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

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2014-004851-30-DE
• Date of registration: 17/06/2016
• Prospective Registration: Yes
• Primary sponsor: PHARM – Pharmaceutical Research Management srl
• Public title: Efficacy and safety study to compare gabapentin versus tramadol in paediatric patients affected by chronic moderate to severe pain
• Scientific title: 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. - Efficacy and safety study to compare gabapentin versus tramadol in paediatric patients
• Target sample size: 94
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004851-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: Double dummy; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Albania, France, Germany, Greece, Netherlands, Poland, Ukraine, United Kingdom

Contacts

• Name: Trial Management
• Affiliation: PHARM – Pharmaceutical Research Management srl

• Name: Trial Management
• Affiliation: PHARM – Pharmaceutical Research Management srl

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female, aged 3 months to less than 18 years at screening (V1).
Recruitment will start with patients = 3 years until results from the ongoing non-clinical toxicological study will confirm the safety of gabapentin in the age subset 3 months - 3 years
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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 94
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 born prematurely, before the 36th week of gestational age, if recruited during the first year of age.
14. Subjects with a body mass index (BMI) for age and gender of < 5th percentile or > 95th percentile.
15. Subjects with glomerular filtration rate < 90 mL/min/1.73 m2.
16. 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.
17. Subjects with known allergy, hypersensitivity or clinically significant
intolerance to gabapentin or tramadol or any component found in the
study drugs.
18. Subject with fructose intolerance, diabetes, glucose-galactose
malabsorption or lactase-isomaltase deficiency.
19. Subjects with clinically relevant abnormal ECG.
20. Subjects participating in another clinical interventional trial.
21. Subjects scheduled for surgery or in recovery from surgery occurring
within 3 months of baseline assessment.
22. Female subjects who are pregnant or currently lactating.
23. Subjects that failed screening or were previously enrolled in this
study.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Chronic pain of neuropathic or mixed origin
MedDRA version: 20.0 Level: LLT Classification code 10054095 Term: Neuropathic pain System Organ Class: 100000014315

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: gabapentin
Pharmaceutical Form: Syrup
INN or Proposed INN: gabapentin hydrochloride
CAS Number: 60142-95-2
Current Sponsor code: not applicable
Other descriptive name: GABAPENTIN HYDROCHLORIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Syrup
Route of administration of the placebo: Oral use

Trade Name: TRAMADOL EG
Product Name: tramadol
Pharmaceutical Form: Oral drops, solution
INN or Proposed INN: tramadol hydrochloride
CAS Number: 27203-92-5
Current Sponsor code: not applicable
Other descriptive name: TRAMADOL HYDROCHLORIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Oral drops, solution
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: 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

Secondary Objective: 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.

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).

Timepoint(s) of evaluation of this end point: Baseline, End of study

Secondary Outcome(s)

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

Secondary end point(s): a) Percentage of responders to treatments, defined as subjects with a 30% reduction from baseline or below or equal to 3/10 in pain intensity assessed by appropriate scale (FLACC, FPS-R, NRS-11).
b) Daily pain intensity assessed by age appropriate scale (FLACC, FPS-R or NRS-11) during dose optimisation .
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 the 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 treatmentemergent
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 at the end 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.

Secondary ID(s)

2014-004851-30-NL

GABA-1

Source(s) of Monetary Support

European Commission – FP7-HEALTH-2013- INNOVATION-1 Grant Agreement n. 602962