Network building


Apr, 2021

Adequate Daclatasvir exposures in children 14-35 Kg with available adult formulations


Authors: Cressey RT, Abbassi M, Lallemant M, Indolfi G, Al-Nahari M, Farid S, Easterbrook P, Penazzato M,  El-Sayed HM

Published in: CROI 2021


Abstract: World Health Organization 2018 guidelines recommend Sofosbuvir (SOF)/Daclatasvir (DCV) as a pangenotypic regimen for the treatment of adults with chronic HCV infection. SOF/DAC is widely available as low-cost generic formulation in low and middle-income countries (LMICs). Recent studies in adolescents (?12 to <18) using SOF/DCV 400/60 mg once-daily (OD) adult dose reported excellent efficacy and safety. DCV pharmacokinetic (PK) data in younger children are lacking. Within the framework of the Global Accelerator for Pediatric Formulations (GAPf), we performed a population PK analysis using data from adolescents to predict DCV exposure in children <35 kg to determine the lowest body weight children could be treated with the available DCV formulations (60 and 30 mg).

Data from HCV-infected adolescents receiving SOF/DCV (400/60 mg, OD) who participated in a PK study in Egypt were used for PK model development. Intensive PK sampling was performed pre-dose, then 0.5, 1.0, 1.5, 2, 4, 8, 12, and 24 hrs post-dose. PK parameters were estimated using a population approach (NONMEM VII). Monte Carlo simulations were run for virtual children between 10 to <35 kg receiving 60 mg or 30 mg OD and DCV exposures (AUC0-24) were compared with the expected adults range (6.15 to 20.63 µ

Seventeen HCV-infected adolescents (13 males) provided 151 DCV concentrations. Median (range) age was 14 (11-18) years and weight 50 (32-63) kg. DCV plasma concentrations were best described by a 1-compartment model with transit absorption compartments. Body weight (allometrically scaled) and albumin influenced DCV PK parameters. DCV oral clearance and volume of distribution were 7.05 L/hr/70kg and 95.8 L/70kg. In adolescents using 60 mg DCV OD, mean (SD) DCV AUC0-24, Cmax, and Clast were 12,004 (4,916), 1,182 (393) ng/mL and 194 (168) ng/mL, respectively; while predicted to be 9,808 (3,949), 1,039 (316) ng/mL and 148 (129) ng/mL in children 17 to <35 kg receiving 30 mg OD. Simulations showed that the proportion of children with DCV exposures above expected range rapidly increased for children <30 kg using 60 mg OD; and similarly for children 10-14 kg using 30 mg (Fig 1).

DCV 30 mg OD is expected to provide exposures comparable to adult values in children 14-35 kg. Our results suggest that children could be treated using currently available low-cost DCV formulations together with approved doses of pediatric SOF formulations, thus expanding access to HCV treatment.


Watch presentation slide video

Listen to presentation audio


Nov, 2020

Tools for Healthcare Workers to measure Health Research Capacity Development at an Individual Level



Author: Bilardi D, Rapa E, Bernays S, & Lang T

Published in: European Academy of Pediatric Societies


Background: Despite health research capacity development (HRCD) in low and middle-income countries (LMICs) being recognised as a critical element to overcoming global health challenges, insufficient actions have been taken to tackle major barriers to HRCD. A key barrier in supporting HRCD is the lack of empirical measurement of competencies to assess skills and identify gaps in research activities. An effective tool to measure HRCD would help drive more capable teams to undertake more locally-led research.

Aims: Primary aim: Systematically search the existing literature to investigate the nature, the scope and the extensiveness of existing tools created to measure HRCD at personal level in healthcare workers (HCW) working in LMICs. Secondary aims: identify a tool using a global evidence- based competency framework suitable for a comparable, standardised and consistent analyses of long term research competency acquisition in HCW in LMICs.

Methodology: Eleven databases were searched from inception to 16 January 2020. The first 10 pages of results from Google Scholar were also considered. The search was limited to English language publications. Two authors independently screened and reviewed studies using Covidence, extracted data and performed quality assessments using the extraction log validated against the CASP qualitative checklist. The content method was used to define a meta-narrative analysis.


View poster



Oct, 2020

European research networks to facilitate drug research in children



Author: Mark A. Turner, Katharine Cheng, Saskia de Wildt, Heidrun Hildebrand, Sabah Attar, Paolo Rossi, Donato Bonifazi, Adriana Ceci, Joana Claverol, Begonya Nafria, Carlo Giaquinto

Published in: British Journal of Clinical Pharmacology

Abstract: Paediatric drug development faces several barriers. These include fragmentation of stakeholders and inconsistent processes during the conduct of research. This review summarises recent efforts to overcome these barriers in Europe. Two exemplar initiatives are described. The European Paediatric Translational Research Infrastructure facilitates preclinical research and other work that underpins clinical trials. conect4children facilitates the design and implementation of clinical trials. Both these initiatives listen to the voices of children and their advocates. Coordination of research needs specific effort that supplements work on science, resources and the policy context.




Jul, 2020

Harmonisation preserves research resources


Authors: Vasconcelos MK, Epalza C, Renk H, Tagarro A, Bielicki JA

Published in: Lancet Infect Dis. 2020;24

In their Comment, the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) clinical characterisation group outline how harmonisation of clinical characterisation studies is achieved through their collaborative resource-sharing and data-sharing platform. We fully agree with both the importance of international harmonisation and the authors’ approach. Yet, in our opinion, they could have expressed more clearly how important harmonisation is to use resources in research responsibly and efficiently.




Apr, 2020

Respiratory pathogens detected in children with community-acquired sepsis-like syndrome in 6 European countries


Authors: V. Matheeussen, K. Loens, K. Jacobs, P. Horby, H. Goossens, M. Kohns Vasconcelos, M. Sharland, M. De Jong, M. P. G. Koopmans, P. Fraaij, M. Ieven

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: The management of infants admitted to hospital with sepsis-like syndrome (SLS) without apparent focus remains challenging. There is growing evidence indicating that this clinical picture is triggered by viral pathogens, like adenovirus, enterovirus or parechovirus with a possible respiratory point of entry. We aimed to identify an association in the presence of respiratory pathogens in nasopharyngeal swabs between children with SLS and controls.

Materials/methods: A total of 102 children (≤ 6 months old) admitted to hospital with community-acquired SLS and 308 asymptomatic controls (0-6 years old) were enrolled in a prospective case-control study as part of the MERMAIDS Trial (Multi-centre EuRopean study of MAjor Infectious Disease Syndromes, in 12 hospitals in 6 European countries. The Fast Track Diagnostics Respiratory pathogens 21 plus real-time PCR assay was used to determine the presence of respira- tory pathogens in nasopharyngeal swabs

Results: The most prevalent respiratory viral targets detected in the nasopharyngeal swabs of SLS patients were rhinovirus (28%), RSV A/B (9%), enterovirus (8%) and parainfluenzavirus (5%). All other viruses (influenzavirus, coronavirus, parechovirus, human metapneumovirus, adenovirus and bocavirus) were detected in <5%. Also bacterial targets like Staphylococcus aureus and Streptococcus pneumoniae, possibly colonizers, were often detected, both in 30% of the samples. Neither Myco- plasma pneumoniae, Chlamydophila pneumoniae nor Haemophilus influenzae type B were present. Compared to the control group, enterovirus and RSV A/B were detected more frequently in the SLS patients (8 versus 2% for enterovirus, p=0.01 and 9 versus 2% for RSV A/B, p=0.01). Adeno- and bocavirus were found more often in the control group (7 versus 1% for both viruses, p=0.02). No respiratory target was detected in 25% of the SLS samples.

Conclusions: Most (75%) of the nasopharyngeal samples from SLS patients contained one or more viral or bacterial respiratory targets. In our study, the role of influenza viruses was relatively limited. The possible role of enterovirus and RSV A/B in the pathophysiology of SLS should be further elucidated.


Apr, 2020

Aetiology and outcome of children hospitalised for acute respiratory tract infections in Europe: findings from a multi-country combined case-control and cohort study


Authors: M. Kohns Vasconcelos; on behalf of the PED-MERMAIDS Study Group

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Recently, major aetiology and outcome studies on paediatric acute respiratory tract infections (ARI) have been reported from LMICs. In contrast, studies using standardised protocols across Europe are lacking.

Materials/methods: The EU-funded Paediatric Multi-centre EuRopean study of MAjor Infectious Disease Syndromes (PED-MER- MAIDS) enrolled children under 5 years hospitalised for ARI and well controls across 11 EU countries. Information on symptoms, course of disease and clinical management was collected prospectively. Admission day nasopharyngeal swabs were analysed for influenza, parainfluenza, rhinovirus, coronavirus, metapneumovirus, bocavirus, respiratory syncytial virus (RSV), parechovirus, enterovirus and adenovirus and Streptococcus pneumoniae (Sp), Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae and Staphyloccous aureus.

Results: 353 ARI children, median age 1.13 years (IQR:0.44-2.56) and 352 controls, median age 1.76 years (IQR:0.96-3.73) were enrolled over 21⁄2 years. Swabs were analysed from 327 ARI children and 302 controls. No potential pathogen was detect- ed in 4.6% of ARI, only bacteria in 10.9%, only viruses in 33.9% and both bacterial and viral potential pathogens in 51.4%. Codetection of multiple (up to 4) viruses occurred in 31.2% of ARI and codetection of multiple bacteria in 16.9%. The most commonly detected pathogens are listed in table 1. Respiratory pathogens were detected in 62.8% of controls. Of the frequently detected pathogens, only RSV and influenza were strongly associated with hospitalisation for ARI (table 1). The population attributable fractions (PAF) were 33.6% for RSV and 18.0% for Sp. 209 ARI children (60.6%) received antibiotics, but this was not associated with detection of bacterial pathogens in study samples (OR=0.78, 95%-CI:0.48-1.28). Length of stay in hospital ranged between 0 and 49 days (median 3, IQR:2-5) and no child in the study died after admission for ARI.

Conclusions: Similarly to LMIC studies, RSV had the highest PAF for ARI hospitalisation in Europe, but with considerably lower mortality.


Sep, 2019

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


Authors: Kaguelidou F, Le Roux E, Mangiarini L, et al.; GAPP consortium

Published in: BMJ Open. 2019;9(2):e023296

Introduction 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.

Objectives 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.

Methods and analysis 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.

Ethics and dissemination 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.



Sep, 2019

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


Authors: de Leeuw TG, Mangiarini L, Lundin R, et al; GAPP consortium

Published in: Trials. 2019; 20(1):368

Background 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.

Methods/design 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.

Discussion 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.


We would like to update you on our recent activities