these goals. Reviewing exercises 
will demonstrate that the patient has learned exercises through observational learning from the therapist and 
peer models on the exercise videos.  In-person sessions will also allow the therapist to provide reinforcement 
for the patient’s progress.   
If the patient or the study team are unable to meet in person the intervention specialist will contact the patient 
via their prefer contact method (phone call, email, Skype). These sessions will follow the format of the in-
person sessions. Education, assessment of difficulty level, set exercise goals and plan will all be discussed 
during the remote check-in.  
Home Exercise Sessions: 
At baseline, participants will have access to the exercise videos via the study website or they will be 
downloaded to the study tablet, with 3 chapters of EX sessions to be completed at home with video instruction.  
Patients will be asked to complete home EX sessions 6 times per week for 8 weeks (week 6 through week 13) 
during the consolidation phase of treatment.  A Daily Exercise Log is available to record exercise chapters, 
fatigue level and time of day exercised (See Appendix III). Patients may choose their rest day each week. Each 
EX session will last approximately 15 minutes.  The at-home videos will have the therapist and three children 
and AYA who are of similar age to the patients demonstrate the exercises. This design is critical for supporting 
the observational learning component of the intervention.  Two videos will be available for the study: one for 
ages 5 – 10; one for ages 11 – 25.  
The EX intervention includes both Resistance Training and Aerobic Training. Each patient will receive an EX 
video with three chapters of Resistance Training and three chapters of Aerobic Training.  Resistance Training 
is the use of resistance to muscular contraction to build strength, endurance, and size to the muscles involved. 
It also strengthens joints involved within the skeletal system. A beginner chapter, an intermediate chapter, and 
an advanced chapter will be designed for patients to have the option to advance as their bodies become more 
or less conditioned.  Beginner level EXs will be a whole-body seated muscle fatigue chapter, the intermediate 
EXs will be a whole-body Thera-band bridge chapter, and the advanced chapter will be a whole-body 
calisthenics chapter.  
The three Aerobic Training chapters will be similar in design to the Resistance Training chapters. Aerobic 
Training is various sustained exercises that stimulate and strengthen the heart and lungs, thereby improving 
the body’s utilization of oxygen. A beginning chapter, an intermediate chapter and an advanced chapter will be 
designed. The beginning Aerobics Training chapter will be a seated program for the least conditioned patients. 
The intermediate chapter will be a bridge chapter for those patients where more strenuous aerobic training can 
be incorporated, and the advanced chapter will be a whole-body aerobics training chapter (consisting of a 
variety of gross motor movements; often rhythmical without equipment or apparatus) for patients with the most 
conditioned overall major muscle groups who can safely participate in whole-body aerobic training against 
gravity. 
Each EX chapter will be designed with three core, three lower body, and three upper body EXs. Each EX 
within a chapter will last fifty seconds for a total of ten minutes for the EX portion of each chapter. An additional 
two and a half minutes of warm-up and cool-down at the beginning and end of each session will total one 
fifteen minute session (See Appendix I for EX schedule). The EX intervention is designed for patients to 

15 
 
 
 
gradually progress through the different EX chapters.  Thus, patients can start at a level (e.g., chair EXs) that 
will likely be within their capabilities and provide a sense of accomplishment.  
Each EX chapter will EX muscle groups in the following order: 1) lower body EXs, 2) upper body EXs and, 
3) core strengthening EXs. Each muscle group will follow the order of largest muscle group to smallest 
muscle group. The EX chapters will follow a Recovery Program format in which larger muscle groups are 
exercised before smaller muscle groups to prevent fatigue and optimize adherence. The Whole-Body 
Recovery Program will ensure that the weakest or the most deconditioned muscle groups will have the 
chance to become reconditioned as all muscle groups (agonist and antagonist) are utilized. Engaging all 
major muscle groups simultaneously will strengthen all joints involved. 
I.4 
Demographic and Clinical Data Collection/Measures 
Demographic and Medical Information 
Demographic data obtained at time of consent will include race, age, gender, ethnicity, and pre-diagnosis 
exercise level prior to diagnosis. We will use age and baseline exercise level as covariates. Exercise levels will 
be determined by the exercise therapist based on the recommendations from the World Health Organization 
for children 5-17 which is seven hours per week of aerobic activity76. The therapist will ask the child about their 
pre-diagnosis activity level and record it on the physical assessment form. The categories will be as follows: 
below recommended level of activity, at recommended level of activity, and above recommended level of 
activity. All medical information (dates and doses of vincristine) will be collected by the study coordinator from 
the subject’s medical records. 
Vincristine-induced Peripheral Neuropathy  
Total Neuropathy Score - Pediatric Vincristine (TNS-PV): The TNS-PV is a multidimensional instrument that 
will be used to measure peripheral neuropathy symptoms and signs in children from 5-25 years old receiving 
vincristine. Modified from the original Pediatric Total Neuropathy Score (Ped-TNS)5, the instrument assesses 
proximal extension of numbness, tingling, and neuropathic pain, vibration and temperature sensation, strength, 
tendon reflexes, constipation (autonomic neuropathy), and hoarseness/voice (cranial nerve neuropathy) 77. A 
multiplexed measuring system was developed that simultaneously ranks the 8-10 subjective and objective 
parameters. These parameters provide qualitative information on symptoms, nerve conduction and sensory 
tests on a scale of 0 for ‘none’ to 4 for ‘severe’. The individual scores are added together to provide a single 
measure of neuropathy called a Total Neuropathy Score (See Appendix IV).  
Total Neuropathy Score – Clinical Evaluation (TNSc): The best acknowledged method to assess the severity 
and changes in chemotherapy-induced peripheral neurotoxicity is through determination of the Total 
Neuropathy Score. The TNSc is an instrument that will be used to measure peripheral neuropathy symptoms 
and signs in young adults from 19-25 years old receiving vincristine. The TNSc (See Appendix V) consists of 
seven items with scores correlating significantly with the National Cancer Institute-Common Toxicity Criteria v. 
2.0  (p < 0.001, r2 = 0.77, r = 0.88, 95% confidence limits 0.849–0.914). With a test-retest coefficient of 0.86-
0.87 (Academy of Oncologic Physical Therapy). The TNSc is more sensitive than the NCI-CTC 2.0 in detecting 
mild sensory damage because it detected changes in the range of 1–3 points even in 50% of those patients 
who were scored as unchanged using the NCI-CTC 2.0 score78.  
 
Pediatric Chemotherapy-Induced Neuropathy (P-CIN) Survey: the Pediatric Chemotherapy-Induced 
Neuropathy Survey (P-CIN) is a self-report measure of pain for ages 5-17. The P-CIN is designed to rate 
symptoms of CIPN (numbness, tingling and pain over the past 2-3 days). The P-CIN consists of 13 items for 
ages 5-17. Each of the 12 items is rated using the 6-point Faces Pain Scale (See Appendix VIII). 
Neuropathic Pain 

16 
 
 
 
Pediatric Neuropathic Pain Scale (NPS) - Five: The Neuropathic Pain Scale (NPS) was designed to assess the 
distinct pain qualities associated with neuropathic pain. The NPS consists of 5 items which are rated on a scale 
of 0 to 10 (0="no pain" to 10="severe pain"). Each question examines an individual aspect of pain and is 
measured independently15. The rating scale is based on the Faces Pain Rating Scale – Revised (FPS-R) 
which is a self-report measure of pain intensity that was developed for children79 (See Appendix VII and VIII). 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) V4.02: This scale grades adverse events 
occurring after chemotherapy in cancer patients and explores the quality of life (QOL) findings among post 
therapy cancer patients. The NCI CTCAE is a descriptive terminology that can be utilized for pain (Appendix 
IX) reporting and is required to be completed for all cancer studies80. 
 
Quality of Life  
Pediatric Quality of Life Inventory (PedsQL 4.0): The PedsQL is a modular approach to measuring health-
related quality of life in healthy children and those with acute and chronic health conditions. The PedsQL 
integrates generic core scales and disease-specific modules into one measurement system (Appendix X). The 
23-item PedsQL generic core scales and disease-specific scales were designed to measure the core 
dimensions of health as delineated by the World Health Organization, as well as role (school) functioning.  For 
the purpose of this study, we will only be utilizing the generic core scales section of the inventory. This 
measure is tailored to 5 different age groups: toddlers (2-4); children (5–7); children (8-12); teens (13-18); and 
young adults (18-2). The Child and Parent Reports (ages 5-7), Children (ages 8-12) and Teens (ages 13-18) 
are made up of 23 items comprising 4 dimensions: Physical functioning; Emotional functioning; Social 
functioning, and School functioning. Patient participants will complete the child-report questionnaire, and their 
parents will complete the parent-report version (See Appendix X). 
Ferrans & Powers Quality of Life Index: Total quality of life will be measured using the Ferrans and Powers 
Quality of Life Index Version III and is a 66-question index designed to evaluate social, psychological, family, 
and health satisfaction (See Appendix XI). This assessment is valid for ages 19 and above. Higher scores 
indicate greater satisfaction in quality of life with an internal Cronbach's alpha of 0.9381. 
 
Social Learning Theory Questionnaire  
Self-Efficacy: There is currently no exercise self-efficacy scale for children and AYA’s with cancer.  We have 
adapted the Bartholomew physical activity self-efficacy scale for children and AYA’s for use in our study82 We 
have adapted the original self-efficacy scale by adding two questions that are specifically neuropathy related 
and replaced the term exercise where physical activity had been used. Responses to the questions are limited 
to Yes/No and not applicable. (See Section 1 Appendix XII). 
Support:  The support module was taken from a larger validated scale developed by Liang et al (2014) which 
measures physical activity self-efficacy, enjoyment, and exercise social support for children83. The support 
section of the questionnaire consists of 10 questions rated on a 5 point scale from None to Very often. The 
items assess support children and AYA’s receive from parents and peers to facilitate exercise. We have 
adapted the term physical activity to the term exercise for this study (See Section 2 Appendix XII). 
Outcome Expectations:  We adapted an existing exercise outcomes expectations questionnaire from the adult 
literature for the purposes of our study.  The survey consists of 10 items targeting exercise outcome 
expectations.  Patients are asked to rate each item on a 5 point scale.  Items were edited for developmental 
level/appropriateness84. (See Section 3 Appendix XII) 
Physiological Parameters  

17 
 
 
 
Fitbit activity tracker: All patients will be instructed to wear their Fitbit activity trackers every day during waking 
hours throughout the intervention period. The Fitbit activity tracker (specifically the Charge 2) has a five-day 
battery life and an “always-on” heart rate tracking system. It is an accelerometer that is worn like a small 
wristband and records data on movement (steps, HR, distance and activity), total activity minutes, heart rate 
and total minutes of inactivity including sleep. The data is stored on the device and then can be downloaded 
wirelessly to a computer 75. 
An integral component of wearable activity trackers, such as Fitbit, is the automation of real-time physical 
exercise tracking and heart rate 85. The Fitbit activity tracker builds upon pedometer-based activity 
interventions with a more sophisticated interface using the Internet or a mobile application. This allows for the 
implementation of behavioral change techniques, tailoring of goals, tracking of progress and documenting 
adherence to home-based EX protocol with minimal use of resources 85,86. There is an exercise study which 
shows that children wearing Fitbits use them to self-regulate and as a result increase their activity levels as 
shown by an increase in their overall steps64. 
Even though the EX sessions are not purely aerobic EX, the Fitbit can detect increases in heart rate during 
these sessions. Specifically, the EX sessions include aerobic EX, dynamic resistance training, and isometric 
EXs and thus, will rely on both aerobic and anaerobic energy sources. During aerobic components of the 
program, the heart must do more work to pump an increased cardiac output to working muscles, and heart rate 
generally increases in a linear fashion to increases in EX intensity.  Heart rate increases during dynamic 
resistance EX will be due initially to vagal withdrawal and then stimulation of sympathetic nervous system by 
central command and from muscle chemo and mechanoreceptors. During isometric EX, muscle fibers 
compress small blood vessels, preventing new oxygen-laden blood from reaching affected muscle tissue.  
Thus, as long as the muscle contraction is maintained, heart rate will steadily rise. Therefore, detectable 
elevations in heart rate are expected during EX sessions, albeit through several different mechanisms. 
Although the immediate effect of isometric exercises is to inhibit blood flow and therefore oxygen to the 
muscles, the long-term effects are vasodilation, thus an increase in oxygen. In addition, isometric exercises 
help maintain strength of the muscles and enhance stabilization. These types of exercises are often included in 
rehabilitation situations and therefore can contribute to improving neuropathy87.  
 
Six Minute Walk Test: The Six- minute walk test (6MWT) is used to assess subjects’ functional exercise 
capacity. This assessment will be conducted by an exercise professional during week 7 (T1) and week 15 (T2) 
physiological assessments. The 6MWT will be conducted following the  American Thoracic Society Guidelines 88 
and our standard operating procedures. Subjects will be asked to walk as far as possible for 6 minutes. They 
will be assessed on how far of a distance is walked over the course of these six minutes. Subjects will be 
allowed to slow down, stop and rest as needed. They will be asked to resume walking with they are able. This 
assessment will be performed at all sites.  
 Romberg Balance Test: The Romberg Balance is an assessment of the subjects balance and proprioception89. 
The patient will be asked to remove their shoes, stand with their feet together, arms held to their side or 
crossed in front of their chest. They will be asked to stand quietly with their eyes open and subsequently with 
their eyes closed. The assessor will maintain close proximity to the subject in case there is a loss of balance. 
Subjects will then be asked to stand heel to toe with one front directly in front of the other. Similar to the first 
portion of the test patients will be asked to perform this assessment with eyes open and eyes closed.  Subjects 
will be assessed by counting the second they are able to maintain balance.    

18 
 
 
 
 
 
The baseline Standardized Fitness Assessment: The fitness assessment will evaluate the general health and 
physical characteristics of each patient (See Appendix XIII). Specifically, data will be collected regarding 
height, weight, resting heart rate, blood pressure, body composition (ratio of lean body mass to fat mass), 
lower back and hamstring flexibility, aerobic fitness and physical strength. All tests will be age appropriate. This 
information will be used to determine the initial exercise level most appropriate for the subject to begin the 
intervention study. 
Adherence 
Adherence will be measured by self-report of session completion (See Appendix III) and activity tracking via 
FitBit.  All participants will be asked to fill out a short 5 question survey following their EX session regarding 
their workout, energy level, food intake, and sleep quality. Parents will be asked to initial and review the 
questions and add any additional comments they feel would be helpful for us to know. The Daily Log is 
designed not just to aid the child in planning and goal setting, but also to give parents an opportunity to provide 
positive reinforcement for the child’s daily exercise. The patients will also be asked to hit a start EX button on 
the FitBit at the beginning of the intervention which shows that they have started the video and then hit it again 
upon completion. The instructor in the video will prompt the child to start and stop their FitBit as a reminder.  
Acceptability 
Patient Satisfaction Survey: This satisfaction survey was adapted from an existing exercise intervention 
satisfaction survey 90. The satisfaction survey consists of 13 items, and they will be asked to respond to each 
item using a 5 point scale.  Patients will provide feedback on the exercise program, exercise videos and 
therapist support. There is also an open response question for additional feedback (See Appendix XIV). 
Parent Satisfaction Survey: Parents will also be asked to complete a satisfaction survey regarding the exercise 
program, exercise videos, and therapist support. To assess the satisfaction of the parents/caregivers of 
pediatric cancer patients (peripheral neuropathy symptoms) while participating in an exercise intervention 
during the Consolidation Phase of chemotherapy90. The satisfaction survey consists of 13 items, and they will 
be asked to respond to each item using a 5 point scale. (See Appendix XV) 
 
Fitbit Charge HR 

19 
 
 
 
Domain, Measurements and Schedule for Study Outcomes 
Domain 
Measure 
# Items 
Schedule 
T1 
T2 
Predictors 
  
  
  
  
Demographics 
Gender, age, race/ethnicity, pre-
diagnosis exercise level 
  
X 
  
Medical Characteristics 
Neuropathy, Weight, ALL/LL diagnosis 
  
X 
  
Physical Functioning 
Baseline Standardized Fitness 
Assessment 
13 
X 
  
Self-efficacy 
SLT Exercise Questionnaire 
10 
X 
  
Outcome Expectations 
SLT Exercise Questionnaire 
10 
X 
X 
Support  
SLT Exercise Questionnaire                       
10 
X 
X 
Primary Outcome 
Feasibility 
Percentage of subjects that can  
complete the 8-week intervention             
FitBit data  
6 
Weeks 6-13 
Daily Log 
Acceptability 
Patient Satisfaction Survey                 
Parent Satisfaction Survey 
13        
13  
  
X 
Secondary Outcomes 
Physical Activity 
  
  
  
  
Total Activity Time during study 
FitBit Tracker                                                 
Daily Log 
8 
Weeks 6-13 
Heart Rate  
FitBit Tracker 
NA 
Exercise 
Fitbit Tracker                                             
Daily Log 
8 
Biomarkers 
  
  
  
  
Germline DNA                                                 
Chemerin levels                                              
PDGF-BB levels                                                
IL-13 levels                                                       
GAP 43                                                              
Synapsin                                                           
NGF                    
Blood Draw 
NA 
X 
X 

20 
 
 
 
Neuropathy 
  
  
  
  
  
NCI CTCAE Version 4.02 
2 
  
X 
  
Total Neuropathy Score - Pediatric 
Vincristine (TNS-PV) 
25 
X 
X 
  
Total Neuropathy Score - Clinical (TNSc) 
7 
X 
X 
Pain 
  
  
  
  
  
P-CIN Pediatric Chemotherapy-Induced 
Neuropathy Patient Reported Outcome 
13 
X 
X 
  
Pediatric Neuropathic Pain Scale - Five 
6 
X 
X 
Quality of Life 
 
  
 
 
  
Peds QL V4 Scale 
23 
X 
X 
  
Ferrans and Powers  
66 
X 
X 
 
 
 
 
 
 
I.5 
Blood Sample Collection 
This study will include collection of a minimum of 15 mL of whole blood at 2 time points: baseline or pre-
intervention (week 6) and post-intervention (week 14). Blood samples will be stored at -80°C until analysis for 
germline DNA, chemerin levels, NGF, SNAP1, GAP43 and cytokines PDGF-BB and IL-13.  Whenever 
possible, blood will be drawn at the same time as blood is drawn for routine clinical purposes. Blood will always 
be drawn by trained technicians. Please refer to the Laboratory Manual for this study for blood collection, 
processing, transfer and storage instructions. 
I.6 
Data Processing and Storage 
Survey Data: All survey study data collected will be stored in the Research Electronic Data Capture (REDCap) 
database. REDCap is managed through the Department of Biostatistics in the Indiana University School of 
Medicine. Access to the password-protected database will be limited to study personnel, and any data shared 
outside of the study team will be de-identified prior to distribution.  
Fitbit Data: The Fitbit data will be automatically imported to a Fitbit application on the company’s secure server 
and then uploaded automatically to an excel file. The data will be downloaded weekly to a password protected 
master excel file folder stored on a university secured server and managed by the Bioinformatics core (See 
human subjects section for further details). All physiological measures: Heart Rate, Steps, Distance and 
Activity, will be captured using the Fitbit Charge HR. 

21 
 
 
 
OnCore®: Individual patient registration will be done in the OnCore® database. All protocol deviations, study 
status updates (IRB approval, open to accrual, etc.), IRB approvals, current protocol and consent, and any 
serious adverse events should they occur. The OnCore® database is a comprehensive, web-based, Clinical 
Trial Management System (CTMS) which utilizes an Oracle database. OnCore® was developed by Forte 
Research Systems, Inc. and is used by the IUSCC Clinical Trials Office (CTO) and supported by the Indiana 
Clinical and Translational Sciences Institute (CTSI).  OnCore® properly used is compliant with Title 21 CFR 
Part 11.  
OnCore® provides users secure access with unique IDs/passwords and restricts access by assigned roles, 
from any location, to record, manage, and report on data associated with the operation and conduct of clinical 
trials. 
All source documents are to remain in the patient’s clinic file.  All documents should be kept according to 
applicable federal guidelines.  Clinical trial data in OnCore® are periodically monitored by the IUSCC Data 
Safety Monitoring Committee (DSMC).   
I.7 
Treatment fidelity  
Treatment fidelity will be ensured by instruction from the Ex therapists at the initial study visit, every other week 
check-in sessions, and home practice with the exercise videos.  At check-in sessions, therapists will review 
Exs with participants and instruct them in new Exs. Further, videos are tailored to participant age and level of 
physical functioning. All EXs will be prescribed by the Ex therapist using the Karvonen Formula. The Karvonen 
Formula is a mathematical formula that helps you determine your target heart rate (HR) training 
zone. This formula uses maximum and resting heart rate with the desired training intensity to determine a 
target heart rate zone. 
  
Treatment Fidelity Focus 
Description of Treatment Fidelity Indicators 
Design 
The intervention was developed based on Social Learning Theory with main construct 
focus on self-efficacy. 
Training 
The therapists are trained exercise professionals. They are designing and leading the EX 
program and will perform all individual exercises together to ensure agreement of the 
performance expectation. One or both therapist will train the children and AYA’s who will 
demonstrate the exercise on the video.  
Delivery 
Each participant will receive a video of the exercises that are age appropriate and are 
suitable to their physical abilities. The videos will allow for a standardized intervention 
delivery for each subject. 
Receipt 
Each participant will wear a Fitbit and upon starting the EX session will click the button on 
the side of the device to record the activity. All subjects will be reminded to start and stop 
their Fitbits by the children and AYA’s demonstrating the exercises on the video. All data 
from the Fitbit is collected via Fitabase (secure data site). There is also a pre and post 
survey each participant completes prior to and after their session (8 questions in total). 
The parent may add comments to the survey if they desire, but their initials are required.  
I.8  
Compensation for Participation 
Upon completion of the study, each subject will get to keep the Fitbit device that has been utilized for physical 
and aerobic training tracking. Upon completion of this study a small end-of-study token in appreciation of the 
study participant’s participation may be given.  

22 
 
 
 
J. 
DATA ANALYSIS 
J.1 
Baseline Analysis 
Baseline analysis.  Baseline demographic characteristics as well as baseline general health and physical 
characteristics will be summarized for all patients.  Descriptive statistics (N, mean, standard deviation, median, 
minimum, and maximum) will be provided for all continuous variables and frequency and percent will be 
provided for all categorical variables.  All continuous scale outcomes will assessed for normality.  If normality 
does not seem plausible for a given outcome, than Wilcoxon-signed rank tests will be used.  Additionally, to 
examine reasons for attrition, baseline measures will be compared between patients that complete the 
intervention and those that do not.   Continuous measures will be compared with a t-test or Wilcoxon-rank sum 
test and categorical variables will be compared using a Chi-square test or Fisher’s exact test.   
 
J.2 
Aim 1 & 2 Analysis 
To address Aim 1, adherence in the intervention group will be measured through a 5 question survey at each 
treatment and also through start/stop on the Fitbit.  Adherence scores will be summarized across time with 
descriptive statistics (N, mean, SD, median, minimum, and maximum).  From start/stop information, the 
proportion of exercise sessions completed and the proportion of patients which complete at least 50% of the 
exercise sessions along with associated 95% confidence intervals will be estimated. Additionally, descriptive 
statistics will be provided for the patient satisfaction survey provided at the end of the study. 
To address Aim 2, we will use paired t-tests to examine change from baseline (T1) to 14 weeks (T2).  For 
outcomes which are known to be non-normal such as biomarkers, we will use Wilcoxon-signed rank tests.  We 
plan an intent-to-treat analysis.  Even if we do not see significant differences, descriptive statistics including 
means, SD, and effect sizes (differences in means between the two time points divided by pooled SD) will be 
reported for outcomes along with 95% confidence intervals.  All analysis will include checking of assumptions.  
Additionally, we will also use repeated measures ANOVA to estimate the contrast of interest (change from 
baseline at 14 weeks) for primary and secondary outcomes, after adjusting for age and baseline activity level. 
For activity outcomes obtained from the FitBit, such as patients’ daily number of steps, distance, active 
minutes, and heart rate, we will start with simple techniques such as paired t-tests or Wilcoxon signed-rank 
tests to compare the mean change in activity level from baseline (T1: summarized over week 6) to treatment 
end (T2: summarized over week 13).  As an exploratory analysis, we will also use a generalized linear mixed 
model with appropriate distribution (e.g. Poisson) and link function fit to all weekly outcomes to examine 
changes over time using time as a continuous variable.  We expect to have an abundance of information 
provided from the Fitbit, thus we will estimate descriptive statistics (N, mean, SD, median, minimum, and 
maximum) for all outcomes (i.e., number of steps, distance, active minutes, and heart rate) at each week to aid 
in planning future studies. 
Based on our conceptual model, we will also examine associations between change scores for predictors and 
change scores for primary and secondary outcomes.  For example, we will estimate Pearson correlations 
between changes in self-efficacy, outcome expectations, support, neuropathy, pain, and quality of life.   
We will also examine whether or not the circulating protein biomarkers at T1 are associated with VIPN severity 
at T1 using Spearman correlations and whether initial or dynamic levels of the circulating biomarkers are 
predictive of intervention efficacy. The associations between VIPN and the genetic and circulating biomarkers 
will be analyzed through generalized linear mixed models, which includes a random subject effect to account 
for the correlation of observations from the same subject. 

23 
 
 
 
J.3 
Missing Data 
We expect minimal dropout at 14 weeks (primary endpoint for the proposed trial) and have inflated the sample 
size to account for the expected 15% attrition, so we anticipate it will not create any substantial bias in the 
results. To aid in future studies, we will compare baseline characteristics among those who complete the study 
and those who do not to determine if there are any characteristics associated with study completion. 
K. RISKS OF PARTICIPATION AND PROTECTION OF HUMAN SUBJECTS 
K.1 
Risks 
Possible risks to participation in this study are breach of confidentiality, physical distress or emotional distress 
due to study participation. All contact with the participant will be documented beginning at the consent process 
through completion of the study. All documentation will be reviewed regularly. Any events that might indicate 
increased participant physical distress or emotional distress will be promptly brought to the attention of the PI 
and reported to the IRB and DSMC per reporting guidelines listed below. We will promptly report to the IRB 
any instances of consent withdrawal due to distress. The IRB will be informed at least annually of our data and 
safety monitoring, summary of participant status, and any changes in the risk of the study. 
Prevention of injuries have been addressed through 1) video design, 2) safety reminders during videos and 
fitness assessment and 3) muscle soreness. The video design is based on a specific gradual workout design 
to ensure safety for the most deconditioned patients. The study has incorporated beginner (seated or bed), 
intermediate (bridge between beginner and advanced) and advanced EX chapters.  
Reminders of safety will be discussed during the fitness assessment and also incorporated into all videos. The 
reminders will address proper footwear, proper clothing, workout areas clear of objects, availability of water 
bottle, ensure someone else is in the house while exercising, finally, if experiencing dizziness, chest pain or 
injury to stop immediately and tell a parent. Treatment for muscle soreness is to 1) not skip the warm-up or 
cool down sections of the video, massage the affected muscle groups or soak in a warm tub. 
Any injury will be reported per the study guidelines. Video reminders for injury will include 1) knowing where 
the First Aid Kit is located, 2) knowing where the closest phone is, 3) always reporting an injury to the 
parent/care-giver and  in case of severe injury to dial 911. Each patient and parents will have the phone 
number to both of the study therapist’s to answer any questions. In general, exercise does not provoke 
cardiovascular events in healthy individuals with normal cardiovascular systems. The risk of sudden cardiac 
arrest or myocardial infarction is very low in apparently healthy individuals performing moderate intensity, 
physical activity (Ref. ACSM’s Guidelines for Exercise Testing and Prescription, Ninth Edition, 2014, p. 9, 
Chapter 1, Section: Risks Associated with Exercise).     
K.2 
Protection 
The following measures will be implemented to protect participants against these risks:  
All personnel will be trained in the importance of and measures to protect patient confidentiality. Several 
measures will be taken to protect patient confidentiality. One measure will be assigning each participant a 
unique 6-digit identification number and using this number to identify the participant on all data collection 
forms. All data collected from participants will be kept separate from identifying information by the use of this 
unique identification number. Any information collected on paper forms or by phone will be entered into the 
REDCap database by a study team member. The paper forms will be filed in a locked file cabinet in the locked 
office space of the PI or project manager at Riley Hospital. Only those study team members who need access 
to this information will be allowed by the PI or project manager. 

24 
 
 
 
Analyses will include only summaries of data; personal identifiers will be excluded. All personnel who are 
involved in the design or conduct of this research will have demonstrated successful completion of human 
subjects training. 
Since this study involves a very large amount of data to be collected from the Fitbit tracker, we have put 
procedures in place to ensure the integrity of the data transmitted and to allow consistent handling of the 
clinical data. The Bioinformatics Core team at Indiana University has developed a web-based platform for the 
collection, integration, analysis and dissemination of both the clinical and biomarker data.  The platform 
provides a framework for the collection of biomarker data (i.e. cytokines and chemerin levels), the collection 
and the analysis of the data.  The web-based platform is easy to use with all the necessary securities to protect 
the confidentiality and integrity of the data.  All data are stored in a deidentified/HIPAA compliant manner.  The 
platform is developed using the Linux-Apachedcmx,m, xz-MySQL-PHP platform and CakePHP. This platform 
is widely used across the Internet.  Security is obtained by encryption (SSL). 
K.3 
Reporting to the IRB  
1. Unanticipated problems involving risks to subjects or others will be reported promptly to the IRB if they:  
• 
unexpected; 
• 
related or possibly related to participation in the research; and 
• 
suggest that the research places subjects or others at a greater risk of harm than was previously known 
or recognized.   
If the serious adverse event does not meet all three (3) criteria listed above, the event does not have to be 
promptly reported to the Indiana University IRB.  However, it will be reported at the time of continuing review. 
2. Prompt reporting of unanticipated problems to the IRB is defined as within 5 days from becoming aware of 
the event. 
K.4 
Reporting to the IUSCC Data Safety Monitoring Committee  
Regardless of study sponsorship, the study team must enter all initial and follow-up SAE, expedited, and 
noncompliance reports into OnCore® for review by the DSMC chair and/or coordinator. Expedited reports may 
include IRB Prompt Report Forms and additional SAE forms as required by the sponsor. When follow-up 
information is received, a follow-up report should also be created in OnCore®. This DSMC reporting 
requirement is in addition to any other regulatory bodies to be notified (i.e. IRB, FDA, pharmaceutical company, 
etc.). The DSMC chair and/or coordinator will review all SAE, expedited, and noncompliance reports monthly. 
IUSCC Data Safety Monitoring Plan (DSMP) 
Investigators will conduct continuous review of data and patient safety. Quarterly review meetings for low risk 
trials are required and will include the principal investigator, clinical research specialist and/or research nurse 
(other members per principal investigator’s discretion). Quarterly meeting summaries should include review of 
data, the number of patients, significant toxicities as described in the protocol, and responses observed. 
Summaries will be submitted quarterly and reviewed by the DSMC for review. Submit to DSMC@iupui.edu.  
Study Auditing and Monitoring  
All trials conducted at the IUSCC are subject to auditing/monitoring. Reports will be forwarded to the DSMC for 
review.  
Early Study Closure  
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or benefits) to 
the patient warrant early closure of the study, this recommendation should be made in writing to the Data 
Safety Monitoring Committee. Alternatively, the DSMC may initiate suspension or early closure of the study 
based on its review of the investigator reports.  

25 
 
 
 
Reporting Guidelines  
The DSMC has streamlined the reporting process by utilizing reports from OnCore®. This has allowed direct 
view of reports within the Clinical Trials Management System (CTMS); thus discontinuing paper reports. SAE 
reports are entered into OnCore® and reviewed by the DSMC chair and/or coordinator monthly.  
Study Accrual Oversight  
Accrual data will be entered into the IU Simon Cancer Center OnCore®   system. The Protocol Progress 
Committee (PPC) reviews study accrual twice per year while the PPC coordinator reviews accrual quarterly. 
Protocol Deviations  
Protocol deviations are entered into OnCore® and reviewed by the DSMC chair and/or coordinator monthly.  
L. 
STUDY WITHDRAWAL/DISCONTINUATION 
Criteria for removal from the study are as follows:  
• 
The participant expresses significant distress related to completion of the study (the PI will refer the 
participant to clinical services if needed). 
• 
The participant provides verbal or written notification that s/he has decided to discontinue study 
participation. 
Any other reason for which the principal investigator believes the participant should be withdrawn. 
M. 
PATIENT CONSENT AND PEER JUDGEMENT 
The protocol and informed consent form for this study must be approved in writing by the appropriate 
Institutional Review Board (IRB) prior to any patient being registered on this study.   
Changes to the protocol, as well as a change of principal investigator, must also be approved by the Board. 
Records of the Institutional Review Board review and approval of all documents pertaining to this study must 
be kept on file by the investigator and are subject to inspection at any time during the study. Periodic status 
reports must be submitted to the Institutional Review Board at least yearly, as well as notification of completion 
of the study and a final report within 3 months of study completion or termination.   
The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 21 
CFR parts 56 & 50), state or local laws.  
N. 
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31 
 
 
 
O. 
APPENDICES 
All appendices listed below can be found in a separate PDF document. 
APPENDIX I – Exercise Schedule  
APPENDIX II – Exercise Video Outline 
APPENDIX III – Daily Exercise Log   
APPENDIX IV – Neuropathy: Total Neuropathy Score (TNS-PV) 
APPENDIX V – Clinical Total Neuropathy Score (TNSc) 
APPENDIX VI - Pediatric Chemotherapy-Induced Neuropathy Patient v4 (P-CIN) Survey  
APPENDIX VII – Pediatric Neuropathic Pain Scale Five  
APPENDIX VIII – Pain: FACES Pain Rating Scale 
APPENDIX IX – Adverse Events: NCI CTCAE V4.02 
APPENDIX X – Quality of Life: Pediatric Quality of Life Inventory: Peds QL Scale 4.0 
APPENDIX XI – Ferrans and Powers Quality of Life Cancer v3  
APPENDIX XII - Self-efficacy, Support and Outcome Expectations Questionnaire 
APPENDIX XIII – Standardized Fitness Assessment 
APPENDIX XIV – Patient Satisfaction Survey 
APPENDIX XV - Parent/Care Giver Satisfaction Survey