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Efficacy and Safety Study of Gabapentin as add-on to Morphine in Paediatric Patients Affected by Chronic Pain (GABA-2)

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ClinicalTrials.gov Identifier: NCT03275012
Recruitment Status : Not yet recruiting
First Posted : September 7, 2017
Last Update Posted : July 10, 2018
Sponsor:
Collaborator:
European Commission
Information provided by (Responsible Party):
Pharmaceutical Research Management srl

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.

Condition or disease Intervention/treatment Phase
Chronic Pain Drug: Gabapentin + Morphine Drug: Placebo + Morphine Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Chronic Pain

Arm Intervention/treatment
Experimental: Group 1
Gabapentin + Morphine
Drug: Gabapentin + Morphine

Gabapentin: liquid oral formulation (syrup) - 75 mg/ml-three times daily. The starting dose during the optimization period will be defined according to 2 weight groups (5-15kg and >15kg). Dose will be scaled at Day 1,3,5,14,and 21 according to a specific schedule. Maintenance dosing will be scheduled in accordance to the body weight.

Morphine: background therapy as oral, liquid and solid formulations. Patients with BW≤30kg :liquid oral formulation four times daily throughout the whole treatment period. Patients with BM>30kg : immediate release solid and/or liquid oral formulation four times daily during titration phase and an extended release solid oral formulation twice daily during the maintenance period.


Placebo Comparator: Group 2
Placebo + Morphine
Drug: Placebo + Morphine
Placebo liquid oral formulation. Morphine: background therapy as oral, liquid and solid formulations. Patients with BW≤30kg :liquid oral formulation four times daily throughout the whole treatment period. Patients with BM>30kg : immediate release solid and/or liquid oral formulation four times daily during titration phase and an extended release solid oral formulation twice daily during the maintenance period.




Primary Outcome Measures :
  1. Pain scores [ Time Frame: on average of 16 weeks ]

    Pain scores in the two treatment groups assessed at baseline and at the end of the treatment by age-appropriate pain scales. FLACC (the Faces, Legs, Arms, Cry and Consolability - pts aged 3-24 months) scale 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 scale (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



Secondary Outcome Measures :
  1. Percentage of responders to treatments [ Time Frame: on average of 16 weeks ]

    Percentage of responders to treatments, defined as subjects with a pain intensity reduction of 30% from baseline. Pain intensity is evaluated using age-appropriate pain scale (FLACC, FPS-R, NRS-11).

    the FLACC (the Faces, Legs, Arms, Cry and Consolability- pts aged 3-24-months) 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.


  2. Daily pain intensity [ Time Frame: an average of 3 weeks ]

    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- pts aged 3-24-months) 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.


  3. Observational assessment of pain [ Time Frame: on average of 16 weeks ]

    Observational assessment of pain using the NRS-11 completed by parents and Investigator (or caregiver) at each visit.

    NRS-11 (Numerical Rating Scale): numerical rating scale where 0=no pain and 10=worst possible pain.


  4. Self-assessment of pain for children ≥8 years of age [ Time Frame: on average of 16 weeks ]

    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.


  5. Extent of pain [ Time Frame: on average of 16 weeks ]

    Extent of pain evaluated as the 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.


  6. Number of episodes of breakthrough pain [ Time Frame: on average of 15 weeks ]
    Number of episodes of breakthrough pain (>7/10 pain score and use of rescue medications) during treatment period

  7. Number of rescue interventions required during treatment period [ Time Frame: on average of 15 weeks ]
    Number of rescue interventions required during treatment period.

  8. Number of pain-free days [ Time Frame: on average of 15 weeks ]
    Number of pain-free days (<4/10 average pain score without the use of rescue medications) during treatment period

  9. Participant dropouts [ Time Frame: up to 21 weeks ]
    Participant dropouts due to lack of adequate pain response.

  10. The total cumulative weight normalized dose of each rescue drug. [ Time Frame: on average of 16 weeks ]
    The total cumulative weight normalized dose of each rescue drug.

  11. Total Summary Score from PedsQL™ scale [ Time Frame: on average of 15 weeks ]

    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)


  12. Physical Health Summary Score from PedsQL™ scale [ Time Frame: on average of 15 weeks ]

    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).


  13. Psychosocial Health Summary Score from PedsQL™ scale [ Time Frame: on average of 15 weeks ]

    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).


  14. Acceptability of treatment [ Time Frame: at week 16 ]

    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).


  15. Global satisfaction with treatment [ Time Frame: at week 16 ]

    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


  16. Clinical Global Impression of Severity of the subject's condition [ Time Frame: an average of 15 weeks ]

    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.


  17. Clinical Global Impression of Improvement for pain [ Time Frame: an average of 15 weeks ]

    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.


  18. Patient/parent Global Impression of Change [ Time Frame: an average of 12 weeks ]

    Patient/parent Global Impression of Change (PGIC; by parent, patient) at V6 and 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.


  19. CL/F [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Primary pharmacokinetic parameters for gabapentin: 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)

  20. Vd/F [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Primary pharmacokinetic parameter for gabapentin: 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)

  21. ka [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Primary pharmacokinetic parameter for gabapentin: 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)

  22. AUC [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Secondary pharmacokinetic parameter for gabapentin: 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)

  23. Cmax [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Secondary pharmacokinetic parameter for gabapentin: 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)

  24. Tmax [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Secondary pharmacokinetic parameter for gabapentin: 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)

  25. Css [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Secondary pharmacokinetic parameter for gabapentin: 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)

  26. Cmin [ Time Frame: at week 3 or at week 4 or at week 16 ]
    Secondary pharmacokinetic parameter for gabapentin: 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)

  27. Systemic exposure to investigational product [ Time Frame: an average of 12 weeks ]
    Systemic exposure to investigational product during maintenance period, as assessed by predicted steady-state concentrations.

  28. Incidence of Adverse Events [ Time Frame: up to 21 weeks ]
    Incidence of Adverse Events at all visits

  29. Percentage of subjects discontinuing the Trial [ Time Frame: up to 21 weeks ]
    Percentage of subjects discontinuing the Trial due to treatment-emergent adverse events

  30. Aggressive behaviour in children aged >6 years [ Time Frame: an average of 15 weeks ]

    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.


  31. Suicidal ideation/behaviour in subjects aged 6 years and older [ Time Frame: an average of 16 weeks ]

    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).

    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)


  32. Assessment of blinding [ Time Frame: at week 16 ]
    Assessment of blinding: guess of the subject's treatment group (by Investigator, parents and subject if at adequate maturity level) at V10.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   3 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03275012


Contacts
Contact: Donato Bonifazi, Dr +393287919866 donatobonifazi@pharmsrl.com

Locations
Albania
Qendra Spitalore Universitare Nene Tereza Not yet recruiting
Tirana, Albania
France
Centre Hospitalier Regional Universitaire de Lille
Lille, France
Assistance Publique-Hopitaux de Marseille
Marseille, France
Assistance Publique Hopitaux De Paris - Hopital Necker de Paris
Paris, France
Hopital Robert Debré Assistance Publique-Hopitaux de Paris Not yet recruiting
Paris, France
Germany
Universitaetsklinikum Erlangen Department of Paediatrics and Adolescent Medicine Not yet recruiting
Erlangen, Germany
Greece
Geniko Nosokomeio Paidon I Agia Sofia Not yet recruiting
Athens, Greece
Italy
Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
Bari, Italy
Istituto Giannina Gaslini Not yet recruiting
Genova, Italy
Azienda Ospedaliera di Padova Withdrawn
Padova, Italy
Netherlands
Erasmus Unversitair Medisch Centrum Rotterdam Not yet recruiting
Rotterdam, Netherlands
University Medical Center Utrecht, Wilhelmina Kinderziekenhuis
Utrecht, Netherlands
Sponsors and Collaborators
Pharmaceutical Research Management srl
European Commission
Investigators
Principal Investigator: Saskia De Wildt, MD-PhD Erasmus Medical Center

Additional Information:
Publications:
Responsible Party: Pharmaceutical Research Management srl
ClinicalTrials.gov Identifier: NCT03275012     History of Changes
Other Study ID Numbers: 2014-004897-40
First Posted: September 7, 2017    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Chronic Pain
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Morphine
Gabapentin
gamma-Aminobutyric Acid
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anticonvulsants
Antiparkinson Agents
Anti-Dyskinesia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Antimanic Agents
GABA Agents