Title: Evaluation and validation of a breath ammonia measurement technology for the improved management of patients with urea cycle defects
Funder: Department of Health and Social Care

Abstract: A detailed Gantt chart is given in Fig. 3. WP1: Project management (M1-M21) Monitoring and controlling progress, budget and risk Monitoring and guiding ethics, IP and validation WP2: Patient and public involvement (M1-M21) Recruitment of patient/carer contributors to Steering Committee and PPI Advisory Group On going support of both research team (on PPI) and patient/carer contributors PPI contribution to all other work packages, in particular WP1, WP4, WP5 and WP7 WP3: Preparation of AmBeR system prototype for clinical evaluation (M1) Supply, installation and training of four AmBeR instruments at clinical sites Supply of sensors, consumables and operational maintenance of instruments MS1: Availability of four clinic ready AmBeR system prototypes for performance evaluation (TRL 5) &ndash; M1 WP4: Clinical performance evaluation (M1&ndash;M12) Recruitment of 63 patients across four centres with age and sex-matched non-UCD controls Testing (standard of care, blood and breath ammonia; 2 repeats) of patients on multiple occasions on both a planned and opportunistic basis Qualitative data relating to the test, use of the device and user experience will be recorded Formal calibration of the device using paired blood and breath ammonia levels Quantification of the normal range using the age and sex matched control subjects. Clinical range &ndash; Approx 50 ppbv breath ammonia to an upper value TBD Assess accuracy at predicting blood ammonia levels or for assessing change from an individual patient s healthy levels Bland-Altman plot to demonstrate limits of agreement across clinically relevant range. Assess measurement reproducibility, reliability, repeatability under different conditions or ages of patients Sensitivity and selectivity to demonstrate clinical blood ammonia cut offs (35 and 100 &micro;M) with 95% confidence intervals Identify cut-offs for home testing to identify 99.9% of patients who require clinical intervention. MS2: Verification of device performance specification for measurement of breath ammonia in UCD patients in clinical environment (TRL 6) &ndash; M9 WP5: Design revision of AmBeR UCD system prototype (M1-M12) Gathering of design inputs from clinicians, patients and regulatory requirements Preparation of revised performance specification Analytical (TRL 5) and clinical (TRL 6) revalidation of the AmBeR UCD prototypes Acceptance criteria to be defined by revised performance specification MS3: Verification and validation of AmBeR UCD device performance specification for measurement of breath ammonia in UCD patients in clinical environment (TRL 6) &ndash; M12 WP6: Regulatory compliance and certification (M1 &ndash; M18) Certification and approval of AmBeR UCD device to harmonised medical equipment standards, principally IEC 60601 and others (M12) Risk analysis within an ISO 14971:2012 framework Instrument manufacture within an ISO 13485 compliant production process Definition of approval requirements for a self-use diagnostic device under 98/79/EC and FDA regulations (M18) WP7: Home healthcare evaluation (M12 to M21) Patients/carers will undergo training on the use of the AmBeR UCD system (20 systems, five managed by each clinical site) Implementation of a home testing protocol Monitoring and recording of breath ammonia levels and user experiences and patient condition Processing and analysis of breath ammonia levels &ndash; comparison with clinical measurements; trend analysis; correlation with patient health status; algorithm development Investigation of potential for a remote monitoring regime MS4: Determination of the potential of AmBeR UCD for remote management of urea cycle defects &ndash; M21 WP8: Health economic analysis (M16 to M21) Collect reasons/number of hospital admissions and doctors contacts Measure parental days off work for childcare Measure child and parental quality of life MS5: Estimation of NHS costs and quality of life for children and parents living with UCD &ndash; M21

Lay abstract: There is a group of rare genetic disorders termed Urea Cycle Defects (UCDs) which mostly affect children. When you eat protein, it contains the element nitrogen, which can be poisonous if not removed from your body. Nitrogen is normally safely removed in urine as part of a larger molecule called urea. However, children with UCDs are not able to change the nitrogen to urea. Instead, the nitrogen can become part of another molecule called ammonia. You may have heard of ammonia being used as a chemical, for instance, as cleaning fluid and so it can be quite dangerous. It is also poisonous if it builds up inside the body. This is what can happen to children with UCDs. If this happens, the ammonia can poison the brain, leaving the children with learning difficulties or can lead to coma and death. In many cases, there is no cure for this disease and these children and their families live with this condition all of their lives. Mostly, they are quite healthy; as long as they are careful about how much protein they eat and never leave it too long between carbohydrate meals. Most patients also need to take medication to help clear the ammonia that builds up naturally in order that it can be removed by the kidneys. However, if they become unwell with something like a cold or a tummy bug, this can upset their ammonia levels and they can become extremely unwell very quickly. It is very difficult for their parents to be sure whether they are just a little bit sick, or whether they will get really sick with high ammonia and so they must always bring them into the hospital to have their ammonia levels checked. This causes daily worry and regular disruption to their lives. At the moment, the best way the doctor can tell if a child is sick is to test the ammonia in their blood, which is particularly difficult to do, as well as not being pleasant for the patient. What might help patients would be a way that they could easily monitor their own ammonia levels at home, regularly and conveniently, so that they could be sure if their child was developing high ammonia levels or not. This could even mean that the doctors could tell the parents what to do to make things better, without having to go to the hospital, or at least only having to bring them in because they really were sick. A device has been invented which measures the ammonia in your breath. It is believed that the ammonia in your breath is related to how much ammonia is in your blood. However, this needs to be properly tested. If this were found to be true, and if the patients and their families could regularly measure the breath ammonia by themselves, it might allow children with UCDs to live longer, healthier, happier lives, while also saving money. This research wants to see if this is the case.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE