Personalized vs Standardized PN for Preterm Infants >1250g

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

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.

Study Overview

• Status: Recruiting
• Conditions: Growth; Parenteral Nutrition; Infant,Premature
• Intervention / Treatment: Drug: Personalized-parenteral nutrition (P-PN); Drug: Standardized-parenteral nutrition (S-PN)

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Virgilio P Carnielli, MD, PhD; Phone Number: +39 071 596 2045; Email: v.carnielli@univpm.it
• Study Contact Backup: Name: Alessio Correani, MSc, PHD; Phone Number: +39 071 596 2888; Email: alessio.correani@gmail.com

Study Locations

• Italy
  • Ancona, Italy, 60123
    • Recruiting
    • Ospedali Riuniti Ancona
    • Contact: Virgilio Carnielli, MD, PhD; Phone Number: +390715962045
  • Padova, Italy
    • Recruiting
    • Azienda Ospedaliera Di Padova
    • Contact: Giovanna Verlato, MD, PhD
• Spain
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: Miguel Pipaon, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 8 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Personalized-Parenteral Nutrition (P-PN); 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); 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.
Experimental: Standardized-Parenteral Nutrition (S-PN); 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); 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).

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Ospedali Riuniti Ancona
• Collaborators: Azienda Ospedaliera di Padova; Hospital Universitario La Paz

Publications and helpful links

General Publications

• Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006 Apr;117(4):1253-61. doi: 10.1542/peds.2005-1368.
• Schoeller DA, Ravussin E, Schutz Y, Acheson KJ, Baertschi P, Jequier E. Energy expenditure by doubly labeled water: validation in humans and proposed calculation. Am J Physiol. 1986 May;250(5 Pt 2):R823-30. doi: 10.1152/ajpregu.1986.250.5.R823.
• Evering VH, Andriessen P, Duijsters CE, Brogtrop J, Derijks LJ. The Effect of Individualized Versus Standardized Parenteral Nutrition on Body Weight in Very Preterm Infants. J Clin Med Res. 2017 Apr;9(4):339-344. doi: 10.14740/jocmr2893w. Epub 2017 Feb 21.
• Smolkin T, Diab G, Shohat I, Jubran H, Blazer S, Rozen GS, Makhoul IR. Standardized versus individualized parenteral nutrition in very low birth weight infants: a comparative study. Neonatology. 2010;98(2):170-8. doi: 10.1159/000282174. Epub 2010 Mar 16.
• Dice JE, Burckart GJ, Woo JT, Helms RA. Standardized versus pharmacist-monitored individualized parenteral nutrition in low-birth-weight infants. Am J Hosp Pharm. 1981 Oct;38(10):1487-9.
• Yeung MY, Smyth JP, Maheshwari R, Shah S. Evaluation of standardized versus individualized total parenteral nutrition regime for neonates less than 33 weeks gestation. J Paediatr Child Health. 2003 Nov;39(8):613-7. doi: 10.1046/j.1440-1754.2003.00246.x.
• Mutchie KD, Smith KA, MacKay MW, Marsh C, Juluson D. Pharmacist monitoring of parenteral nutrition: clinical and cost effectiveness. Am J Hosp Pharm. 1979 Jun;36(6):785-7.
• Kreissl A, Repa A, Binder C, Thanhaeuser M, Jilma B, Berger A, Haiden N. Clinical Experience With Numeta in Preterm Infants: Impact on Nutrient Intake and Costs. JPEN J Parenter Enteral Nutr. 2016 May;40(4):536-42. doi: 10.1177/0148607115569733. Epub 2015 Feb 5.
• Namgung R, Tsang RC, Sierra RI, Ho ML. Normal serum indices of bone collagen biosynthesis and degradation in small for gestational age infants. J Pediatr Gastroenterol Nutr. 1996 Oct;23(3):224-8. doi: 10.1097/00005176-199610000-00004.
• Rossi L, Branca F, Cianfarani S. Collagen cross-links and early postnatal growth in newborns with intrauterine growth retardation. Metabolism. 2000 Nov;49(11):1467-72. doi: 10.1053/meta.2000.17670.
• Jones PJ, Winthrop AL, Schoeller DA, Swyer PR, Smith J, Filler RM, Heim T. Validation of doubly labeled water for assessing energy expenditure in infants. Pediatr Res. 1987 Mar;21(3):242-6. doi: 10.1203/00006450-198703000-00007.
• van Marken Lichtenbelt WD, Westerterp KR, Wouters L. Deuterium dilution as a method for determining total body water: effect of test protocol and sampling time. Br J Nutr. 1994 Oct;72(4):491-7. doi: 10.1079/bjn19940053.

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2021
• Primary Completion (Anticipated): August 31, 2023
• Study Completion (Anticipated): October 31, 2024

Study Registration Dates

• First Submitted: September 26, 2018
• First Submitted That Met QC Criteria: September 28, 2018
• First Posted (Actual): October 2, 2018

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 22, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Growth; Infant; Parenteral Nutrition; Preterm
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth
• Other Study ID Numbers: SP-PP18; 2018-004946-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No