A Phase II, Randomized, Placebo-controlled, Double Blind, Cross-over, Study of the Effects of Gabapentin on Chronic Irritability in Neurologically Impaired Children
Phase: PHASE2
Conditions: Neurologically Impaired, Irritable Mood, Signs and Symptoms, Digestive, Sleeplessness, Chronic Pain
Sponsor: Gillette Children's Specialty Healthcare

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University of Minnesota
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Appendix 6-A
Clinical Protocol
A phase II, randomized, placebo-controlled, double blind, cross-over,
study of the effects of Gabapentin on chronic irritability in
neurologically impaired children.
Regulatory Sponsor:
Funding Sponsor:
Study Product:
Dr. Scott Schwantes
Pediatrics
Gillette Children's Specialty Healthcare
200 University Ave. E.
St. Paul, MN 55101
651-229-3818
Medical Education and Research Association (MERA)
Gillette Children's Specialty Healthcare
200 University Ave E
St. Paul, MN 55101
Attn: Joyce Trost
651-229-1745
Gabapentin (Neurontin®)
IND Number:
112909
Date:
14 July 2011;
Version 2
Amended:
26 April 2013
Administrative Change:
CONFIDENTIAL
ThisdocumentisconfidentialandthepropertyoftheUniversityofMinnesota.No
partofitmaybetransmitted,reproduced,published,orusedbyotherpersons
withoutpriorwrittenauthorizationfromthestudysponsor.

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University of Minnesota
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Table of Contents
Study Summary....................................................................................................................... 14
1.0 Introduction....................................................................................................................... 15
1.1 Background................................................................................................................... 15
1.2 Investigational Agent.................................................................................................... 17
1.3 Pre-Clinical Data........................................................................................................... 18
1.4 Clinical Data to Date..................................................................................................... 20
1.5 Dose Rationale and Risk/Benefits ................................................................................ 22
2.0 Study Objectives ............................................................................................................... 23
3.0 Study Design..................................................................................................................... 23
3.1 General Study Design ................................................................................................... 23
3.2 Primary Study Endpoints .............................................................................................. 23
3.3 Secondary Study Endpoints .......................................................................................... 23
4.0 Subject Selection and Withdrawal.................................................................................... 24
4.2 Exclusion Criteria ......................................................................................................... 24
4.3 Exit Criteria................................................................................................................... 24
4.4 Subject Recruitment and Screening.............................................................................. 24
4.5 Early Withdrawal of Subjects ....................................................................................... 25
4.5.1 When and How to Withdraw Subjects................................................................... 25
4.5.2 Data Collection and Follow-up for Withdrawn Subjects....................................... 25
5.0 Study Drug........................................................................................................................ 25
5.1 Description.................................................................................................................... 25
5.2 Treatment Regimen....................................................................................................... 25
5.3 Method for Assigning Subjects to Treatment Groups .................................................. 26
5.4 Preparation and Administration of Study Drug ............................................................ 27
5.5 Subject Compliance Monitoring................................................................................... 28
5.6 Prior and Concomitant Therapy.................................................................................... 28
5.7 Packaging...................................................................................................................... 29
5.8 Blinding of Study Drug................................................................................................. 29
5.9 Receiving, Storage, Dispensing and Return.................................................................. 29
5.9.1 Receipt of Drug Supplies ....................................................................................... 29
5.9.2 Storage ................................................................................................................... 29
5.9.3 Dispensing of Study Drug...................................................................................... 29
5.9.4 Return or Destruction of Study Drug..................................................................... 30

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6.0 Study Procedures .............................................................................................................. 30
7.0 Statistical Plan................................................................................................................... 32
7.1 Sample Size Determination........................................................................................... 32
7.2 Statistical Methods........................................................................................................ 32
7.3 Subject Population(s) for Analysis ............................................................................... 32
8.0 Safety and Adverse Events ............................................................................................... 32
8.2 Recording of Adverse Events ....................................................................................... 34
8.3 Reporting of Serious Adverse Events ........................................................................... 35
8.3.1 Study Sponsor Notification by Investigator........................................................... 35
8.3.2 IRB Notification by Investigator............................................................................ 35
8.3.3 FDA Notification by Sponsor ................................................................................ 35
8.4 Unblinding Procedures.................................................................................................. 36
8.5 Stopping Rules.............................................................................................................. 36
8.6 Medical Monitoring ...................................................................................................... 36
9.0 Data Handling and Record Keeping ................................................................................. 36
9.1 Confidentiality .............................................................................................................. 36
9.2 Source Documents ........................................................................................................ 37
9.3 Case Report Forms........................................................................................................ 37
9.4 Records Retention......................................................................................................... 37
10.0 Study Monitoring, Auditing, and Inspecting .................................................................. 37
10.1 Study Monitoring Plan................................................................................................ 37
10.2 Auditing and Inspecting.............................................................................................. 38
11.0 Ethical Considerations .................................................................................................... 38
12 Study Finances................................................................................................................... 39
12.1 Funding Source........................................................................................................... 39
12.2 Conflict of Interest ...................................................................................................... 39
12.3 Subject Stipends or Payments..................................................................................... 39
13 Publication Plan ................................................................................................................. 39
14 References.......................................................................................................................... 39
15 Attachments ....................................................................................................................... 40

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List of Abbreviations
AE
Adverse Event
CFR
Code of Federal Regulations
CRF
Case Report Form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICH
International Conference on Harmonization
IDS
Investigational Drug Service
IRB
Institutional Review Board
ITT
Intent to Treat
NCCPC-R
Non-Communicating Children's Pain Checklist-Revised
PHI
Protected Health Information
REPA
Report of External Professional Activities
SAE
Serious Adverse Event
UPIRTSO
Unanticipated Problems Involving Risk to Subjects or Others

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Study Summary
Title
A phase II, randomized, placebo-controlled, double blind, cross-
over, study of the effects of Gabapentin on chronic irritability in
neurologically impaired children
Short Title
Effects of Gabapentin on chronic irritability in neurologically
impaired children.
Phase
Phase II
Methodology
The study is a randomized, placebo-controlled cross-over.
Study Duration
The estimated duration of the study is 12 months
Study Center(s)
This is a single center study to be conducted at Gillette Children's
Specialty Hospital, 200 University Ave. E., St. Paul, MN 55101.
Objectives
To determine if gabapentin provides symptom relief for chronic
irritability in neurologically impaired children despite medical
management for identified sources of symptoms or if no etiology
is identified.
Number of Subjects 40 evaluable subjects
Diagnosis and Main
Inclusion Criteria
Neurological impairment and chronic irritability suggesting pain.
Study Product,
Dose, Route,
Regimen
Gabapentin (Neurontin®), to be administered as an oral solution
titrated over a 22 day period, followed by a 7 day stable dose
period (40 mg/kg/day over 3 dosages), followed by a 9 day taper
and washout period
Duration of
administration
Subjects will receive drug for 34 days, and placebo for 34
days, with a 3 day washout period in between.
Reference therapy
Reference therapy for this study is the placebo as there is
no standard of care.
Statistical
Methodology
The study will utilize non-parametric descriptive statistics
to compare subject questionnaire responses after drug and
placebo exposures.
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight
Formatted: Highlight

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1.0 Introduction
This document is a protocol for a human research study. This study is to be
conducted according to US and international standards of Good Clinical Practice
(21 CFR 312 and International Conference on Harmonization guidelines),
applicable
government
regulations
and
Institutional
research
policies
and
procedures.
1.1 Background
Irritability in nonverbal neurologically impaired children (neuro-irritability)
is often considered to indicate pain in such children. Children with
neurological impairment experience pain more frequently than the general
pediatric population". In one study, 44% of children with severe cognitive
impairment were reported by caregivers to experience pain each week during
a four-week interval. Pain frequency was highest in the most impaired group
of children.2 Caregivers of children with moderate to severe cerebral palsy
reported over a 4-week interval that 26% experienced pain or discomfort
"once or twice", 19% "a few times", 10% "fairly often", 2.5% "very often",
and 8% "every/almost every day".3 In a study of nonverbal cognitively
impaired children, caregivers reported that 62% experienced five or more
separate days of pain, and 23.5% experienced pain almost daily.4
Identifying a source of pain in a nonverbal child with neurological
impairment poses a unique and significant challenge. Common recognized
pain sources in these individuals include acute sources such as fracture,
urinary tract infection, or pancreatitis and chronic sources such as
gastroesophageal reflex (GER), constipation, feeding difficulties from
delayed gut motility, positioning, spasticity, hip pain, or dental pain. Table 1
outlines etiologies of acute and chronic pain to consider.
Pain in neurologically impaired children is typically thought to be
nociceptive in origin. Experience shows that a pain source may not be
identified or pain may continue despite treatment of an identified source.
Greco et al5 identified the category "Screaming of unknown origin" to
indicate children with neurologic disorders, severe developmental delay,
neurodegeneration, or severe motor impairments with persistent agitation,
distress, or screaming. Evaluation may identify a specific nociceptive cause
but in many other cases, these evaluations can be frustrating for patients,
families,
and
clinicians.
In
the chapter "Pain
and
Children
with
Developmental Disabilities", Oberlander and Craig review that pain in
neurologically impaired children is typically thought to be nociceptive in
origin; however, after repeated injury or surgery, neuropathic pain may also
occur.6
Because
of
the
confusing
neurologic
and
clinical
picture,
identification of neuropathic pain is challenging. Neuropathy may be another
source of ongoing and poorly treated pain in such children.

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Parents commonly identify the gastrointestinal tract as a source of pain in
neurologically impaired children. Breau et al'' 7 identified gastrointestinal as
the second most common pain source category, after accidental causes, yet
the most frequent source of all episodes of pain in children with severe
cognitive impairment. Roughly half with gastrointestinal pain experienced
pain classified as 'bowels' but not due to constipation and a similar number
experienced episodes classified as 'digestive' due to 'gas' or `gastrointestinal'
problems without identification of cause or 'location. Pain of unknown cause
was
the
most
intense,
followed
by pain
attributed
to
the
bowels,
gastrointestinal tract and digestive pain. Houlihan et a13 reported significantly
higher rates of pain in children with a gastrostomy tube and those taking
medications for feeding, gastroesophageal reflux or gastrointestinal motility.
Table 1. Etiology of pain/irritability in nonverbal neurologically
impaired children
Head, Eyes, Ears, Nose, Throat (HEENT)
Acute otitis media, pharyngitis, sinusitis, dental abscess/gingival
inflammation, corneal abrasion, glaucoma, ventriculoperitoneal shunt
malfunction
Chest
Pulmonary aspiration/pneumonia, esophagitis, pericardial effusion,
supraventricular tachycardia, cardiac ischemia
Abdomen
Gastrointestinal: gastroesophageal reflux disease, gastritis/gastric ulcer,
peptic ulcer disease, food allergy, appendicitis, intussusception,
constipation, delayed/impaired motility, rectal fissure, visceral
hyperalgesia
Liver/gallbladder: hepatitis, cholecystitis
Pancreas: pancreatitis
Renal: urinary tract infection, nephrolithiasis, neuropathic bladder,
obstructive uropathy
Genitourinary: inguinal hernia, testicular torsion, ovarian torsion/cyst,
menstrual cramps
Skin
Pressure sore/decubitus ulcer
Extremities
Fracture, hip subluxation, osteomyelitis, hair tourniquet
Psychosocial
Loss of caregiver, change in home environment, non-accidental trauma
General
Medication toxicity, sleep disturbance
The association between pain and the gastrointestinal tract led to speculation
that visceral hyperalgesia is a source of chronic irritability and agitation in
neurologically impaired children. Zangen et al8 identified visceral

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hyperalgesia as a source of feeding difficulty in 12 of 14 neurologically
impaired children with refractory, persistent food refusal, retching and
vomiting despite maximal medical therapy and Nissen fundoplication. All
patients had gastrointestinal motility and/or sensory abnormalities. Twelve
of the 14 patients showed a low threshold for gastrointestinal sensory
symptoms.
Seven
patients
demonstrated
both
motility
and
sensory
impairment. Only two patients had abnormal motility without sensory
involvement. Tricyclic antidepressants and gabapentin successfully managed
the symptoms identified in these patients. In a retrospective series of nine
neurologically impaired children who experienced significant unexplained
pain and irritability, marked symptom improvement was identified when the
children received gabapentin therapy titrated to standard doses.9 For such
children with persistent irritability, we suggest use of medications, such as
gabapentin, that have demonstrated benefit for neuropathic pain syndromes.
Gabapentin is a medication utilized for treating neuropathic pain and has the
safest side effect profile of medications used for neuropathic pain. These
investigators have observed benefit without harm in use of gabapentin for
neurologically impaired children with chronic irritability. There is no
standard of care for this problem.
1.2 Investigational Agent
Gabapentin (Neurontin®) is described as 1-(aminomethyl)cyclohexaneacetic
acid with a molecular formula of C9Hi7NO2 and a molecular weight of
171.24. The structural formula of gabapentin is:
Gabapentin is a white to off-white crystalline solid with a pKai of 3.7 and a
pKa2 of 10.7. It is freely soluble in water and both basic and acidic aqueous
solutions. The log of the partition coefficient (n-octanol/0.05M phosphate
buffer) at pH 7.4 is
1.25. The oral solution contains 250 mg/5 mL of gab
apentin. The inactive ingredients for the oral solution are glycerin, xylitol,
purified water and artificial cool strawberry anise flavor.
The mechanism by which gabapentin exerts its analgesic action is unknown,
but in animal models of analgesia, gabapentin prevents allodynia (pain-
related behavior in response to a normally innocuous stimulus) and
hyperalgesia (exaggerated response to painful stimuli).
In particular,
gabapentin prevents pain-related responses in several models of neuropathic
pain in rats or mice (e.g. spinal nerve ligation models, streptozocin-induced
diabetes model, spinal cord injury model, acute herpes zoster infection
model). Gabapentin also decreases pain-related responses after peripheral
inflammation (carrageenan footpad test, late phase of formalin test).

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Gabapentin did not alter immediate pain-related behaviors (rat tail flick test,
formalin footpad acute phase, acetic acid abdominal constriction test, footpad
heat irradiation test). The relevance of these models to human pain is not
known.
The mechanism by which gabapentin exerts its anticonvulsant action is
unknown, but in animal test systems designed to detect anticonvulsant
activity, gabapentin prevents seizures as do other marketed anticonvulsants.
Gabapentin exhibits antiseizure activity in mice and rats in both the maximal
electroshock and pentylenetetrazole seizure models and other preclinical
models (e.g., strains with genetic epilepsy, etc.). The relevance of these
models to human epilepsy is not known.
All pharmacological actions following gabapentin administration are due to the
activity of the parent compound as gabapentin is not appreciably metabolized
in humans. Adult subjects with compromised renal function require dosage
adjustment. Pediatric subjects with renal insufficiency have not been studied.
Dosage adjustment is also required for subjects undergoing hemodialysis. The
apparent oral clearance of gabapentin decreased with increasing age, largely
due to age related decline in renal function. Although formal studies comparing
gender and race have not been studied, no significant gender or race differences
are expected.
1.3 Pre-Clinical Data
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding
site in areas of rat brain including neocortex and hippocampus. A high-affinity
binding protein in animal brain tissue has been identified as an auxiliary subunit
of voltage-activated calcium channels. However, functional correlates of
gabapentin binding, if any, remain to be elucidated.
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly
high incidence of pancreatic acinar adenocarcinomas was identified in male, but
not female, rats. The clinical significance of this finding is unknown. Clinical
experience during gabapentin's premarketing development provides no direct
means to assess its potential for inducing tumors in humans.
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to
rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant
increase in the incidence of pancreatic acinar cell adenomas and carcinomas was
found in male rats receiving the high dose; the no-effect dose for the occurrence
of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin
in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma
concentrations in humans receiving 3600 mg per day, and in rats receiving 1000
mg/kg/day peak plasma concentrations were 6.5 times higher than in humans
receiving 3600 mg/day.

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The pancreatic acinar cell carcinomas did not affect survival, did not
metastasize and were not locally invasive. The relevance of this finding to
carcinogenic risk in humans is unclear.
Studies designed to investigate the
mechanism of gabapentin-induced
pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA
synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a
tumor promoter by enhancing mitogenic activity. It is not known whether
gabapentin has the ability to increase cell proliferation in other cell types or in
other species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in three in
vitro and four in vivo assays. It was negative in the Ames test and the in vitro
HGPRT forward mutation assay in Chinese hamster lung cells; it did not
produce significant increases in chromosomal aberrations in the in vitro Chinese
hamster lung cell assay; it was negative in the in vivo chromosomal aberration
assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it
was negative in the in vivo mouse micronucleus assay; and it did not induce
unscheduled DNA synthesis in hepatocytes from rats given gabapentin.
Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs.
These effects occurred when pregnant mice received oral doses of 1000 or 3000
mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the
maximum dose of 3600 mg/day given to epileptic patients on a mg/m2 basis. The
no-effect level was 500 mg/kg/day or approximately 1/2 of the human dose on a
mg/m2 basis.
When rats were dosed prior to and during mating, and throughout gestation,
pups from all dose groups (500, 1000 and 2000 mg/kg/day) were affected. These
doses are equivalent to less than approximately 1 to 5 times the maximum
human dose on a mg/m2 basis. There was an increased incidence of hydroureter
and/or hydronephrosis in rats in a study of fertility and general reproductive
performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a
teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a
perinatal and postnatal study at all doses studied (500, 1000 and 2000
mg/kg/day). The doses at which the effects occurred are approximately 1 to 5
times the maximum human dose of 3600 mg/day on a mg/m2basis; the no-effect
doses were approximately 3 times and approximately equal to the maximum
human dose on a mg/m2 basis. Other than hydroureter and hydronephrosis, the
etiologies of which are unclear, the incidence of malformations was not
increased compared to controls in offspring of mice, rats, or rabbits given doses
up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily
dose on a mg/kg basis, or 4

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times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a
mg/m2 basis.
In a teratology study in rabbits, an increased incidence of postimplantation fetal
loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than
approximately 'A to 8 times the maximum human dose on a mg/m2 basis. There
are no adequate and well-controlled studies in pregnant women. This drug should
be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
1.4 Clinical Data to Date
Neurontin® was evaluated for the management of postherpetic neuralgia
(PHN) in 2 randomized, double-blind, placebo-controlled, multicenter
studies; N=563 patients in the intent-to-treat (ITT) population (Table 2).
Patients were enrolled if they continued to have pain for more than 3
months after healing of the herpes zoster skin rash.
TABLE 2. Controlled PHN Studies: Duration, Dosages, and Number of
Patients
Study
Study
Duration
Gabapentin
(mg/day)* Target
Dose
Given in 3 divided
doses (TM)
Patients
Receiving
Gabapentin
Patients
Receiving
Placebo
1
8 weeks
3600
113
116
2
7 weeks
1800, 2400
223
111
Total
336
227
Each study included a 1-week baseline during which patients were screened
for eligibility and a 7- or 8-week double-blind phase (3 or 4 weeks of
titration and 4 weeks of fixed dose). Patients initiated treatment with
titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages
were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day
intervals to target dose over 3 to 4 weeks. In Study 1, patients were
continued on lower doses if not able to achieve the target dose. During
baseline and treatment, patients recorded their pain in a daily diary using an
11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst
possible pain). A mean pain score during baseline of at least 4 was required
for randomization (baseline mean pain score for Studies 1 and 2 combined
was 6.4). Analyses were conducted using the ITT population (all
randomized patients who received at least one dose of study medication).
Both studies showed significant differences from placebo at all doses tested.

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A significant reduction in weekly mean pain scores was seen by Week 1
in both studies, and significant differences were maintained to the end of
treatment. Comparable treatment effects were observed in all active
treatment arms. Phannacokinetic/pharmacodynarnic modeling provided
confirmatory evidence of efficacy across all doses. Figures 1 and 2 show,
these changes for Studies 1 and 2.
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population):
Study 1
Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population):
Study 2
The proportion of responders (those patients reporting at least 50%
improvement in endpoint pain score compared with baseline) was
calculated for each study (Figure 3).

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Figure 3. Proportion of Responders (patients with >50% reduction in pain score)
at Endpoint: Controlled PHN Studies
No other clinical research information could be found to date for pain or
irritability in non-verbal children.
1.5 Dose Rationale and Risk/Benefits
The dose protocol (see Section 5.2.) is based upon ideal dosing ranges, with
sensitivity paid to titrating up and down slowly to minimize potential side effects
and withdrawal symptoms. Additionally, the rationale of the increased dose in the
evening is related to the known effect of inducing tiredness in some individuals.
The decision to use the liquid form is to allow for tight titration of medications,
and to prevent the need for "pill-splitting"
to achieve precise dosing.
Additionally, the liquid form may be easy to administer to patients with
gastrostomy tubes. Finally, the liquid form will also be better tolerated by those
patients without gastrostomy tubes but have difficulty manipulating pills.
Potential risks of Gabapentin include (from most common to least common):
somnolence, dizziness, increase in hostility, nausea/vomiting, increased chance for
viral infections and fevers, ataxia, fatigue, emotional lability, increased weight, and
hyperkinesia.
Risks to unborn children are unknown. Therefore, parents of females who have
reached puberty will be asked to allow a pregnancy test to be done. If applicable, a
urine pregnancy test will be done on Day 0.
There is a risk for loss of privacy; however, study personnel will take precautions to
prevent loss of privacy.
The risks of the medication are expected to be minimal compared to the benefit of
relief from distressing symptoms (neuroirritability). Establishment of Gabapentin
as an effective therapy for neuroirritability will help many children in the future
be appropriately treated for the underlying condition without the need for other
more dangerous medications (benzodiazepenes).

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The patient population for this study is comprised of severely cognitively and
often developmentally impaired children. Therefore, it is not applicable to screen
for suicidality in this population.
2.0 Study Objectives
Primary Aim: To determine if gabapentin provides symptom relief for chronic
irritability in neurologically impaired children despite medical management for
identified sources of symptoms or if no etiology is identified,
Primary Hypothesis: Gabapentin is beneficial and safe for neurologically
impaired children with chronic irritability that persists despite identification and
appropriate management of symptom sources.
3.0 Study Design
3.1 General Study Design
The design of this study is a prospective, randomized, double blind, placebo-
controlled,
crossover
clinical
trial.
The
study
will
involve
a
22-day
medication/placebo titration period, 7-day stable dosing, 9-day taper and
washout, followed by crossover, The length of the study is 12 months.
3.2 Primary Study Endpoints
Evaluation and Outcome Measures:
Frequency and results of diagnostic studies obtained for evaluation of
cause of pain/irritability with analysis of yield of testing
Parental reporting of frequency and duration of pain episodes
Parental reporting of associated gastrointestinal and sleep problems
Symptom
assessment
using
the
NCCPC-R
(Non-Communicating
Children's Pain Checklist-Revised), a standardized pain assessment tool
for
nonverbal
neurologically impaired
children, validated
to be
significantly related to pain intensity ratings provided by caregivers,
consistent over time, and sensitive and specific to pain
Parental satisfaction
3.3 Secondary Study Endpoints
Secondary Aims:
To describe results of diagnostic studies obtained in neurologically
impaired children with chronic irritability
To identify associated gastrointestinal and sleep problems
To determine if start or escalation of symptoms is temporally related to
surgical interventions
Secondary Hypotheses:
Repeating diagnostic studies when irritability persists adds limited benefit
Gastrointestinal symptoms (feeding intolerance and symptoms associated
with gas and bowel movements) and disrupted sleep are frequently
associated with chronic irritability and improve with gabapentin

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Escalation of symptoms often has a temporal relationship with a surgical
procedure.
4.0 Subject Selection and Withdrawal
4.1 Inclusion Criteria
Subjects are eligible to participate in the study if all of the following
conditions exist:
1.
Male or female, age 1 month to 16 years at enrollment
2.
Neurological impairment defined as subnormal (-2 S.D.) motor and/or
cognitive ability from a variety of etiologies
3.
Chronic irritability defined as symptoms suggesting pain to the child's
caregiver occurring recurrently over a 4-week or greater time period
4.
Subject must have an acceptable surrogate capable of giving consent on
the subject's behalf
4.2 Exclusion Criteria
Subjects will be excluded from participation in the study if any of the
following conditions exist:
1.
Children with resolved symptoms after treatment of identified sources
2.
Identified potential source of irritability without adequate trial of
appropriate management
3.
Ketogenic diet
4.
Renal insufficiency or failure
5.
Current treatment with gabapentin or pregabalin for another existing
condition
4.3 Exit Criteria
Subjects will exit the study if any of the following conditions exist:
1.
Subject voluntarily withdraws from the study.
2.
Subject death.
3.
Subject acquires any of the listed exclusion criteria.
4.
Subject completes the protocol.
5.
Subject is non-compliant with the study protocol. Subject non-
compliance is defined in Section 5.5.
Subjects exiting the study prior to completion of the protocol will be
withdrawn as per Section 4.5.
4.4 Subject Recruitment and Screening
Gillette Children's Specialty Healthcare clinicians and nurses that treat
children with neurological impairment will be infoinied of the study. Targeted
clinics within Gillette include pediatric neurology, pediatric gastroenterology,
and pediatric pain, along with other pediatric clinics that provide a model of
chronic care for children with chronic complex medical conditions. If a patient
is seen within a clinic that has been informed of the study, an introduction
letter for the study will be handed out to potential candidate families. Database
searches will also be conducted for potential

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subjects. If a candidate is found in a database search, that family will be
mailed the introduction letter, and receive a follow-up telephone call two
weeks later to determine if the family is interested. The introduction letter will
also contain contact information for the investigators and the clinical research
coordinator.
4.5 Early Withdrawal of Subjects
4.5.1 When and How to Withdraw Subjects
Subjects may withdraw from the study at any time by withdrawing their
consent. They must agree to be contacted (for safety reasons) for survival
data. Subjects who do not adhere to the study drug dosing may also be
withdrawn from the study to preserve the data collection.
If the subject withdraws from the study, it will be recommended to titrate
off the medication per the chart depending on current dose.
4.5.2 Data Collection and Follow-up for Withdrawn Subjects
Subjects who are withdrawn from the study will be contacted for
survival data. At least 5 phone calls will be attempted, after which 3
letters will be sent from the site. Subjects who do not answer these
calls or letters will be considered lost to follow-up. We will attempt to
determine any deaths via our databases, newspaper announcements,
and telephone listings for parents.
5.0 Study Drug
5.1 Description
The study drug is the commercial product, Neurontin® (gabapentin) 250
mg/5 ml by Pfizer/Parke Davis. The active drug is in a flavored glycerin
based solution.
The placebo will be also be a glycerin based clear solution that is flavored similar
to the commercial product (see Section 5.4 below).
5.2 Treatment Regimen
Doses will be given in liquid form through gastrointestinal tubes (if the child
already has one) or orally. Children will be put on the following dosage
regimen:
Day
Morning
Afternoon
Evening
5 mg/kg
1 - 3
4 - 6
2.5 mg/kg
2.5 mg/kg
5 mg/kg
7 - 9
2.5 mg/kg
2.5 mg/kg
10 mg/kg
10 - 12
5 mg/kg
5 mg/kg
10 mg/kg

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University of Minnesota
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13 - 15
5 mg/kg
5 mg/kg
15 mg/kg
16 - 18
7.5 mg/kg
7.5 mg/kg
15 mg/kg
19 - 21
7.5 mg/kg
7.5 mg/kg
20 mg/kg
22 - 28
10 mg/kg
10 mg/kg
20 mg/kg
29
7.5 mg/kg
7.5 mg/kg
20 mg/kg
30
7.5 mg/kg
7.5 mg/kg
15 mg/kg
31
5 mg/kg
5 mg/kg
15 mg/kg
32
5 mg/kg
5 mg/kg
10 mg/kg
33
2.5 mg/kg
2.5 mg/kg
10 ing/kg
34
5 ing/kg
35 - 37
off for 3 days then crossover
Weight
Day
Morning
Afternoon
Evening
1 - 3
5 mg/kg
4 - 6
2.5 mg/kg
2.5 mg/kg
5 ing/kg
10
7 - 9
2.5 mg/kg
2.5 mg/kg
10 - 12
5 mg/kg
5 mg/kg
10 mg/kg
13 - 15
5 mg/kg
5 mg/kg
15 ing/kg
16 - 18
7.5 mg/kg
7.5 mg/kg
15 mg,/kg
19 - 21
7.5 mg/kg
7.5 mg/kg
20 mg/kg
22 - 28
10 mg/kg
10 mg/kg
20 mg/kg
29
7.5 mg/kg
7.5 mg/kg
20 mg/lcg
30
7.5 mg/kg
7.5 mg/kg
15 mg/kg
31
5 mg/kg
5 mg/kg
15 mg/kg
32
5 mg/kg
5 mg/kg
10 mg/kg
5.3 Method for Assigning Subjects to Treatment Groups
A randomization table will be made before the study begins. Each patient added
will be entered into their group as the randomization table dictates. This table
will be kept in the pharmacy, and a copy will be maintained by the research
coordinator to keep track of which group each subsequent subject will be
assigned. Access to the table with patient names and doses of drug or placebo
will be available in the pharmacy 24 hours x 7 days per week for safety
precautions and unblinding.

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5.4 Preparation and Administration of Study Drug
The study drug and the placebo will be prepared in the Gillette Hospital Pharmacy.
The study will also be registered with the Investigational Drug Service (IDS)
pharmacy IDS #4109RO.
Neurontin (gabapentin) Oral Solution 250 mg/5 ml by Pfizer Labs
Appearance:
clear solution
Inactive ingredients:
glycerin, xylitol, purified water and artificial
cool strawberry anise flavor.
Storage Requirements:
Must be refrigerated
Placebo formulation:
Appearance:
clear solution
Inactive ingredients:
see below
Storage Requirements:
Must be refrigerated
Placebo Ingredients
Ora Sweet Sugar Free (Paddock Labs)
Strawberry Flavoring (Gallipot Labs)
Licorice Flavoring (LorAnn Oils, Inc.)
Raspberry Flavoring (Gallipot Labs)
Sterile Water (Baxter)
0.5 ml
0.2 ml
0.05 ml
2 ml
15ml
Compound Instructions
1.
Mix all flavoring ingredients and Ora Sweet Sugar Free in a
prescription vial.
2.
Add the sterile water and shake well.
3.
Label and refrigerate with a 60 day expiration date
Stock Supply Label: Gabapentin Placebo Oral Solution
Refrigerate Control #
Exp: (60 days from compounding)
A sufficient amount would be dispensed for a 34 days' supply dependent on the
weight of the patient.
The active or placebo drug will be dispensed on a randomized manner. A log of
the patient name/weight/address/phone # 1 will be kept together with the control
# of the active drug and placebo.
The blinded study code can only be broken upon a request of the Principal
Investigator.
A dosing chart will be printed out for patient's family/caregiver for both the
active drug and the placebo. Only a 34 days' supply will be dispensed at one

Investigational New Drug Application
University of Minnesota
28
Medication Bottle with Oral
Syringe Adapter
time: So if the placebo was dispensed for the first 34 days the next supply for
34 days (active drug) - the family would have to pick up the new supply.
The study treatment will be administered orally or via a gastrointestinal tube 3
times daily, with dose specified for the parent or guardian in a customized table
for each study subject.
5.5 Subject Compliance Monitoring
Compliance will be monitored by having the parents of the subject bring any
unused drug back to Gillette Children's Specialty Healthcare each time they
visit for the study. Amount of unused drug will be measured by the pharmacy
before the subjects can get their next supply of study drug. Subjects will also
be called every two weeks to assess any AEs and any positive effects subjects
are experiencing. They will be asked how the customized drug plan for them
is working. If a subject is found to be noncompliant with the study drug, the
subject will be withdrawn from the study, with all withdrawal procedures
followed. A subject will be defined as noncompliant if more than three days
of doses of drug are missed.
5.6 Prior and Concomitant Therapy
During the history and physical, it will be determined if the patient is now or
has been treated with Gabapentin or pregabalin. If currently receiving
Gabapentin or pregabalin, the patient will be excluded from the study. No
restrictions on other medications and therapies will be placed on the patient
other than the ketogenic diet, and use of Gabapentin or pregabalin.
Gabapentin Study
Oral Syringe Adapter
1 ml 3 ml 5 ml 10 ml 20 ml
Figure 4. Study Drug Packaging
Appropriate size oral syringe is inserted
in bottle adapter.
From the dosing chart, the dose required
is drawn up in syringe, administered via
G tube.
Dose volume administered is
documented on chart.

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5.7 Packaging
The study drug or placebo will be packaged as a 34 day supply in an amber
bottle with an oral syringe adapter and accompanying appropriately sized
syringes. The bottles will be labeled with the subject's name, address, date,
control number, expiration date, storage requirements and dosing instructions.
5.8 Blinding of Study Drug
The Gillette Children's Specialty Healthcare pharmacy will assign subjects to
either the study drug or placebo as per the randomization table as described in
Section 5.3. The pharmacy will prepare and label the study drug or placebo with
a coded control number indicating group assignment.
5.9 Receiving, Storage, Dispensing and Return
5.9.1 Receipt of Drug Supplies
The study drug is Nuerontin (gabapentin) 250 mg/5 ml 470 ml bottle
solution by Pfizer/Parke Davis Pharmaceutical Company. It will be
obtained by Gillette Hospital Pharmacy commercially from McKesson
Wholesaler in St. Paul, MN
5.9.2 Storage
Nuerontin Solution must be stored in a refrigerator between 2-8 °C or
36-46 °F. The commercial bottle is an amber light resistant glass
container. It will be placed in a special labeled container in the
refrigerator "Gabapentin Study Drug".
5.9.3 Dispensing of Study Drug
Each patient will have its own unique record with the patient's clinical
information together with address, parent or care giver's name & phone.
The drug is prescribed on a mg/kg basis with 22 day medication/placebo
titration period, 7-day stable dosing, 9-day taper and washout. The drug
or placebo will be labeled identically except for a unique control number
on the label. The label will state that the drug must be kept in the
refridgerator.
Each study patient will have a chart with each day dosing given in the
morning, afternoon and evening be printed with the volume (ml's) to be
administered. Example: a 10 kg child on day #4 needs 2.5 mg/kg (25 mg)
in morning and afternoon plus a 5 mg/kg (50 mg) in evening. The dosing
chart would have on day #4 to give 0.5 ml (25 mg) in the morning and
afternoon plus 1 ml (50 mg) in the evening. Gabapentin solution is 250
mg/5m1 or 50 mg/ml. This dosing chart is included with this application.

Investigational New Drug Application
University of Minnesota
30
The total volume need for this 10 kg patient for the entire 34 day study
would be less than 15 ml. We could dispense 20 ml in a 30 ml container
with a oral syringe dispense cap.
The care giver would document each dose administered on this chart so
we can reconcile the amount in the container plus the doses
administered be the amount dispensed.
5.9.4 Return or Destruction of Study Drug
All study drug/placebo left over will be returned to Gillette Pharmacy for
final reconciliation and destruction.
6.0 Study Procedures
Outline of procedure plan
1.
Recruitment
from
clinics
including:
chronic
care,
neurology,
gastroenterology, and pain
2.
History and physical examination completed as part of routine assessment
and management for chronic irritability
3.
Determine if evaluation for potentially treatable causes of chronic irritability
has been completed.
4.
Parental consent
5.
Parental questionnaire #1 and NCCPC-R rating 3 typical irritable events
6.
Randomization: gabapentin or placebo
7.
Titration schedule
8.
Day 6
phone call by study staff (or closest week day)
9.
Day 13
NCCPC-R, questionnaire #2, and phone call follow-up (or closest
week day)
10. Day 24
NCCPC-R, questionnaire #2, and phone call follow-up (or closest
week day)
If no improvement (dose 40 mg/kg/day) begin taper early(step #11) and set
up visit with Research Coordinator (Step #12)
11. Day 29
Begin medication taper
12. Day 34 to 38
Family comes in to meet with the Research Coordinator.
Subject is weighed. Perceived benefits and side effects of the drug are
discussed. Report any concerns to the PI, if any. Subject is provided new drug
at this visit. The old bottle will be taken back, along with the dosing chart.
Remaining drug will be measured.
13. Day 38
Crossover
14. Repeat steps 7
11
15. At completion Research Coordinator contacts family by telephone to discuss
perceived benefits/side effects of round 2 drug. Reports concerns to PI, if any
Parents complete one questionnaire #1, four questionnaires #2, and six
NCCPC-R
Questionnaire # 1: includes 60 questions that require identifying the appropriate
response from the items listed and 5 questions that require a written response.

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Information obtained includes: frequency and duration of pain episodes along with
associated gastrointestinal symptoms and sleep disturbance. The questionnaire takes
approximately 15 minutes to complete.
Questionnaire #2: includes 24 questions that require identifying the appropriate response
from the items listed and 2 questions that require a written response. Information
obtained includes: frequency and duration of pain episodes along with associated
gastrointestinal symptoms and sleep disturbance. The questionnaire takes approximately
5 minutes to complete.
NCCPC-R: Pain behavior in nonverbal neurologically impaired children can be
measured using the Non-Communicating Children's Pain Checklist-Revised (NCCPC-
R).10,
11 The scale consists of seven domains including Vocal, Eating/Sleeping,
Social/Personality, Facial Expression, Activity, Body/Limbs, and Physiological. The
NCCPC-R has shown validity and reliability for everyday pain among children with
developmental disabilities and was applied to study the incidence of pain in children
with severe neurological impairments. Cut-off scores based on receiver operating
characteristics suggest a score of 7 or greater on the NCCPC-R as indicative of pain in
such children. The NCCPC-R takes approximately 5 minutes to complete.
Schedule of Events
Day
Pre-
screen
Informed
Consent
Medical
History
Physical
Exam
Phone
Check
NCCPC-
R
Ql
Q2
0
X
X
X
X
X
X
6
X
13
X
X
X
24
X
X
X
28
X
34-37
X
X
X
38
X
44
X
51
X
X
X
62
X
X
X
76
X
The Day 0 visit occurs as an office visit at the Gillette Children's Specialty Healthcare
facility. A medical history and physical examination will be completed as part of routine
assessment and management for chronic irritability. Determine if evaluation for
potentially treatable causes of chronic irritability has been completed. The first round of
drug will be dispensed. Families will be asked to mark off each dose they take out of the
bottle with an X on the dosing sheet. Another visit with the research coordinator will
occur once the drug has been tapered, during the washout period. During that visit, the
subject will be re-weighed, the old drug bottle will be taken and the remaining drug
measured, and

Investigational New Drug Application
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the old dosing sheet will be taken. Any benefits or side effects will be discussed
at this visit, and the new drug bottle will be dispensed. Once drug has been
tapered the second time, patients will be instructed to return the bottle when they
return for their next standard of care appointment at Gillette Children's Specialty
Healthcare.
Unscheduled visits
If any unscheduled visits occur due to side effects, another physical exam will be
done and side effects will be recorded. Standard of care treatment will be
administered for side effects. The NCCPR-C and Questionnaire #2 will be done
as well.
7.0 Statistical Plan
7.1 Sample Size Determination
Power Calculations: A minimum sample size of 40 patients was determined
by estimating a 15 point difference using the NCCPC-R pain assessment tool
(90 points total) pre and post gabapentin, with a SD of 25 and within-person
correlation of 0.6, accounting for recruitment and retention.
7.2 Statistical Methods
Simple descriptive statistics will be utilized to compare differences between
the treatment and placebo groups with respect to frequency and duration of
pain episodes, and frequency of gastrointestinal and sleep problems.
Parent/caregiver reported questionnaires will be compared between groups.
The NCCPC-R assessments will be scored and compared between groups,
with a 15 point difference considered a significant difference.
7.3 Subject Population(s) for Analysis
The subject population to be analyzed includes all protocol compliant
subjects. Subjects who are not compliant with the protocol will be withdrawn
as described in Section 5.5
8.0 Safety and Adverse Events
8.1 Definitions
Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that
develops or worsens in severity during the course of the study. Intercurrent
illnesses or injuries should be regarded as adverse events. Abnormal results
of diagnostic procedures are considered to be adverse events if the
abnormality:
results in study withdrawal.
is associated with a serious adverse event.
is associated with clinical signs or symptoms.
leads to additional treatment or to further diagnostic tests.
is considered by the investigator to be of clinical significance.

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Serious Adverse Event
A serious adverse event (SAE) is any AE that is:
fatal.
life-threatening.
requires or prolongs hospital stay.
results in persistent or significant disability or incapacity.
a congenital anomaly or birth defect.
Important medical events may be considered SAEs. Important medical events
are those that may not be immediately life threatening, but are clearly of major
clinical significance. They may jeopardize the subject, and may require
intervention to prevent one of the other serious outcomes noted above. For
example, drug overdose or abuse, a seizure that did not result in in-patient
hospitalization, or intensive treatment of bronchospasm in an emergency
department would typically be considered serious.
Adverse Event Reporting Period
The study period during which adverse events must be reported is normally
defined as the period from the initiation of any study procedures to the end of
the study treatment follow-up. For this study, the study treatment follow-up is
defined as 30 days following the last administration of study treatment.
Preexisting Condition
A preexisting condition is one that is present at the start of the study. A
preexisting condition should be recorded as an adverse event if the frequency,
intensity, or the character of the condition worsens during the study period.
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a
preexisting condition. At the end of the study, any new clinically significant
findings/abnormalities that meet the definition of an adverse event must also
be recorded and documented as an adverse event.
Post-study Adverse Event
All unresolved adverse events should be followed by the investigator until the
events are resolved, the subject is lost to follow-up, or the adverse event is
otherwise explained. At the last scheduled visit, the investigator should
instruct each subject to report any subsequent event(s) that the subject, or the
subject's personal physician,
believes
might reasonably be related to
participation in this study.
Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an adverse event if
any one of the following conditions is met:

Investigational New Drug Application
University of Minnesota
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The laboratory abnormality is not otherwise refuted by a repeat test to
confirm the abnormality
The abnormality suggests a disease and/or organ toxicity
The abnormality is of a degree that requires active management; e.g. change
of dose, discontinuation of the drug; more frequent follow-up assessments,
further diagnostic investigation, etc.
Hospitalization, Prolonged Hospitalization or Surgery
Any adverse event that results in hospitalization or prolonged hospitalization
should be documented and reported as a serious adverse event unless
specifically instructed otherwise in this protocol. Any condition responsible for
surgery should be documented as an adverse event if the condition meets the
criteria for and adverse event.
Neither the condition, hospitalization, prolonged hospitalization, nor surgery
are reported as an adverse event in the following circumstances:
Hospitalization or prolonged hospitalization for diagnostic or elective
surgical procedures for a preexisting condition. Surgery should not be
reported as an outcome of an adverse event if the purpose of the surgery was
elective or diagnostic and the outcome was uneventful.
Hospitalization or prolonged hospitalization required to allow efficacy
measurement for the study.
Hospitalization or prolonged hospitalization for therapy of the target disease
of the study, unless it is a worsening or increase in frequency of hospital
admissions as judged by the clinical investigator.
8.2 Recording of Adverse Events
At each contact with the subject, the investigator must seek information on
adverse events by specific questioning and, as appropriate, by examination.
Information on all adverse events should be recorded immediately in the source
document, and also in the appropriate adverse event module of the case report
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic
procedures results should recorded in the source document, though should be
grouped under one diagnosis.
All adverse events occurring during the study period must be recorded. The
clinical course of each event should be followed until resolution, stabilization,
or until it has been determined that the study treatment or participation is not
the cause. Serious adverse events that are still ongoing at the end of the study
period must be followed up to determine the final outcome. Any serious
adverse event that occurs after the study period and is considered to be possibly
related to the study treatment or study participation should be recorded and
reported immediately.

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8.3 Reporting of Serious Adverse Events
8.3.1 Study Sponsor Notification by Investigator
A serious adverse event must be reported to the study sponsor by
telephone within 24 hours of the event. A Serious Adverse Event
(SAE) form must be completed by the investigator and faxed to the
study sponsor within 24 hours. The investigator will keep a copy of
this SAE form on file at the study site. Report serious adverse events
by phone and facsimile to:
Scott Schwantes, MD
651.229.3818 (phone)
651.265.7416 (fax)
At the time of the initial report, the following information should
be provided:
Study identifier
Study Center
Subject number
A description of the
event
Date of onset
Current Status
Whether study treatment
was discontinued
The reason why the event
is classified as serious
Investigator assessment
of the association
between the event and
study treatment
Within the following 48 hours, the investigator must provide further
information on the serious adverse event in the form of a written
narrative. This should include a copy of the completed Serious
Adverse Event form, and any other diagnostic information that will
assist the understanding of the event. Significant new information on
ongoing serious adverse events should be provided promptly to the
study sponsor.
8.3.2 IRB Notification by Investigator
Reports of all serious adverse events (including follow-up information)
must be submitted to the IRB within 10 working days if it falls under the
UPIRTSO guidelines. Copies of each report and documentation of IRB
notification and receipt will be kept in the Clinical Investigator's binder.
8.3.3 FDA Notification by Sponsor
The study sponsor shall notify the FDA by telephone or by facsimile
transmission of any unexpected fatal or life-threatening experience
associated with the use of the drug as soon as possible but no later than 7
calendar days from the sponsor's original receipt of the information.
If a previous adverse event that was not initially deemed reportable is
later found to fit the criteria for reporting, the study sponsor will submit

Investigational New Drug Application
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the adverse event in a written report to the FDA as soon as possible, but no
later than 15 calendar days from the time the determination is made.
8.4 Unblinding Procedures
Unblinding of this study can be done by calling or contacting Gillette
Pharmacy 24 hrs a day x 7 days a week. Only the approved providers can
get access to this code.
8.5 Stopping Rules
The study will be interrupted or stopped in the following circumstances:
1.
A separate body (e.g. FDA) deems Gabapentin to be unsafe for human use
2.
The identification of a serious adverse event (fatality, life-threatening
event, increased seizure activity, prolonged hospital stay), attributable to
Gabapentin.
8.6 Medical Monitoring
It is the responsibility of the Principal Investigator to oversee the safety of the
study at his/her site. This safety monitoring will include careful assessment
and appropriate reporting of adverse events as noted above, as well as the
construction and implementation of a site data and safety-monitoring plan
(see section 9 Auditing, Monitoring and Inspecting). Medical monitoring will
include a regular assessment of the number and type of serious adverse
events.
9.0 Data Handling and Record Keeping
9.1 Confidentiality
Information about study subjects will be kept confidential and managed
according to the requirements of the Health Insurance Portability and
Accountability Act of 1996 (HIPAA). Those regulations require a signed
subject authorization informing the subject of the following:
What protected health information (PHI) will be collected from subjects in
this study
Who will have access to that information and why
Who will use or disclose that information
The rights of a research subject to revoke their authorization for use of
their PHI.
In the event that a subject revokes authorization to collect or use PHI, the
investigator, by regulation, retains the ability to use all information collected
prior to the revocation of subject authorization. For subjects that have revoked
authorization to collect or use PHI, attempts should be made to obtain
permission to collect at least vital status (i.e. that the subject is alive) at the end
of their scheduled study period.

Investigational New Drug Application
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9.2 Source Documents
Source data is
all information,
original records of
clinical findings,
observations, or other activities in a clinical trial necessary for the
reconstruction and evaluation of the trial. Source data are contained in source
documents. Examples of these original documents, and data records include:
hospital records, clinical and office charts, laboratory notes, memoranda,
subjects' diaries or evaluation checklists, pharmacy dispensing records,
recorded data from automated instruments, copies or transcriptions certified
after verification as being accurate and complete, microfiches, photographic
negatives, microfilm or magnetic media, x-rays, subject files, and records kept
at the pharmacy, at the laboratories, and at medico-technical departments
involved in the clinical trial.
Data generated by the methods described in the protocol will be recorded in
the subjects' medical records and/or study progress notes. Data may be
transcribed legibly on CRFs supplied for each subject or directly inputted into
an electronic system or any combination thereof.
9.3 Case Report Forms
The study case report form (CRF) is the primary data collection instrument for
the study. All data requested on the CRF must be recorded. All missing data
must be explained. If a space on the CRF is left blank because the procedure was
not done or the question was not asked, write "N/D". If the item is not applicable
to the individual case, write "N/A". Al] entries should be printed legibly in black
ink. If any entry error has been made, to correct such an error, draw a single
straight line through the incorrect entry and enter the correct data above it. All
such changes must be initialed and dated, DO NOT ERASE OR WHITE OUT
ERRORS, For clarification of illegible or uncertain entries, print the clarification
above the item, then initial and date it.
9.4 Records Retention
It is the investigator's responsibility to retain study essential documents for at
least 2 years after the last approval of a marketing application in their country
and until there are no pending or contemplated marketing applications in their
country or at least 2 years have elapsed since the formal discontinuation of
clinical development of the investigational product. These documents should
be retained for a longer period if required by an agreement with the sponsor. In
such an instance, it is the responsibility of the sponsor to inform the
investigator/institution as to when these documents no longer need to be
retained.
10.0 Study Monitoring, Auditing, and Inspecting
10.1 Study Monitoring Plan
This study will be monitored by the Clinical and Translational Science
Institute's Clinical Monitoring Service (CTMS) in accordance with the

Investigational New Drug Application
University of Minnesota
38
attached Clinical Trial Monitoring Plan. The investigator will allocate
adequate time for such monitoring activities. The Investigator will also ensure
that the monitor or other compliance or quality assurance reviewer is given
access to all the above noted study-related documents and study related
facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space
to conduct the monitoring visit.
10.2 Auditing and Inspecting
The investigator
will
permit
study-related
monitoring, audits,
and
inspections by the IRB, the sponsor, government regulatory bodies, and
University compliance and quality assurance groups of all study related
documents (e.g. source documents, regulatory documents, data collection
instruments, study data etc.). The investigator will ensure the capability for
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic
laboratory, etc.).
Participation as an investigator in this study implies acceptance of
potential
inspection
by
government
regulatory
authorities
and
applicable University compliance and quality assurance offices.
11.0 Ethical Considerations
This study is to be conducted according to US and international standards of
Good Clinical Practice (FDA Title 21 part 312 and International Conference on
Harmonization guidelines), applicable government regulations and Institutional
research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted
independent Institutional Review Board (IRB), in agreement with local legal
prescriptions, for formal approval of the study conduct. The decision of the IRB
concerning the conduct of the study will be made in writing to the investigator and
a copy of this decision will be provided to the sponsor before commencement of
this study.
All subjects for this study will be provided a consent form describing this study
and providing sufficient information for subjects to make an informed decision
about their participation in this study. The consent form will be submitted with the
protocol for review and approval by the IRB for the study. The formal consent of a
subject, using the IRB-approved consent form, must be obtained before that
subject is submitted to any study procedure. This consent form must be signed by
the subject or legally acceptable surrogate, and the investigator-designated
research professional obtaining the consent.

Investigational New Drug Application
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39
12 Study Finances
12.1 Funding Source
This study is financed through a grant from the Gillette Children's Foundation
Medical Education and Research Association (MERA).
12.2 Conflict of Interest
Any investigator who has a conflict of interest with this study (patent
ownership, royalties, or financial gain greater than the minimum allowable by
their institution, etc.) must refer to the Regents Policies on Individual Conflict
of Interest Policy or Institutional Conflict of Interest Policy. These policies
require University Faculty and staff to report external professional activities
and business and significant financial interests related to his or her University
activities by submitting a REPA (Report of External Professional Activities) at
least once per year. Faculty and staff should also file a REPA when substantial
changes in business or financial interests occur, when an activity that presents a
potential conflict of interest is anticipated, or when submitting an application
for research support or technology transfer, submitting research protocols to the
IRB, or receiving financial contributions. All University of Minnesota
investigators will follow the University conflict of interest policy.
12.3 Subject Stipends or Payments
Subjects will receive a Target gift card for $50 at the end of the study for their
time. Families will also receive parking vouchers for each visit completed. If a
subject leaves the study early, that family will receive parking vouchers for
each visit they completed.
13 Publication Plan
Neither the complete nor any part of the results of the study carried out under this
protocol, nor any of the information provided by the sponsor for the purposes of
performing the study, will be published or passed on to any third party without the
consent of the study sponsor. Any investigator involved with this study is obligated
to provide the sponsor with complete test results and all data derived from the study.
14 References
1. Perquin CW, Hazebroek-Kampschreur AA, Hunfeld JA, Bohnen AM, van
Suijlekom-Smit LW, Passchier J, van der Wouden JC. Pain in children and
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University of Minnesota
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15 Attachments
Dosing Chart
Questionnaire #1
Questionnaire #2
NCCPC-R
Clinical Monitoring Plan: Clinical and Translational Science Institute