Investigating a New Way of Giving Medicine to Newborn and Preterm Babies

Osteopenia of Prematurity Clinical Trial

Official title: Oral Potassium Acid Phosphate Supplementation for Preterm Neonates; a Comparison of Oral Thin Films and Standard Oral Therapy.

Status Not yet recruiting

Clinical Trial Summary

There is a deficit in the number of 'age-appropriate' formulations available for the delivery of medicines to children. Liquid preparations are considered the 'gold standard' for delivering medicines to children however many of these are formulated using ingredients which can be toxic to children (e.g. preservatives, alcohols), particularly to neonatal babies (< 4 weeks old) who do not possess the metabolic processes and mature organ function of older children or adults. Rapidly dissolving oral thin films (OTFs) dissolve quickly in the saliva, releasing the active ingredient(s) without the need for chewing or water, making them ideally suited to patients who find it difficult to swallow other oral dosage forms such as tablets or capsules. The aim of this study is to demonstrate that OTFs can offer a safe and effective alternative for oral administration of phosphate supplements to neonatal infants for the treatment of hypophosphataemia and osteopenia of prematurity. It is hypothesised that this treatment will be equal to standard therapy using an oral solution. Babies born before 32 weeks gestational age are routinely supplemented with oral phosphate as soon as they have been established on oral feeds in order to prevent bone disorders such as osteopenia. Babies recruited to this study will be given phosphate supplementation as per NHS Greater Glasgow and Clyde guidelines. This single-centre cross-over study will take place in the intensive care and special care baby units at the Princess Royal Maternity in Glasgow. The investigators aim to recruit 20-30 babies and will use blood phosphate levels (obtained from routine sampling only) to evaluate treatment effect. Babies will be randomised to receive either OTFs or oral solution of potassium acid phosphate for 2 weeks followed by 2 weeks of the other therapy. The investigators hypothesise that OTF treatment will be equivalent to standard oral solution.

Clinical Trial Description

There is a lack of 'age-appropriate' formulations available for delivering medicines to children. Liquid formulations are considered the 'gold standard' for delivering medicines to children. However, many of these are formulated using ingredients which can be toxic to children, and particularly to neonates (children <4 weeks old), who do not possess the metabolic processes and mature organ function of adults. For example, many liquid formulations contain preservatives such as benzoic acid to improve the shelf-life of the product, or include solvents such as propylene glycol or ethanol to improve solubility. Many of these additional, functional ingredients can product toxic effects in children. For example, neonates are unable to metabolise benzoic acid, resulting in the accumulation of this ingredient and potentially serious neurological and respiratory effects known as 'gasping syndrome'. Additionally, the lack of suitable licensed formulations for children leads to the routine prescribing of medicines outside the terms of their product license and/or the manipulation of medicines to make them suitable for children e.g. grinding up tablets. Further manipulation of products increases the risk of inaccurate dosages being administered, and adds a risk of error where additional calculations are required. There are also concerns over compatibility when medicines are, for example, mixed with foods or drinks in an attempt to improve acceptability. Looking specifically at prescribing within neonatal intensive care, up to 90% of medicines prescribed are unlicensed or off-label i.e. used in a way not covered by the product licence. Therefore, there is a need for more age-appropriate solid formulations suitable for delivering medicines to children. By formulating the medicine in a solid dosage form, the need for excipients such as preservatives can be removed. Within the last few years, rapidly dissolving oral thin films (OTFs) have been developed as a novel solid dosage platform for drug delivery. They were first established as breath fresheners and have since progressed towards delivery of active pharmaceutical ingredients (APIs). Approximately the size of a postage stamp, OTFs dissolve quickly in the saliva, releasing the drug(s) without the need for chewing or water. They are ideally suited to patients who find it difficult to swallow other oral dosage forms such as tablets or capsules. Paediatric and elderly patients are particularly suited to this dosage design. Flavourings and sweeteners can be included in the films to mask a bitter tasting medicine if necessary. The films are discreet, easy to use and convenient. They have a history of uses in oral hygiene products and medical devices. Recent developments have seen their use in over-the-counter cough and cold remedies and anti-allergy products. In 2010, Zuplenz® became the first FDA approved prescription only medicine in an OTF formulation for the delivery of ondansetron in the treatment of chemotherapy-induced nausea and vomiting. Most recently in February 2012, Applied Pharma Research (APR) were successful in marketing a prescription only zolmitriptan based OTF product for the treatment of migraine. A basic thin film formulation can contain very few ingredients and since they are presented as a solid dosage form, they do not require the addition of preservatives. In the USA, Novartis has already marketed several thin film products under the brand Triaminic® which are aimed at children from as young as four for the treatment of coughs, colds, and allergies. In order to investigate whether OTFs are a safe alternative for drug delivery to neonates, an OTF containing potassium acid phosphate (KAP) has been formulated. KAP was chosen for this study since it is a non-toxic mineral supplement routinely given to preterm infants to improve bone health. The majority of fetal uptake of calcium and phosphorus occurs during the third trimester of pregnancy and so preterm infants are born with reduced body stores of these minerals. Hypophosphataemia (low blood phosphorus) results in increased levels of calcitriol, the active form of vitamin D, and subsequent demineralisation of bone (osteopenia). The association between low birth weight, hypercalcaemia (high blood calcium) and hypophosphataemia was first identified in the early 1980s. It was identified that active demineralisation of bone was occurring in order to maintain the blood levels of phosphate required for other cellular functions and tissue growth. Reduced bone mineral density or metabolic bone disease in very low birth weight premature infants can lead to complications such as fractures and reduced growth. Preterm infant milk formulas and human breast milk fortifiers are supplemented with phosphate, and in addition within NHS Greater Glasgow and Clyde it is routine clinical practice to provide all preterm infants born before 32 weeks' gestational age with an oral phosphate supplement. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypophosphataemia
• Hypophosphatemia
• Osteopenia of Prematurity
• Premature Birth

• NCT number: NCT01676844
• Study type: Interventional
• Source: University of Strathclyde
• Contact: Helen Mactier, MB ChB
• Phone: 011441412115249
• Email: Helen.Mactier@ggc.scot.nhs.uk
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 2013
• Completion date: November 2013