The article “Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years – evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial.” has been recently published on behalf of GAPP Consortium.

Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose.

Here you can find the link to the publication.

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The article “Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: the GABA-1 trial-a study protocol.” has been recently published on behalf of GAPP Consortium.

Gabapentin is currently used “off-label” in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking. The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population. The trial is a multicentre, double-blind, double-dummy, randomised, active- controlled, non-inferiority trial. Participants aged from 3 months to <18 years of age with moderate to severe (≥4/10 in age-appropriate pain scales) chronic neuropathic or mixed pain will be recruited in 14 clinical sites in eight European countries. A total of 94 subjects will be randomised to receive gabapentin and tramadol placebo or tramadol and gabapentin placebo throughout 16-19 weeks (including 3 weeks of titration [optimisation period], 12 weeks of treatment at a stable dose [maintenance period] and 1-4 weeks of tapering [discontinuation period]). The primary objective is to assess the efficacy of gabapentin relative to tramadol for the treatment of moderate to severe chronic neuropathic or mixed pain by comparing the difference in average pain scores (assessed by age- appropriate pain scales) between intervention arms after 15 weeks of treatment. Secondary objectives include the assessment of the safety, quality of life and global satisfaction with treatment and the description of the pharmacokinetic- pharmacodynamic relationship of gabapentin liquid formulation and tramadol oral drops to validate the recommended paediatric doses. Only rescue pain medication by paracetamol and/or ibuprofen is allowed during the trial. Ethic approval was obtained in the eight participating countries. Results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.

Here you can find the link to the publication.

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• regulatory status – agreements – sites activation – readiness to patients’ enrolment;
• actual patients’ enrolment status among the active investigational sites and identified issues;
• nonclinical safety study;
• suggestions for clinical staff.

You can donwnload the Newsletter here.

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The review assessed the characteristics and quality of randomized controlled trials (RCTs) evaluating the use of pharmacological or non-pharmacological interventions in children and adolescents (3 months-18 years) with pain persisting or re-occurring for more than 3 months.

A total of 58 RCTs were identified through a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. Median sample size was 47.5 participants and the 45% of RCTs included both adults and children. The median of the mean ages at inclusion was 12.9 years and the majority of the RCTs selected focused on the evaluation of non-pharmacological interventions in children with headache – migraine or abdominal pain and none involved children of <2 years of age.

Clinical trials to evaluate intervention to treat chronic pain are difficult to design, conduct and interpret even in adult practice considering the absence of diagnostic tools and the difficulties in classifying chronic pain. However, as stated by the authors, paediatric pain research has to face additional challenges such as the small number of children and adolescents presenting certain types of chronic pain and the difficulties in the choice of an adequate comparator to test therapeutic interventions since placebo-controlled trials (the gold standard for drug testing) are not ethically acceptable in many of these situations. Moreover, recruitment and retention difficulties represent other challenges observed in the RCTs analysed.

For all these reasons, pharmacological intervention in chronic paediatric pain remains empirical and mainly based on extrapolation of therapeutic options from adults. To tackle the challenges highlighted, the authors suggested three possible ways. Firstly, they underlined the need to develop appropriate diagnostic tools to properly identifying ongoing painful conditions in children and adolescents. Moreover, they suggested to evaluate, behind pain intensity, also the quality of life or satisfaction with treatment to better evaluate benefits of the promising therapies. Finally, they underlined that there is an urgent requirement of innovative methodologies in this specific field that could be addressed within international expert initiatives.

Here you can find the link to the publication.

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The meeting will be focused on a general update of the project activities, the progresses and achievements and the planning of future steps. In particular, the GABA-1 e GABA-2 protocol procedures will be presented in order to prepare the ground for the starting of the recruitment phase.

More details on the event and the scientific program is available here.

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In Germany, we have received the positive opinion both from the Ethics Committee and the Competent Authority. The latter requested further clarifications about the level of the impurity A, a degradation product of gabapentin. Together with the German Competent Authority, it has been decided to start with the recruitment of patients above 3 years of age while waiting for the results of the toxicological tests in animal study. If the results of the animal study (or toxicological tests) will be favourable in terms of safety, children below 3 years of age will be recruited.

Following the approach adopted in Germany, we decided to start with the recruitment of patients above 3 years of age in all of the 5 countries already authorized (the Netherlands, France, Greece, Germany and Italy). To this aim, the first Site Initiation Visits (SIVs) in Athens (May 19^th), Rotterdam (May 22^nd) and Paris (June 14^th) has been organised following the correct reception of the IMPs at the sites.

The recruitment of the first patient is expected in June.

The GABA-1 study has been submitted in Serbia and received the positive opinion from the Local Ethics Committee of Belgrade and will be submitted to the Serbian Competent Authority.

Furthermore, submission in Albania is underway and the study protocol will be submitted in UK, Poland and Ukraine.

According to the protocol, 94 patients will be enrolled in the study.

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The Clinical Trial Authorisation has already been obtained in France by the Competent Authority, Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) and we are waiting for the approval of the Ethics Committee.

We are confident that the study will be quickly approved also in the other participating countries, according to the VHP procedure!

Another great result has been achieved!

The study aims to assess the efficacy of gabapentin combined with morphine compared to morphine alone and the drug exposure using sparse sampling techniques in children with severe chronic neuropathic or mixed pain persisting for at least 3 months.

According to the protocol, 66 patients will be enrolled in the study.

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TransCelerate BioPharma Inc. is a non-profit organization dedicated to improving the health of people around the world by accelerating and simplifying the research and development (R&D) of innovative new therapies. Consorzio per Valutazioni Biologiche is recognised as an accredited training provider at international level with the GAPP “ICH-Good Clinical Practice (GCP) Training Course”.

Donato Bonifazi, Chief Executive Officer at CVBF commented at this recognition: “We are pleased that the TransCelerate member companies recognise that our ICH-GCP training course reflects their best practices for training. The course is based on the international E6 ICH Good Clinical Practice (R2) and is aimed at providing a guide for all individuals that are involved in clinical research and clinical trials and they need to acquire GCP knowledge. In this way, the participant will be aware of his/her role and responsibilities and will understand how GCP can be applied practically in the research setting“.

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This is the assumption at the basis of development of the GAPP age-tailored information materials for clinical trials in children and young people that have been developed in a collaborative effort among pharmacologists, pediatricians, child psychologists and illustrators and already translated into seven languages: Albanian, Dutch, English, French, German, Greek and Italian.

In particular, the age-tailored information booklets and assent forms have been developed with a language and a wording appropriate to age, psychological and intellectual maturity, taking into account the cultural and linguistic differences. The informative documents are designed to inform the participant on the study’s objectives and procedures and to obtain his/her assent to participate in the study. Moreover, two animated videos, for children and adolescent respectively, have been developed with the aim to present in plain language general information on clinical trials.

A patient diary has been also developed to register specific daily data on the use of the IMPs, rescue and concomitant medication, pain scores and adverse effects when the patient is at home. It also contains instructions for the use of the IMP, troubleshooting and contact details of the study medical staff.

The information materials are available at the dedicated “Patients & Families” page of the GAPP Project.

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