TINALL: Therapeutic Interventions For Pain Induced By Vincristine Treatment For Childhood Acute Lymphoblastic Leukemia (ALL)

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01506453
• Collaborator: (none)
• Enrollment: 51
• Location: 1
• Arms: 2
• Actual Duration (Months): 71.3
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia; Neuropathy; Neuropathic Pain	Drug: gabapentin; Drug: placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Supportive Care
• Official Title: Therapeutic Interventions For Peripheral Neuropathy/Neuropathic Pain Induced By Vincristine Treatment For Childhood Acute Lymphoblastic Leukemia (ALL) On Total XVI Protocol
• Actual Study Start Date: Jan 24, 2012
• Actual Primary Completion Date: Jan 2, 2018
• Actual Study Completion Date: Jan 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Gabapentin Active treatment arm.	Drug: gabapentin; 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.; Other Names: Treatment Arm
Placebo Comparator: Placebo Placebo arm.	Drug: placebo; 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.; Other Names: Placebo Arm

Outcome Measures

Primary Outcome Measures

1. Daily Total Dose of Oral Morphine (mg/kg/Day). [Daily beginning day 1 for a maximum of 21 days.]

   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. 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 Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised (FPS-R) Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain Scale-Revised (FPS-R) Pain score 0 means no pain and 10 means worst pain. The scale information for the FLACC and FPS-R scales are similar.

Secondary Outcome Measures

1. Pain Scores Right Now [Daily beginning day 1 through a maximum of 21 days.]

   A score ranging from 0 to 10, measured by age appropriate validated pain scale. Because there was only one patient during day 21 time point for this treatment group, the mean and standard deviation could not be calculated. 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 Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised (FPS-R) Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain Scale-Revised (FPS-R) Pain score 0 means no pain and 10 means worst pain.The scale information for the FLACC and FPS-R scales are similar.

2. Pain Score During the Previous 24 Hours [Daily beginning day 1 through a maximum of 21 days]

   A score ranging from 0 to 10, measured by age appropriate validated pain scale. Because there was only one patient during day 21 time point for this treatment group, the mean and standard deviation could not be calculated.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 Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised (FPS-R) Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain Scale-Revised (FPS-R) Pain score 0 means no pain and 10 means worst pain.The scale information for the FLACC and FPS-R scales are similar.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant is enrolled on Total XVI or who are being treated "as per TOTXVI protocol"

• Participant is 1 year of age or older

• Participant has symptoms of NP/PN with onset no more than 7 days after one of the following vincristine doses ± 3 days: protocol week 1, week 2 (induction), week 7 (reinduction I), or week 17 (reinduction II).

• Patient is expected to receive 2 doses of vincristine in weekly intervals as outlined by the Total XVI protocol (or for those being treated "as per TOTXVI" protocol) while on study drug (i.e. no known dosage reductions or planned missed doses).

Participant is able and willing to take oral medications.

Exclusion Criteria:

• Previous participation in this study

• Participant is receiving gabapentin for another indication at the time of diagnosis of NP/PN or has received gabapentin previously.

• 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.

• Impaired renal function: decreased eGFR (<60ml/min/1.73m^2 as estimated by the revised Schwartz equation)

• Participant has allergy or other contraindication for either morphine or gabapentin therapy.

• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• St. Jude Children's Research Hospital

Investigators

• Principal Investigator: Doralina Anghelescu, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 24, 2016

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT01506453
• Other Study ID Numbers: TINALL; NCI-2012-00413
• First Posted: Jan 10, 2012
• Last Update Posted: Jun 19, 2019
• Last Verified: Apr 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by St. Jude Children's Research Hospital: Acute Lymphoblastic Leukemia; Neuropathy; Neuropathic Pain; Vincristine; TOTAL XVI Protocol
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Neuralgia; Gabapentin

Study Results

Participant Flow

Recruitment Details	51 participants were enrolled and screened between January 2012 and October 2016.
Pre-assignment Detail	The remaining 51 participants were randomized to take gabapentin or placebo.

Arm/Group Title	Gabapentin	Placebo
Arm/Group Description	Active treatment arm. gabapentin: 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.	Placebo arm. placebo: 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.
Period Title: Overall Study
STARTED	25	26
COMPLETED	25	24
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Gabapentin	Placebo	Total
Arm/Group Description	Active treatment arm gabapentin: 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.	Placebo arm placebo: 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.	Total of all reporting groups
Overall Participants	25	26	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.88 (5.69)	7.08 (3.90)	7.48 (4.83)
Sex: Female, Male (Count of Participants)
Female	11 44%	10 38.5%	21 41.2%
Male	14 56%	16 61.5%	30 58.8%
Race/Ethnicity, Customized (Count of Participants)
Asian and White	0 0%	1 3.8%	1 2%
Black	1 4%	2 7.7%	3 5.9%
Black and White	1 4%	2 7.7%	3 5.9%
White	23 92%	21 80.8%	44 86.3%
Region of Enrollment (Count of Participants)
United States	25 100%	26 100%	51 100%
Daily "pain score right now" (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.12 (1.86)	3.58 (1.42)	3.35 (1.65)
baseline pain score last 24 hours (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.08 (1.66)	4.31 (1.76)	4.20 (1.70)

Outcome Measures

1. Primary Outcome

Title	Daily Total Dose of Oral Morphine (mg/kg/Day).
Description	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. 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 Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised (FPS-R) Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain Scale-Revised (FPS-R) Pain score 0 means no pain and 10 means worst pain. The scale information for the FLACC and FPS-R scales are similar.
Time Frame	Daily beginning day 1 for a maximum of 21 days.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Gabapentin	Placebo
Arm/Group Description	Active treatment arm. gabapentin: 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.	Placebo arm. placebo: 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.
Measure Participants	25	24
Day 1	0.38267 (0.28921)	0.27433 (0.19299)
Day 2	0.43685 (0.33788)	0.31816 (0.16012)
Day 3	0.37281 (0.32935)	0.27961 (0.18509)
Day 4	0.40384 (0.32469)	0.35343 (0.18688)
Day 5	0.37662 (0.31263)	0.37920 (0.22471)
Day 6	0.45679 (0.45450)	0.43972 (0.19838)
Day 7	0.50961 (0.43643)	0.37181 (0.22883)
Day 8	0.50767 (0.53570)	0.38188 (0.28251)
Day 9	0.49234 (0.33366)	0.34524 (0.20164)
Day 10	0.44392 (0.37244)	0.34660 (0.15843)
Day 11	0.50981 (0.67516)	0.29937 (0.14111)
Day 12	0.57798 (0.51346)	0.40090 (0.21956)
Day 13	0.68183 (0.51698)	0.45933 (0.32854)
Day 14	0.53028 (0.57870)	0.34957 (0.15460)
Day 15	0.55939 (0.69755)	0.36731 (0.23170)
Day 16	0.37643 (0.37817)	0.48481 (0.37075)
Day 17	0.38837 (0.30190)	0.54960 (0.47579)
Day 18	0.65013 (0.96603)	0.13605 (NA)
Day 19	0.84586 (1.08656)	0.14123 (0.00740)
Day 20	1.12358 (1.37790)	0.15108 (NA)
Day 21	0.14981 (NA)

2. Secondary Outcome

Title	Pain Scores Right Now
Description	A score ranging from 0 to 10, measured by age appropriate validated pain scale. Because there was only one patient during day 21 time point for this treatment group, the mean and standard deviation could not be calculated. 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 Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised (FPS-R) Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain Scale-Revised (FPS-R) Pain score 0 means no pain and 10 means worst pain.The scale information for the FLACC and FPS-R scales are similar.
Time Frame	Daily beginning day 1 through a maximum of 21 days.

Outcome Measure Data

Analysis Population Description

There were participants in the Gabapentin and Placebo groups that did not have pain assessments at various time points. Pain score was 0 for each placebo participant on days 19, 20 and 21.

Arm/Group Title	Gabapentin	Placebo
Arm/Group Description	Active treatment arm. gabapentin: 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.	Placebo arm. placebo: 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.
Measure Participants	25	24
Day 1	1.64000 (1.89033)	1.69565 (2.09837)
Day 2	2.00000 (2.19848)	1.16667 (1.57885)
Day 3	1.88000 (2.60320)	0.75000 (1.25974)
Day 4	1.92000 (2.64449)	0.83333 (1.30773)
Day 5	1.64000 (1.97653)	1.00000 (1.44463)
Day 6	1.40000 (1.75594)	0.79167 (1.38247)
Day 7	2.20000 (2.17945)	0.91667 (1.50121)
Day 8	1.32000 (1.90875)	0.56522 (1.23679)
Day 9	1.48000 (2.06398)	0.86957 (1.63219)
Day 10	1.16000 (1.65025)	0.39130 (0.83878)
Day 11	1.16000 (1.90788)	0.82609 (1.26678)
Day 12	1.21739 (1.88189)	1.00000 (1.50756)
Day 13	1.04348 (1.46095)	0.69565 (1.39593)
Day 14	0.82609 (1.11405)	0.52174 (1.23838)
Day 15	0.90909 (1.63034)	0.60870 (1.23359)
Day 16	1.29412 (1.99263)	0.31250 (0.87321)
Day 17	0.40000 (0.91026)	0.21429 (0.80178)
Day 18	1.45455 (2.54416)	0.25000 (0.86603)
Day 19	1.00000 (1.41421)	0 (0)
Day 20	1.33333 (1.15470)	0 (0)
Day 21	0 (0)

3. Secondary Outcome

Title	Pain Score During the Previous 24 Hours
Description	A score ranging from 0 to 10, measured by age appropriate validated pain scale. Because there was only one patient during day 21 time point for this treatment group, the mean and standard deviation could not be calculated.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 Older children (ages 4 to 7 years) who can self-report, use the Faces Pain Scale-Revised (FPS-R) Ages >7 years, Self report using a numeric scale 0-10 without reference to Faces Pain Scale-Revised (FPS-R) Pain score 0 means no pain and 10 means worst pain.The scale information for the FLACC and FPS-R scales are similar.
Time Frame	Daily beginning day 1 through a maximum of 21 days

Outcome Measure Data

Analysis Population Description

There were participants in the Gabapentin and Placebo groups that did not have pain assessments at various time points. Pain score was 0 for each placebo participant on days 20 and 21.

Arm/Group Title	Gabapentin	Placebo
Arm/Group Description	Active treatment arm. gabapentin: 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.	Placebo arm. placebo: 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.
Measure Participants	25	24
Day 1	3.48000 (2.50200)	3.41667 (2.39414)
Day 2	3.16000 (2.37487)	2.20833 (2.14637)
Day 3	3.08000 (2.28983)	1.87500 (1.87228)
Day 4	2.80000 (2.43242)	2.12500 (2.64267)
Day 5	2.80000 (2.61406)	2.00000 (2.14679)
Day 6	2.28000 (1.92614)	1.91667 (2.20507)
Day 7	2.96000 (2.22636)	1.16667 (1.60615)
Day 8	2.76000 (2.24128)	1.69565 (1.91726)
Day 9	2.16000 (2.21133)	1.34783 (1.74795)
Day 10	2.16000 (2.24870)	1.43478 (1.64665)
Day 11	2.32000 (2.05589)	1.56522 (1.67403)
Day 12	2.41667 (2.43018)	1.52174 (1.90381)
Day 13	2.50000 (2.20671)	1.60870 (1.85225)
Day 14	2.60870 (2.27115)	1.56522 (1.64665)
Day 15	2.54545 (2.15423)	1.39130 (1.67167)
Day 16	2.23529 (1.82104)	1.56250 (1.82460)
Day 17	1.40000 (1.59463)	1.92857 (2.01778)
Day 18	2.36364 (3.00908)	1.00000 (1.65145)
Day 19	1.40000 (1.34164)	0.40000 (0.89443)
Day 20	2.33333 (0.57735)	0 (0)
Day 21	0 (0)

Adverse Events

Time Frame	through study completion, up to 21 days
Adverse Event Reporting Description	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.
Arm/Group Title	Gabapentin		Placebo
Arm/Group Description	Active treatment arm. gabapentin: 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.		Placebo arm. placebo: 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.
All Cause Mortality
	Gabapentin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)
Serious Adverse Events
	Gabapentin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Gabapentin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/25 (20%)		5/24 (20.8%)
Nervous system disorders
Depressed level of consciousness	5/25 (20%)	5	5/24 (20.8%)	6
Psychiatric disorders
Anxiety	1/25 (4%)	1	0/24 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.