Clinical trial NCT01506453
Conditions: Acute Lymphoblastic Leukemia Neuropathy Neuropathic Pain
Keywords: Acute Lymphoblastic Leukemia Neuropathy Neuropathic Pain Vincristine TOTAL XVI Protocol
Sponsor: St. Jude Children's Research Hospital
Start date: 2012-01-24; Completion date: 2018-01-02
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Neuropathic pain / peripheral neuropathy (NP/PN) is a known painful complication of vincristine (VCR) therapy; evidence supporting the best treatment plan for pediatric patients is limited. Gabapentin is frequently used for VCR-related NP/PN, with variable dosing and scheduling regimens, and with varying measures of success. The hypothesis of the study is that gabapentin will reduce the severity of NP/PN in patients receiving vincristine during treatment for ALL on the Total XVI protocol (or for those being treated "as per TOTXVI protocol"), as measured by two outcome measures: the daily dose of morphine used as needed for pain in addition to either gabapentin or placebo, as randomized, and the pain scores assessed daily.

Detailed description:
Patients with ALL on Total XVI ((or for those being treated "as per TOTXVI protocol") who experience NP/PN after specific doses of vincristine are eligible to enroll in the study as soon as the diagnosis of NP/PN related to VCR is established. The qualifying doses of vincristine have been selected because they fall in the schedule of weekly vincristine doses as per Total XVI, and 2 additional weekly vincristine doses are anticipated according to the protocol. Participants will be randomized to receive gabapentin or placebo upon enrollment. Morphine will be available to both groups as needed for pain at any time on the study. At the time of enrollment, and daily thereafter until completion of the study drug, data will be collected for pain assessment, and the daily dose of oral morphine used will be collected. Data regarding the pain type, quality, and location, as well as treatments used to manage pain will be assessed on a daily basis for the diagnostic event and for the period following the next two administrations of VCR treated with the study drug.

Primary Objective: To assess the analgesic efficacy of gabapentin in controlling VCR-related NP/PN in participants with ALL, by comparing the morphine daily dose (mg/kg/day) used to control NP/PN as a primary or a rescue regimen in the gabapentin vs. placebo groups.

Secondary Objective: To compare the pain scores in the gabapentin and placebo groups as recorded by pain score right now and pain score average for previous 24 hours.

Arms: arm 1: Active treatment arm. arm 2: Placebo arm.
Interventions: intervention 1: gabapentin intervention 2: placebo
Intervention descriptions: intervention 1: Participants randomized to the active treatment arm will receive gabapentin 20mg/kg/day PO divided into 3 doses and rounded to the nearest 100 mg for capsules and 10 mg for liquid preparation. intervention 2: Participants randomized to the placebo treatment arm will receive look-alike capsules or liquid in a respective capsule size or liquid measure equivalent to the active treatment arm, but which contain no active treatment.

Protocol documents:
Prot_SAP_000.pdf: 
St. Jude 
TINALL NCT01506453 
Initial version, dated:  07-5-2011 (IRB Approved: 10-07-2011) Activation Date:  00-00-00 
     Resubmitted to CT-SRC 08/11/2011 (CT-SRC Approved: 08/23/2011) 
Amendment 1.0, dated 11-14-2011 (IRB Approved: 12-13-11) Activation Date: 01-24-12 
Amendment 2.0, dated 04-24-2012 (IRB Approved: 05-26-12) Activation Date: 06-11-12 
Revision 2.1, dated 08-16-2013 (IRB Approved: 08-20-2013) Activation Date: 08-28-2013 
Revision 2.2, dated 04/29/2015 (IRB Approved: 05/06/2015) Activation Date: 05/11/2015 
Revision 2.3, dated 05/10/2016 (IRB Approved: 05/24/2016) Activation Date: 05/25/2016 
 
 
 
 
THERAPEUTIC INTERVENTIONS FOR PERIPHERAL 
NEUROPATHY/NEUROPATHIC PAIN INDUCED BY VINCRISTINE TREATMENT 
FOR CHILDHOOD ALL ON TOTAL XVI PROTOCOL 
IND# 113597 
 
 
Principal Investigator 
 
Doralina Anghelescu, MD1 
 
 
 
 
 
Co-Investigators 
Sima Jeha, MD2,  
Becky B. Wright, MD1 
 Luis Trujillo, MD1,  
  John T. Sandlund, MD2 
 Mary V. Relling, PharmD3 
 Cheng Cheng, PhD4 
 Deqing Pei4 
 Jennifer Pauley, PharmD 
 Ching-Hon Pui , MD2 
 
1Departments of Anesthesiology, 2Oncology, 3Pharmaceutical Sciences, 4Biostatistics  
 
 
 
 
 
St. Jude Children's Research Hospital 
 
262 Danny Thomas Place 
 
Memphis, Tennessee  38105-3678 
 
Telephone:  (901) 595-3300 
 
Contents of this document may not be extracted without permission from  
the Principal Investigator.
 


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TINALL - Therapeutic Interventions for Peripheral Neuropathy/Neuropathic Pain 
Induced by Vincristine Treatment for Childhood ALL on Total XVI Protocol 
 
Principal Investigator: Doralina Anghelescu, MD 
 
IND Holder: St. Jude Children’s Research Hospital; IND #113597 
 
Brief Overview: Neuropathic pain / peripheral neuropathy (NP/PN) is a known painful 
complication of vincristine (VCR) therapy; evidence supporting the best treatment plan for 
pediatric patients is limited.  Gabapentin is frequently used for VCR-related NP/PN, with 
variable dosing and scheduling regimens, and with varying measures of success. The 
hypothesis of the study is that gabapentin will reduce the severity of NP/PN in patients 
receiving vincristine during treatment for ALL on the Total XVI protocol, as measured by 
two outcome measures: the daily dose of morphine used as needed for pain in addition to 
either gabapentin or placebo, as randomized, and the pain scores assessed daily. 
 
Intervention: Randomized, placebo-controlled study of gabapentin 20mg/kg/day divided 
in three doses; open label morphine for breakthrough pain as needed for both arms. 
 
Brief Outline of Treatment Plan:  
Patients with ALL on Total XVI or “as per TOTXVI” who experience NP/PN after 
specific doses of vincristine are eligible to enroll in the study as soon as the diagnosis of 
NP/PN related to VCR is established. The qualifying doses of vincristine have been 
selected because they fall in the schedule of weekly vincristine doses as per Total XVI, 
and 2 additional weekly vincristine doses are anticipated according to the protocol. 
Participants will be randomized to receive gabapentin or placebo upon enrollment.  
Morphine will be available to both groups as needed for pain at any time on the study. At 
the time of enrollment, and daily thereafter until completion of the study drug, data will be 
collected for pain assessment, and the daily dose of oral morphine used will be collected.    
Data regarding the pain type, quality, and location, as well as treatments used to manage 
pain will be assessed on a daily basis for the diagnostic event and for the period following 
the next two administrations of VCR treated with the study drug.   
 
Objectives: 
Primary Objective:  
To assess the analgesic efficacy of gabapentin in controlling VCR-related NP/PN in 
participants with ALL, by comparing the morphine daily dose (mg/kg/day) used to control 
NP/PN as a primary or a rescue regimen in the gabapentin vs. placebo groups. 
 
Secondary Objective: 
To compare the pain scores in the gabapentin and placebo groups as recorded by pain score 
right now and pain score average for previous 24 hours. 
 
Responsible Investigator: Doralina Anghelescu, MD 
Statistician: Cheng Cheng, Ph.D. 
Estimated date for completion of data collection: December 2015 
 
 


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TINALL - Therapeutic Interventions for Peripheral Neuropathy/Neuropathic Pain 
Induced by Vincristine Treatment for Childhood ALL on Total XVI Protocol 
 
Hypotheses/Estimates:  The hypothesis is that treatment with gabapentin has better 
analgesic efficacy than placebo in the treatment of VCR-related NP/PN.  Based on the 
current enrollment on the Total XVI protocol, the projected enrollment, the incidence of 
NP/PN of 34.9% as determined in our previous study of NP/PN associated with the Total 
XV protocol, we estimate that 60 study participants will be eligible to enroll in this study 
during the duration of the Total XVI study. To achieve a total of 60 evaluable patients, up 
to 80 participants may be enrolled. 
 
Criteria for Evaluation:  
Safety: Any adverse events will be recorded and reported. 
Efficacy: Efficacy will be evaluated based on two outcome measures:  the daily dose of 
oral morphine used as needed for pain (mg/kg/day) and the pain scores daily, during the 
treatment course with either gabapentin or placebo. 
 
Study Design: Randomized placebo controlled phase II study 
 
Study Population: 
 
Inclusion Criteria: 
1. Participant is enrolled on Total XVI or “as per TOTXVI”.  
2. Participant is 1 year of age or older. 
3. Participant has symptoms of NP/PN with onset no more than 7 
days after one of the following vincristine doses dates ± 3 days:  
protocol week 1, week 2 (induction), week 7 (reinduction I), or 
week 17 (reinduction II). 
4. Patient is expected to receive 2 doses of vincristine in weekly 
intervals as outlined by the Total XVI or “as per TOTXVI” 
protocol while on study drug (i.e. no known dosage reductions or 
planned missed doses). 
5. Participant is able and willing to take oral medications. 
 
Exclusion Criteria: 
1. Previous participation in this study 
2. Participant is receiving gabapentin for another indication at the 
time of diagnosis of NP/PN or has received gabapentin previously. 
3. Pregnancy. Female participants of childbearing potential must have 
documented negative urine or serum pregnancy test result not older 
than 7 days. Male patients with reproductive potential will be 
counseled not to procreate during the study. 
4. Impaired renal function: decreased eGFR (< 60ml/min/1.73m2 
as estimated by the Schwartz equation). 
5. Participant has allergy or other contraindication for either 
morphine or gabapentin therapy. 
6. Inability or unwillingness of research participant or legal 


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TINALL - Therapeutic Interventions for Peripheral Neuropathy/Neuropathic Pain 
Induced by Vincristine Treatment for Childhood ALL on Total XVI Protocol 
 
guardian/representative to give written informed consent. 
 
Sample Size: The sample size will depend on the incidence of NP/PN in the eligible 
population.  Based on our retrospective data from Total XV, we expect a sample size of 
60, with 30 to be randomized to the gabapentin arm or the placebo arm, respectively. 
However we will enroll and randomize all eligible and consented patients in the remainder 
of Total XVI. To achieve a total of 60 evaluable patients, up to 80 participants may be 
enrolled. 
 
Randomization: Patients with ALL on Total XVI or “as per TOTXVI” who experience 
NP/PN after certain doses of vincristine are eligible to enroll in the study as soon as the 
diagnosis of NP/PN related to VCR is established. Participants will be randomized to 
receive gabapentin or placebo and continue taking the study drug until 2 doses of 
vincristine have been completed, and for 7 days after the second dose of vincristine.  
Morphine will be available to both groups as needed for pain at any time on the study. 
 
Data Analyses: Two efficacy measurements will be analyzed: the average daily morphine 
dosage and the average daily pain score during the maximum 21-day treatment period. We 
will test the null hypothesis that the expected average daily morphine dosage and pain 
score are the same in the gabapentin and the placebo group vs. a one-sided hypothesis that 
the expected average daily morphine dosages and pain scores are lower in the gabapentin 
group. 
 
Anticipated Primary Completion Date:  December 2016 
Anticipated Study Completion Date:  December 2018 
Timeframe for Primary Outcome Measure:   
Data Management: Data management and statistical analysis will be provided locally 
by the Department of Anesthesiology and Biostatistics Department at St. Jude Children’s 
Research Hospital, respectively. 
 
Human Subjects: The risk to subjects is related to the side effects of gabapentin. The 
most common side effect is somnolence. Patients will be informed of this and other 
minor side effects during informed consent. Adverse events will be monitored and 
reported and treated appropriately.  
 


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Table of Contents 
 
List of Collaborating Investigators/Institutions 
Protocol Summary 
 
1.0     OBJECTIVES ..................................................................................................1 
1.1   Primary Objective....................................................................................1 
2.0     BACKGROUND AND RATIONALE ............................................................1 
2.1   Background .............................................................................................1 
2.2   Rationale ..................................................................................................2 
3.0     RESEARCH PARTICIPANT ELIGIBILITY CRITERIA 
          AND STUDY ENROLLMENT ......................................................................3 
3.1   Inclusion Criteria .....................................................................................3 
3.2   Exclusion Criteria ....................................................................................4 
3.3   Research Participant Recruitment and Screening ...................................4 
3.4   Enrollment on Study ................................................................................4 
3.5   Procedures for Identifying and Randomizing Research Participant……5 
4.0     TREATMENT PLAN ......................................................................................6 
4.1   Study Treatment ......................................................................................7 
4.2   Breakthrough Pain Control……………………………………………. 7 
4.3   Dose Modifications .................................................................................8 
4.4   Definitions of Dose-Limiting Toxicity....................................................8 
4.5   Concomitant Therapy ..............................................................................8 
4.6   Supportive Care .......................................................................................8 
5.0     DRUG INFORMATION .................................................................................8 
          5.1    Gabapentin (Neurontin)…………………………………………………8 
          5.2    Placebo…………………………………………………………………..9 
6.0     REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ................10 
6.1   Pre-Study Evaluations .............................................................................10 
6.2   Evaluations during Therapy ....................................................................10 
6.3   Response Evaluations ..............................................................................10 
6.4   Off-Study Evaluations .............................................................................10 
6.5   Long-Term Follow-up Evaluations .........................................................11 
7.0     EVALUATION CRITERIA ............................................................................11 
7.1   Response Criteria ....................................................................................11 
7.2   Toxicity Evaluation Criteria  ...................................................................11 
8.0     OFF THERAPY AND OFF STUDY CRITERIA ...........................................11 
8.1  Off-Study Criteria .....................................................................................11 
8.2  Off-Therapy Criteria. ................................................................................12 
9.0    SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS .........12 
9.1   Reporting Serious Adverse Events ..........................................................12 
           9.2   Reporting to the IRB ...............................................................................12 
10.0    DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY
....................................................................................................................................12 
10.1  Data Collection .......................................................................................13 
10.2  Study Monitoring....................................................................................13 
10.3  Confidentiality ........................................................................................13 


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11.0    STATISTICAL CONSIDERATIONS………………………………………13 
11.1  Primary Objective……………………………………………………...13 
11.2  Randomization…………………………………………………………14 
12.0    OBTAINING INFORMED CONSENT…………………………………….14 
12.1    Consent at Age of Majority…………………………………………..15 
13.0    REFERENCES………………………………………………………………16 
Appendices 
Appendix I: Example of a schedule of evaluations 
Appendix II: Research Activities 
Appendix III:  Pain Scales 


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1.0 
OBJECTIVES 
 
The investigators propose to study the analgesic efficacy of gabapentin for the 
treatment of neuropathic pain/peripheral neuropathy (NP/PN) associated with 
vincristine therapy in the context of treatment of childhood ALL on Total XVI 
protocol.  
 
1.1 
Primary Objective 
 
To assess the analgesic efficacy of gabapentin in controlling VCR-related 
NP/PN in participants with ALL, by comparing the morphine daily dose 
(mg/kg/day) used to control NP/PN as a primary or a rescue regimen in 
the gabapentin vs. placebo groups. 
 
1.2 
Secondary Objective 
 
To compare the pain scores in the gabapentin and placebo groups as 
recorded by pain score right now and pain score average for previous 24 
hours. 
 
2.0  
BACKGROUND AND RATIONALE 
 
 
2.1 
Background 
 
Children with cancer experience a significant symptom burden during the 
course of treatment1,2, and pain is the most frequent, most severe and most 
distressful of symptoms. The impact of pain experienced during treatment 
for cancer has long term implications after completion of therapy 3,4.   
 
Neuropathic pain and related neuropathy symptoms have been directly 
correlated with chemotherapeutic agents 5, vincristine in particular 6 and 
have been reported during therapy for childhood cancers 7,8.    
 
Neurotoxicity, the dose-limiting side effect of vincristine, most often 
causes mixed sensorimotor neuropathy (loss of deep tendon reflexes, 
paresthesias, neuritic pain, and wrist or foot drop) or autonomic neuropathy 
(constipation, abdominal pain, paralytic ileus, bladder atony with retention 
of urine, and orthostatic hypotension).  On the rare occasions in which 
vincristine-associated neurotoxicity involves the cranial nerves, it produces 
transient cortical blindness, oculomotor nerve dysfunction with ptosis and 
diplopia, jaw pain, facial palsy, hearing loss, and vocal cord paresis or 
paralysis 5. 
 
The incidence of peripheral neuropathy related to vincristine during 
treatment of childhood ALL per protocol Total XIIIB in our institutional 
experience has been 17.5% (42 of 240) 9 and peripheral 
neuropathy/neuropathic pain were identified as adverse events in 34.9% of 


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children treated on protocol Total XV (174 of 498) 10. Due to the higher 
vincristine dose used in our current institutional protocol for treatment of 
childhood ALL, Total XVI, and knowing that vincristine toxicity is related 
to higher individual doses as well as cumulative dose, we expect an even 
higher incidence during Total XVI treatment.  
2.2 
Rationale 
 
Given the significance of the problem of neuropathic pain during cancer 
treatment in children, the associated suffering, and the long term impact, 
we propose to prospectively investigate the value of two therapeutic 
intervention arms for NP/PN, in children with ALL treated per Total XVI 
or “as per TOTXVI” protocol.  Furthermore, our retrospective analysis did 
not demonstrate conclusively the analgesic efficacy of gabapentin, although 
clinical applications of gabapentin for VCR-neuropathy continue to persist 
with varying treatment regimens and despite the lack of data from relevant 
clinical trials. 
 
The design of the study is a randomized placebo-controlled study, 
comparing a regimen based on opioid only to a regimen comprised of 
opioid and gabapentin.  Existing data from clinical trials has failed to show 
the best treatment regimen to control or prevent VCR-induced NP/PN in 
children.  There are indications in the literature in adult neuropathic pain 
syndromes such as diabetic neuropathy and postherpetic neuralgia that dual 
therapy of opioid and gabapentin has better analgesic efficacy than either 
individual therapy11; nevertheless, no such investigations have explored 
therapies for neuropathic pain in children.   
 
Rationale for dose selection and duration of gabapentin therapy  
 
The gabapentin dose selection for this study is based on the data in the 
literature describing the clinical use of gabapentin in children with 
neuropathic pain12-19 and on our institutional experience with gabapentin 
in a retrospective study evaluating neuropathic pain in children with ALL 
during Total XV therapy10.  There are no PK data supportive of 
gabapentin dose regimens for neuropathic pain in children. 
 
Three case reports17-19 and 5 small series12-16 describe the use of 
gabapentin as an adjuvant analgesic in children with NP under diverse 
circumstances: after thoracotomy17, after multilevel orthopedic surgery 14, 
and for complex regional pain syndrome15,18, systemic lupus 
erythematous13, cancer-related pain12,19, neck pain12, and phantom limb 
pain16. These studies included 24 children, and the dose regimen of 
gabapentin was described for only 17 of them12,14,16,17. Analgesic efficacy 
was reported at 22.5 mg/kg/day in a 12-year-old with post-thoracotomy 
NP17, 14-40 mg/kg/day in 7 patients 7 to 28 years old with phantom limb 
pain16, 19-32.6 mg/kg/day in 4 children 11 to 17 years old with NP after 


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multilevel orthopedic  surgery14, and 10-30 mg/kg/day in 5 children with 
cancer-related pain (n=4) or neuropathic neck pain (n=1)12.   
 
Dosing and safety information for the pediatric use of gabapentin has been 
defined only for anti-seizure therapy20.  Most pediatric pain specialists 
recommend the anti-seizure dose regimen for children with NP, starting at 
10 mg/kg/day and titrating upward to 50 to 70 mg/kg/day.  Gabapentin is 
currently the first-line therapy for NP at our institution.  In our 
retrospective review of neuropathic pain during Total XV protocol for 
ALL at St. Jude, we found treatment data for 180 of 207 episodes of NP in 
153 of 174 patients; the missing data reflect treatment at a site other than 
St. Jude.  Gabapentin was used to treat 62.2% of episodes (112 of 180) in 
65.4% of patients (100 of 153); the remaining 37.8% of episodes (68 of 
180) in 34.6% of patients (53 of 153) were treated with opioids.  The 
selection of gabapentin or opioids did not appear to be influenced by the 
pain intensity score at the time of diagnosis of NP (p=0.91).  The mean 
starting dose used for the 112 episodes was 15.5 mg.kg/day (SD 7.9)10.  In 
this study we found the median starting dose to be 14.2 mg/kg/day.  In the 
absence of a uniform approach to the use of gabapentin, prospective 
studies are needed to determine the optimal regimen. There is some 
evidence that concurrent use of gabapentin and morphine provide better 
analgesia at doses lower than those used for single-agent therapy11. 
 
The duration of gabapentin therapy of up to 21 days is based on the pattern 
of administration of the trigger agent for neuropathic pain in ALL. We 
have selected the phases of the Total XVI or “as per TOTXVI” protocol 
during which VCR is administered most intensely, in weekly doses. 
Indeed, data from Total XV and preliminary data from Total XVI or “as per 
TOTXVI support the highest cumulative incidence of neuropathic pain at 
the time of induction, reinduction I and II. The duration of gabapentin 
therapy reflects the duration of vincristine administration. 
 
3.0  
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY  
ENROLLMENT  
 
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background.  Institutional experience 
confirms broad representation in this regard. 
 
3.1 
Inclusion Criteria 
 
3.1.1 Participant is enrolled on Total XVI 
3.1.2 Participant is age 1 year or older. 
3.1.3 Participant has symptoms of NP/PN with onset within 7 days 
after one of the following vincristine doses dates ± 3 days:  
protocol week 1 or week 2 (induction), week 7 (reinduction 
I), or week 17 (reinduction II). 


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3.1.4 Patient is expected to receive 2 weekly doses of vincristine 
as outlined by the Total XVI or “as per TOTXVI” protocol 
while on study drug (i.e. no known dosage reductions or 
planned missed doses).3.1.5 Participant is able and willing 
to take oral medications. 
3.2 
Exclusion Criteria 
 
3.2.1 Previous participation in this study 
 
3.2.2 Participant is receiving gabapentin for another indication at the 
time of diagnosis of NP/PN or has received gabapentin previously 
3.2.3 Pregnancy. Female participants of childbearing potential must have 
documented negative urine or serum pregnancy test result not older 
than 7 days. Male patients with reproductive potential will be 
counseled not to procreate during the study. 
 
3.2.4 Decreased GFR (<60ml/min/1.73m2 as estimated by the 
revised Schwartz equation21,22). 
 
3.2.5 Participant has allergy or other contraindication for morphine or 
gabapentin therapy. 
 
3.2.6 Inability or unwillingness of research participant or legal  
guardian/representative to give written informed consent.  
 
 
3.3 
Research Participant Recruitment and Screening 
 
Participants will be identified by referral to the study team (Pain Service) 
from the primary clinical team (Leukemia Service), upon diagnosis of 
NP/PN.  In addition to referrals from the Leukemia Service, the study 
team will screen the clinical notes of potentially eligible Total XVI or “as 
per TOTXVI patients for documentation of new onset NP/PN and determine 
eligibility.  With the agreement of the primary clinical team, a study team 
member will approach the potentially eligible participant to initiate 
informed consent discussions.  
 
When informed consent is obtained and the patient is enrolled, a member 
of the study team will inform the pharmacy and the randomization 
procedure will be initiated. The pharmacy order sets will be activated for 
the study drug and open label oral morphine. 
 
 
3.4 
Enrollment on Study at St. Jude 
 
A member of the study team will confirm potential participant eligibility 
as defined in Section 3.1-3.2, complete and sign the ‘Participant Eligibility 


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Checklist’.  The study team will enter the eligibility checklist information 
into the Patient Protocol Manager (PPM) system. Eligibility will be 
reviewed, and a research participant-specific consent form and assent 
document (where applicable) will be generated. The complete signed 
consent/assent form(s) must be faxed to the CPDMO to complete the 
enrollment process. 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A 
staff member is available by pager Saturday, Sunday, and holidays from 
8:00 am to 5:00 pm. 
 
3.5 
Procedures for Identifying and Randomizing Research Participants 
 
The PI or other study team member will approach the parent and 
participant regarding the study. If both the research participant and parent 
agree to participate, the randomization plan established by the study 
biostatistician will be accessed according to Section 11.  
 


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4.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study day 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
1. Daily study drug (TID) 
2. Morphine PRN 
3. Daily pain assessments 
*Qualifying VCR dose – dose falling on a weekly interval with at least 2 more weekly doses expected.  Includes vincristine dose dates: Induction week 1 ± 3 days, 
Induction week 2 ± 3 days, Reinduction I (week 7) ± 3 days or Reinduction II (week 17) ± 3 days. 
VCR dose 
expected ± 
3 days 
VCR dose 
expected ± 3 
days 
1. Eligibility verification 
2. Consent / Enrollment 
3. Randomization 
4. Begin study drug 
1. Discontinue study drug 
2. Refer ongoing pain to 
primary clinic or pain 
team 
Off Study 
Qualifying 
VCR dose* 
± 3 days 
Diagnosis of NP occurs 


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4.1 
Study treatment  
 
Upon each participant’s enrollment, study staff will randomize the 
participant to one of 2 possible treatment arms (see section 11 for 
randomization procedure) and order the study treatment.  The pharmacy 
will dispense a supply of the study treatment (gabapentin vs. placebo) 
sufficient to last through the end of the study (not more than 21 days), as 
well as the oral morphine for use as needed. 
 
The pharmacy order will read “Gabapentin/Placebo study drug 
(TINALL)” and doses will be calculated as 20 mg/kg/day PO divided into 
3 doses and rounded to the nearest 100 mg for capsules and 10 mg for 
liquid preparation.  Neither the ordering clinician nor the participant / 
family will be informed of the treatment assignment. 
 
Study treatment order entry will be managed by study staff according to 
pharmacy and institutional policy for medication administration.  Any 
modifications to the study treatment (dose, duration, frequency, or 
discontinuation) will be done by the study team. 
 
4.1.1 Active treatment arm  
 
Participants randomized to the active treatment arm will receive 
gabapentin 20mg/kg/day PO divided into 3 doses and rounded to 
the nearest 100 mg for capsules and 10 mg for liquid preparation.  
 
4.1.2 Placebo treatment arm 
 
Participants randomized to the placebo treatment arm will receive 
look-alike capsules or liquid in a respective capsule size or liquid 
measure equivalent to the active treatment arm, but which contain 
no active treatment. 
 
4.2 
Breakthrough pain control 
All participants, regardless of treatment assignment, will receive open-
label oral morphine (0.15 mg/kg/dose every 2 hours, rounded to the  
nearest tablet size or measurable liquid quantity), as needed for pain.  
Morphine orders and dosages will be managed by the pain team according 
to clinical indication and following institutional and pharmacy policy for 
prescription and administration of controlled substances. 
 
Substitution of other opioids for morphine should be avoided and 
performed only upon consultation with the PI. 
 
 


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4.3 
Dose Modifications 
 
The most common side effect of gabapentin is sedation/drowsiness.  
Participants who experience unacceptable side effects will have dosage 
adjustments at the discretion of the PI, or will be taken off therapy. If dose 
adjustment is indicated, study treatment will be reduced by 5-10 
mg/kg/day.  
 
Elimination of gabapentin can be affected by renal impairment which 
could increase drug exposure.  Patients who are found to have renal 
impairment while on the study (defined as GFR < 60ml/min/1.73m2 as 
estimated by the Schwartz equation21,22) will be taken off therapy.  
Renal function of participants will be reviewed at least weekly while 
on study. 
 
4.4 
Definitions of Dose-Limiting Toxicity 
 
The most common side effect of gabapentin is sedation/drowsiness.  
Participants who experience unacceptable side effects will have dosage 
adjustments or will be removed from the study (see section 4.3) 
 
4.5 
Concomitant Therapy 
 
It is expected that participants in this study will receive numerous 
concomitant therapies unrelated to the research interests of this study.  
Only the study treatment and pain control treatments will be analyzed to 
determine the study outcomes.  Exposure to vincristine (dose preceding 
NP event, as well as total cumulative dose) will be recorded. 
 
4.6 
Supportive Care 
 
Morphine is prescribed for use as needed for breakthrough pain.  See 
sections 4.1 and 4.3. 
 
 
5.0 
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION  
 
 
5.1 
GABAPENTIN (Neurontin®) 
 
Source and Pharmacology: Gabapentin is a white to off-white crystalline 
solid that is freely soluble in water. Its mechanism of action in preventing 
seizures is not known. Gabapentin is not appreciably metabolized in 
humans; pharmacological effects are from the activity of the parent 
compound. It is eliminated unchanged in the urine. Patients with renal 
impairment should have dosage adjustments.  Higher doses are less 
bioavailable than lower doses after oral administration, but across the 
recommended dose range of 300 mg to 600 mg T.I.D., the bioavailability 


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is approximately 60%. Administration with food has little effect on 
absorption of gabapentin.  
 
Formulation and Stability: Gabapentin is supplied as 100 mg, 300 mg, 
and 400 mg capsules, and as an oral solution containing 50 mg/ml. The 
tablets and capsules can be stored at room temperature, and the oral 
solution must be refrigerated.  
 
Toxicity:  Patients 3 – 12 years old treated with gabapentin for epilepsy 
reported the following central nervous system related adverse events: 
emotional lability, hostility, thought disorder and hyperkinesia in addition 
to CNS depression (dizziness, somnolence, fatigue, ataxia, and 
nystagmus). In placebo controlled trials of gabapentin in children taking 
other antiepileptic drugs, the following were also seen at higher frequency 
in the treatment group than the placebo group: viral infection, bronchitis, 
pharyngitis, rhinitis,  respiratory infection, coughing, otitis media, fever, 
nausea and/or vomiting, diarrhea, depression, headache, diplopia, blurred 
vision, nervousness, seizures, pruritus, dyspepsia, constipation, weight 
gain, anorexia, leukopenia, back pain, and peripheral edema.  
 
Supplier: Commercially available 
 
Dosage and Route of Administration: Participants randomized to the 
active treatment arm will receive gabapentin 20mg/kg/day PO divided into 
3 doses and rounded to the nearest 100 mg for capsules and 10 mg for 
liquid preparation. 
 
Do not administer within two hours of aluminum or magnesium 
containing antacids. Abrupt withdrawal of gabapentin therapy may 
precipitate seizures.   
 
5.2 
PLACEBO 
 
Placebo capsules contain microcrystalline cellulose as filler to a weight 
equivalent to the active agent.  The capsules should be stored at room 
temperature in the pack provided.  The expiration date will be listed on the 
product label.  Placebo capsules will be compounded for patients by Regel 
PharmaLab (a local compounding pharmacy) to match the active capsules 
in appearance as closely as possible. St Jude pharmacy will dispense the 
capsules and keep accountability records as per randomized assignment.  
 
Placebo syrup will be compounded with simple syrup diluted with normal 
saline with flavoring added.  The solution should be stored in the 
refrigerator.  The expiration date will be listed on the product label.  
Placebo syrup will be prepared by the St. Jude Children’s Research 
Hospital Pharmacy for distribution to the patient. 
 


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To allow for the study team and participants to remain blinded to the 
treatment assignment, the study drug will be labeled by the pharmacy as 
“TINALL study treatment (gabapentin vs. placebo)” followed by 
applicable dose and administration instructions. 
  
 
 
6.0  
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
Subsections of 6.0 are outlined in tabular form in Appendix I.   
 
6.1 
Pre-Study Evaluations 
 
The eligibility depends on establishing the initial diagnosis of NP/PN 
related to vincristine; this is a clinical diagnosis that is documented in the 
medical record and does not require any additional tests.  Documentation 
of NP/PN made in the medical record by any St. Jude clinician will serve 
as the source for this diagnosis and for determining eligibility. 
 
Female participants of childbearing potential must have documentation of a 
negative pregnancy test not older than 7 days at the time of enrollment; if 
this is not available, the study team will order the test to be performed and 
reviewed prior to starting study drug.   
 
Clinically obtained creatinine levels will be used to estimate the GFR 
using the Schwartz equation21,22.  Patients with estimated GFR 
<60ml/min/1.73m2 will not be enrolled. 
 
6.2 
Evaluations During Therapy 
Participants will be evaluated daily by pain intensity assessments, using  
                       age appropriate tools, until completion of the study treatment. The   
                       maximum duration of the study cannot exceed 21 days. The pain  
                       assessment tools are the FLACC scale (0-10) for participants younger than  
                       years of age or other children who cannot self report 23, the Faces Pain  
           Scale-Revised (FPS-R) (0-10) for ages 4-7 24, and the numeric scale (0-10)      
           for ages older than 7 25,26. This assessment can be obtained during a clinical  
           evaluation or by phone interview, if a clinical visit is not feasible.  
 
Additional data will be obtained regarding location and descriptors of pain 
(daily) and the daily dose of morphine used during the study.  
 
The GFR of participants will be monitored at least weekly while on 
study, using clinically obtained creatinine levels to estimate GFR using 
the Schwartz equation21,22.  Patients who develop renal impairment 
(estimated GFR < 60ml/min/1.73m2) will be taken off therapy. 
 
 


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6.3     Response Evaluations 
 
Evaluations will continue as described in section 6.2. 
 
 
6.4     Off-Study Evaluations 
 
 
  
Patients will be off study when the patient has completed the study 
treatment and applicable pain assessments have been collected.  If pain 
symptoms persist at the completion of the study, the patient will continue to 
be treated as needed, with gabapentin and/or morphine, either by the pain 
team or the leukemia team, but no additional data will be collected for this 
study. 
 
 
6.5 
Long-Term Follow-up Evaluations 
 
This study will not evaluate NP events or long term results beyond the off 
study evaluation. 
 
Participants will be notified of their treatment assignment (gabapentin or 
placebo) after the completion of data collection for the last participant 
enrolled.  Notification will be performed by a member of the study team in 
person (when feasible) or by letter at the earliest convenience of the study 
team and documented in the study files. 
 
 
7.0  
EVALUATION CRITERIA 
 
7.1 
Response Criteria 
 
The response to therapy will be measured by pain intensity scores and 
daily use of morphine doses for breakthrough pain as described in the 
study objectives.  Daily assessments will continue during treatment with 
the study drug (gabapentin or placebo) irrespective of patient response to 
study treatment. 
 
7.2 
Toxicity Evaluation Criteria 
 
Participants who experience unacceptable side effects will have dosage 
adjustments or will be removed from the study (see section 4.4).  The 
decision to adjust the study treatment dose or to discontinue study 
treatment will be made by the PI and in the context of the participant’s 
clinical situation. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND  
OFF-STUDY CRITERIA 


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8.1 
Off-study criteria 
 
8.1.1 Completion of study therapy and assessments 
8.1.2 Death 
8.1.2 Lost to follow-up 
8.1.3 Request of the Patient/Parent 
8.1.4 Discretion of the Study PI, such as the following  
• 
The researcher decides that continuing in the study would be 
harmful  
• 
New information is learned that a better treatment is available, 
or that the study is not in the participant’s best interest 
 
8.2 
Off-therapy criteria 
 
8.2.1 Development of unacceptable toxicity during treatment 
 
8.2.2 Development of renal impairment, defined as GFR less than 
60ml/min/1.73m2 as estimated by the Schwartz equation21,22. 
 
8.2.3 Refusal of therapy 
 
8.2.4 Unblinding of participant or study team to participant’s 
treatment assignment (see section 9.3) 
 
 
 
9.0  
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
9.1 
Reporting Serious Adverse Events 
 
 
9.1.1    IRB Notification by Investigator 
 
Adverse events (AEs) will be graded according to the CTCAE 
version 4.0.  All study-related anticipated AEs of grade 3 or higher 
will be reported to the IRB via institutional reporting mechanisms.  
Those AEs grade 2 or below will be reported to the IRB at the time 
of continuing review.  All serious, related (or possibly related), and 
unexpected AEs of all grades will be reported to the IRB within 48 
hours of discovery of the event. Others will be reported within 10 
working days of discovery of the event. 
 
Adverse events determined by the PI to be unrelated to the study 
treatment will be reported by the procedures outlined in the 
primary treatment protocol (Total XVI). 
    
9.1.2 Recording Adverse Events and Serious Adverse Events 
 


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Adverse events will be submitted by a member of the study team to 
the IRB using the existing institutional online reporting 
mechanisms.  All study-related AEs will be collected in the 
database, regardless of their grade.   
 
 
9.2 
Reporting to the IRB 
In addition to the continuing review reports to the IRB, the Principal 
Investigator is responsible for reporting all serious and unexpected 
adverse events that impact the safety of risk to study research participants.  
Unexpected death will be reported to the IRB office immediately at 
SJCRH.  Serious unexpected events will be reported within 48 hours, and 
all others within 10 working days. 
 
9.3 
Emergency Unblinding 
 
In the case of a medical emergency or in the event of a serious medical 
condition, when knowledge of the investigational product is essential 
for the clinical management or welfare of the subject, an investigator 
or other physician managing the subject may decide to unblind that 
subject’s treatment code. 
 
The physician managing the medical emergency or serious condition 
should attempt to contact the principal investigator to discuss options 
prior to unblinding, and the principal investigator should approve the 
unblinding, when applicable.  However, ensuring patient safety is the 
primary objective when the decision to unblind the treatment 
assignment is made.   
 
The principal investigator or designated study personnel will complete 
an off therapy request with the rationale to unblind study drug listed.  
The principal investigator or designated study personnel will contact 
pharmacy to determine the unblinding information. 
 
Any patient whose treatment assignment is unblinded will be removed 
from study treatment and followed off-therapy. The study team will 
continue to follow the patient status regarding the serious adverse 
event(s) for which the patient’s treatment was unblinded until 
resolved or improved to baseline. The patient can receive off-study 
treatment as necessary. 
 
All occurrences of emergency unblinding will be reported to the IRB 
according to the criteria established in protocol section 9.0, and the 
FDA, when applicable. 
 
 
 


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9.4 
Criteria for Unblinding 
 
The occurrence of a serious adverse event that is both unexpected and 
considered by the reporting investigator to be associated with the use 
of study drug, and the knowledge of the treatment assignment is 
deemed essential for the patient’s care in treatment of the event.  This 
criteria includes known overdose of study drug. 
 
 
 
10.0 
DATA COLLECTION, STUDY MONITORING, AND 
CONFIDENTIALITY 
 
10.1 
Data Collection  
 
A member of the TINALL study team will complete documentation in 
MILLI for each study encounter (“anesthesia research note”). Data will 
then be entered into a secure database, which serves as the electronic case 
report forms (eCRFs). Records from the study which identify the study 
participant will be kept confidential in a secured area.  
 
10.2 
Study Monitoring 
 
Source document verification of eligibility for all SJCRH cases will be 
performed within two weeks of completion of enrollment. This will 
include verification of appropriate documentation of consent. Monitoring 
of timeliness of adverse and serious adverse event reporting will be done 
as events are reported. Monitoring of protocol compliance, adverse event 
reporting, and data completeness will be conducted according 
to recommended schedule for this study.  
 
 
 
10.3 
Confidentiality 
 
Study numbers will be used in place of an identifier such as a medical 
record number. No research participant names will be recorded on the data 
collection forms. The list containing the study number and the medical 
record number will be maintained in a locked file and/or in a password 
protected database and will be destroyed after all data have been analyzed.  
 
The medical records of study participants may be reviewed by the St. Jude 
IRB, FDA, clinical research monitors, etc. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1  Primary Objective 
 


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This study has the following single primary objective: 
 
To assess the analgesic efficacy of gabapentin in controlling VCR-related 
NP/PN in participants with ALL, as reflected by the morphine daily dose 
(mg/kg/day) used to control NP/PN as a primary or a rescue regimen, and 
by daily pain scores in the gabapentin vs. placebo groups. 
 
Accrual: The eligibility criteria requires that a patient can be enrolled in 
this study only if a VCR-induced NP not previously treated by gabapentin 
occurred after vincristine doses administered at the following time points: 
Induction Week1± 3 days, Induction week 2 ± 3 days, Continuation Week 
7 (Re-induction I) ± 3 days or Week 17 (Re-induction II) ± 3 days  of 
Continuation. A review of Total XVI or “as per TOTXVI” patients up to the 
date of this protocol development showed that respectively 33, 29, 5, and 
1 patient satisfied the condition at the time points. A review of Total XV 
showed a similar pattern. Thus we expect to enroll for this study at least 
60 patients in the remainder of Total XVI or “as per TOTXVI. We will enroll 
and randomize all eligible and consented patients in the remainder of Total 
XVI or “as per TOTXVI”.  To achieve a total of 60 evaluable patients, up to 
80 participants may be enrolled. 
 
Study Design: Placebo-controlled, randomized Phase-II trial. Sixty (60) 
participants will be randomized into the treatment (gabapentin) and the 
placebo group, with 30 patients per group. 
 
Analysis: For each subject a pre-treatment (baseline) pain score will be 
obtained from the leukemia clinic. This score serves as the baseline level 
of pain and is used in stratified randomization (see below); and if 
necessary, as a covariate in modeling the daily morphine dosage used for 
pain control. The daily morphine dosage will be modeled as longitudinal 
observations with treatment (gabapentin vs. placebo) group, and if 
necessary, other clinical factors such as age category for pain assessment 
(0-3yr, 4-7yr, >7yr), baseline pain score, and ALL risk classification, as 
explanatory factors, using repeated measure linear models.  
 
 
Multiple test adjustment will not be made.  Participants whose doses of 
vincristine are delayed or those who are taken off study drug will be 
included in the analysis according to “intent to treat”. 
 
11.2 
Randomization  
 
Randomization will be performed in SJCRH pharmacy by a research 
pharmacist, using the randomization program developed by the 
Department of Biostatistics.  The randomization will be stratified by the 
three age categories for which distinct pain assessment tools are applied, 
and by two categories of the baseline pain score (<5, ≥5).The joint 
distribution of the age and baseline pain score categories in the enrolled 


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patients may be skewed with either null or small odd-numbered (1, 3, 5) 
cell sizes, and consequently stratification may still not able to guarantee 
balance. If it so happens, the age categories and baseline pain score will be 
included in the longitudinal model as covariates (see above).  
 
11.3 
Secondary Objective 
 
Daily “pain score right now” and “pain score average last 24 hours” will 
be compared between the gabapentin and place groups using longitudinal 
models, with pain treatment group and if necessary, other clinical factors 
as explanatory variables. For “pain score right now”, time since last 
morphine use will be used as an explanatory variable as well. The pain 
scores are discrete, thus a proper link function (such as Poisson) will be 
applied. 
 
12.0  OBTAINING INFORMED CONSENT 
 
Eligible patients will be approached by a member of the study team regarding the 
study purpose, methods and design details. Both verbal and written assent and 
consent procedures will be completed in a private room and follow our 
institutional guidelines. Verbal assent will be obtained from participants 7 to less 
than 14 years old and written assent from participants 14 to less than 18 years old.  
 
The consent/assent process will be documented in the medical record per 
institutional guidelines. Research participants and parents may decline 
participation without repercussions. Refusals will be documented in the research 
records and examined for any possible patterns. All research participants who 
meet eligibility criteria regardless of gender or minority status are fully eligible to 
participate in this study. All data will be kept confidential and stored in a locked 
file inside locked offices. 
 
 
 
12.1 
Consent at Age of Majority 
 
The age of majority in the state of Tennessee is 18 years old.  The 
PI/designee will identify study participants requiring consent at age 18 
years. Active research participants must be consented at the next clinic 
visit after their 18th birthday.   
 


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13.0 
REFERENCES 
 
1. 
Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in 
children with cancer. N Engl J Med. Feb 3 2000;342(5):326-333. 
2. 
Wolfe J, Hammel JF, Edwards KE, et al. Easing of suffering in children with 
cancer at the end of life: is care changing? J Clin Oncol. Apr 1 2008;26(10):1717-
1723. 
3. 
LeBaron S, Zeltzer L. Assessment of acute pain and anxiety in children and 
adolescents by self-reports, observer reports, and a behavior checklist. J Consult 
Clin Psychol. Oct 1984;52(5):729-738. 
4. 
Jacobsen PB, Manne SL, Gorfinkle K, Schorr O, Rapkin B, Redd WH. Analysis 
of child and parent behavior during painful medical procedures. Health Psychol. 
1990;9(5):559-576. 
5. 
Tuxen MK, Hansen SW. Neurotoxicity secondary to antineoplastic drugs. Cancer 
Treat Rev. Apr 1994;20(2):191-214. 
6. 
Bradley WG, Lassman LP, Pearce GW, Walton JN. The neuromyopathy of 
vincristine in man. Clinical, electrophysiological and pathological studies. J 
Neurol Sci. Feb 1970;10(2):107-131. 
7. 
Anghelescu DL, De Armendi AJ, Thompson JW, Sillos EM, Pui CH, Sandlund 
JT. Vincristine-induced vocal cord paralysis in an infant. Paediatr Anaesth. Feb 
2002;12(2):168-170. 
8. 
Woods WG, O'Leary M, Nesbit ME. Life-threatening neuropathy and 
hepatotoxicity in infants during induction therapy for acute lymphoblastic 
leukemia. J Pediatr. Apr 1981;98(4):642-645. 
9. 
Kishi S, Cheng C, French D, et al. Ancestry and pharmacogenetics of 
antileukemic drug toxicity. Blood. Jan 30 2007. 
10. 
Anghelescu DL, Faughnan LG, Jeha S, et al. Neuropathic pain during treatment 
for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. Feb 11 2011. 
11. 
Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, 
gabapentin, or their combination for neuropathic pain. N Engl J Med. Mar 31 
2005;352(13):1324-1334. 
12. 
Butkovic D, Toljan S, Mihovilovic-Novak B. Experience with gabapentin for 
neuropathic pain in adolescents: report of five cases. Paediatr Anaesth. Mar 
2006;16(3):325-329. 
13. 
Harel L, Mukamel M, Brik R, Blau H, Straussberg R. Peripheral neuropathy in 
pediatric systemic lupus erythematosus. Pediatr Neurol. Jul 2002;27(1):53-56. 
14. 
Lauder GR, White MC. Neuropathic pain following multilevel surgery in children 
with cerebral palsy: a case series and review. Paediatr Anaesth. May 
2005;15(5):412-420. 
15. 
Low AK, Ward K, Wines AP. Pediatric complex regional pain syndrome. J 
Pediatr Orthop. Jul-Aug 2007;27(5):567-572. 
16. 
Rusy LM, Troshynski TJ, Weisman SJ. Gabapentin in phantom limb pain 
management in children and young adults: report of seven cases. J Pain Symptom 
Manage. Jan 2001;21(1):78-82. 
17. 
McGraw T, Stacey BR. Gabapentin for treatment of neuropathic pain in a 12-
year-old girl. Clin J Pain. Dec 1998;14(4):354-356. 


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                                  IRB Approval date: 05/24/2016 
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18. 
Wheeler DS, Vaux KK, Tam DA. Use of gabapentin in the treatment of childhood 
reflex sympathetic dystrophy. Pediatr Neurol. Mar 2000;22(3):220-221. 
19. 
Keskinbora K, Pekel AF, Aydinli I. The use of gabapentin in a 12-year-old boy 
with cancer pain. Acta Anaesthesiol Scand. May 2004;48(5):663-664. 
20. 
Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: 
improving the safety and efficacy of pediatric therapies. JAMA. Aug 20 
2003;290(7):905-911. 
21. 
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in 
adolescent boys. The Journal of pediatrics. Mar 1985;106(3):522-526. 
22. 
Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in 
children with CKD. J Am Soc Nephrol. Mar 2009;20(3):629-637. 
23. 
Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: A behavioral 
scale for scoring postoperative pain in young children. Pediatr Nurs. May-Jun 
1997;23(3):293-297. 
24. 
Hockenberry M, Wilson D. Wong's Essentials of Pediatric Nursing. 8th ed. St. 
Louis: Mosby; 2009. 
25. 
von Baeyer CL. Children's self-reports of pain intensity: Scale selection, 
limitations and interpretation. Pain Res Manag. Autumn 2006;11(3):157-162. 
26. 
von Baeyer CL, Spagrud LJ, McCormick JC, Choo E, Neville K, Connelly MA. 
Three new datasets supporting use of the Numerical Rating Scale (NRS-11) for 
children's self-reports of pain intensity. Pain. Jun 2009;143(3):223-227. 
 
 
 
 


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APPENDIX I 
EXAMPLE OF A SCHEDULE OF EVALUATIONS:  
 
Upon confirmation of eligibility (any time between days 1 and 7 after qualifying vincristine 
dose, see section 3.0):  
• Informed consent discussion 
• Enrollment data obtained by study team 
• Baseline pain assessment by study team 
• Participant receives prescription for morphine PRN (see section 4.2) 
• Participant is randomized and begins study drug (see section 4.1) 
 
Enrollment through Day 21 
• Daily pain assessment by study team 
• Daily AE assessment by study team  
• Refill morphine if needed 
• Patient/family education regarding study drug 
 
Day 21 
• Complete last dose of study drug 
• Complete last daily pain assessment and AE assessment 
• Refer persistent pain to pain team or primary clinic for treatment as clinically 
indicated 
 
 
 
 
 
 
 
 
 


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APPENDIX II 
RESEARCH ACTIVITIES 
 
Study day 
Confirm 
enroll-
ment 
criteria 
Informed 
consent 
Random-
ization 
VCR dose 
(expected 
or actual) 
Pain 
score 
right 
now 
Average 
Pain for 
24h 
Pain 
location 
Pain 
descriptor 
Order 
Morphine 
PRN 
Study 
drug 
TID 
Assess 
opioid 
use 
Assess 
study 
drug 
use 
Assess 
AE 
Off 
Study 
pre-
enrollment 
  
  
  
actual 
  
  
  
  
  
  
  
  
  
  
Diagnosis 
of NP (any 
day 
between 1 
and 7) 
x 
x 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
7 
  
  
  
expected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
8 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
9 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
10 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
11 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
12 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
13 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
14 
  
  
  
expected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
15 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
16 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
17 
  
  
  
  
x 
x 
x 
x 
x 
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18 
  
  
  
  
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19 
  
  
  
  
x 
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20 
  
  
  
  
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21 
  
  
  
  
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TINALL 
Page 21 
 
Revision 2.3, dated: 05/10/2016 
 
 
                                  IRB Approval date: 05/24/2016 
Protocol document date: 02/13/2018 
 
APPENDIX III 
PAIN ASSESSMENT TOOLS 
 
The pain assessment scoring tools for this study are currently used at St. Jude in standard 
care as directed by the hospital policy; they are included here for reference purposes. 
 
Assessment 
• Always assume child’s pain report is valid 
• Infants and toddlers (less than age 4 years) or other children who cannot self report, use 
the FLACC Scale 
• Score each component as a subscore (face, legs, activity, cry, consolability) 
• Total subscores to determine FLACC score 
 
FLACC scale 
Categories  
Scoring  
 
0 
1  
2  
Face  
No particular 
expression or smile  
Occasional grimace or 
frown, withdrawn, 
disinterested  
Frequent to constant 
quivering chin, 
clenched jaw  
Legs  
Normal position or 
relaxed  
Uneasy, restless, tense  
Kicking or legs drawn 
up  
Activity  
Lying quietly, normal 
position, moves easily  
Squirming, shifting 
back and forth, tense  
Arched, rigid or 
jerking  
Cry  
No cry (awake or 
asleep)  
Moans or whimpers; 
occasional complaint  
Crying steadily, 
screams or sobs, 
frequent complaints  
Consolability  
Content, relaxed  
Reassured by 
occasional touching, 
hugging or being talked 
to distractible  
Difficult to console or 
comfort  
Each of the five categories (F)Face; (L)Legs; (A)Activity; (C)Cry; (C) Consolability is 
scored from 0-2, resulting in a total score range of 0 to 10.  
 
• Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised 
(FPS-R) 
 
 
 
 


TINALL 
Page 22 
 
Revision 2.3, dated: 05/10/2016 
 
 
                                  IRB Approval date: 05/24/2016 
Protocol document date: 02/13/2018 
 
 
 
 
Say to the child, "The first face (point to face 0), has no pain. The last face, (point 
to face 10), has the worst pain ever. Point to the face that shows how you are 
feeling." 
 
• Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain 
Scale-Revised (FPS-R)