GAbapentin in Paediatric Pain

Final Report Summary - GAPP (GAbapentin in Paediatric Pain)

Executive Summary:
Neuropathic pain in children has been considered rare although in the most recent years the prevalence seems increasing particularly in the contest of serious medical conditions. Pain can negatively affect all aspects of daily life, including physical activities, school attendance, sleep patterns and can lead to distress, anxiety, depression and negative copying behaviour.
To date, opioids, non-steroid anti-inflammatory drugs (NSAIDs), antidepressants and anticonvulsants are used to treat pain also in children. However, no single class of drugs has been found to be effective in all type of pain syndromes, probably because of the different underlined aetiologies. In addition, long-term pain, from any cause, rarely responds to a single analgesic medication or pain management strategy.
Chronic pain, a continuous or recurrent condition that persists for more than 3 months, is estimated to affect 15-20% of children with varying disabilities. One important issue in the management of chronic pain is the paucity of clinical information and appropriate medicinal products for paediatric patients. As a result children are under-treated, causing profound impact on their quality of life. Often, the drugs medications used for treating pain in adults are used off-label for children, thus exposing children to unnecessary risks of dosing errors and increasing Adverse Reactions. In addition, because of the lack of a stringent regulation in the need of paediatric data at the time of the marketing authorization, the few available analgesic drugs used in paediatric pain have a very different authorization profile across Europe.
Accordingly, the “WHO guidelines on the pharmacological treatment of persisting pain in children with medical illness” (2012) calls upon the scientific community to invest in clinical research on the safety and efficacy of pain-relieving medicines in children with persisting pain. The Guideline Development Committee has prioritized a list of research areas which include, among the others, the research with gabapentin for persisting neuropathic pain in children.
Gabapentin has shown efficacy in a wide range of pain syndromes especially with neuropathic or mixed components and is marketed for the treatment of peripheral neuropathic pain in adults. Although paediatric pain specialists have extensive experience with gabapentin off-label use for children, the potential benefits of gabapentin in treating neuropathic chronic pain were never demonstrated in children in the context of appropriately-designed clinical efficacy/safety studies.
The GAPP (GAbapentin in Paediatric Pain) project aims to increase the availability of paediatric medicines, by developing a full clinical strategy on gabapentin tested in chronic pain.
The development plan to be implemented in the project was approved by the PDCO (EMEA-001310-PIP01-12) which endorsed the overall objectives. The agreed specifications provide a comprehensive drug development package which includes:
• a liquid oral gabapentin formulation to be developed for the needs of the paediatric population (>3 months to <18 years of age);
• two controlled, parallel-arm efficacy-safety clinical trials in patients aged from 3 months to less than 18 years with moderate and severe pain (GABA-1 e GABA-2 respectively);
• a modelling bridging study to specifically address the paucity of data from children from 3 months to 3 years;
the completion of a preclinical toxicokinetic study for the investigation of the potential effects of gabapentin on the Central Nervous System development.
Project Context and Objectives:
Background
Pain is defined as: “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (the International Association for the Study of Pain).
Pain can negatively affect all aspects of daily life, including physical activities, school attendance, sleep patterns and can lead to distress, anxiety, depression and negative copying behaviour.
On the basis of the underlying pathophysiological causes different types of pain can be identified:
• Nociceptive pain: visceral or somatic, determined by stimulation of pain receptors by tissue inflammation, mechanical deformation, ongoing tissue injury. Responds well to common analgesic medications and non-drug strategies.
• Neuropathic pain: involves the peripheral or central nervous system. It does not respond predictably to conventional analgesics. Neuropathic pain is also associated to cancer and HIV treatment.
• Mixed or of undetermined pathophysiology: when neuropathic pain may coexist with nociceptive pain (examples include trauma that damages tissue and nerves, burns, and cancer that causes external nerve compression as well as infiltration).
• Psychologically-based: pain syndromes for which traditional analgesia is not indicated.
Chronic pain is defined as “continuous pain that persists for long periods (at least 3 months) or may recur due to persistence of noxious stimuli or repeated exacerbation of an injury”. Chronic pain may also arise and persist in the absence of identifiable pathophysiology or medical illness.
Several classification systems are used for pain, both in adults and children, and the most common are based on the duration of pain (acute or chronic) and the pathophysiological mechanisms of pain (nociceptive or neuropathic pain).
The more relevant causes of chronic pain in children may result from:
• Chronic diseases such as arthritis, sickle cell disease and rheumatologic disorders that constitute important causes of musculoskeletal pain. In addition, chronic conditions such as inflammatory bowel disease can cause recurrent abdominal pain.
• Trauma – physical, thermal, electrical and chemical injuries (e.g. burns), phantom limb pain or lower back pain.
• Life threatening diseases such as simultaneous acute and chronic pain in cancer and HIV/AIDS.
Being almost considered incurable, chronic pain has become a major epidemiologic issue and a serious social problem in both paediatric and adult patients. It has been estimated that between 25% and 46% of patients younger than 18 years of age throughout the world have experienced pain on a daily basis for more than three months (Perquin CW et al., 2000).
Although no specific figure is available regarding the cost associated with the treatment of chronic pain in the paediatric population, it is reasonable to estimate that it is significant. Data documenting the medical cost for adults with non-malignant chronic pain in USA is nearly $70 billion/year, which doubles if factoring in the lost productivity resulting from their inability to work (Gatchel RJ and Okifuji A, 2006).
Neuropathic Pain in children
Neuropathic pain in children has been considered rare although in the most recent years the prevalence seems increasing particularly in the contest of serious medical conditions.
Causes of peripheral neuropathic pain in children include nerve injury, nerve entrapment or external compression by space-occupying lesion (tumour or abscess); nerve damage caused by HIV infection or by the toxic effects of antiretroviral therapy; benign tumours of the nerve (neurofibroma or scar neuroma after trauma or surgery); phantom limb pain; nerve infiltration by cancers and nerve damage caused by cancer treatment (e.g. chemotherapy, radiation).
Causes of central neuropathic pain include pain due to spinal cord injury.
Furthermore, children can be affected by other neuropathic pain syndromes, such as congenital degenerative peripheral neuropathies and inflammatory neuropathies (e.g. Guillain-Barré syndrome, Walco GA et al., 2010). An increased number of children are diagnosed with Chemotherapy Induced Peripheral Neuropathy (CIPN). Finally, some cases of neuropathic pain are relatively unique to the paediatric population, including toxic and metabolic neuropathies (i.e. lead, mercury, alcohol and infection), hereditary neurodegenerative disorders (i.e. Fabry disease), mitochondrial and other rare disorders. A strong neuropathic component can also be present in the so called “mixed pain” syndromes derived from trauma, burns and, again, cancer.
Pain treatment
To date, opioids, non-steroid anti-inflammatory drugs (NSAIDs), antidepressants and anticonvulsants are used to treat pain also in children. However no single class of drugs has been found to be effective in all type of pain syndromes, probably because of the different underlined aetiologies. While non-steroidal anti-inflammatory drugs and opioid medications may be the standard therapy for mild and severe non-neuropathic pain, opioids appear to be less efficacious for neuropathic pain syndromes. Nevertheless, long-term pain, from any cause, rarely responds to a single analgesic medication or pain management strategy. In addition, epidemiologic studies suggest that many children do not receive appropriate help or treatment (Goodman JE and McGrath PJ, 1991; Perquin CW et al., 2000; Schanberg LE et al., 2003).
Suffering from pain can limit a child’s ability to attend school, socialize with peers, and participate in physical activity. The quality of life for children with chronic pain has been compared to that of young people with cancer or other chronic diseases (Gold JI, 2009).
Thus, according to the aims of the paediatric regulation, the European Medicine Authority (EMA) Pediatric working part has considered the development of new drugs for chronic pain in children an open issue and some active substances and off-patents drugs have been included in the Priority List for which a paediatric indication is requested.
The “WHO guidelines on the pharmacological treatment of persisting pain in children with medical illness” (2012) calls upon the scientific community to invest in clinical research on the safety and efficacy of pain-relieving medicines in children with persisting pain. The Guideline Development Committee has prioritized a list of research areas which include, among the others, the research with gabapentin for persisting neuropathic pain in children.
Gabapentin
Gabapentin is now approved in several European Member States and is currently indicated as adjunctive therapy in the treatment of partial seizures in adults and children aged 6 years and above (in some Countries from 3 years) and as monotherapy in the treatment of partial seizures in adults and adolescents aged 12 years and above.
In adults gabapentin is also indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, however, in lack of specific paediatric studies, the same indication is not approved in the paediatric population, but the existing therapeutic need has led to a large off-label use in the treatment of many pain conditions (Mellegers MA et al., 2001). Moreover, the paediatric use of gabapentin in children is hampered by two main factors:
1- the lack of a suitable oral formulation that complicates the treatment in the younger patients also in the approved indication (epilepsy). The main concern with the already available formulations in Europe relates to the difficulty children aged < 6-8 years to swallow tablets. Currently in many hospitals or home settings tablets are crushed and diluted in various drinks. This is a very risky practice, in particular when these extemporaneous preparations are made at home without any appropriate control. Thus, an ad hoc strength adequate for young children is required to allow appropriate and controlled administration of active substance without gross errors;
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.
For the above listed reasons, gabapentin was included in the “Revised priority list for studies into off-patent paediatric medicinal products currently used off-label” (Doc. Ref. EMA/98717/2 012), intended to address unmet therapeutic needs in children and to increase information on drug uses in paediatrics. According to the list, paediatric data on efficacy and safety are requested for the treatment of chronic pain with gabapentin.
The GAPP project
The GAPP (GAbapentin in Paediatric Pain) project aims to expand the availability of medicines for children in a condition (chronic pain) where the paediatric therapeutic need is very high and well recognised.
GAPP objectives
The primary objective of this application is to develop an age appropriate oral liquid formulation for the conduction of appropriately designed paediatric studies with gabapentin for a new paediatric indication (treatment of chronic pain of neuropathic origin), as included in the agreed PIP and in view of applying for a Paediatric Use Marketing Authorization (PUMA) of gabapentin as a treatment for chronic neuropathic or mixed pain in children from 3 to 17 years.
Specific objectives addressed by the present grant proposal are:
• to perform a juvenile animal toxicity study (pre-GABA) for the investigation of the potential effects of gabapentin on the central nervous system development;
• to develop a new liquid oral formulation of gabapentin at a dosage suitable for small children
• to perform two controlled, parallel-arm efficacy-safety clinical trials in patients aged from 3 months to less than 18 years with moderate and severe pain (GABA-1 e GABA-2 protocol studies respectively);
• to collect the main pharmacokinetics parameters using population pharmacokinetic modelling aimed to identify optimal paediatric dosages;
• to perform a bridging study to specifically address the paucity of data in children from 3 months to 3 years. This innovative approach will integrate data of the clinical studies proposed above and is designed to confirm the dose rationale for this specific population (GABA-3).

Additional objectives of the project are:
• to identify the pharmacogenomics and metabolomics profile of gabapentin in neuropathic pain patients;
• to set-up an international, scientifically sound and experienced paediatric network able to plan and manage the trials, recruit the adequate number of patients, evaluate the results of the studies and assure high level ethic and quality standards for the conduction of these studies;
• to develop a market analysis and produce an HTA analysis aimed to clarify the sustainability under an economic and industrial point of view of the development of a new liquid formulation; an HTA report will integrate this analysis in a social, medical and ethic perspective;
• to make results available for a PUMA application to be completed within seven years from the beginning date of the GAPP Project, thus expanding the availability of drugs for children use.
The GAPP Consortium is composed by an international, scientifically experienced paediatric network committed to conduct the trials adopting sound ethical and quality standards and make the results available for a marketing authorization thus expanding the number of drugs suitable for children.
The project implementation posed special difficulties due to the small patient population and the need to involve a large number of recruiting centres. In addition, the heterogeneity of paediatric pain management across the different European and non-European clinical sites and the paucity of any data (and treatment) for paediatric neuropathic pain required in depth discussion among the involved clinicians and paediatric pain experts. We are at a critical step of the project were all the study specific infrastructure(s) have been set up and are ready to recruit the patients.
Project Results:
The overall project strategy is aimed to provide the data package necessary to proceed successfully to a PUMA application for gabapentin. To achieve this goal all the planned activities were dedicated to the achievement of the project specific objectives and the implementation of the developmental plan agreed upon the Paediatric Committee.
Paediatric Investigation Plan
In compliance with the Paediatric Regulation (EC) 1901/2006, a Paediatric Investigation Plan (PIP) was submitted to the Paediatric Committee (PDCO) in June 2012. Its regulatory and scientific evaluation process led to the approval of the gabapentin PIP in November 2011 and a final EMA decision in March 2013.
During the study protocols drafting (GABA-1 and GABA-2) some specific issues regarding the implementation of key quality and clinical measures as set in the PIP that had already been approved by the PDCO at the EMA were identified. The heterogeneity of paediatric pain management across the different European and non-European clinical sites and the paucity of any data (and treatment) for paediatric neuropathic pain revealed that some clinical key elements discussed and agreed with the PDCO were rather empirical and of difficult implementation in the clinical practice. The issues were addressed through a thorough review of literature carried out by the specific Working Groups established in the context of WP2 and by the DSMC. The suggestions for improvement deriving from this exercise were implemented in the GABA-1 and the GABA-2 protocols.
However, such changes to the protocols implied misalignment to the key binding elements of the quality and clinical measure as previously defined in the PIP, which was agreed with the EMA’s PDCO on 23/03/2013 (PDCO decision 001310-PIP01-12). Consequently, after consultation with the PDCO, two separate PIP modifications were deemed necessary: one related to the request for modification of the clinical measures dated 10/07/2015 (PDCO decision 001310-PIP01-12-M01) and the subsequent one on the quality measures dated 30/10/2015 (PDCO decision 001310-PIP01-12-M02).
The quality measure modification in the PIP implied that the developed gabapentin paediatric liquid formulation had to be modified, changing the levels of one of the excipients. This led to a delay in the delivery of the first IMP clinical batches.
The PDCO acknowledged the challenges posed by the proposed development plan in an almost undiscovered area with high unmet medical needs but with very little evidence-based medical information and, after repeated consultation, an agreement was reached with the regulatory agency on the final development plan.
These measures received positive opinion by the European Medicine Agency (EMEA-001310-PIP01-12-M02; P/020/2015) on October 30th 2015:
http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500199395.pdf.
It was only after the approval received from the PDCO that the two Study Protocols and Statistical Analysis Plans for both GABA-1 and GABA-2 as well as the IMPD for gabapentin could be further elaborated and finalized.
Pharmaceutical development
A liquid oral solution containing 75mg/ml of gabapentin to support use in the paediatric patient population has been developed by Dompè Farmaceutici S.P.A in compliance to the applicable rules and guidelines including GMP (EMA/CHMP/QWP/180157/2011) and the “Reflection paper: formulations of choice for the paediatric population” (EMEA/CHMP/PEG/194810/2005).
Because of the unpleasant (metallic and bitter) taste of the drug substance an accurate search and testing of aromatic mixture of flavours and excipients has been performed to reach a final liquid formulation with masked and acceptable taste using excipients known not to affect the drug’s gastrointestinal transit or absorption or the in vivo solubility or stability of the active substance.
The Gabapentin qualitative and quantitative composition is provided in following Table 1 (please refer to Annex-1).
Different natural and artificial substances were tested for their ability to block the tongue receptors and to work as taste masking agents. Neotame plays a key role in the transduction of the bitter, sweet and umami tastes and gave the best results. To reach a better masking of the gabapentin glycamil and sucrose were also added as sweeteners.
The use of sucrose for masking the bitter taste of gabapentin is not considered of concern in children as Diabetic Neuropathy (DPN), although constitutes a very common source of distress and suffering in adults, it is very rarely symptomatic in children and only when duration of diabetes is superior to 10 years. Consequently, the diabetic paediatric population is unlikely to benefit from gabapentin liquid treatment. On the other hand, the inner bitter taste of gabapentin constitutes a major obstacle to acceptable palatability and therefore to good compliance to treatment, particularly in the youngest patients. The proposed strategy for masking the bitter taste was evaluated and approved by the EMA-PDCO Formulation Group.
A number of solubilizing agents at different percentages were tried, among these Kolliphor RH40 presented better properties of gabapentin solubilisation. The amount of Kolliphor was originally set at 3% w/v and then lowered to 2.5%w/v after agreement with the EMA-PDCO Formulation Group.
Several flavouring agents were tested; the best formulation, according to stability studies, was the cherry flavour.
Methylparaben has been selected as antimicrobial preservative.
With regard to the manufacturing process, the main critical step was the control of the pH of the solution to ensure the chemical stability of the active ingredient.
The entire formulation development process is described in WP5 and includes the following main steps: stability in buffered systems, accelerated stability testing, organoleptic optimization, sweetening and flavouring agents’ selection.
Performed stability and microbiological tests of the IMP are described in the IMPD. The IMP is provided as 75 mg/ml gabapentin oral solution in a 200 ml amber glass bottle. 500 Patient Visit Kits, each of them containing 2 bottles of 200 ml gabapentin/placebo syrup and 5 bottles of 10 ml tramadol (comparator)/placebo has been released and shipped to Clinical Sites and are ready to be distributed to the recruited patients.
Non clinical development.
A juvenile repeated rat toxicity study for the investigation of the potential effects of gabapentin on the central nervous system (CNS) development has been requested by the PDCO during the PIP evaluation phase in order to investigate the potential effects of gabapentin on the CNS in juvenile animals. This study was included by PDCO among the Opinion’s binding elements of the PIP on the reasoning that:
1- available data on young children demonstrates that in children gabapentin exposure/plasma concentration inversely correlates to age. Thus, there is the concern that in children increased dosage may determine increased number or severity of adverse events;
2- gabapentin data are available in children > 3 years, while the proposed trials are designed to include children > 3 months for which there is a high therapeutic need. It would be unethical to include this age subset without first investigating the potential toxic effects (particularly in CNS).
The toxic potential of gabapentin was evaluated by Dompè Farmaceutici S.p.A.in juvenile rats treated twice daily for 25 days. In summary treatment with gabapentin by oral gavage in male and female Wistar Han rats at dose levels of 500, 1000 and 2000 mg/kg/day revealed no direct relevant toxicity up to the highest dose level tested. An increased incidence of hydronephrosis was observed in treated female. However, considering the different anatomy of the renal pelvis between rat and human this is likely to have no relevant meaning for humans. Details are described in WP6.
Regulatory Activities
Preparation of informative for parents
As a minor is legally unable to provide informed consent to participate in research, a legal representative (LAR), such as the parent, must be informed and give the written authorization, thus taking the responsibility for the participation of the child to clinical studies. The information document and consent form for parents and LAR provide details about the aim and the procedure outlined in the clinical study, the privacy of the acquired medical and personal data, the clinical outcomes and the benefits and burden due to the participation to the study.
As the GABA-1 and GABA-2 trials include two exploratory pharmacogenetics and metabolomics assessments which are entirely voluntary, separate dedicated information document and consent form were prepared for parents of children asked to participate to these two sub-studies.
Preparation of informative for minors
Besides the legally required informed consent for the LARs, when appropriate, the informed assent are collected from the minors participating to GABA studies. In line with the Directive 2001/20/EC and the “Ethical Considerations for Clinical Trials on medicinal products performed in Children - Recommendations of the Ad Hoc Group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use” (EC 2008.), minors also have the right to be informed about the risks and the benefits regarding the trial and their explicit wish to accept or refuse to participate should be considered whenever possible. As the capacity to make voluntary, informed decisions for a child, i.e. to assent, evolves with age, maturity and previous life experience, it is acknowledged that involving children in the discussion and decision-making process related to their participation to a clinical trial is advisable but should be done in the respect of their emerging maturity.
In order to provide detailed age-appropriate information to the children to be enrolled, the informative documents and assent forms have been developed in a language and wording supported by drawings which are tailored to the patients’ age. The provided information are in line with the maturity and the child‘s capacity of understanding and include the description of the procedures to be conducted during the trial, the nature of the material to be collected (e.g. biological samples, medical data). Three informative booklets were prepared for children of 0-6 years of age, 7-11 years and 12-17 years.
Two assent forms for children aged 7-11 years and 12-17 years are provided. Besides asking to give their assents to the study participation the assent forms underline the patients’ legal rights, including the voluntary nature of the participation and the possibility to withdraw from the trial any time.
A Patient Advisory Board (PAB), consisting of a panel of paediatricians, clinical experts in pain management and paediatric experts on Ethics with consultative functions was established to advice on contents and language to be used and critically revise all the documents developed for minors.

Protocol submission and authorization
The GABA-1 protocol and all the relative documentation were submitted to the National Competent Authorities (CA) of the participating countries and obtained the favourable opinions from the Ethics Committee (EC) and CAs of France, Germany, Greece, Italy and The Netherlands. The approval from the EC and CA of Albania is pending.
The GABA-1 protocol faced several challenges during the authorization phase, particularly in Germany and in France where the requests from the corresponding CAs determined a delay in the approval time. In addition, the substantial modifications to the study protocol, the preparation of a new batch of IMP and the implementation of a new preclinical toxicological study were deemed necessary.
Of note, even if the GABA-1 study received the CAs and ECs approval without delay and without substantial modifications from The Netherlands and Italy, these countries could not initiate the patient recruitment given the substantial issues raised from the CAs of Germany and France. Due to the different protocol modifications required from the national CAs a protocol amendment is being submitted to the national CAs of participating countries.
New clinical sites in UK, Poland, Serbia and Ukraine have been contacted. The complete submission package, implemented with additional documents as requested by national legislation, have been prepared. The study has been submitted to the CA in UK (MHRA) and has already received the favourable opinion from the EC in Belgrade (Serbia).
Considering the time required in obtaining the GABA-1 authorization and the substantial number of protocol changes, the Sponsor decided to submit the GABA-2 protocol via the Voluntary Harmonization Procedure (VHP) that offers an alternative to the country-by-country approval since it allows to obtain a coordinated assessment of the clinical trial application that is to be conducted in several European countries. The VHP is a process established in 2004 by the Clinical Trial Implementation Group with the aim to implement the good clinical practice and to harmonise the conduct of the clinical trials in European Countries. The harmonisation implies the generation of a single package of protocol-related documents (protocol, Investigators Brochure, Investigational Medicinal Product Dossier, GMP manufacturing certificates and IMP labels) to be agreed from different CAs. The GABA-2 clinical study obtained the VHP approval on April 2017 and has been submitted to the national CAs of France, Germany, Italy and The Netherlands. All the involved CAs approved the study. The approval from the corresponding ECs is pending.
Clinical development
The GAPP final clinical plan agreed with the EMA-PDCO includes the following main aspects:
a) Condition: Chronic neuropathic or mixed pain
b) Age Groups: paediatric population from 3 months to less than 18 years of age
c) GABA-1 efficacy and safety study of gabapentin compared to tramadol
d) GABA-2 efficacy and safety study of gabapentin plus morphine
e) GABA-3 model-based bridging of clinical data for children from 3 months to less than 3 years.

Protocol studies
GABA-1: randomized, double-blind, double-dummy, active controlled, multicentre, non-inferiority phase-III study to compare the pharmacokinetic, efficacy and safety of gabapentin liquid formulation to tramadol in children from 3 months to less than 18 years of age experiencing moderate to severe chronic neuropathic or mixed pain (EudraCT: 2014-004851-30).
Primary objective
• To evaluate the efficacy of gabapentin in the treatment of moderate to severe chronic pain.
Secondary objective
• To assess the safety of gabapentin
• To assess drug exposure in both treatment arms using sparse sampling techniques
• To characterise the PKPD relationship and provide confirmation of the recommended paediatric dose.
Study population and subset definition
• Children with moderate to severe (pain score > 4/10) chronic continuous or recurrent neuropathic or mixed pain persisting at least 3 months; aged from 3 months to 17 years of age.
Number of study participants by paediatric subset
• At least 94 evaluable patients for the primary analysis divided in the following subsets: 3 months to 2 years (at least 12 patients), 3-7 years (at least 30 patients); 8-17 years (at least 40 patients); randomization 1:1; stratification of randomization by age group.
Pain degree for inclusion
• Pain level > 4/10 measured at screening using an appropriate pain scale according to patients’ age. Face, Legs, Activity, Cry, Consolability scale (FLACC) in children from 3 months to 2 years; Face Pain Scale-Revised (FPS-R) in children from 3 to 7 years of age; Pain Numeric Rating Scale (NRS-11) in children from 8 to 17 years of age.
Control
• gabapentin placebo + Tramadol
GABA-1 is an efficacy, safety, non-inferiority trial in patients aged from 3 months to less than 18 years with ‘moderate’ to ‘severe’ neuropathic or mixed pain of both genders. Subjects are treated with increased dose of gabapentin depending of body weight (BW) (up to 63 mg/kg/day for patients < 15kg BW or 45 mg/kg/day for patients >15 kg BW) according to a predefined matrix, until satisfactory analgesia is reached. The study includes an optimization phase of up to 3 weeks where the gabapentin dose is gradually increased and a treatment phase of 12 weeks with fixed dose of gabapentin. Study duration for each participant is 18-22 weeks from screening to follow up visit. Pain duration lasting > 3 months and pain intensity from moderate to severe (pain score >4/10) are key inclusion criteria. Patients with known intolerance to trial treatments, subjects with any acute or chronic medical or psychiatric condition or that are considered at risk of suicide are excluded from the trial. Gabapentin will be compared to tramadol (initial dosage of 1 mg/kg t.i.d. to be increased up to a maximum of 2,3 mg/kg t.i.d.). The choice of tramadol as comparator has been agreed with the EMA-PDCO within the terms specified in the Study Protocol.
Furthermore, two voluntary exploratory studies on pharmacogenetics and metabolomics: additional exploratory objectives are added to the core study to collect information on the metabolomics profile following drug treatments and to explore genetic polymorphisms and their impact on pharmacokinetics (PK) and pharmacodynamics (PD). The aim of these two studies is to collect information on the molecular mechanisms leading to neuropathic pain and the response to the treatment.
The primary endpoint of the study is the average pain score at the end of the treatment period assessed by age-appropriate pain scales
The secondary endpoints are:
• percentage of responders to treatment,
• daily pain intensity during dose optimization,
• number of episodes of breakthrough pain (pain score > 4/10 ) during treatment period,
• number of rescue interventions required during treatment period,
• number of pain-free days (pain score < 4/10) during treatment period,
• quality of life, physical, emotional, social and school functioning and quality of sleep,
• pharmacokinetic parameters for gabapentin and tramadol,
• number of adverse events.

The GABA-1 protocol study is described in the WP7. The clinical study has been designed, drafted and finalized in collaboration with the Trial Clinical Leader, the person responsible for the pharmacokinetic assays and the modelling study, the statisticians and the quality assurance.
Study approval The GABA-1 study has received Competent Authority and ethics approval in 11 experimental centres and is under evaluation from the competent authorities of UK, Albania and Ukraine.
The clinical site feasibility check was performed through a submission of a specific questionnaire to the Principal Investigators of each participating clinical site. The ability to recruit potential patients, to perform the clinical tests required by the protocol, to store the IMP and the blood samples for the Pharmacokinetics, metabolomics, pharmacogenomics tests and to conduct the trial in compliance the Good Clinical Practice (GCP) were considered essential prerequisite for study participation.
Pre-site qualification visits (PSQV) were performed after the centres received the necessary regulatory authorization to start the clinical trial. In the PSQV the available patient population, site resources, local facilities and associated challenges were assessed.
Separate agreements between the Sponsor, the Principal Investigator(s) and the clinical site(s) involved in the trial have been signed.
The “Clinical start-up phase” has been implemented at clinical sites located in Italy, France, Greece, The Netherlands and includes the shipment of the Investigational Medicinal Product (IMP) at the Pharmacy of recruiting centres, the set-up of the trial Investigator Folder al the Centre with all the documentation as required by GCP and the Trial Master File at the Sponsor site. Study specific procedures and study manuals have been prepared and released to the involved clinical centres. Training to the appointed Clinical Research Associates (CRA) on protocol study specific topics were performed by webinars. An electronic infrastructure (eCRF) has been set up and validated, ensuring standardized procedures for the data capture, collection, transmission, integrity and security. Protocol-specific statistical analysis plan and data management plan have been developed.
In view of the patients recruitment phase the clinical trial infrastructure was defined and organised in the context of WP4 and sets the bases for the initiation of the studies and enrolment of the patients. Furthermore, a Data Safety Monitoring Committee (DSMC) in charge for both studies was established to overlook on patients’ safety throughout the trials.
Site Initiation Visits (SIV) were conducted to provide in-depth protocol training, data entry training, laboratory requirements, safety assessment and reporting to investigators. Visits by appointed monitors included the eCRF training to request the credentials to the database access by the clinical staff.
To assure the trials activities coordination a study team composed by the Sponsor, the trial clinical leader, the regulatory submission manager, the clinical operations manager, the data manager, the drug manager and the clinical trial archivist has been established.
In summary, as for the GABA-1 clinical trial all the critical steps related to the study planning and design, the regulatory activities and the start-up activities were performed. Many of the Clinical centres involved in the study are ready for patient recruitment and study conduct.
GABA2: Randomized, double-blind, placebo controlled, multi-center 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 (EudraCT: 2014-004897-40).
Primary objective:
• To evaluate the efficacy of gabapentin as adjunctive therapy to morphine in the treatment of severe chronic pain.
Secondary objectives:
• To assess the safety of gabapentin combined with morphine compared to morphine alone.
• To assess drug exposure in both treatment arms using sparse sampling techniques.
Study population and subset definition.
• Children with severe (pain score >7/10) chronic continuous or recurrent neuropathic or mixed pain persisting at least 3 months; aged from 3 months to less than 18 years of age.
Number of study participants by paediatric subset.
• At least 66 evaluable patients for the primary analysis divided in the following subsets: 3 months to 2 years (at least 5 patients), 3-7 years (at least 15 patients); 8-17 years (at least 20 patients); randomization 1:1; stratification of randomization by age group.
Pain degree for inclusion.
• At screening a Face, Legs, Activity, Cry, Consolability scale (FLACC) score equal to or greater than 7/10 in children from 2 months to 3 years; a Face Pain Scale-Revised (FPS-R) pain score equal to or greater than 7/10 in children from 3 to 7 years of age; a Pain Numeric Rating Scale (NRS-11) score equal to or greater than 7/10 in children from 8 to 17 years of age.
Control.
• Placebo + morphine arm. Morphine will be started at 200 micrograms/kg every 4 hours with a gradual daily increase if the patient experience pain.
GABA-2 is an efficacy and safety trial in which 66 patients aged from 3 months to less than 18 years with ‘severe’ neuropathic or mixed pain of both genders will be treated with gabapentin as add-on to morphine and compared to morphine alone. Gabapentin will be added to the same morphine’s doses as monotherapy and titrated up to 63 mg/kg/day (for patients < 15kg BW) or 45 mg/kg/day (for patients >15 kg BW) according to a predefined matrix. The study includes an optimization phase of up to 3 weeks where the gabapentin dose is gradually increased and a treatment phase of 12 weeks with fixed dose of gabapentin. Study duration for each participant will be 18-22 weeks from screening to follow up. Pain duration lasting > 3 months and severe pain intensity are key inclusion criteria. Patients with known intolerance to trial treatments and any acute or chronic medical or psychiatric condition or that are considered at risk of suicide will be excluded from the trial. Morphine will be started at 200 micrograms/kg every 4 hours during the optimization period with a gradual daily increase.
To facilitate accurate dosing to the patients and administer doses as closely as possible to the appropriate therapeutic range, different formulations of morphine and varying daily doses are used.
Patients < 30kg BW: oral liquid morphine formulation, 4 times daily throughout the study
Patients > 30kg BW: morphine tablets
- optimization phase: immediate release tablets 4 times daily,
- treatment phase: extended release tablets 2 times daily
The primary endpoint is the difference between average pain scores in the two treatment groups at the end of the study period using age-appropriate pain scales.
The secondary endpoints are:
• percentage of responders to treatment,
• daily pain intensity during dose optimization,
• number of episodes of breakthrough pain (pain score > 7/10 ) during treatment period,
• number of rescue interventions required during treatment period,
• number of pain-free days (pain score < 4/10) during treatment period,
• quality of life, physical, emotional, social and school functioning and quality of sleep,
• pharmacokinetic parameters for gabapentin and morphine,
• number of adverse events.

The GABA-2 protocol study is described in the WP8. The protocol has been designed, drafted and finalized in collaboration with the Trial Clinical Leader, the person responsible for the pharmacokinetic assays and the modelling, the statisticians and the quality assurance.
Study approval. The study obtained the approval from the national CAs of France, Germany, Italy and The Netherlands. All the clarification issues asked by the EC of France, Germany and The Netherlands are being addressed and their favourable opinion is pending.
The clinical site feasibility check was performed through the submission of a specific questionnaire to the Principal Investigators of each clinical Site as for the GABA-1 study. In addition, the availability of morphine (pharmaceutical formulations and unit dose) at the pharmacy of each site were assessed.
Pre Site Qualification Visits are planned in the next months after obtaining the Ethics favourable opinion.
GABA-3: Model-based bridging of clinical data for children from 3 months to less than 3 years of age

Whilst there has been extensive evaluation of the efficacy in neuropathic pain, evidence of the dosing requirements for chronic pain remains empirical due to the use of titration to response in neuropathic pain patients. Assuming comparable aetiologies and pathophysiological mechanisms in children and adults, the dose rationale for the proposed studies is to ensure systemic exposure equivalent to the levels observed in adult patients responding to treatment.
The assessment of efficacy across different age groups also raises the question about the relevance and feasibility of making use of extrapolations to avoid unnecessary studies in the target population for ethical reasons, and to allocate resources to areas where studies are the most needed.
In the GABA-3 study clinical data obtained in GABA-1 and GABA-2 will provide the basis for a subsequent bridging study (described in WP9) aimed at confirming the PK and PKPD relationships in children aged less than 3 years, for which data collected in the studies may be insufficient due to the rarity of the condition.
The implementation of this study requires the clinical data obtained from the GABA-1 and GABA-2 protocol studies and thus is postponed.
Potential Impact:
Socio-economic Impact
Beneficial impacts can include: improvement of the quality of life of the paediatric population, a better standard of living due to increased access to employment, business opportunities, training and education, greater access to and from a community and, increased funding to improve social infrastructure and cultural maintenance programs. However, we must take into consideration the fact that by the time of the end date of the EU funded GAPP project, 30.06.2017 the main activities of the Project, such as patient recruitment, have not been yet started so the provided impact is partial.
The expected impact is to expand the availability of paediatric medicines appropriately studied in children. The acquired knowledge should aim at the Paediatric Use Marketing Authorisations (PUMA) for gabapentin.
PUMA is the instrument that the Paediatric Regulation has identified to stimulate paediatric studies on off-patent drugs frequently used off-label, so as to increase the paediatric information included in the Summary of Product Characteristic (SPC) and Package Leaflet (PL), giving to a drug the Paediatric Medicine Status.
Despite constituting a major epidemiologic issue and an important social problem, paediatric patients suffering from pain are still under-treated. To date children often do not receive sufficient analgesia, because their discomfort is different from that of adults. The result is that in clinical practice, due to the paucity of clinical information and appropriate medicinal products, as well as the adoption of different cultural approaches, paediatric patients unfortunately are often under-treated.
A recent analysis on the drugs approved for paediatric pain in Europe conducted within a FP6 funded Programme, TEDDY NoE (Task-force for Drug Development for the Young), coordinated by CVBF, highlighted that out of the 734 new and innovative drugs so far approved by European Medicines Agency (EMA), 10 products were authorized for pain, but none of these includes a paediatric indication. The analysis also underlines that there are many differences in terms of authorized age groups and approved indications. The main reason for having very few approved drugs for pain in children is the well-recognized ethics, methodological, recruitment difficulty in the conduction of paediatric studies.
Thus the present project is expected to cover the existing therapeutic gap and to provide reliable data in support of the use of gabapentin for the treatment of chronic pain in paediatrics, a patient population where the need of treatment for this indication is particularly high. In addition, by proposing innovative study designs (modelling), the project will contribute to advance the search for new methodologies (applicable to registrative studies) in small patients population for whom the conventional efficacy-safety study designs are not feasible or difficult to implement.
Improving Child Health
The results of the GAPP project are expected to determine an improvement of the clinical management of chronic pain in the paediatric population. At the end of the project, gabapentin can be made available throughout Europe with age-appropriate formulations and clear dosage indications and information in the product documentation. In addition data on safe dosages to be used when gabapentin is associated to morphine will be, for the first time, provided by the study.
Importance of a European approach
There are three main reasons for carrying out the research at a European level as opposed to national, regional or local level:
1. Necessity of combining resources and knowledge: The scale and scope of the problem addressed requires the synergy of different multidisciplinary areas of expertise, knowledge and research capacities on a European scale. The Consortium is built around the necessary expertise and resources to realise the objectives pursued. Being a research project developed in collaboration with the TEDDY network members and coordinated by CVBF, it can also count on the expertise of researchers, scientists and health experts working together to identify the most appropriate common rules that reflect the specificity of the patient population.
2. The difficulties in the recruitment of paediatric patients require the involvement of many clinical centres: the involvement of a particularly vulnerable population (paediatrics) renders the recruitment of patients a difficult task. To be able to evaluate the efficacy and safety of gabapentin in children and adolescent affected by a chronic condition, it is essential to be able to perform the corresponding studies on a wide perspective. Only multicentre large trials will be able to answer in a scientifically correct manner the questions that arise regarding the use of gabapentin in the paediatric population. Therefore, the involvement of many specialised clinical centres in several European countries and research institutions is key for obtaining the data requested by the call.
3. Necessity for multinational endorsement of results: this collaborative project addresses a public health problem concerning all European Member States, as well as non-European countries. New knowledge and treatment is not an achievement in itself. It must be compliant with a PIP as approved by the EMA - PDCO and should involve all interested parties (scientists, clinicians, patients, policy makers, scientific societies, etc.). All combined, the Partners in the Consortium have access to a wide audience of colleague scientists, industry and patients, thus creating a natural platform for the subsequent uptake of the project results that would not exist without this European level approach. Furthermore, TEDDY network is working to favor awareness on the topics of paediatric research and to spread information on the rational use of paediatric medicines to identify unmet medical needs in paediatrics.
Dissemination activities and exploitation of results
The GAPP Project’s dissemination activities were distributed during the entire Studies’ duration.
In compliance with the European Commission’s open access pilot policy launched in 2008, results from clinical trials are published and released on-line to ensure free Internet access to research outputs. Each Partner has to ensure that the foreground of which it has ownership is disseminated as swiftly as possible. However dissemination activities must be compatible with the protection of intellectual property rights, confidentiality obligations and the legitimate interests of the owners of the foreground. For this reason, the Partners of the GAPP project established that any foreground capable of industrial or commercial application (even if it requires further research and development and/or private investment), will be protected in an adequate and effective manner in conformity with the relevant legal provisions.
Work package 10 (WP10) was aimed to ensure efficient communication with stakeholders outside the project in order to raise awareness about GAPP activities and results and to establish a consistent strategy for maximising the impact and efficiency of the communication efforts. In this sense, dissemination played an essential role in the GAPP project in contributing to its cohesion and success both in terms of well-planned coordination among the stakeholders and of results to be released to the public not directly involved in the project.
Dissemination activities carried out in the context of the GAPP project included:
• the set-up and maintenance of means of dissemination through the design of a dedicated graphical identity and the definition of communication channels (electronic mailing list, the project website, external conferences, Partners’ website and other portals);
• the production of communication materials (website contents, newsletters, press releases, teaser video and other informative materials);
• the production of informative materials (age appropriate booklets and assent forms as well as animated videos for children and teenagers).
A Communication Plan was developed to identify the communication activities to be performed in the framework of the GAPP project and to make the projects results public among the different stakeholders in an appropriate, effective and efficient manner.
Communication activities have been designed for specific target audiences in order to give maximum visibility to the Project and its results. All members of the Consortium have contributed to these dissemination activities by participating and giving presentations at conferences, publishing papers, networking and similar activities within the range of their scientific networks and affiliations, in order to ensure that the foreground of which they have ownership is disseminated as swiftly as possible, as requested by the European Commission. To this aim, a variety of channels such as a project website, scientific publications, partners’ websites and other portals, social networks and the GAPP newsletters have been used, as reported below.
1. Project website. The GAPP project website (Annex-2, in attachment) is available at the following link: www.pediatricpain.eu and represents the Project’s main interface with the public, covering the project’s goals, objectives, accomplishments, background information and partner’s role and contribution. It is an interactive website, accessible to the public and different stakeholders with an easy-to-use interface, based on the project’s graphical identity. It was designed with the aim to:
a) meet all the communication needs of GAPP partners and stakeholders;
b) provide a flexible, easy to use communication instrument;
c) provide update about on-going activities;
d) maximise awareness of the Project within the public audience.
It evolved in parallel with the Project’s progresses in order to provide timely and appropriate information, and was therefore constantly updated with Project news and downloadable versions of documents.
The GAPP Website includes the following sections:
• “Project Overview” section, providing a general description on the Project in plain language.
• “Research” section, including information on the Project background and the cause of neuropathic pain in children; a focus on the pain assessment and a section dedicated to the neuropathic pain treatment in children. It also provides information on gabapentin, the reason why it is tested in children and the obstacles to the use of the gabapentin medication in the treatment of neuropathic chronic pain in children.
• “Project Outline” section, including information on the main goals of the GAPP Project with reference to each part of the study including Formulation, Clinical Trial, PUMA. It also provides a list of all Work Packages with a brief description of the specific objectives of each (details of the WP Leaders and the partners involved).
• “Management” section, containing a list of all partners, a description of their organisation and their main tasks in the Project. It also includes the profiles of the GAPP key members and Boards: GAPP Ethics Board (EB), Data Safety Monitoring Board (DSMC), General Assembly (GA), Project Scientific Committee (PSC) and Scientific Coordination Body (SCB).
• “Media” section. It was regularly updated with news and events, press releases and Project newsletters in order to keep the public and consortium members informed. The media section also includes a section to download all Project presentations as well as the communication materials issued by the consortium regarding the Project.
• “Patients and families” section including the informative materials (booklets, assent forms and animated videos) for clinical trials in children and young people developed with the aim to inform the participant child on the study objectives and procedures and obtain his/her assent to participate in the study. They have been translated into the seven languages of the Project.
• “Resources” section including useful links to other websites containing information relevant to the Project and a Toolkit.
• “Contact”, containing the contact details of the Project Coordinator Office and an online form for use by members of public who would like further information or to give feedback.
The website also contains a “reserved area”, which is the password-protected area aimed to facilitate the exchange of information within the Consortium. It was regularly updated with deliverables submitted to the European Commission, Project presentations and meeting documents, communication materials and was dedicated to project participants, in order to facilitate cooperation and management task.
More information on the statistics of visitors, who clicked links from Search Engines pages (Google Search) to get to the GAPP website as well as the monthly number of accesses are available in the Deliverable D10.4 “Report on Website results and success”.
GAPP visual identity is the “soul” of the Project and represents its personality and philosophy, helping the project to be easily recognisable also outside the Consortium and allowing a wide dissemination of its results. It has been applied to all communication materials.
The GAPP logo (Annex-3, in attachment) is represented by a rabbit coming from the letter P of the acronym and is characterised by the orange colour that has thus been identified as the project’s identity’s main colour for its association with positivity: indeed, in colour psychology it is said that the orange colour radiates warmth and happiness, combining the physical energy and stimulation of red with the cheerfulness of yellow. A series of different versions of the project logo have been developed, that may be suitable for use in various contexts (wide vs compact, high res vs low res, single colour vs double colour, etc.).
2. Promotional teaser video. The GAPP Teaser video was developed with an “emotional cut” and a dynamic style, where scientists, patients and patient families were called to describe the project in its scope and objectives. The video includes touching moments resulting from the personal and direct experiences of children affected by chronic pain, who were interviewed in December 2014 in Athens with the collaboration of AGIA SOPHIA, reporting their situation, describing how their diseases are affecting their daily life and how they live with their pain. The GAPP teaser video was officially presented during the Second General Assembly meeting held in Paris on 18th - 19th June, 2015 (https://www.pediatricpain.eu/2nd-gapp-general-assembly-in-paris/). The video is available in English on YouTube (https://www.youtube.com/watch?v=eBFmCKCfavo&feature=youtu.be) and published in the GAPP website in the “Communication Tools” section (https://www.pediatricpain.eu/communication-tools/). More details on the video are available in the Deliverable D10.3 “Video on pain management”.
3. Informative booklets. Children have the right to know in advance which medicines they need and why. They should be allowed to express their own views and granted the right to participate in the decision-making process concerning their own health. Moving from such assumptions, the GAPP Project has developed age-tailored information booklets and assent forms with a language and a wording appropriate to age, psychological and intellectual maturity, and taking into account the cultural and linguistic differences. The informative documents have been designed to inform the participant on the study’s objectives and procedures and to obtain his/her assent to participate in the study. They were developed within a collaborative effort between pharmacologists, paediatricians, child psychologists and illustrators and translated in the seven languages of the project:
• Information booklets for children aged 0-6, 7-11, 12-17 for both GABA-1 and GABA-2.
• Assent form for patients aged 7-11, 12-17 for both trials GABA-1 and GABA-2
• Two animated videos for children and teenagers were created to present in plain language general information on clinical trials (available in the “Communication Tools” section (https://www.pediatricpain.eu/communication-tools/).
4. Newsletters. Three issues of the Project newsletter and one Addendum have been released to raise awareness about the Project, to keep audiences informed, to promote Project outcomes, events and initiatives and to continue stimulating interest. They have been distributed and shared with more than 2,000 contacts including the GAPP partners and a general audience in order to provide them with updates on the main project results and accomplishments in a plain language. Newsletters have been edited in English and are available to read on the webpage in the “Media” section in the “Newsletter” page (https://www.pediatricpain.eu/newsletters/).
It is furthermore possible for new users to subscribe to the newsletter by filling in the form on the lower side of the GAPP homepage.
5. Scientific publications and press releases. Producing scientific publications is an important activity to disseminate project progresses and results. In order to coordinate the publication strategy, ensure transparency within the Consortium, boost the publication activities of project results and define the procedure for preparing, reviewing, submitting and maximizing diffusion of scientific publications and dissemination material, a SOP for “Scientific publications and dissemination activities” (see Annex-4) has been prepared. It applies to all public scientific publications including: peer reviewed papers, oral presentations, reports, posters, abstracts, journal articles, newspaper interviews or any other public dissemination of results based on studies undertaken under the auspices of the GAPP Project.
Progresses and results of the GAPP project have been disseminated also by means of publication of abstracts, posters and press releases. The detailed list is available in the Table 2 “list of all dissemination activities” attached to the report. Manuscripts of original papers and review(s) on pain management and modelling of exposure to study drugs (gabapentin and tramadol) are drafted and ready for submission on peer reviewed journals.
6. Presentation at scientific events. GAPP Project dissemination goals have been achieved by efforts of all the partners in exploiting opportunities to generate exposure of the project. Partners have been encouraged to get involved in the dissemination activities. In particular, according to the Grant Agreement, Annex II, art.II.30 each beneficiary shall ensure that the foreground of which it has ownership is disseminated as swiftly as possible and all dissemination activities shall be compatible with the protection of intellectual property rights, confidentiality obligations and the legitimate interests of the owner(s) of the foreground.
All members of the Consortium have contributed to the dissemination activities by participating and giving presentations at conferences and other major events related to the main topics of the project, publishing papers, networking and similar activities within the range of their scientific networks and affiliations, in order to give rise to deeper discussions on its results and benefit from possible feedback from other experts in the GAPP research area.
7. Networking. Dissemination activities have also been fostered through the participation in national and international professional networks that can allow project visibility as well as the sharing of their channels and in particular the use of their existing mailing lists, newsletters and meetings to cover a wider dissemination. Members of the GAPP Consortium are in fact members of various paediatric scientific and clinical research associations as well as national, international and specialty networks. These networks’ platforms have been used to disseminate the progresses and results of the project as well as to foster access to the wider professional community. In particular, the GAPP Project actively collaborates with the TEDDY Network (European Network of Excellence for Paediatric Clinical Research), to which most of the GAPP Beneficiaries adhere), which is an independent multidisciplinary, multinational Network, born in 2005 as FP6 project, aimed at facilitating the performance of good quality paediatric studies and research. TEDDY is a category 1 member of the Enpr-EMA, the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA).
Moreover, networking with stakeholders was promoted through participation in the II Edition of the European Projects Forum “Nextwork” 2015 and in the third DEEP scientific Open Meeting. The GAPP project was also integrated in the websites of the DEEP Project, the Rare Disease Day promoted by EURORDIS and the Nextwork Forum.
Management of knowledge and intellectual property
Intellectual property rights (IPR) of the data has been held by the participants actively involved in the GAPP project. IPR handling has been tackled from the beginning of the project and has been specifically supported by management activities in WP1 and in WP10. Confidentiality among participants during the project development and confidentiality towards external participants, access rights, ownership and protection of results, just to mention a few aspects related to IPR handling, were covered in detail within the Consortium Agreement.
During the project, the Project Management Team, WP10 Leader and all other WP leaders have coordinated dissemination of foreground and results (in particular, decisions related to scientific publications and dissemination strategies to target groups). Dissemination plans and strategies have been updated, discussed and approved during meetings of the Management team.
Intellectual property and exploitation of results have been dealt within the Consortium Agreement in accordance with the indications reported in the Rules for Participation (RfP) and in the EC model Grant Agreement (ECGA).
* The address of the project public website, if applicable as well as relevant contact details.
Furthermore, project logo, diagrams or photographs illustrating and promoting the work of the project (including videos, etc...) as well as the list of all beneficiaries with the corresponding contact names can be submitted without any restriction.
List of Websites:
http://www.pediatricpain.eu/

Final Report Summary - GAPP (GAbapentin in Paediatric Pain)

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