Safe Excipient Exposure in Neonates and Small ChildreN

• Conditions: Excipient Exposure; Neonatal; Pediatric
• Interventions: Other: Exposure to ethanol; Other: Exposure to propylene glycol; Other: Exposure to benzyl alcohol; Other: Exposure to acesulfam potassium; Other: Exposure to aspartame; Other: Exposure to glycerol; Other: Exposure to sorbitol; Other: Exposure to methyl-p-hydroxybenzoate; Other: Exposure to propanyl-p-hydroxybenzoate; Other: Exposure to polysorbate-80

• Registration Number: NCT02545712
• Lead Sponsor: Bispebjerg Hospital

Brief Summary

The purpose of this study is to explore the quantity of excipient exposure in neonatal and young pediatric patients in a Danish Hospital. The focus will be on the preservatives ethanol, propyl glycol, benzyl alcohol, methyl-p-hydroxybenzoate and propanyl-p-hydroxybenzoate and the artificial sweeteners acesulfam potassium, aspartame, glycerol and sorbitol.

Detailed Description

Studies have previously examined whether or not neonatal nor pediatric patients are exposed to excipients and what excipients they are possibly exposed to. They have shown that practically all neonatal patients receive one or more drug containing an excipient, known to be harmful. This observational study will look at both registered drugs and extemporaneous pharmaceuticals as possible sources of excipients. Based on information provided by the manufacturer (ex. the index-list), the investigator will calculate the amounts of excipients administered to the patient a week after hospitalisation. The investigator will calculate the blood alcohol content when the neonatal patient are exposed to ethanol and/or propylene glycol.

By grouping the patients according to age and subgrouping according to diagnosis/affected organ system and compare the amount of excipient exposure in each group, the study aims at identifying the most vulnerable neonatal and/or pediatric patients in terms of the amount and identity of excipients accumulated in the patient.

The study will use a descriptive, parametric statistic analysis to identify

* an average exposure rate (concentration i mg/l or amount in mg) of each of the listed excipients

* how much the average patient in each age-group is exposed to each excipient

* how much the average patient in each "affected organ system"-subgroup is exposed to each excipient

Study Timeline

• Study First Submitted: 2015-09-03
• Study First Submitted QC: 2015-09-09
• Study First Posted: 2015-09-10
• Study Start: 2016-01
• Status Verified: 2017-02
• Last Update Submitted: 2017-02-04
• Last Update Posted: 2017-02-07
• Primary Completion: 2017-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 630

Inclusion Criteria

• if < 28 days: must receive 2 or more prescriptions a day
• if 28 days ≤ 5 years: must receive 3 or more prescriptions a day
• must have been/be submitted and treated at the neonatal department (units 5021, 5023, 5024) or pediatric department (units 5061, 5062, 5054, 4144) of Rigshospitalet

Exclusion Criteria

• no up-dated weight is listed
• > 5 years old

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Pediatric patients (28 days ≤ 5 years)	Exposure to methyl-p-hydroxybenzoate	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to acesulfam potassium	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to glycerol	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to methyl-p-hydroxybenzoate	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to ethanol	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to propylene glycol	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to propanyl-p-hydroxybenzoate	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to polysorbate-80	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to benzyl alcohol	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to benzyl alcohol	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to glycerol	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to sorbitol	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to acesulfam potassium	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to aspartame	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Neonatal patients	Exposure to sorbitol	Receiving 2 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to propylene glycol	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to polysorbate-80	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to ethanol	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to aspartame	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.
Pediatric patients (28 days ≤ 5 years)	Exposure to propanyl-p-hydroxybenzoate	Receiving 3 or more drugs at one day during their hospitalisation. For each drug, it is listed whether it is an extemporaneous, registered, the preparation, dosis, amount, interval, formulation and route of administration. It is noted if the drug contains ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propanyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerin and/or sorbitol.

Primary Outcome Measures

Name	Time	Method
Blood alcohol content measured in per mille (grams of ethanol and propylene glycol pr. kilograms of blood) in the patient	Single day	Both concentrations of ethanol and propylene glycol are included in the calculations. with propylene glycol 1/3 as intoxicating as ethanol.
Concentration (mg/kg/day) of polysorbate-80 in the patient	Single day
Concentration (mg/kg/day) of acesulfam potassium in the patient	Single day
Concentration (mg/kg/day) of aspartame in the patient	Single day
Concentration (mg/kg/day) of glycerin in the patient	Single day
Concentration (mg/kg/day) of propyl-p-hydroxybenzoate in the patient	Single day
Concentration (mg/kg/day) of benzyl alcohol in the patient	Single day
Concentration (mg/kg/day) of sorbitol in the patient	Single day
Concentration (mg/l) of methyl-p-hydroxybenzoate in the patient	Single day

Secondary Outcome Measures

Name	Time	Method
Identification of patient group (according to age-interval) most vulnerable to excipient exposure (measured in number of excipients)	During the participants hospitalization, an expected average of 2 months	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.
Identification of patient group (according to age-interval) most vulnerable to excipient exposure (amounts of each excipient measured in (mg/l))	During the participants hospitalization, an expected average of 2 months	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.
Identification of patient group (according to affected organ system) most vulnerable to excipient exposure (measured in number of excipients)	During the participants hospitalization, an expected average of 2 months	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.
Identification of patient group (according to affected organ system) most vulnerable to excipient exposure (amounts of each excipient measured in (mg/l))	During the participants hospitalization, an expected average of 2 months	The excipients (ethanol, propylene glycol, benzyl alcohol, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, acesulfam potassium, aspartame, glycerol, polysorbate-80 and sorbitol) will be ranked according to which excipient is most often present in the medicine administered to the patients.
Identification of number of patient exposed to ethanol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of ethanol to daily tolerance limit
Identification of number of patient exposed to propylene glycol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of proplyene glycol to daily tolerance limit
Identification of number of patient exposed to benzyl alcohol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of benzyl alcohol to daily tolerance limit
Identification of number of patient exposed to methyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of methyl-p-hydroxy-benzoate to daily tolerance limit
Identification of number of patient exposed to propyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of propyl-p-hydroxy-benzoate to daily tolerance limit
Identification of number of patient exposed to sodium-propyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of sodium-propyl-p-hydroxy-benzoate to daily tolerance limit
Identification of number of patient exposed to sorbitol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of sorbitol to daily tolerance limit
Identification of number of patient exposed to sodium-methyl-p-hydroxy-benzoate levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of sodium-methyl-p-hydroxy-benzoate to daily tolerance limit
Identification of number of patient exposed to polysorbate-80 levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of polysorbate-80 to daily tolerance limit
Identification of number of patient exposed to aspartame levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of aspartame to daily tolerance limit
Identification of number of patient exposed to glycerol levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of glycerol to daily tolerance limit
Identification of number of patient exposed to acesulfame potassium levels above tolerance levels proposed by international medicines agencies like EMA and FDA	Single day	Comparison of each patient daily exposure rate of acesulfame potassium to daily tolerance limit