Personalized vs Standardized PN for Preterm Infants >1250g

Study Overview
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Brief Summary
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Preterm infants (gestational age between 189 and 258 days) with a birth weight (BW) greater than 1250 grams will be randomized to personalized-parenteral nutrition (P-PN) or standardized-parenteral nutrition (S-PN). The aim of the study is to evaluate the effect of S-PN versus P-PN on growth of preterm infants with BW>1250 grams.

Detailed Description
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Parenteral nutrition (PN) is a crucial part of the clinical care of preterm infants. Traditionally different components of PN are prescribed individually considering requirements of an individual infant (P-PN). Recently, standardized PN formulations (S-PN) for preterm infants have been assessed and may have advantages including a better provision of nutrients, less prescription and administration errors, decreased risk of infection, and cost savings. The recent introduction of triple-chamber bags that provides total nutrient admixture for infants may have the additional advantage of decreased risk of contamination and ease of administration. The proposed intervention and hypothesis: The investigators propose a multi-centered Phase IV RCT to compare S-PN versus P-PN, that is the usual care for preterm infants with a birth weight >1250 grams requiring PN in the intensive care units involved in the study. The investigators hypothesize that weight gain during PN of preterm infants with a BW greater than 1250 grams who received S-PN is not statically inferior (< 2g/kg/d) to that of infants who received P-PN (Non-inferiority study). Study design: Preterm infants (gestational age between 189 and 258 days) with a BW greater than 1250 grams will be enrolled during hospitalization after the informed consent is drawn from parents or legal guardians. All infants will undergo a physical examination and the need of PN will be judged by the caring physician according to predefined criteria. Infants requiring PN will be divided into 3 clinical groups: Group A or EARLY HIGH-RISK INFANTS: these infants present in rather severe conditions at birth or soon after birth which make enteral nutrition (EN) impossible or non-desirable. In this group of infants, the investigators will include patients with Perinatal asphyxia, Perinatal shock (Cardiovascular or Septic), GI malformations, Severe Intra-uterine growth retardation (IUGR) with markedly abnormal prenatal doppler, and Miscellanea. These infants will have a central venous access soon after birth. Group B or INSUFFICIENT EN INTAKE: these Infants are in rather stable conditions after birth, however these infants may exhibit gastrointestinal (GI) intolerance of any origin. These patients will be randomized after 72 hours of life if the mean EN volume of the first 72-hrs of life will be less than 30 ml/kg/d or if EN intake on the third day will be less than 45 ml/kg/d. In this category, the investigators will include also those infants who will have their EN intake reduced below 30 ml/kg for 3 consecutive days (usually from day 3 through day 6) because of PDA treatment. These infants will have a central venous access inserted on the 3rd or 4th day of life if not already in place. Group C or LATE SICKNESS: these are the infants that experience a major sickness after a variable period of good gastrointestinal tolerance. In this group, the investigators will have infants with Necrotizing Enterocolitis (NEC), Severe Sepsis with abdominal distension and poor peristalsis, Septic Shock, or other severe unexpected conditions such as volvulus etc. These infants will also have a central venous access. Study infants within each clinical group will be divided into 2 blocks on the basis of their BW: 1250-1750 g (Block A) e >1750 g (Block B). Infants of each study group will be then randomly assigned to P-PN or S-PN (Intervention-arm). The study PN bags will be used until the study infants will not be able to tolerate 135 ml/kg/d enterally (range: 120-160 ml/kg/d according to the local practice) or until day 28 of PN (after the 28th day of PN, patients will receive PN according to the normal clinical practice).

Official Title
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Personalized Versus Standardized Parenteral Nutrition for Preterm Infants With a Birth Weight Greater Than 1250 Grams: a Multicenter Randomized Phase IV Clinical Trial

Conditions
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Infant,Premature, Parenteral Nutrition, Growth

Intervention / Treatment
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* Drug: Standardized-parenteral nutrition (S-PN)
* Drug: Personalized-parenteral nutrition (P-PN)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Birth weight greater than 1250 grams, Gestational age between 189 and 258 days, In need of parenteral nutrition (PN), Signed informed consent by at least one parent or legal guardian. Exclusion Criteria: Genetic, metabolic, or endocrine disorders diagnosed before/after enrolment Ceftriaxone or Coumarin therapy before/after enrolment, Calcium therapy before enrolment, Cholestasis or hepatic insufficiency before enrolment, Renal insufficiency before enrolment, Hyponatremia before enrolment, Hypertriglyceridemia before enrolment, Hypersensitivity reaction to components of parenteral nutrition before/after enrolment, Off-label use of drug therapy before/after enrolment, Absent informed consent.

Ages Eligible for Study
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Minimum Age: 189 Days
Maximum Age: 258 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Personalized-Parenteral Nutrition (P-PN)<br>These patients will receive personalized parenteral nutrition (PN) as it is customary in the participating centers. Dosing range: glucose from 9 to 13 g/kg/d, AA from 2.0 to 3.0 g/kg/d, and FAT from 1.5 to 2.5 g/kg/d. Intravenous macronutrient intakes: PN day 1: 2.0 g/kg of AA, 1.6 g/kg of FAT and 9 g/kg of glucides. PN day 2: 2.5 g/kg of AA, 2.0 g/kg of FAT and 11 g/kg of glucides. PN day 3 and the days after: 3.0 g/kg of AA, 2.5 g/kg of FAT and 13 g/kg of glucides. Intravenous vitamins will be supplied according to local clinical practice. Variations in macronutrient intakes will be tolerated within ±20%. Nutritional goal: to ensure at least 2.5 g/kg/d of AA and 70 kcal/kg/d of no protein energy (NPE) from PN day 2. | Drug: Personalized-parenteral nutrition (P-PN)<br>* Intravenous glucose will be dextrose 50%, amino acids (AA) will be Primene® and lipids (FAT) will be Clinoleic®. Parenteral nutrition bags will be prepared by the hospital pharmacy according to the prescription of the attending neonatologist.<br>|
| Experimental: Standardized-Parenteral Nutrition (S-PN)<br>These patients will receive standardized parenteral nutrition (PN) by using a triple chamber bag (Numeta G13%E®). Dosing range: 80-300 ml/d. Intravenous macronutrient intakes: 65 ml/kg at PN day 1, 80 ml/kg at PN day 2 and then 100 ml/kg from PN day 3. Nutritional goal: to ensure at least 2.5 g/kg/d of amino acids (AA) and 70 kcal/kg/d of no protein energy (NPE) from PN day 2. | Drug: Standardized-parenteral nutrition (S-PN)<br>* NUMETA G13%E 300 mL is a triple-chamber (lipid emulsion, amino acids solution with electrolytes, and glucose solution), ready-to-use parenteral nutrition product available to treat preterm infants (less than 37 weeks gestational age).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WEIGHT CHANGE | Daily weight change (g/kg/d) during parenteral nutrition (PN) | From the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). At least 7 days of PN will be required to calculate weight gain during PN. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MUSCLE ULTRASOUND (optional) | Ultrasound measurement of mid thigh and mid arm muscle thickness (cm). | At the start of PN, after 7, 14 and 28 days (+-1 d). | 
| ADIPOSE TISSUE ULTRASOUND (optional) | Ultrasound measurement of mid thigh and mid arm adipose tissue thickness (cm). | At the start of PN, after 7, 14 and 28 days (+-1 d). | 
| BONE ULTRASOUND (optional) | Metacarpus speed of sound (m/s) and metacarpus bone transmission time (ms). | At the start of PN, after 7, 14 and 28 days (+-1 d). | 
| WEIGHT | Weight measured by a digital infant scale (grams) | Daily up to 42 weeks of post menstrual age or discharge if it comes first. | 
| TOTAL BODY LENGTH | Total body length measured by a neonatal stadiometer (cm) | Weekly up to 42 weeks of post menstrual age or discharge if it comes first. | 
| HEAD CIRCUMFERENCE | Head circumference measured by a flexible non-stretchable tape (cm) | Weekly up to 42 weeks of post menstrual age or discharge if it comes first. | 
| GLUCIDE TOLERANCE | Blood glycemia (mg/dl). | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| AMINO ACID TOLERANCE | Plasma and urinary urea concentrations (mg/dl). | At the start of PN, at PN day 7 (+-1 d) and 14 (+-1 d), and then every 2 weeks until the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| TRIGLYCERIDE CONCENTRATION | Plasma triglycerides (TG; mg/dl). | At PN day 3 (+-1 d) and 7(+-1 d), and then every 7 days (+-1 d) until the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| FATTY ACID CONCENTRATION (optional) | Plasma fatty acid concentration (FA; mg/dl). | At PN day 7 (+-1 d). | 
| DICARBOXYLIC AND HYDROXYL FATTY ACID CONCENTRATION (optional) | Urinary dicarboxylic acids (DCA; mmol/mol creatinine) and hydroxyl fatty acids (H-FA; mmol/mol creatinine). | At PN day 7 (+-1 d). | 
| ELECTROLYTE CONCENTRATION | Hemogasanalysis (Na+, mmol/l; K+, mmol/l; Ca2+, mg/dl; Cl-, mmol/l) and SBE (standard base excess, mmol/L) | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| HYPER AND HYPO-NATREMIA, -KALEMIA, -CHLOREMIA, -PHOSPHATEMIA, -CALCEMIA, AND -PARATHYROIDISM | Episodes of Hyper/Hypo Natremia, -KaIemia, -Chloremia, -Phosphatemia, -Calcemia, and -Parathyroidism (number). | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| METABOLIC ACIDOSIS | SBE < -7.5 mmol/L. | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| BONE MINERALIZATION-1: CALCIUM and PHOSPHORUS CONCENTRATIONS | Plasma and urinary calcium and phosphorus concentrations (mg/dl). | At the start of PN and at PN day 7 (+-1 d). An additional measurement will be done at PN day 28 (+-1 d) in patients requiring long term PN. | 
| LIVER FUNCTION: ALP, AST, ALT AND GGT CONCENTRATIONS | Plasma alkaline phosphatase (ALP; UI/L), aspartate transaminase (AST; UI/L), alanine transaminase (ALT; UI/L), and gamma-glutamyl transpeptidase (GGT, UI/L). | At the start of PN and at PN day 7 (+-1 d). An additional measurement will be done at PN day 28 (+-1 d) in patients requiring long term PN. | 
| BONE MINERALIZATION-2: PTH CONCENTRATIONS | Plasma parathormone concentrations (PTH; pg/ml). | At the start of PN and at PN day 7 (+-1 d). An additional measurement will be done at PN day 28 (+-1 d) in patients requiring long term PN. | 
| BONE MINERALIZATION: PYD, PICP and ICTP CONCENTRATION (optional) | Urinary pyridinoline crosslinks of collagen (Pyd; nmol/L), serum carboxyterminal propeptide of type I procollagen (PICP; ng/mL) and serum cross-linked carboxyterminal telopeptide of type I collagen (ICTP; ng/mL) | At the start of PN and at PN day 28 (+-1 d) (endpoint). | 
| BILIRUBIN CONCENTRATION | Plasma bilirubin (total and conjugated; mg/dl) | At PN day 7 (+-1 d). An additional measurement will be performed at PN day 14 (+-1 d) in case of PN duration >14 days. | 
| MORBIDITY - 1 | The incidence of the main complication of prematurity (intraventricular hemorrhage of 3° and 4° grade; Periventricular leukomalacia; Patent ductus arteriosus; Retinopathy of Prematurity; Bronchopulmonary dysplasia and Sepsis). | Up to 42 weeks of post menstrual age or discharge if it comes first. | 
| MORBIDITY - 2 | The incidence of Cholestasis and Renal and Hepatic Insufficiency. | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| MORTALITY BEFORE 42 WEEKS POST MENSTRUAL AGE | Death before 42 weeks post menstrual age (number). | At 42 weeks of post menstrual age or discharge if it comes first. | 
| MORTALITY DURING PARENTERAL NUTRITION | Death during PN (number). | From the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| ENTERAL NUTRITION INTAKES | Enteral nutrition intakes (ml/kg). | Daily from the start of PN to day 28 of life. | 
| PARENTERAL NUTRITION INTAKES: AMINO ACIDS | Intravenous amino acid intakes (g/kg). | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| PARENTERAL NUTRITION INTAKES: LIPIDS | Intravenous lipid intakes (g/kg). | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| PARENTERAL NUTRITION INTAKES: GLUCOSE | Intravenous glucose intakes (g/kg). | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| PARENTERAL NUTRITION DURATION | PN duration (days). | Daily from the start to the stop of PN (endpoint: PN day 28 if PN duration >28 days). | 
| MECHANICAL VENTILATION | Mechanical ventilation duration and oxygen therapy duration (days). | Up to 42 weeks of post menstrual age or discharge if it comes first. | 
| DRUG THERAPIES | Drug therapy duration (hours). | Up to 42 weeks of post menstrual age or discharge if it comes first. | 
| PHARMACOECONOMICS | Healthcare costs (euro). | Up to 42 weeks of post menstrual age or discharge if it comes first. | 
| METABOLIC COMPLICATIONS | Number of hypertriglyceridemic episodes (plasma triglycerides>265mg/dL), hyperglycemic and hypoglycemic episodes (blood glycaemia>175 mg/dL and <40 mg/dL, respectively) and elevated urea (blood urea>100 mg/dL). | Up to 42 weeks of post menstrual age or discharge if it comes first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm, Infant, Parenteral Nutrition, Growth