| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Chronic pain of neuropathic or mixed origin | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10054095 | | E.1.2 | Term | Neuropathic pain | | E.1.2 | System Organ Class | 100000004852 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | 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. | |
| E.2.2 | Secondary objectives of the trial | 1.To assess the effect of gabapentin as adjunctive therapy to morphine compared to morphine alone on quality of life (physical, emotional, social and school functioning) and global satisfaction with treatment.
2.To assess the safety of gabapentin combined with morphine compared to morphine alone in the treatment of severe neuropathic or mixed pain in children from 3 months to less than 18 years of age.
3.To characterise the population pharmacokinetic-pharmacodynamic (PKPD) relationship of gabapentin liquid formulation with and without morphine and provide confirmation of the recommended paediatric dose.
Additional exploratory objectives of the study are:
4.To explore the metabolomic profile of drug treatments.
5.To explore genetic polymorphisms and their impact on pharmacokinetics (PK) and pharmacodynamics (PD).
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Male or female, aged 3 months to less than 18 years at screening (V1)
2.Informed consent by parent(s) and/or legal guardian according to each country legal requirement.
3.Assent, where applicable, according to each country legal requirement.Informed (co-) consent of child, 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.
6.Subject that present with severe pain as defined by average pain intensity of ≥7 /10 as assessed during a 3-day screening period
7.Stable underlying disease condition and treatment.
8.Patients with Chemotherapy Induced Peripheral Neuropathy, when in clinical remission or maintenance phase of their therapeutic protocol.
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| E.4 | Principal exclusion criteria | 1.Pain duration of more than 5 years.
2.Current use of gabapentin.
3.Current use of strong opioids (morphine, methadone, fentanyl, ketamine, oxycodone).
4.History of failure to respond to adequate treatment by gabapentin or opioids for neuropathic pain.
5.History of epileptic condition (except febrile seizure disorder).
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 or current suicidal ideation or behaviour.
10.Subjects with history of substance abuse in particular opioids.
11.Subjects under prohibited concomitant medication .
12.Subjects with a body mass index (BMI) for age and gender of < 5th percentile or > 95th percentile (charts provided as Appendix 3).
13.Subjects with significant renal impairment, i.e., glomerular filtration rate < 90 mL/min/1.73 m2 (Revised Schwarz equation).
14.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.
15.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.
16.Subjects with clinically relevant abnormal ECG at the screening visit in the discretion of the Investigator/cardiologist.
17.Subjects with known allergy, hypersensibility or clinically significant intolerance to gabapentin or any component found in the study drugs.
18.Subjects with fructose intolerance, diabetes, glucose-galactose malabsorption or lactase-isomaltase deficiency.
19.Subjects participating in another clinical interventional trial.
20.Subjects scheduled for surgery or in recovery from surgery occurring within 3 months of baseline assessment.
21.Female subjects who are pregnant or currently lactating.
22.Subjects that failed screening or were previously enrolled in this study
23.Patients with Chemotherapy Induced Peripheral Neuropathy, when in induction phase of their therapeutic protocol | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Average pain scores in the two treatment groups (average of 2 measures each day for 3 days before end of study visit V10) assessed by age-appropriate pain scales (FLACC. FPS-R, NRS-11). | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | 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 (FLACC, FPS-R or NRS-11) during dose optimization.
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) Extent of pain evaluated as the number of painful areas using the pain charts at screening visit (V1), randomisation (v2) and EOS visit (V10).
f) Number of episodes of breakthrough pain (>7/10 pain score and use of rescue medications) during treatment period.
g) Number of rescue interventions required during treatment period.
h) Number of pain-free days (<4/10 average pain score without the use of rescue medications) during treatment period.
i) Participant dropouts due to lack of adequate pain response.
j) The total cumulative weight normalized dose of each rescue drug.
k) 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).
l) Acceptability of treatment (Five Point Facial Hedonic Scale) at EOS visit (V10).
m) Global satisfaction with treatment (NRS-11, by parent, patient) at EOS visit (V10).
n) Clinical Global Impression of Change (CGI-S, CGI-I; by Investigator) at randomization (V2) for CGI-S and V6 and EOS visit (V10) for CGI-I.
o) Patient/parent Global Impression of Change (PGIC; by parent, patient) at V6 and EOS visit (V10).
p) Primary (CL/F, Vd/F, Ka) and secondary (AUC, Cmax, Tmax, Css and Cmin) pharmacokinetic parameters for gabapentin.
q) Systemic exposure to investigational product during maintenance period, as assessed by predicted steady-state concentrations.
r) Incidence of Adverse Events at all visits.
s) Percentage of subjects discontinuing the Trial due to treatment-emergent adverse events.
t) Aggressive behaviour in children aged >6 years using the Retrospective Modified Overt Aggression Scale (R-MOAS) at V2, V6 and EOS visit (V10).
u) 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, EOS visit (V10) and taper visit (V11).
v) Assessment of blinding: guess of the subject’s treatment group (by Investigator, parents and subject if at adequate maturity level) at V10.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point | a) Baseline, end of study
b) Daily during dose optimisation
c) Monthly
d) Monthly
e) Daily during treatment period
f) Daily during treatment period.
g) Daily during treatment period.
h) Daily during treatment period
i) End of study
j) End of study
k) Randomisation, end of study
l) End of study
m) End of study
n) Randomisation, end of optimisation phase, end of study
o) End of optimisation phase, end of study
p) Sparse sampling during study or end of study
q) Sparse sampling during study or end of study
r) Monthly
s) End of study
t) Randomisation, end of optimisation phase, end of study
u) Screening, End of optimisation phase, end of study, end of taper
v) End of study | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
