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The study was early terminated due to insufficient recruitment
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| Name | Class |
|---|---|
| European Commission | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| gabapentin / placebo tramadol | Experimental | gabapentin 75 mg/ml syrup / placebo tramadol, 3 times/day for 15 weeks. |
|
| tramadol / placebo gabapentin | Active Comparator | tramadol oral drops 100 mg/ml / placebo gabapentin, 3 times/day for 15 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| gabapentin | Drug | 75 mg/ml gabapentin syrup |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Pain score | Pain score (0-10) measured at baseline (before starting the therapy) and at the end of the treatment in: patients aged 3-24 months using FLACC pain scale, patients aged 3-7 years using FPS-R scale, patients aged 8-17 years using NRS-11. The FLACC (the Faces, Legs, Arms, Cry and Consolability) scale is composed by 5 categories. Each category is scored on the 0-2 scale, which results in a total score of 0-10, where 0=Relaxed and comfortable, 4-6=Moderate pain, 1-3=Mild discomfort, 7-10=Severe discomfort or pain or both. FPS-R (Faces Pain Scale - Revised - pts aged 3-7 years). Score is associated with face 0, 2, 4, 6, 8, or 10, where 0 = no pain and 10=very much pain. NRS-11 (Numerical Rating Scale - pts aged 8-17 years): numerical rating scale where 0=no pain and 10=worst possible pain. | an average of 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of responders to treatment | Subjects with a pain intensity reduction of 30% from baseline or below or equal to 3/10, assessed by age-appropriate pain scale. FLACC (the Faces, Legs, Arms, Cry and Consolability) scale (pts aged 3-24-months) is composed by 5 categories. Each category is scored on the 0-2 scale, which results in a total score of 0-10, where 0=Relaxed and comfortable, 4-6=Moderate pain, 1-3=Mild discomfort, 7-10=Severe discomfort or pain or both. FPS-R (Faces Pain Scale - Revised - pts aged 3-7 years). Score is associated with face 0, 2, 4, 6, 8, or 10, where 0 = no pain and 10=very much pain. NRS-11 (Numerical Rating Scale - pts aged 8-17 years): numerical rating scale where 0=no pain and 10=worst possible pain. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Florentia Kaguelidou | Center Clin Investig INSERM CIC 1426 H. R Debré APH de Paris | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Universitaets klinikum Erlangen | Erlangen | Germany | ||||
| Erasmus Universitair Medisch Centrum Rotterdam |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21170362 | Background | 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. | |
| 11783808 | Background | 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. |
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| ID | Term |
|---|---|
| D059350 | Chronic Pain |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077206 | Gabapentin |
| D014147 | Tramadol |
| ID | Term |
|---|---|
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D005680 | gamma-Aminobutyric Acid |
| D000613 | Aminobutyrates |
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| tramadol |
| Drug |
100 mg/ml tramadol oral drops |
|
| placebo tramadol | Other | placebo tramadol oral drops |
|
| placebo gabapentin | Other | placebo gabapentin syrup |
|
| an average of 16 weeks |
| Daily pain intensity | Daily pain intensity, assessed by age-appropriate scale (FLACC, FPS-R or NRS-11) during dose optimization. The FLACC (the Faces, Legs, Arms, Cry and Consolability) scale (pts aged 3-24-months) is composed by 5 categories. Each category is scored on the 0-2 scale, which results in a total score of 0-10, where 0=Relaxed and comfortable, 4-6=Moderate pain, 1-3=Mild discomfort, 7-10=Severe discomfort or pain or both. FPS-R (Faces Pain Scale - Revised - pts aged 3-7 years). Score is associated with face 0, 2, 4, 6, 8, or 10, where 0 = no pain and 10=very much pain. NRS-11 (Numerical Rating Scale - pts aged 8-17 years): numerical rating scale where 0=no pain and 10=worst possible pain. | an average of 3 weeks |
| Observational assessment of pain | Observational assessment of pain using the NRS-11 completed by parents and Investigator (or caregiver) at each visit. NRS-11: numerical rating scale where 0=no pain and 10=worst possible pain | an average of 16 weeks |
| Self-assessment of pain for children ≥8 years of age | Self-assessment of pain for children ≥8 years of age using the FPS-R pain scale at each visit. FPS-R (Faces Pain Scale - Revised) Score is associated with face 0, 2, 4, 6, 8, or 10, where 0 = no pain and 10=very much pain. | an average of 16 weeks |
| Extent of pain | number of painful areas using the pain charts at screening visit (V1), randomisation (v2) and EOS visit (V10). The pain charts are body maps (front and back) in which each body section is identified with a number. | an average of 16 weeks |
| Number of episodes of breakthrough pain | Number of episodes of breakthrough pain (> 4/10 pain score and use of rescue medications) during treatment period. | an average of 16 weeks |
| Number of rescue interventions | Number of rescue interventions required during treatment period | an average of 15 weeks |
| Number of pain-free days | Number of pain-free (< 4/10 average pain score without the use of rescue medications) days during treatment period | an average of 15 weeks |
| Number of participant dropouts | Number of participant dropouts due to lack of efficacy | up to 21 weeks |
| The total cumulative weight normalized dose of each rescue drug | The total cumulative weight normalized dose of each rescue drug | up to 21 weeks |
| Total Summary Score from PedsQL™ scale | Total score obtained using the PedsQL 4.0 Generic Core Scales (by parent, patient aged 3-17years) and PedsQL Infants Scales (by parent of pts aged 3-24months) at randomisation (V2) and at EOS (V10). The total score is a measure of Health Related Quality of life (HRQoL). Higher scores indicate better HRQOL. PedsQL 4.0 Generic Core Scales is composed by 4 multidimensional scales (Physical Funct, Emotional Funct, Social Funct, School Funct) and 3 summary scores (Total Scale Score, Physical Health Summary Score, Psychosocial Health Summary Score). Scoring is based on a 5-point Likert scale from 0 (Never) to 4 (Almost always). PedsQL Infant Scales is composed by 5 multidim. scales (Physical Functioning, Physical Symptoms, Emotional Functioning, Social Functioning, Cognitive Functioning) and 3 summary scores (Total Scale Score, Physical Health Summary Score, Psychosocial Health Summary Score). The scoring is based on a 5-point Likert scale from 0 (Never) to 4 (Almost always) | an average of 15 weeks |
| Physical Health Summary Score from PedsQL™ scale | Physical Health Score obtained using the PedsQL™ 4.0 Generic Core Scales (by parent, patient aged 3-17 years) and PedsQL™ Infant Scales (by parent, aged 3-24 months) at randomisation (V2) and at EOS (V10). PedsQL™ 4.0 Generic Core Scales is composed by 4 multidimensional scales (Physical Funct, Emotional Funct, Social Funct, School Funct) and 3 summary scores (Total Scale Score, Physical Health Summary Score, Psychosocial Health Summary Score). Scoring is based on a 5-point Likert scale from 0 (Never) to 4 (Almost always). PedsQL™ Infant Scales is composed by 5 multidimensional scales (Physical Functioning, Physical Symptoms, Emotional Functioning, Social Functioning, Cognitive Functioning) and 3 summary scores (Total Scale Score, Physical Health Summary Score, Psychosocial Health Summary Score). The scoring is based on a 5-point Likert scale from 0 (Never) to 4 (Almost always). | an average of 15 weeks |
| Psychosocial Health Summary Score from PedsQL™ scale | Psychosocial Health Score obtained using the PedsQL™ 4.0 Generic Core Scales (by parent, patient aged 3-17 years) and PedsQL™ Infant Scales (by parent, aged 3-24 months) at randomisation (V2) and at EOS (V10). PedsQL™ 4.0 Generic Core Scales is composed by 4 multidimensional scales (Physical Funct, Emotional Funct, Social Funct, School Funct) and 3 summary scores (Total Scale Score, Physical Health Summary Score, Psychosocial Health Summary Score). Scoring is based on a 5-point Likert scale from 0 (Never) to 4 (Almost always). PedsQL™ Infant Scales is composed by 5 multidimensional scales (Physical Functioning, Physical Symptoms, Emotional Functioning, Social Functioning, Cognitive Functioning) and 3 summary scores (Total Scale Score, Physical Health Summary Score, Psychosocial Health Summary Score). The scoring is based on a 5-point Likert scale from 0 (Never) to 4 (Almost always). | an average of 15 weeks |
| Acceptability of treatment | Acceptability of treatment (Five-Point Facial Hedonic scale) at EOS visit (V10). Each face in the scale is related to a score (1=unpleasant; 2=not sure; 3=pleasant). | at week 16 |
| Global satisfaction with treatment | Global satisfaction with treatment (NRS-11, by parent, patient) at EOS visit (V10). The satisfaction is measeured by the numerical rating scale NRS-11 where 0=not satisfied and 10=fully satisfied | at week 15 |
| Clinical Global Impression of Severity of the subject's condition | Clinical Global Impression of Severity (CGI-S) for Neuropathic or Mixed Pain Overall Severity Prior to Study Treatment (at randomization - V2) assessed by Investigator. Investigators will rate their impression of the severity of the subject's condition. Scoring: Normal: no signs of pain, Borderline painful, Mildly painful, Moderately painful, Markedly painful,Severely painful, Among the most extremely painful patients. | an average of 15 weeks |
| Clinical Global Impression of Improvement for pain | Clinical Global Impression of Improvement (CGI-I) for Neuropathic or Mixed Pain Overall at V6 and EOS visit (V10) assessed by Investigator. Investigators will rate their impression of any change of the subject's overall condition of neuropathic or mixed pain since randomization in the study. Scoring are: Very much improved since the initiation of treatment; Much improved; Minimally improved; No change from baseline (the initiation of treatment); Minimally worse; Much worse; Very much worse since the initiation of treatment. | an average of 15 weeks |
| Patient/parent Global Impression of Change | Patient/parent Global Impression of Change (PGIC; by parent, patient) at V6 and at EOS visit (V10). Patient/parent will rate their impression of any change of the subject's overall condition of neuropathic or mixed pain since randomization in the study. Scoring are: Very much improved since the initiation of treatment; Much improved; Minimally improved; No change from baseline (the initiation of treatment); Minimally worse; Much worse; Very much worse since the initiation of treatment. | an average of 12 weeks |
| CL/F | Primary pharmacokinetic parameters for gabapentin and tramadol: assessment of apparent clearance (CL/F) and of its variability and precision. In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| Vd/F | Primary pharmacokinetic parameter for gabapentin and tramadol: assessment of apparent volume of distribution (Vd/F) and of its variability and precision. In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| ka | Primary pharmacokinetic parameter for gabapentin and tramadol: assessment of absorption rate constant (Ka) and of its precision and variability. In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| AUC | Secondary pharmacokinetic parameter for gabapentin and tramadol: assessment of Area under the Concentration curve (AUC). In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| Cmax | Secondary pharmacokinetic parameter for gabapentin and tramadol: assessment of peak plasma concentration (Cmax). In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| Tmax | Secondary pharmacokinetic parameter for gabapentin and tramadol: assessment of time at which the Cmax is observed (Tmax). In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| Css | Secondary pharmacokinetic parameter for gabapentin and tramadol: assessment of steady state Concentrations (Css). In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| Cmin | Secondary pharmacokinetic parameter for gabapentin and tramadol: assessment of minimum concentration (Cmin). In total, 4 samples will be collected, 1 before dosing and again at 3 different time windows post-dosing (0 - 2 h; 2 - 4 h and 4 - 6 h) | at week 3 or at week 4 or at week 16 |
| Systemic exposure to investigational products during maintenance period | Systemic exposure to investigational products during maintenance period, as assessed by predicted steady-state concentrations. | an average of 12 weeks |
| Incidence of Adverse Events at all visits | Incidence of Adverse Events at all visits | up to 21 weeks |
| Percentage of subjects discontinuing the trial due to treatment-emergent adverse events. | Percentage of subjects discontinuing the trial due to treatment-emergent adverse events. | up to 21 weeks |
| Aggressive behaviour in children aged >6 years | Aggressive behaviour in children aged >6 years using the Retrospective-Modified Overt Aggression Scale (R-MOAS) at V2, V6 and EOS visit (V10). The scale includes 4 domains (Verbal Incidents, Incidents Toward Other People, Incidents Involving Property, Incidents Directed Toward Self) each one describing different behaviours. Parents rate the frequency of 16 aggressive behaviors (referred to the past week) in the 4 areas. Numeric weighting amplifies the seriousness of more harmful behaviors in the total score. Higher score indicating more aggressive behavior. | an average of 15 weeks |
| Suicidal ideation/behaviour in subjects aged 6 years and older | Suicidal ideation/behaviour in subjects aged ≥ 6 years using the Columbia - Suicide Severity Rating Scale (C-SSRS) before IMP (screening V1), V6, EOS visit (V10) and end of taper visit (V11). The C-SSRS is divided into 2 sections: Suicidal Ideation and Suicidal Behaviour containing each one 5 "yes" or "no" questions. Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the CSSRS) present at the assessment. A score of 0 is assigned if no ideation is present. Composite endpoints are defined below: Suicidal ideation: A "yes" answer at any time during treatment to any one of the five suicidal ideation questions (Categories 1-5). Suicidal behavior: A "yes" answer at any time during treatment to any one of the five suicidal behavior questions (Categories 6-10). Suicidal ideation or behavior: A "yes" answer at any time during treatment to any one of the ten suicidal ideation and behavior questions (Categories 1-10) | an average of 16 weeks |
| Assessment of blinding | Assessment of blinding: guess of the subject's treatment group (by Investigator, parents and subject if at adequate maturity level) at V10. | at week 16 |
| Rotterdam |
| Netherlands |
| 30787078 | Derived | 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. |
| D002087 |
| Butyrates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D003511 | Cyclohexanols |
| D000441 | Hexanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D004123 | Dimethylamines |
| D008744 | Methylamines |
| D008055 | Lipids |