Please select the eligibility criteria that correspond to the clinical trial below.
Title: Prevention of Parenteral Nutrition-Associated Cholestasis With Cyclic Parenteral Nutrition in Infants
Brief Summary: Hypothesis to be Tested:

Since the first description of intravenous alimentation over half a century ago, parenteral nutrition (PN) has become a common nutritional intervention for conditions characterized by inability to tolerate enteral feeds such as Short Bowel Syndrome, Chronic Intestinal Pseudoobstruction, Microvillus Inclusion Disease, Crohn's disease, multi-organ failure and prematurity. Parenteral Nutrition-Associated Liver Disease (PNALD) encompasses a spectrum of disease including cholestasis, hepatitis, steatosis and gallbladder sludge/stones which may progress to liver cirrhosis and even failure.

There is a direct correlation between duration of parenteral nutrition and development of cholestasis in infants. There is evidence in animals and humans that cycling of parental nutrition, defined as infusing nutrients over a time period shorter than 24 hours, reduces cholestasis. There is also data that premature infants with gestational age (GA) \< 32 weeks and birth weight \<1500g, as well as infants with congenital anomalies of the gastrointestinal tract, are among those at highest risk of developing Parenteral Nutrition-Associated Cholestasis (PNAC).

We therefore hypothesize that infants with gestational age (GA) \<32 weeks and birth weight (BW) between \<1500g, or with congenital anomaly of the gastrointestinal tract regardless of GA or BW, receiving PN over a period of 20 hours will have a decrease severity of PNAC, demonstrated by a lower peak direct bilirubin, compared to a similar control population receiving standard 24 hour infusion.


Options:
A: Inclusion Criteria:

* Children with documented cow's milk allergy, confirmed by one of the following criteria, within six months prior to study start (visit 2):

  * Positive double-blind, placebo-controlled oral food challenge (DBPCFC) with cow's milk OR
  * Positive open or single-blind oral food challenge with cow's milk carried out under the supervision of a specialist in children with clear immediate reactions and a positive test for specific IgE (in serum \[sIgE\>0,35 KUI/L\] or skin prick test \[SPT ≥ 3 mm\]) OR
  * Reported convincing allergic symptoms following an exposure to milk or a milk-containing food product and detectable serum milk-specific IgE or positive skin prick test
* Aged ≤12 years of age at screening.
* Expected consumption of a minimum of 250ml of study formula per day during the open challenge.
* Written informed consent from one or both parents (depending on the local legislation) or legal representative.

Exclusion Criteria:

* Children who receive breastfeeding at study enrolment.
* Had any chronic medical diseases, chromosomal or major congenital anomalies, or major gastrointestinal disease/abnormalities (other the CMPA); had immunodeficiency; antihistamine \[excluding eye drops\] use in 7 days prior to a food challenge or oral steroid use within 14 days prior to enrolment; unstable asthma; severe uncontrolled eczema;
* Severe anaphylactic reaction \[required ≥ 2 doses of epinephrine\] to milk or breast milk within the past 2 years;
* Existing illness that could interfere with formula acceptance or identification of allergic reactions.
* Investigator's uncertainty about the willingness or ability of the parents to comply with the protocol requirements.
* Participation in any other studies involving investigational or marketed products concomitantly or within two weeks prior to entry into the study.
B: Inclusion Criteria

o Aged older than 1 week with an established diagnosis of CPSD or OTCD (as follows):

* Diagnosed with late-onset CPSD confirmed by detection of pathogenic mutation(s), and/or decreased (\<20% of control) CPS enzyme activity in liver OR
* Diagnosed with late-onset OTCD by detection of pathogenic OTC mutation, OR decreased (\<20% of control) OTC enzyme activity in liver OR elevated urinary orotate (greater than 20 µM/mM) following allopurinol loading with the absence of argininosuccinic acid

AND: Subject or subject's first-degree relative had plasma ammonia level ≥100 μmol/L \>1 week of age

OR

o An established diagnosis of PA or MMA (as follows):

- Diagnosed with PA by semi-quantitative urine organic acid analysis, defined as the presence of elevated Methylcitric acid and normal methylmalonic acid levels and no evidence of biotin related disorders in the organic acid analysis

OR

- Diagnosed with MMA by semi-quantitative urine organic acid analysis, defined as an elevation of methylmalonic acid and no evidence of vitamin B12 dependent disorder on plasma amino acid analysis (B12 dependency is defined by documented B12 responsiveness)

AND: Subject or subject's first-degree relative had plasma ammonia level at any time ≥100 μmol/L

* Able to receive medications orally, by nasogastric (NG)-tube or by gastric (G)-tube
* No concomitant illness which would preclude safe participation as judged by the investigator
* If post-menarcheal must have a negative pregnancy test prior to administration of study drug at each episode
* Signed informed consent by the subject or the subject's legally acceptable representative

Exclusion Criteria

* Administration of NCG within 7 days of participation in the study
* Use of any other investigational drug, biologic, or therapy
* Planned participation in any other clinical trial
* Diagnosis of any medical condition causing hyperammonemia which is not PA/MMA, CPSD or OTCD. Other urea cycle disorders will be excluded from this study
* Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at additional risk by participating in this study
* Has had a liver transplant
* Is not expected to be compliant with this study in terms of returning to the site for subsequent episodes of hyperammonemia crises
* Is pregnant
C: Inclusion Criteria:

* Children with cow's milk allergy

Exclusion Criteria:

* Children without cow's milk allergy
D: Inclusion Criteria:

1. Infants expected to need prolonged PN (receiving \>75% PN on dol 7) with the following risk factors:

   1. Prematurity with gestational age (GA) \<32 weeks AND birth weight \<1500g. OR
   2. Congenital anomaly of the gastrointestinal tract regardless of GA or BW
2. Screening direct bilirubin prior to the initiation of parenteral nutrition \<2mg/dL.

Exclusion Criteria:

1. Infants with major congenital anomalies, other than those of the gastrointestinal tract.
2. Infants with known obstruction of the hepatobiliary tract.
3. Infants with suspected congenital infection or suspected genetic/metabolic syndrome predisposing them to cholestasis based on direct bilirubin \> 2mg/dL prior to instituting PN.

Answer: D