Clinical trial NCT02722603: Study to Compare Gabapentin to Tramadol in Children With Chronic Neuropathic or Mixed Pain
Official title: Randomized, Double-blind, Double-dummy, Active Controlled, Multicentre, Non-inferiority Phase-III Study to Compare Gabapentin Liquid Formulation to Tramadol in Children Experiencing Moderate to Severe Chronic Neuropathic or Mixed Pain
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Chronic Pain
Lead sponsor: Pharmaceutical Research Management srl
Sponsor class: INDUSTRY
Collaborators: name: European Commission
First posted: 2016-03-30
Enrollment: 2
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the efficacy and safety of gabapentin relative to tramadol for the treatment of chronic, neuropathic or mixed pain in the paediatric population. Children from 3 months to less than 18 years of age experiencing moderate to severe chronic pain will receive either gabapentin or tramadol for 15 weeks. The difference in average pain scores between treatment arms at the end of the treatment period will be assessed.

Detailed description: Gabapentin is indicated for the treatment of peripheral neuropathic pain in adults. In the absence of specific paediatric studies, it is not approved for the same condition in children.

The paediatric use of gabapentin is hampered by a) the lack of a suitable paediatric formulation, b) the significant variability of gabapentin pharmacokinetics profile and c) efficacy and safety data in this specific population.

The GABA-1 study is designed to demonstrate the efficacy of gabapentin oral solution relative to tramadol and to document the Pharmacokinetic and safety profile of gabapentin in this indication.

GABA-1 is a non-inferiority trial because gabapentin is expected to be equally effective but better tolerated than tramadol, thus providing a clinical benefit to affected children.

Eligibility criteria: Inclusion Criteria:

1. Male or female, aged 3 months to less than 18 years at screening.
2. Informed consent by parent(s) and/or legal guardian according to each country legal requirement.
3. Assent by the patient, where applicable, according to each country legal requirement.
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. Duration of pain will be determined from the date of the first pain experienced.
6. Subjects that present with at least moderate pain as defined by average pain intensity of ≥4/10 as assessed during a 3-day screening period
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 during participation to the present study.

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 such as severe depressive conditions or psychosis.
9. Subjects with history of suicidal ideation or behaviour.
10. History of substance abuse in particular opioids.
11. Subjects under prohibited concomitant medication
12. Subjects in need for corticosteroid oral treatment or corticosteroid infiltrations to treat pain caused by infiltration or compression of neural structures, e.g. peripheral nerves or spinal cord.
13. Subjects born prematurely at ≤ 36 weeks 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 (Schwarz equation).
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. Subjects with fructose intolerance, diabetes, glucose-galactose malabsorption or lactase-isomaltase deficiency.
19. Subjects with clinically relevant abnormal ECG at the screening visit in the discretion of the Investigator/cardiologist.
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.

Primary outcomes:
measure: Pain score
timeFrame: an average of 16 weeks
Secondary outcomes:
measure: Percentage of responders to treatment
timeFrame: an average of 16 weeks
measure: Daily pain intensity
timeFrame: an average of 3 weeks
measure: Observational assessment of pain
timeFrame: an average of 16 weeks
measure: Self-assessment of pain for children ≥8 years of age
timeFrame: an average of 16 weeks
measure: Extent of pain
timeFrame: an average of 16 weeks
measure: Number of episodes of breakthrough pain
timeFrame: an average of 16 weeks
measure: Number of rescue interventions
timeFrame: an average of 15 weeks
measure: Number of pain-free days
timeFrame: an average of 15 weeks
measure: Number of participant dropouts
timeFrame: up to 21 weeks
measure: The total cumulative weight normalized dose of each rescue drug
timeFrame: up to 21 weeks
measure: Total Summary Score from PedsQL™ scale
timeFrame: an average of 15 weeks
measure: Physical Health Summary Score from PedsQL™ scale
timeFrame: an average of 15 weeks
measure: Psychosocial Health Summary Score from PedsQL™ scale
timeFrame: an average of 15 weeks
measure: Acceptability of treatment
timeFrame: at week 16
measure: Global satisfaction with treatment
timeFrame: at week 15
measure: Clinical Global Impression of Severity of the subject's condition
timeFrame: an average of 15 weeks
measure: Clinical Global Impression of Improvement for pain
timeFrame: an average of 15 weeks
measure: Patient/parent Global Impression of Change
timeFrame: an average of 12 weeks
measure: CL/F
timeFrame: at week 3 or at week 4 or at week 16
measure: Vd/F
timeFrame: at week 3 or at week 4 or at week 16
measure: ka
timeFrame: at week 3 or at week 4 or at week 16
measure: AUC
timeFrame: at week 3 or at week 4 or at week 16
measure: Cmax
timeFrame: at week 3 or at week 4 or at week 16
measure: Tmax
timeFrame: at week 3 or at week 4 or at week 16
measure: Css
timeFrame: at week 3 or at week 4 or at week 16
measure: Cmin
timeFrame: at week 3 or at week 4 or at week 16
measure: Systemic exposure to investigational products during maintenance period
timeFrame: an average of 12 weeks
measure: Incidence of Adverse Events at all visits
timeFrame: up to 21 weeks
measure: Percentage of subjects discontinuing the trial due to treatment-emergent adverse events.
timeFrame: up to 21 weeks
measure: Aggressive behaviour in children aged >6 years
timeFrame: an average of 15 weeks
measure: Suicidal ideation/behaviour in subjects aged 6 years and older
timeFrame: an average of 16 weeks
measure: Assessment of blinding
timeFrame: at week 16
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: Universitaets klinikum Erlangen
city: Rotterdam
country: Netherlands
facility: Erasmus Universitair Medisch Centrum Rotterdam
Study officials:
affiliation: Center Clin Investig INSERM CIC 1426 H. R Debré APH de Paris
name: Florentia Kaguelidou
role: PRINCIPAL_INVESTIGATOR
References:
citation: Finnerup NB, Sindrup SH, Jensen TS. Recent advances in pharmacological treatment of neuropathic pain. F1000 Med Rep. 2010 Jul 14;2:52. doi: 10.3410/M2-52.
citation: Mellegers MA, Furlan AD, Mailis A. Gabapentin for neuropathic pain: systematic review of controlled and uncontrolled literature. Clin J Pain. 2001 Dec;17(4):284-95. doi: 10.1097/00002508-200112000-00002.
citation: Kaguelidou F, Le Roux E, Mangiarini L, Lundin R, de Leeuw TG, Della Pasqua O, Felisi M, Bonifazi D, Tibboel D, Ceci A, de Wildt SN, Alberti C; GAPP consortium. Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: the GABA-1 trial-a study protocol. BMJ Open. 2019 Feb 20;9(2):e023296. doi: 10.1136/bmjopen-2018-023296.