Clinical Trials Register

Summary
EudraCT Number:	2014-004851-30
Sponsor's Protocol Code Number:	GABA-1
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2016-09-28
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2014-004851-30

A.3

Full title of the trial

Randomized, double-blind, double-dummy, active controlled, multicentre, non-inferiority phase-III study to compare the pharmacokinetic, efficacy and safety of gabapentin liquid formulation to tramadol in children from 3 months to less than 18 years of age experiencing moderate to severe chronic neuropathic or mixed pain.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and safety study to compare gabapentin versus tramadol in paediatric patients affected by chronic moderate to severe pain

A.3.2

Name or abbreviated title of the trial where available

Efficacy and safety study to compare gabapentin versus tramadol in paediatric patients

A.4.1

Sponsor's protocol code number

GABA-1

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/250/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	PHARM – Pharmaceutical Research Management srl
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Commission – FP7-HEALTH-2013- INNOVATION-1 Grant Agreement n. 602962
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PHARM – Pharmaceutical Research Management srl
B.5.2	Functional name of contact point	Trial Management
B.5.3	Address:
B.5.3.1	Street Address	Via Einstein, Loc. Cascina Codazza
B.5.3.2	Town/ city	Lodi
B.5.3.3	Post code	26900
B.5.3.4	Country	Italy
B.5.4	Telephone number	003903714662684
B.5.5	Fax number	003903714662523
B.5.6	E-mail	trialmanagement@pharmsrl.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	gabapentin
D.3.4	Pharmaceutical form	Syrup
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	gabapentin hydrochloride
D.3.9.1	CAS number	60142-95-2
D.3.9.2	Current sponsor code	not applicable
D.3.9.3	Other descriptive name	GABAPENTIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB126895
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	TRAMADOL EG
D.2.1.1.2	Name of the Marketing Authorisation holder	EG S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	tramadol
D.3.4	Pharmaceutical form	Oral drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	tramadol hydrochloride
D.3.9.1	CAS number	27203-92-5
D.3.9.2	Current sponsor code	not applicable
D.3.9.3	Other descriptive name	TRAMADOL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB04927MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Syrup
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral drops, solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic pain of neuropathic or mixed origin

E.1.1.1

Medical condition in easily understood language

Chronic pain

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10054095
E.1.2	Term	Neuropathic pain
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of gabapentin relative to tramadol for the treatment of moderate to severe chronic neuropathic or mixed pain in children from 3 months to less than 18 years of age assessed by the difference in average pain scores between treatment arms at the end of the treatment period

E.2.2

Secondary objectives of the trial

1. To assess effect of gabapentin relative to tramadol on quality of life (physical, emotional, social and school functioning) and global satisfaction with treatment.
2. To assess safety of gabapentin relative to tramadol for treatment of chronic neuropathic or mixed pain in children 3 months to less than 18 years of age.
3. To characterise the population pharmacokinetic-pharmacodynamic (PKPD) relationship of gabapentin liquid formulation and provide confirmation of the recommended paediatric dose.
Additional exploratory objectives of the study are:
4. To describe the metabolomic profile following drug treatments.
5. To explore genetic polymorphisms and their impact on pharmacokinetics (PK) and pharmacodynamics (PD).
6. To assess the population pharmacokinetics of tramadol and, if feasible, its PKPD relationship in the paediatric population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, aged 3 months to less than 18 years at screening (V1).
IN FRANCE , ONLY SUBJECTS ABOVE 3 YEARS OF AGE WILL BE INCLUDED IN ACCORDANCE WITH THE TRAMADOL MARKETING AUTHORISATHION IN THE COUNTRY.
2. Informed consent by parent(s)/legal guardian.
3. Assent by the patient, where applicable.
4. Subjects that meet the diagnostic criteria for neuropathic or mixed pain.
5. Subjects that present with chronic pain defined as the recurrent or continuous pain persisting more than 3 months.
6. Subjects that present with at least moderate pain as defined by average pain intensity of ≥4/10.
7. Stable underlying disease condition and treatment.
8. In presence of malignant diseases, subjects in clinical remission and/or no expected changes in their therapeutic protocol.

E.4

Principal exclusion criteria

1. Pain duration of more than 5 years.
2. Current use of gabapentin or tramadol.
3. History of failure to respond to adequate treatment by gabapentin or tramadol/opioids for neuropathic pain.
4. History of epileptic condition except febrile seizure disorder.
5. Subjects with sleeping apnoea syndrome of any origin or subjects with history of severe respiratory impairment.
6. Subjects with diagnosis of sickle cell disease.
7. Subjects that present significant cognitive impairment.
8. Subjects that present current, controlled or uncontrolled, co-morbid psychiatric diagnosis that can impair pain diagnosis and assessment.
9. Subjects with history of suicidal ideation or behaviour.
10. Subjects with history of substance abuse in particular opioids.
11. Subjects under prohibited concomitant medication.
12. Subjects in need for corticosteroid oral treatment or corticosteroid infiltration to treat pain caused by infiltration or compression of neural structure..
13. Subjects with a body mass index (BMI) for age and gender of < 5th percentile or > 95th percentile.
14. Subjects with glomerular filtration rate < 90 mL/min/1.73 m2.
15. Subjects with significant hepatic impairment or with Aspartate Transaminase (AST) or Alanine Transaminase (ALT) enzymes 3 times the upper limit of the age-specific reference range.
16. Subjects with known allergy, hypersensitivity or clinically significant intolerance to gabapentin or tramadol or any component found in the study drugs.
17. Subject with fructose intolerance, diabetes, glucose-galactose malabsorption or lactase-isomaltase deficiency.
18. Subjects with clinically relevant abnormal ECG.
19. Subjects participating in another clinical interventional trial.
20. Subjects scheduled for surgery or in recovery from surgery occurring within 3 months of baseline assessment.
21. Female subjects who are pregnant or currently lactating.
22. Subjects that failed screening or were previously enrolled in this study.

E.5 End points

E.5.1

Primary end point(s)

Average pain score at the end of the treatment period ( average of 2 measures each day for 3 days before end of study visit V10) as assessed by age-appropriate pain scale (FLACC, FPS-R, NRS-11).

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, End of study

E.5.2

Secondary end point(s)

a) Percentage of responders to treatments, defined as subjects with a 30% reduction from baseline in assessment scale (FLACC, FPS-R, NRS-11).
b) Average daily pain intensity assessed by age appropriate scale during dose optimisation (FLACC, FPS-R or NRS-11).
c) Observational assessment of pain using the NRS-11 completed by parents and Investigator (or caregiver) at each visit.
d) Self-assessment of pain for children aged 8 years and older using the FPS-R pain scale at each visit.
e) Extent of pain evaluated as the number of painful areas using he pain charts at screening visit (V1), randomization (V2), and EOS visit (V10).
f) Number of episodes of breakthrough pain (> 4/10 pain score and use of rescue medications) during treatment period.
g) Number of rescue interventions required during treatment period.
h) Number of pain-free (< 4/10 average pain score without the use of rescue medications) days during treatment period.
i) Number of participant dropouts due to lack of efficacy.
j) The total cumulative weight normalized dose of each rescue drug.
k) Quality of life, physical, emotional, social and school functioning and quality of sleep on the PedsQL Generic Core Scales (by parent, patient) assessed at randomisation (V2) and at EOS (V10).
l) Acceptability of treatment (Five-Point Facial Hedonic scale) at EOS visit (V10).
m) Global satisfaction with treatment (NRS-11, by parent, patient) at EOS visit (V10).
n) Clinical Global Impression of Change (CGI-S, CGI-I; by Investigator) at randomisation (V2) for CGI-S and V6 and EOS visit (V10) for CGI-I.
o) Patient/parent Global Impression of Change (PGIC; by parent, patient) at V6 and at EOS visit (V10).
p) Primary (CL/F, Vd/F, Ka) and secondary (AUC, Cmax, Tmax, Css and Cmin) pharmacokinetic parameters for gabapentin and tramadol.
q) Systemic exposure to investigational products during maintenance period, as assessed by predicted steady-state concentrations.
r) Incidence of Adverse Events at all visits.
s) Percentage of subjects discontinuing the trial due to treatment-emergent adverse events.
t) Aggressive behaviour in children aged >6 years using the Retrospective-Modified Overt
Aggression Scale (R-MOAS) at V2, V6 and EOS visit (V10).
u) Suicidal ideation/behaviour in subjects aged 6 years and older using the Columbia - Suicide Severity Rating Scale (C-SSRS) scores before IMP (screening V1), V6 and at the EOS visit (V10) and and of taper visit (V11).
v) Assessment of blinding: guess of the subject’s treatment group (by Investigator, parents and subject if at adequate maturity level) at V10.

E.5.2.1

Timepoint(s) of evaluation of this end point

a) Baseline, end of study
b) Daily during dose optimization
c) Monthly
d) Monthly
e)Screening, randomization, end of study
f) Daily during treatment period
g) Daily during treatment period.
h) Daily during treatment period.
i) End of study
j) End of study
k) Randomization, end of study
l) End of study
m End of study
n) Randomization, end of optimization phase, end of study
o) End of optimization phase, end of study
p) Sparse sampling during study or end of study
q) Sparse sampling during study or end of study
r) Monthly
s) End of study
t) Randomization, end of optimization phase, end of study
u) Screening, end of optimization phase, end of study, end of taper
v) End of study

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Metabolomic

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Double dummy

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Albania

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1