Ignite Creation Date:
2024-05-06 @ 10:30 AM
Last Modification Date:
2024-10-26 @ 12:31 PM
Study NCT ID:
NCT03275012
Status:
WITHDRAWN
Last Update Posted:
2019-12-02
First Post:
2017-08-30
Brief Title:
Efficacy and Safety Study of Gabapentin as add-on to Morphine in Paediatric Patients Affected by Chronic Pain
Sponsor:
Pharmaceutical Research Management srl
Organization:
Pharmaceutical Research Management srl
Study Overview
Official Title:
Randomized Double-blind Placebo Controlled Superiority Phase II Study to Evaluate the Safety Pharmacokinetic Efficacy of Gabapentin as add-on to Morphine in Children From 3 Months to Less Than 18 Years
Status:
WITHDRAWN
Status Verified Date:
2019-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Study not started
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GABA-2
Brief Summary:
The objective of the study is to evaluate the efficacy of gabapentin as adjunctive therapy to morphine in the treatment of 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
Detailed Description:
This paediatric trial has the objective to make gabapentin available for children with severe chronic neuropathic or mixed pain This study will be conducted in full conformance with the ethical principles outlined in the Declaration of Helsinki consistent with ICH-GCP including ICH Topic E11 guideline and applicable regulatory requirements including the Paediatric Recommendations CE2008
Gabapentin has been successfully used to treat neuropathic pain in adults In 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 PK profile and c efficacy and safety data in this specific population
GABA-2 is a superiority trial designed to assess the potential benefit of gabapentin oral solution in augmenting the analgesic effect of morphine in children affected by severe chronic pain thus preventing or decreasing opioid tolerance as it has been reported to happen in adults Thus GABA-2 study is an randomized double blind placebo controlled multi-centre study to evaluate the efficacy of gabapentin added to morphine in paediatric patients suffering from severe chronic pain neuropathic or mixed with ascertained neuropathic component The trial will include 66 patients aged from 3 months to less than 18 years affected by severe chronic neuropathic or mixed pain and in need of morphine
Children from 3 months to 3 years of age will participate to GABA-2 on the basis of the nature of the underlying disease suggestive of a neuropathic component
A block randomisation will be applied to assign children to gabapentin and morphine intervention group or gabapentin placebo and morphine control group in a 11 ratio
Randomisation will be stratified by age-group as follows
3 months - 3 years
3 years - 8 years
8 years - 18 years
Recruitment will start with patients 3 years of age Patients than 3 years of age will be recruited when results from the ongoing non-clinical toxicological study in juvenile rats will confirm the safety of gabapentin in the age subset 3 months-3 years
The protocol has been designed to ensure double-blind conditions at randomisation and throughout the treatment period Blinding children caregiver outcome assessor will be ensured by elaborating an identical matching gabapentin placebo
The study comprises 3 stages over 18 to 22 weeks 1st stage screening period of 1 week wash out phase of max 3 days and baseline assessment of 3 days 2nd stage treatment period including an optimization phase of 3 weeks and 12 weeks of maintenance 3rd stage study taper lasting from 0 to 4 weeks and 1 week follow up
The proposed formulation of the IMP test is a liquid oral formulation syrup containing 75 mgml of gabapentin The IMP comparator is the placebo The background therapy is morphine presented as immediate and extended-release tablets and a liquid oral formulation Every participant will be administered morphine and the active product or placebo
For both study drugs dosing will initiate at a starting dose in mgkgday and will be increased according to a predefined matrix to a maximum dose in mgkgday Dosing will be flexibly optimised in order to maximise the potential benefits while minimising risk of AEs There will be a maximum of 5 possible dose adjustments during the 3 weeks optimisation period
Dosing for gabapentin during the optimization period will be defined according to two weight groups 5-15kg and 15kg Current dosing schedule for gabapentin is the following
Day 1 starting dose in mgkgday
Day 3 2 times the starting dose in mgkgday
Day 5 3 times the starting dose in mgkgday
Day 14 2 times the dose of Day 5 in mgkgday
Day 21 3 times the dose of Day 5 in mgkgday
Dosing of morphine is largely based on the WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses 2012 The guidelines recommended starting dose for immediate release formulation of morphine are 80-200 mcgkg every 4 hours for infants and 200-500 mcgkg in 6 divided doses in older children However due to compliance issues a four times daily regimen qid will be used during the titration phase of this protocol for children with body weight 30kg and throughout this study for patients with 30kg body weight
The morphine starting dose in this study reflects the lower end of the WHO recommendation with a titration scheduled to reach a maximum daily dose of 12 mgkgday Patients 30kg BW will have the liquid morphine formulation 4 times daily throughout the study and patients 30kg will receive immediate release tablet 4 times daily during the titration phase and extended release tablets 2 times daily during the maintenance phase
All subjects that are completing the study or are withdrawn early must be tapered off of the gabapentin At the visit of Early Termination or End Of Study visit subjects will be dispensed a taper dose based on their current dose level the dose of the medicinal product taken during the maintenance period and should follow the dose tapering as described in the protocol
Concomitant use of some medications that could interfere with the study will be prohibited Unrestricted use of paracetamol andor ibuprofen alone or in combination will be used as rescue therapy any time the patient experiences pain pain level 410 measured with age- appropriate pain scales FLACC FPS-R or NRS-11 This study includes pharmacokinetic analysis to establish a population pharmacokinetic model adequate to describe the time-course and variability of plasma concentrations of gabapentin and gabapentin plus morphine following repeat dosing in children with chronic pain
The study includes also an optional exploratory pharmacogenomics study which requires a separate Informed Consent if the parent of the subject agrees to participate The aims of the exploratory pharmacogenomic research is to better understand inherited genetic factors and their association with clinical assessments which may include pharmacokinetics of gabapentin relative susceptibility to drug-drug interactions predisposition to side effects andor patients response to treatment with gabapentin
The study foresees also an exploratory metabolomic study that may provide insight in the mechanism of neuropathic pain and the inter-individual variation in drug response
During this study it is expected that a maximum of 159 mL of blood will be taken from every subject male and female Additional 20 ml of blood will be required from females of child bearing age for pregnancy testing
The primary analysis of efficacy will be conducted using ANCOVA with baseline average pain score as a covariate
The study will be conducted under the supervision of an independent Data Safety Monitoring Committee DSMC
Gabapentin has been successfully used to treat neuropathic pain in adults In 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 PK profile and c efficacy and safety data in this specific population
GABA-2 is a superiority trial designed to assess the potential benefit of gabapentin oral solution in augmenting the analgesic effect of morphine in children affected by severe chronic pain thus preventing or decreasing opioid tolerance as it has been reported to happen in adults Thus GABA-2 study is an randomized double blind placebo controlled multi-centre study to evaluate the efficacy of gabapentin added to morphine in paediatric patients suffering from severe chronic pain neuropathic or mixed with ascertained neuropathic component The trial will include 66 patients aged from 3 months to less than 18 years affected by severe chronic neuropathic or mixed pain and in need of morphine
Children from 3 months to 3 years of age will participate to GABA-2 on the basis of the nature of the underlying disease suggestive of a neuropathic component
A block randomisation will be applied to assign children to gabapentin and morphine intervention group or gabapentin placebo and morphine control group in a 11 ratio
Randomisation will be stratified by age-group as follows
3 months - 3 years
3 years - 8 years
8 years - 18 years
Recruitment will start with patients 3 years of age Patients than 3 years of age will be recruited when results from the ongoing non-clinical toxicological study in juvenile rats will confirm the safety of gabapentin in the age subset 3 months-3 years
The protocol has been designed to ensure double-blind conditions at randomisation and throughout the treatment period Blinding children caregiver outcome assessor will be ensured by elaborating an identical matching gabapentin placebo
The study comprises 3 stages over 18 to 22 weeks 1st stage screening period of 1 week wash out phase of max 3 days and baseline assessment of 3 days 2nd stage treatment period including an optimization phase of 3 weeks and 12 weeks of maintenance 3rd stage study taper lasting from 0 to 4 weeks and 1 week follow up
The proposed formulation of the IMP test is a liquid oral formulation syrup containing 75 mgml of gabapentin The IMP comparator is the placebo The background therapy is morphine presented as immediate and extended-release tablets and a liquid oral formulation Every participant will be administered morphine and the active product or placebo
For both study drugs dosing will initiate at a starting dose in mgkgday and will be increased according to a predefined matrix to a maximum dose in mgkgday Dosing will be flexibly optimised in order to maximise the potential benefits while minimising risk of AEs There will be a maximum of 5 possible dose adjustments during the 3 weeks optimisation period
Dosing for gabapentin during the optimization period will be defined according to two weight groups 5-15kg and 15kg Current dosing schedule for gabapentin is the following
Day 1 starting dose in mgkgday
Day 3 2 times the starting dose in mgkgday
Day 5 3 times the starting dose in mgkgday
Day 14 2 times the dose of Day 5 in mgkgday
Day 21 3 times the dose of Day 5 in mgkgday
Dosing of morphine is largely based on the WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses 2012 The guidelines recommended starting dose for immediate release formulation of morphine are 80-200 mcgkg every 4 hours for infants and 200-500 mcgkg in 6 divided doses in older children However due to compliance issues a four times daily regimen qid will be used during the titration phase of this protocol for children with body weight 30kg and throughout this study for patients with 30kg body weight
The morphine starting dose in this study reflects the lower end of the WHO recommendation with a titration scheduled to reach a maximum daily dose of 12 mgkgday Patients 30kg BW will have the liquid morphine formulation 4 times daily throughout the study and patients 30kg will receive immediate release tablet 4 times daily during the titration phase and extended release tablets 2 times daily during the maintenance phase
All subjects that are completing the study or are withdrawn early must be tapered off of the gabapentin At the visit of Early Termination or End Of Study visit subjects will be dispensed a taper dose based on their current dose level the dose of the medicinal product taken during the maintenance period and should follow the dose tapering as described in the protocol
Concomitant use of some medications that could interfere with the study will be prohibited Unrestricted use of paracetamol andor ibuprofen alone or in combination will be used as rescue therapy any time the patient experiences pain pain level 410 measured with age- appropriate pain scales FLACC FPS-R or NRS-11 This study includes pharmacokinetic analysis to establish a population pharmacokinetic model adequate to describe the time-course and variability of plasma concentrations of gabapentin and gabapentin plus morphine following repeat dosing in children with chronic pain
The study includes also an optional exploratory pharmacogenomics study which requires a separate Informed Consent if the parent of the subject agrees to participate The aims of the exploratory pharmacogenomic research is to better understand inherited genetic factors and their association with clinical assessments which may include pharmacokinetics of gabapentin relative susceptibility to drug-drug interactions predisposition to side effects andor patients response to treatment with gabapentin
The study foresees also an exploratory metabolomic study that may provide insight in the mechanism of neuropathic pain and the inter-individual variation in drug response
During this study it is expected that a maximum of 159 mL of blood will be taken from every subject male and female Additional 20 ml of blood will be required from females of child bearing age for pregnancy testing
The primary analysis of efficacy will be conducted using ANCOVA with baseline average pain score as a covariate
The study will be conducted under the supervision of an independent Data Safety Monitoring Committee DSMC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None