Clinical Research

Clinical Research 2019-11-06T10:57:10+00:00

Since 2002 CVBF is involved in clinical trial execution in the field of paediatric and rare diseases acting as Sponsor and Contract Research Organisation (CRO). The activities cover all phases of clinical trial development and management by providing specific services related to clinical trial management, regulatory and ethics, clinical sites selection and contracting, clinical operations and drug management, data management and monitoring, statistical analysis and medical reporting, pharmacovigilance.

CVBF is accredited as a non-profit promoter of clinical trials by the European Medicines Agency (EMA) and as a certified Contract Research Organisation by Italian Medicines Agency (AIFA) since 2009.

Many activities are conducted in the context of EU funded projects and are focused on the development and application of innovative methodologies in clinical trials for small populations (e.g. rare diseases, paediatrics), as well as the management of interventional, non-interventional, health technology assessment, pharmacoeconomic studies, and disease registries.

The regulatory activity includes the development and supervision of dossiers and documentation regarding national and European authorisation procedures for medicinal products (Orphan Designation, Development Plan for Children, Scientific Advice, Centralised Marketing Authorisation, Advanced Therapy, etc.), including authorisation to perform national and multinational clinical trial activities with access to EudraVigilance and EUDRACT.

Experiences

Pharmacovigilance activity in clinical studies of a product intended for the treatment of neonatal sepsis and bacterial meningitis in paediatric patients under 3 months of age 2013
Writing of an Orphan Designation Dossier (ODD) of a product intended for the treatment of hypoxic-ischemic encephalopathy in infants 2012
Preparation of the Paediatric Investigation Plan (PIP) of a product intended for the treatment of chronic pain in paediatric patients 2012
Preparation of the Paediatric Investigation Plan (PIP) of a product intended for the treatment of neonatal bacterial sepsis in paediatric patients under 3 months of age 2012
Preparation of a feasibility study, support to the regulatory procedures of Scientific Advice (SA) and Preparation of a Paediatric Investigation Plan (PIP) for a product intended for the treatment of hypothyroidism 2011
Preparation of the CTA documentation for conducting a clinical trial to evaluate the efficacy and safety of two oral chelators in paediatric patients with transfusion-dependent hemoglobinopathies 2011
Preparation of Paediatric Investigation Plan (PIP) of a product intended for the treatment of iron overload in paediatric patients with transfusion-dependent hemoglobinopathies 2011
Drafting and preparation of the Investigator’s Brochure and IMPD of a product intended for the treatment of neonatal sepsis and bacterial meningitis in paediatric patients under 3 months of age 2010
Preparation of the Paediatric Investigation Plan (PIP) of a product intended for the treatment of neonatal sepsis and bacterial meningitis in paediatric patients under 3 months of age 2010
Qualitative and quantitative assessment of a formulation intended for the treatment of a rare disease in infants 2010
Preparation of a dossier for Orphan Designation (ODA) for the treatment of a chronic myeloproliferative disorder 2009
Preparation of the prevalence section of a dossier for Orphan Designation (ODA) for the treatment of a paediatric brain tumour 2009
Preparation of a dossier for Orphan Designation (ODA) for the treatment of ovarian cancer 2009
Preparation of the Paediatric Investigation Plan (PIP) and of a dossier for Orphan Designation (ODA) for the treatment of a type of juvenile arthritis 2009
Preparation of the Paediatric Investigation Plan (PIP) of a product for the prevention of the complications of bone marrow transplantation 2009
Preparation of a dossier for Orphan Designation (ODA) for the prevention and treatment of a product for the prevention of the complications of bone marrow transplantation 2008
Critical evaluation of the regulatory documentation (CTD) for the registration of a product intended for the newborn 2008
Support to the regulatory procedures of Protocol Assistance for the orphan designation for a rare form of conjunctivitis 2007
Support to the preparation of the clinical protocol and regulatory procedures of Protocol Assistance for the development of a paediatric product with designated orphan indication 2007
Preparation of a dossier for Orphan Designation for the treatment of rare form of autism 2007
Evaluation of the regulatory compliance of anti-asthma products to the procedures established by the Paediatric Regulation 2007
Preparation of the Paediatric Addendum to the Expert Assessment of an antitussive drug product 2004
Proposal for a commercial placement of a dietary supplement in Italy/Europe 2004
Analysis and preparation of the CTD of a product intended for cosmetic sclerotherapy 2004
Conformity assessment of paediatric clinical protocols with national and European guidelines 2004
Feasibility study to extend the market exclusivity of a product intended for the treatment of a rare disease 2004
Preparation of the Protocol Assistance of an orphan product for the prevention of complications of radiotherapy 2004
Preparation of a dossier for Orphan Designation (ODA) of a product for the prevention of complications of radiotherapy 2004
Possible impact on the European market of a new surfactant designated as an orphan medicinal product 2003

TRIAL MANAGEMENT AND MONITORING area is involved in the study management, starting from its planning to publication of results and in monitoring activities.

Activities referring to the area include:

  • coordination necessary for the activation and the management of the centres involved in the clinical studies;
  • evaluation of the timing of the implementation and organization of the monitoring activities;
  • planning and coordination of ad hoc meeting with the study team to ensure the implementation and the realization of the action plans;
  • preparation and participation to the events with the investigators;
  • coordination and support to all the functions involved in both CVBF and external trials.

The monitoring activities consist in the supervision of the trend of the clinical study in order to guarantee that the study is conducted, recorded and reported in compliance with the protocol, the Standard Operative Procedures (SOPs) and the Good Clinical Practice (GCP). In particular, such activities include the qualification visit of the clinical centres (Site Qualification Visit – PSV), the visits at the beginning of the study (Study Initiation Visit – SIV), monitoring at site (Monitoring Visits – MOVs) and the visits at the end of the study (Close-Out Visit – COV) as well as the redaction of the reports (qualification, initiation, monitoring, close-out). In addition, monitoring activities may involve centralized monitoring and periodic contacts with site for enrolment rate verification and solution of problems/pendings.

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The resources operating in this area provide support in the activities of investigational product (IP) management foreseen in the framework of clinical trials.

In particular, the IP management activities are:

  • coordination of the logistic processes of the IP involved in the clinical trials among the Sponsor, Producer/s and clinical centres, facilitating the communication and the document changes;
  • monitoring the processes of shipment, receipt, storage, dispensing and accountability, returning and destruction of the IP, in compliance with the protocol, the Standard Operative Procedures (SOP) and the Good Clinical Practice (GCP);
  • collection of the documentation produced from the abovementioned processes for the traceability and Trial Master File (TMF) archiving purposes;
  • providing support to the Sponsor and/or Producer for the IP packaging and labeling (or relabeling, if required) processes in accordance with the protocol and regulatory requirements;
  • preparing and revising the SOP/s of IP management;
  • participation in the preparation of study documents (i.e. protocols, study manuals, clinical reports);
  • delivering the training on the IP management.

Here is the list of the performed/ongoing studies:

CLINICAL TRIALS

The study intends to provide a prospective validation and clinical evaluation of safety and efficacy of a new posaconazole dosing regimen for children and adolescents with cystic fibrosis and Aspergillus infection.

Prospective multicentre randomised, placebo-controlled double-blind trial to verify the effects of the administration of probiotics on intestinal microflora in paediatric patients with Cystic Fibrosis.
A double blind, randomised, multicentre, active controlled, parallel-group, phase III trial to evaluate the efficacy, safety and pharmacokinetics of intravenous clonidine (hydrochloride) compared to midazolam for sedation in children from birth to less than 18 years of age. The study is aimed at comparing a new paediatric formulation of clonidine with midazolam. It is ongoing and involves 5 EU countries.
Multi-centre, oral single dose experimental and modelling study to evaluate the pharmacokinetics of deferiprone in patients aged from 1 month to less than 6 years of age affected by transfusion-dependent haemoglobinopathies. The study was concluded on February 2014, providing scientific evidence that the dosage of deferiprone used in adults can provide sufficient exposure to ensure efficacy also in small children and allowing children aged under 6 years of age to start to be recruited in DEEP-2 Safety/Efficacy Study. The study has enrolled a total of 23 patients, of which 18 were considered as evaluable.
Multicentre, randomised, open label, non-inferiority active-controlled trial to evaluate the efficacy and safety of deferiprone compared to deferasirox in paediatric patients aged from 1 month to less than 18 years affected by transfusion-dependent haemoglobinopathies. The study is aimed at comparing for the first time the efficacy and safety of deferiprone (DFP) vs deferasirox (DFX) in paediatric patients affected by hereditary haemoglobinopaties requiring chronic transfusions and chelation. The trial is ongoing and involves 344 paediatric patients starting from 1 month of age in EU and non-EU recruiting sites.

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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. The protocol involves the enrolment of 94 patients to test the efficacy and safety of gabapentin monotherapy in the treatment of chronic pain with a neuropathic component.
Randomized, double-blind, placebo controlled, multi-centre, 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. 66 patients will be enrolled to test the efficacy and safety of gabapentin in combination with morphine in the treatment of severe chronic pain with a neuropathic component.

Prospective, monocentric, post-CE mark study to assess efficacy and safety of Hymovis® SPORT (32 mg/4 ml) intra-articular injection in in the management of knee pain and function in active patient affected by knee osteoarthritis due to overuse.

Evaluation of nutritional suitability and tolerability of a Human Milk Oligosaccharide (HMO) Mix Infant Formula for term infants.

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The primary clinical objective of this study is to establish the Optimal Biologic Dose (OBD) of losartan in 30 children aged 8-17 years with OI. Moreover, it aims to determine the changes in proxy efficacy outcomes of bone (mass, architecture and strength) and muscle (strength), and determine changes in quality of life using a validated disease-specific tool.

Efficacy, pharmacokinetics and safety of Meropenem in subjects below 90 days of age (inclusive) with clinical or confirmed late-onset sepsis: a European multicentre randomised phase III trial. The study ended in December 2014 with the enrolment of 272 patients.
Pharmacokinetics and safety of meropenem in infants below 90 days of age (inclusive) with probable and confirmed meningitis: a European multicenter phase I-II trial. The study ended in December 2014 with the enrolment of 51 patients.
Multi-centre randomised open label phase IIb study to compare the efficacy, safety and pharmacokinetics (PK) of an optimised dosing to a standard dosing regimen of vancomycin in neonates and infants aged less than 90 days with late onset bacterial sepsis known or suspected to be caused by Gram-positive microorganisms. The study is expected to start on 1st June 2016 and to enrol 300 patients.

Multi-centre randomized clinical trial to compare the safety and efficacy of Deferasirox and Deferiprone administrated in sequential mode versus Deferasirox or Deferiprone in monotherapy in patients affected by Thalassemia Major.

A Phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of elvitegravir (EVG) administered with darunavir/ritonavir (DRV/r) compared to current standard antiretroviral therapy in HIV-1 infected, virologically suppressed paediatric participants . The study is expected to enroll 300 HIV-1 infected children aged 6 to < 18 years from Western and Eastern Europe, South Africa, Thailand, Uganda and Latin America.
A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care (SOC) in children with HIV infection starting firstline or switching to second-line ART. The study is expected to enroll 700 HIV-1 infected children trial to evaluate the efficacy and safety of once daily DTG-based ART.
A prospective, double blind, randomised, 24 month study to assess the effect of prebiotic Galacto-oligosaccharide/polydextrose (GOS/PDX) supplemented formula compared with standard formula in preventing and modifying the history of allergy and acute infections in infants at risk of atopy.

A 36-months multi-centre randomized interventional pragmatic trial to evaluate the effectiveness and safety of glatiramer-acetate (GA) compared to interferon-beta (IFN-beta) in paediatric patients affected by multiple sclerosis.

A randomized phase II/III trial of doxycycline (versus standard supportive therapy) aimed at establishing whether the addition of the antibiotic doxycycline to anti-plasma cell therapy can reduce early mortality in newly-diagnosed patients with cardiac AL amyloidosis.

A non-pharmacological, prospective, multicentre, randomised, open study with a medical device aimed to demonstrate the major effectiveness of Reveal LINQ device compared to the ECG standard monitoring in the management of the therapeutic strategies for patients undergoing transcatheter aortic valve replacement (TAVR).

A phase 2/3 multicentre, open-label, randomised study aimed at evaluating the safety and antiviral effect of once daily integrase inhibitor administered with darunavir/ritonavir (DRV/r) compared to the current standard antiretroviral therapy in HIV-1 infected, virologically suppressed paediatric participants.

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A multi-centre, randomised, single blind phase II trial to evaluate the pharmacokinetics and PKPD relationship of trazodone after single and repeated oral doses in children from 2 to ≤17 years of age, suffering from insomnia, with autism, intellectual disability or attention deficit hyperactivity disorder (ADHD).

NON-INTERVENTIONAL STUDIES

Non-interventional studies

Long-term observational safety study of deferiprone use in paediatric patients. The study evaluates the nature and incidence of adverse effects of deferiprone (DFP) in children and adolescents with beta-thalassaemia major. Patients treated with deferiprone are followed up throughout their treatment, from its start up to conclusion in October 2015.
Study on Quality of Life, treatment satisfaction and economic burden of disease in patients with b-thalassemia major undergoing iron chelation treatment/Qualità della vita, soddisfazione del paziente e costi della malattia in pazienti affetti da β-talassemia major sottoposti a trattamento di chelazione del ferro (HTA-Thal, “Inter-regional Network for Thalassaemia: HTA for the diagnostic and therapeutic intervention for iron overload”). The study consisted of 24-month observation period with different levels of information recorded in the first and second year of observation. The aim of this study was to assess the economic impact of thalassaemia and the burden of disease in terms of health-related quality of life (HRQoL) in a cohort of 272 adolescent (>12 yrs) and adult thalassaemic patients. The study was also aimed at investigating compliance, quality of life, patients’ satisfaction and costs associated with the different iron chelating treatments, in the perspective of the Italian Health National Care System and the society.
Quality evaluation of the informative booklets for patients involved in the DEEP-2 trial (QuBo). The aim of the study is to investigate the quality of the informative material addressed to paediatric patients involved in the DEEP-2 study, in order to evaluate the level of comprehension and the likeability of the informative documents for paediatric patients. Particularly, QuBo foresees the administration of an age-tailored structured questionnaire to directly collect the children’s and adolescents’ opinion on the DEEP-2 informative material.

OTHER STUDIES

Population pharmacokinetics meta-analysis based on all available published studies and data collected during clinical practice to determine the optimised dosage regimen of vancomycin to be used in children less than 3 months of age.
Model-based bridging of clinical data for children from 3 months to < 3 years to simulate PK/PD, clinical efficacy and safety data of gabapentin in children from 3 years to less than 18 years of age in chronic pain.
A systematic review analysing the methods of treatment of sepsis and the factors causing antibiotic resistance in neonatal population is ongoing. The review is focused on the situation in five major European countries and results will been soon provided to the customer (Chiesi Farmaceutici SpA).

PHARMACOECONOMIC ANALYSES

A pharmacoeconomic and HTA evaluation on the use of deferiprone formulation in paediatrics aimed to guide the inclusion of the drug in the current Protocol and Guidelines.
A market analysis aimed to determine the share of paediatric patients that could be treated with clonidine for sedation including possible competitors and potential profitability.
A HTA report including a cost/benefit evaluation aimed to guide the implementation of clinical recommendations for the use of gabapentin as monotherapy and/or add-on therapy.