Clinical Trial Results:
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.
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Summary
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EudraCT number |
2014-004851-30 |
Trial protocol |
NL DE FR GR GB PL IT |
Global end of trial date |
18 Jun 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Jan 2020
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First version publication date |
04 Jan 2020
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Other versions |
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Summary report(s) |
GABA-1 Study Summary |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GABA-1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02722603 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
PHARM – Pharmaceutical Research Management srl
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Sponsor organisation address |
Via Einstein Loc. Cascina Codazza, Lodi, Italy, 26900
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Public contact |
Trial Management, PHARM – Pharmaceutical Research Management srl, 0039 3287919866, trialmanagement@pharmsrl.com
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Scientific contact |
Trial Management, PHARM – Pharmaceutical Research Management srl, 0039 3287919866, trialmanagement@pharmsrl.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001310-PIP01-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Sep 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Feb 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Jun 2019
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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
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Protection of trial subjects |
Study procedures were compliant with the Convention for the Protection of Individuals with regard to Automatic Processing of Personal Data (Strasbourg, 28.I.1981).
All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave the site have been identified only by the patient sequential number to maintain subject confidentiality.
During the trial, at each visit, all the assessments have been conducted with a constant attention to the minimisation of pain and distress to the patient.
In accordance with applicable country-specific regulatory requirements, the sponsor obtained the authorisation of the regulatory authority and the favourable opinion/approval of the concerned ethics committee to conduct the study prior to a site initiating the study in any country.
Information Sheet was provided and written consent was obtained from the legal guardian for each subject before participation in the study. Children took part in the information process under the responsibility of parents and the investigator according to their age
and maturity level.
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Background therapy |
None | ||
Evidence for comparator |
Tramadol, a weak opioid approved for smaller children throughout Europe, was used as comparator in GABA-1 study. Tramadol has demonstrated efficacy in adults with neuropathic pain and its effectiveness could be extrapolated in children. This approach was discussed within the Paediatric Committee of the EMA (PDCO) that validated the protocol and explicitly requested the inclusion of children from 3 months although recognizing that the diagnosis and treatment of neuropathic pain in this population is currently very empirical and tramadol is only authorized for patients from one year of age. | ||
Actual start date of recruitment |
31 May 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 2
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Worldwide total number of subjects |
2
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EEA total number of subjects |
2
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
2
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The recruitment started on May 2017 and finished on June 2019. 12 clinical centres were involved in 8 EU and non-EU Countries: Albania (1), France (4), Germany (1), Greece (1), Italy (2), Poland (1), The Netherlands (1), the United Kingdom (1). | |||||||||
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Pre-assignment
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Screening details |
The screening period, starting at Day 1 and following consent, was of maximum 7 days to allow for all screening results to be obtained and validated. A wash-out period (max 3 days) could be required if the patient was on an analgesic medication. | |||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
The protocol has been designed to ensure double-blind conditions at randomisation and throughout the treatment period. Blinding was ensured by elaborating identical (matching) placebos for both the investigational (gabapentin) and the comparator (tramadol) drug.
Gabapentin and placebo were indistinguishable in appearance. Also, labelling did not allow recognizing actual treatment. The same for Tramadol and placebo.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Gabapentin | |||||||||
Arm description |
Experimental arm in which patients were administered gabapentin + placebo_tramadol | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Gabapentin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
Route: oral, liquid formulation with unique concentration of 75mg/ml.
Mode of administration: administration of gabapentin oral solution (syrup) three times daily, directly via graduated syringes for oral use without any dilution.
Treatment was initiated at a starting dose in mg/kg/day and was titrated up until clinical response, according to a predefined matrix to a maximum dose in mg/kg/day.
Titration was flexibly optimised in order to maximise the potential benefits while minimising risk of adverse events. There were a maximum of 5 possible dose adjustments during the 3 weeks optimisation period.
Dosing for gabapentin were defined according to 2 weight groups. Dosing schedule for gabapentin is the following:
Day 1 - starting dose in mg/kg/day;
Day 3 - 2 times the starting dose in mg/kg/day;
Day 5 - 3 times the starting dose in mg/kg/day;
Day 14 - 2 times the dose of Day 5 in mg/kg/day;
Day 21 - 3 times the dose of Day 5 in mg/kg/day.
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Arm title
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Tramadol | |||||||||
Arm description |
Comparator arm in which patients were administered tramadol + placebo_gabapentin | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Tramadol
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral drops, solution
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Routes of administration |
Oral use
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Dosage and administration details |
Route: oral drops, solution with unique concentration of 100 mg/mL.
Mode of administration: administration of tramadol oral drops three times daily. The drops should be administered orally and be diluted with water before administration.
Treatment was initiated at a starting dose in mg/kg/day and was titrated up until clinical response according to a predefined matrix to a maximum dose in mg/kg/day. Titration was flexibly optimised in order to maximise the potential benefits while minimising risk of adverse events. There were a maximum of 5 possible dose adjustments during the 3 weeks optimisation period. Dosing of tramadol was performed according to the following dosing schedule:
Day 1 - starting dose = 1 mg/kg/day;
Day 3 - 2 mg/kg/day;
Day 5 - 3 mg/kg/day;
Day 14 - 5 mg/kg/day;
Day 21 - 8 mg/kg/day
The maximum dose of 400mg/day for tramadol is maintained.
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Baseline characteristics reporting groups
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Reporting group title |
Gabapentin
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Reporting group description |
Experimental arm in which patients were administered gabapentin + placebo_tramadol | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tramadol
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Reporting group description |
Comparator arm in which patients were administered tramadol + placebo_gabapentin | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Gabapentin
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Reporting group description |
Experimental arm in which patients were administered gabapentin + placebo_tramadol | ||
Reporting group title |
Tramadol
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Reporting group description |
Comparator arm in which patients were administered tramadol + placebo_gabapentin | ||
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End point title |
Average pain score [1] | ||||||||||||
End point description |
Average pain score at the end of the treatment period (average of two measures each day for 3 days before EOS visit, V10) as assessed by age-appropriate pain scales
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End point type |
Primary
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End point timeframe |
12th of September 2018 - 1st of February 2019
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the limited number of enrolled patients (2), only descriptive analyis have been performed |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
12th of September 2018 - 1st of February 2019
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
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Reporting groups
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Reporting group title |
Gabapentin
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Reporting group description |
Experimental arm in which patients were administered gabapentin + placebo_tramadol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tramadol
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Reporting group description |
Comparator arm in which patients were administered tramadol + placebo_gabapentin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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21 Jul 2017 |
Please find below a summary of the protocol substantial changes:
• the 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.
• One of the secondary endpoints has been modified in order to include, as responders, patients with an average pain score of 4/10 at baseline and an average pain score of 3/10 at the End Of Study;
• Another secondary endpoint has been changed in order to report the daily pain intensity score instead of the average pain.
• Three exclusion criteria have been added to avoid potential side effects due to the administration of the IMPs:
a) subjects with history of severe respiratory impairment;
b) subjects with history of substance abuse in particular opioids;
c) subjects with fructose intolerance, diabetes, glucose – galactose malabsorption or lactase - isomaltase deficiency.
• The exclusion criterion: subjects born prematurely, before 36th week of gestational age, if recruited during the first year of age, has been added to comply with the maximum level of blood volume to be collected in paediatric clinical study.
• The endpoint: extent of pain valuated in visit 1, 2 and 10 using the pain chart, has been added to help physician to localize the painful area.
• The suicide ideation/ behaviour assessment at the end of taper visit (v11) has been added for safety reason.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
