The primary objective of this study is to assess the efficacy of gabapentin as add-on to morphine for the treatment of severe chronic neuropathic or mixed pain in children from 3 months to less than 18 years of age. Secondary objectives 1. To assess…
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Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 scales (FLACC, FPS-R, NRS-11).
Secondary outcome
Secondary endpoints a) Percentage of responders to treatments, defined as
subjects with a 30% reduction from baseline in assessment scale (FLACC, FPS-R,
NRS-11). b) Average daily pain intensity assessed by age appropriate scale
during dose optimisation (FLACC, FPS-R or NRS-11). 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 >8 years of age using
the FPS-R pain scale at each visit. e) Number of episodes of breakthrough pain
(> 4/10 pain score and use of rescue medications) during treatment period. f)
Number of rescue interventions required during treatment period. g) Number of
pain-free (< 4/10 average pain score without the use of rescue medications)
days during treatment period. h) Number of participant dropouts due to lack of
efficacy. i) The total cumulative weight normalized dose of each rescue drug.
j) 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). k) Acceptability of treatment
(Five-Point Facial Hedonic scale) at EOS visit (V10). l) Global satisfaction
with treatment (NRS-11, by parent, patient) at EOS visit (V10). m) 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. n) Patient/parent Global
Impression of Change (PGIC; by parent, patient) at V6 and at EOS visit (V10).
o) Primary (CL/F, Vd/F, Ka) and secondary (AUC, Cmax, Tmax, Css and Cmin)
pharmacokinetic parameters for gabapentin and tramadol. p) Systemic exposure to
investigational products during maintenance period, as assessed by predicted
steady-state concentrations. q) Incidence of Adverse Events at all visits. r)
Percentage of subjects discontinuing the trial due to treatment-emergent
adverse events. s) Aggressive behaviour in children aged >6 years using the
Retrospective-Modified Overt Aggression Scale (R-MOAS) at V2, V6 and EOS visit
(V10). t) 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). u) Assessment of blinding: guess
of the subject*s treatment group (by Investigator, parents and subject if at
adequate maturity level) at V10. Exploratory endpoints v) Metabolomic profile
at screening (V1) and at EOS visit (V10), and in responders and non-responders.
w) PK or PD outcomes based on genetic variation.
Background summary
Gabapentin has been successfully used to treat neuropathic pain in adults and
has been used offlabel to treat children with the same condition. However, the
paediatric use of gabapentin in children is hampered by two main factors: 1.
The lack of a suitable oral formulation 2. The significant variability of
gabapentin PK profile demonstrated in children less than 4 years of age leading
to a variable drug plasma concentration. These differences should be taken into
account to define a safe/efficacious dosing regimen in younger children.
Study objective
The primary objective of this study is to assess the efficacy of gabapentin as
add-on to morphine for the treatment of severe chronic neuropathic or mixed
pain in children from 3 months to less than 18 years of age. Secondary
objectives 1. To assess effect of gabapentin as a add-on to morphine on quality
of life (physical, emotional, social and school functioning) and global
satisfaction with treatment. 2. To assess safety of gabapentin as a add-on to
morphine for treatment of chronic neuropathic or mixed pain in children 3
months to less than 18 years of age. 3. To characterize 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.
Study design
Randomized, double-blind, placebo controlled, multi-centre superiority phase II
study to evaluate the safety, pharmacokinetic, efficacy of gabapentin liquid
formulation as add-on to morphine in children from 3 months to less than 18
years of age experiencing severe chronic neuropathic or mixed pain.
Intervention
IMP test: Gabapentin oral solution (syrup). IMP comparator: Gabapentin placebo
oral solution
Study burden and risks
Risks and burden of participation in the study are related to possible:
1. During the washout period of the medication, before starting the IMP,
the child could experience a period of increase in pain, due to stopping of
their usual pain medication. However, the child will be included in the study,
because the current treatment of the pain is already ineffective. Therefore it
is our opinion that this washout period (and possible short period of increase
in pain) can be justified. Also it is our expectation that the increase in pain
will be limited in this washout period, as the treatment of the pain was
already ineffective. Children who have an effective treatment of their pain
(pain score < 4) are not eligible for inclusion in the study.
2. The risk during the study is that the installed study medication is also
insufficient and the patient remains in significant pain or that the patient
experiences adverse events of the medication, despite slowly up titrating the
dose to prevent side effects. The burden during the study consists of a number
of hospital visits and telephone calls, as well repeated pain scores, other
scores and questionnaires that need to be completed. Also, limited blood
sampling may be burdensome
3. The benefits of the study are that patients may receive treatment that
reduces their pain and (group benefit) that we know better how to treat this
pain for future patients.
Overall, considering the very large burden of untreated severe chronic pain
with a substantial impact on a child*s daily life leading to absence at school,
decreased quality of life, decreased physical exercise, depression and anxiety
and social isolation, we believe that the benefit for both individual patients
in the study and future patients (expected reduction in pain) strongly
outweighs the risks and burdens of the study with short period of possible
increased pain, risk of adverse events (but drug will be decreased when adverse
events will be not tolerable), and the visits/questionnaire time/limited blood
samples.
Via Einstein-Loc Cascina Codazza 2
Lodi 26900
IT
Via Einstein-Loc Cascina Codazza 2
Lodi 26900
IT
Listed location countries
Age
Inclusion criteria
1. 3 months-< 18 years
2. Informed consent
3. Meet diagnostic criteria for chronic neuropathic or mixed pain
4. Severe pain as defined as an average pain score of >= 7/10
5. Stabel underlying disease condition and treatment
6. Patients with chemotherapy induced neuropathic pain: clinical remission or maintenance phase of treatment protocol
Exclusion criteria
1. Pain duration of more than 5 years
2. Current use of gabapentin or strong opoids
3. History of failure to respond to adequate treatment by gabapentin or opioids for neuropathic pain. 4. History of epileptic condition except febrile seizure disorder.
5. Subjects with diagnosis of sickle cell disease.
6. Subjects that present significant cognitive impairment.
7. 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.
8. Subjects with history of or current suicidal ideation or behaviour.
9. Subjects with a history of substance abuse in particular opoids
10. Subjects under prohibited concomitant medication (refer to specific protocol section 5.6.3.1 *Prohibited medications*).
11. 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.
12. Subjects old with a body mass index (BMI) for age and gender of < 5th percentile or > 95th percentile (charts provided as Appendix 5).
13. Subjects with glomerular filtration rate < 90 mL/min/1.73 m2 (Schwarz equation).
14. Subjects with significant hepatic impairment with Aspartate Transaminase (AST) and Alanine Transaminase (ALT) enzymes 3 times the upper limit of the age-specific reference range.
15. Subjects with known allergy, hypersensitivity or clinically significant intolerance to gabapentin or any component found in the study drugs.
16. Subjects with clinically relevant abnormal ECG at the screening visit in the discretion of the investigator/cardiologist.
17. Subjects participating in another clinical interventional trial.
18. Subjects scheduled for surgery or in recovery from surgery occurring within 3 months of baseline assessment.
19. Female subjects who are pregnant or currently lactating.
20. Subjects that failed screening or was previously enrolled in this study.
21. Subjects with fructose intolerance, diabetes, glucose-galactose malabsorption or lactase-isomaltase deficiency.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004897-40-NL |
| CCMO | NL61386.078.17 |