Heart And Lung Failure - Pediatric INsulin Titration Trial

NCT01565941 | Completed Phase 3 Results DMC

• 2 other identifiers: IRB-P00002310U01HL107681
• Study Type: interventional
• Target: 713
• Locations: 3 countries
• Sites: 35

Brief Summary

Stress hyperglycemia, a state of abnormal metabolism with supra-normal blood glucose levels, is often seen in critically ill patients. Tight glycemic control (TGC) was originally shown to reduce morbidity and mortality in a landmark randomized clinical trial (RCT) of adult critically ill surgical patients but has since come under intense scrutiny due to conflicting results in recent adult trials. One pediatric RCT has been published to date that demonstrated survival benefit but was complicated by an unacceptably high rate of severe hypoglycemia. The Heart And Lung Failure - Pediatric INsulin Titration (HALF-PINT) trial is a multi-center, randomized clinical treatment trial comparing two ranges of glucose control in hyperglycemic critically ill children with heart and/or lung failure. Both target ranges of glucose control fall within the range of "usual care" for critically ill children managed in pediatric intensive care units. The purpose of the study is to determine the comparative effectiveness of tight glycemic control to a target range of 80-110 mg/dL (TGC-1, 4.4-6.1 mmol/L) vs. a target range of 150-180 mg/dL (TGC-2, 8.3-10.0 mmol/L) on hospital mortality and intensive care unit (ICU) length of stay (LOS) in hyperglycemic critically ill children with cardiovascular and/or respiratory failure. This will be accomplished using an explicit insulin titration algorithm and continuous glucose monitoring to safely achieve these glucose targets. Both groups will receive identical standardized intravenous glucose at an age-appropriate rate in order to provide basal calories and mitigate hypoglycemia. Insulin infusions will be titrated with an explicit algorithm combined with continuous glucose monitoring using a protocol that has been safely implemented in 490 critically ill infants and children.

Conditions

Heart Failure; Respiratory Failure

Keywords

Cardiovascular; Respiratory; Failure; Heart; Lung; Continuous glucose monitoring; Tight glycemic control; Subcutaneous; Insulin; Algorithm

Outcome Measures

Primary Outcomes (1)

• ICU-Free Days

  28-day hospital mortality-adjusted ICU length of stay.

  Study day 28

Secondary Outcomes (20)

• 90-day Hospital Mortality

  90 days after randomization

• 28-day Hospital Mortality

  28 days after randomization

• Accumulation of Multiple Organ Dysfunction Syndrome (MODS)

  28 days after randomization

• Ventilator-Free Days

  28 days following randomization

• Developmental Neurobehavioral Outcomes: VABS-II Composite

  One year after ICU course

Study Arms (2)

Tight Glycemic Control 1 (TGC-1)

ACTIVE COMPARATOR

Approximately half of the subjects randomized into HALF-PINT will be randomized into TGC-1 which will seek to maintain the subject's blood sugar between 80-110 mg/dL. Intravenous insulin may be administered per insulin algorithm.

Drug: Insulin

Tight Glycemic Control 2 (TGC-2)

ACTIVE COMPARATOR

Approximately half of the subjects randomized into HALF-PINT will be randomized into TGC-2 which will seek to maintain the subject's blood sugar between 150-180 mg/dL. Intravenous insulin may be administered per insulin algorithm.

Drug: Insulin

Interventions

Insulin DRUG

IV insulin titration to target a blood glucose of 80-110 mg/dL

Tight Glycemic Control 1 (TGC-1)

Eligibility Criteria

• Age: 2 Weeks - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Cardiovascular failure and/or respiratory failure:
• Cardiovascular Failure: Dopamine or dobutamine \> 5 mcg/kg/min, or any dose of epinephrine, norepinephrine, phenylephrine, milrinone or vasopressin if used to treat hypotension.
• Respiratory Failure: Acute mechanical ventilation via endotracheal tube or tracheostomy.
• Age \>= 2 weeks and corrected gestational age \>= 42 weeks
• Age \< 18 years (has not yet had 18th birthday)

You may not qualify if:

• Expected to remain in ICU \< 24 hours
• Previously randomized in HALF-PINT
• Enrolled in a competing clinical trial
• Family/team decision to limit/redirect from aggressive ICU technological support
• Chronic ventilator dependence prior to ICU admission (non-invasive ventilation and ventilation via tracheostomy overnight or during sleep are acceptable)
• Type 1 or 2 diabetes
• Cardiac surgery within prior 2 months or during/planned for this hospitalization (extra-corporeal life support or non-cardiac surgery is acceptable)
• Diffuse skin disease that does not allow securement of a subcutaneous sensor
• Therapeutic plan to remain intubated for \>28 days
• Receiving therapeutic cooling with targeted body temperatures \<34 degrees Celsius
• Current or planned ketogenic diet
• Ward of the state
• Pregnancy

Sponsors & Collaborators

• Boston Children's Hospital: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (35)

Miller Children's Hospital Long Beach

Long Beach, California, 90806, United States

Location

Children's Hospital of Los Angelos

Los Angeles, California, 90027, United States

Location

Mattel Children's Hospital

Los Angeles, California, 90095, United States

Location

Children's Hospital & Research Center of Oakland

Oakland, California, 94609, United States

Location

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

UCSF Benioff Children's Hospital

San Francisco, California, 94143, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Yale-New Haven Children's Hospital

New Haven, Connecticut, 06520, United States

Location

Nemours/A.I DuPont Hospital for Children

Wilmington, Delaware, 19803, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Ann & Robert H. Lurie Children's Hospital pf Chicago

Chicago, Illinois, 60611, United States

Location

University of Chicago Comer Children's Hospital

Chicago, Illinois, 60637, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03755, United States

Location

Women and Children's Hospital of Buffalo

Buffalo, New York, 14222, United States

Location

North Shore LIJ Cohen Children's Medical Center

New Hyde Park, New York, 11040, United States

Location

Morgan Stanley Children's Hospital of New York

New York, New York, 10032, United States

Location

The Children's Hospital at Montefiore

The Bronx, New York, 10467, United States

Location

Westchester Medical Center

Valhalla, New York, 10595, United States

Location

Duke Children's Hospital and Medical Center

Durham, North Carolina, 27705, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

The Children's Hospital at OU Medical Center

Oklahoma City, Oklahoma, 73104, United States

Location

Penn State Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Medical City Children's Dallas

Dallas, Texas, 75230, United States

Location

Children's Medical Center Dallas

Dallas, Texas, 75235, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

The Royal Children's Hospital

Melbourne, Victoria, 3052, Australia

Location

CHU Sainte-Justine

Montreal, Quebec, H3T 1C4, Canada

Location

Related Publications (11)

• Agus MS, Hirshberg E, Srinivasan V, Faustino EV, Luckett PM, Curley MA, Alexander J, Asaro LA, Coughlin-Wells K, Duva D, French J, Hasbani N, Sisko MT, Soto-Rivera CL, Steil G, Wypij D, Nadkarni VM. Design and rationale of Heart and Lung Failure - Pediatric INsulin Titration Trial (HALF-PINT): A randomized clinical trial of tight glycemic control in hyperglycemic critically ill children. Contemp Clin Trials. 2017 Feb;53:178-187. doi: 10.1016/j.cct.2016.12.023. Epub 2016 Dec 30.

  PMID: 28042054 BACKGROUND

• LaRovere KL, Asaro LA, Coughlin-Wells K, Nadkarni VM, Agus MSD; Heart and Lung Failure-Pediatric Insulin Titration (HALF-PINT) Study Investigators. Blood Glucose Range for Hyperglycemic PICU Children With Primary Neurologic Diagnoses: Analysis of the Heart and Lung Failure-Pediatric Insulin Titration (HALF-PINT) Trial. Pediatr Crit Care Med. 2025 Apr 1;26(4):e432-e446. doi: 10.1097/PCC.0000000000003689. Epub 2025 Feb 5.

  PMID: 39907523 DERIVED

• Yang JO, Zinter MS, Pellegrini M, Wong MY, Gala K, Markovic D, Nadel B, Peng K, Do N, Mangul S, Nadkarni VM, Karlsberg A, Deshpande D, Butte MJ, Asaro L, Agus M, Sapru A; Study Site Investigators for CAF-PINT. Whole blood transcriptomics identifies subclasses of pediatric septic shock. Crit Care. 2023 Dec 8;27(1):486. doi: 10.1186/s13054-023-04689-y.

  PMID: 38066613 DERIVED

• Yang JO, Zinter MS, Pellegrini M, Wong MY, Gala K, Markovic D, Nadel B, Peng K, Do N, Mangul S, Nadkarni VM, Karlsberg A, Deshpande D, Butte MJ, Asaro L, Agus M, Sapru A. Whole Blood Transcriptomics Identifies Subclasses of Pediatric Septic Shock. Res Sq [Preprint]. 2023 Aug 28:rs.3.rs-3267057. doi: 10.21203/rs.3.rs-3267057/v1.

  PMID: 37693502 DERIVED

• Bellon F, Sola I, Gimenez-Perez G, Hernandez M, Metzendorf MI, Rubinat E, Mauricio D. Perioperative glycaemic control for people with diabetes undergoing surgery. Cochrane Database Syst Rev. 2023 Aug 1;8(8):CD007315. doi: 10.1002/14651858.CD007315.pub3.

  PMID: 37526194 DERIVED

• Zinter MS, Markovic D, Asaro LA, Nadkarni VM, McQuillen PS, Sinha P, Matthay MA, Jeschke MG, Agus MSD, Sapru A; CAF-PINT Investigators of the PALISI Network. Tight Glycemic Control, Inflammation, and the ICU: Evidence for Heterogeneous Treatment Effects in Two Randomized Controlled Trials. Am J Respir Crit Care Med. 2023 Apr 1;207(7):945-949. doi: 10.1164/rccm.202210-1988LE. No abstract available.

  PMID: 36656551 DERIVED

• Hirshberg EL, Alexander JL, Asaro LA, Coughlin-Wells K, Steil GM, Spear D, Stone C, Nadkarni VM, Agus MSD; HALF-PINT Study Investigators. Performance of an Electronic Decision Support System as a Therapeutic Intervention During a Multicenter PICU Clinical Trial: Heart and Lung Failure-Pediatric Insulin Titration Trial (HALF-PINT). Chest. 2021 Sep;160(3):919-928. doi: 10.1016/j.chest.2021.04.049. Epub 2021 Apr 29.

  PMID: 33932465 DERIVED

• LaMarra D, French J, Bailey C, Sisko MT, Coughlin-Wells K, Agus MSD, Srinivasan V, Nadkarni VM; Heart And Lung Failure-Pediatric INsulin Titration (HALF-PINT) Study Investigators. A Novel Framework Using Remote Telesimulation With Standardized Parents to Improve Research Staff Preparedness for Informed Consent in Pediatric Critical Care Research. Pediatr Crit Care Med. 2020 Dec;21(12):e1042-e1051. doi: 10.1097/PCC.0000000000002484.

  PMID: 32740181 DERIVED

• Biagas KV, Hinton VJ, Hasbani NR, Luckett PM, Wypij D, Nadkarni VM, Agus MSD; HALF-PINT trial study investigators; PALISI Network. Long-Term Neurobehavioral and Quality of Life Outcomes of Critically Ill Children after Glycemic Control. J Pediatr. 2020 Mar;218:57-63.e5. doi: 10.1016/j.jpeds.2019.10.055. Epub 2020 Jan 3.

  PMID: 31910992 DERIVED

• Srinivasan V, Hasbani NR, Mehta NM, Irving SY, Kandil SB, Allen HC, Typpo KV, Cvijanovich NZ, Faustino EVS, Wypij D, Agus MSD, Nadkarni VM; Heart and Lung Failure-Pediatric Insulin Titration (HALF-PINT) Study Investigators. Early Enteral Nutrition Is Associated With Improved Clinical Outcomes in Critically Ill Children: A Secondary Analysis of Nutrition Support in the Heart and Lung Failure-Pediatric Insulin Titration Trial. Pediatr Crit Care Med. 2020 Mar;21(3):213-221. doi: 10.1097/PCC.0000000000002135.

  PMID: 31577692 DERIVED

• Agus MS, Wypij D, Hirshberg EL, Srinivasan V, Faustino EV, Luckett PM, Alexander JL, Asaro LA, Curley MA, Steil GM, Nadkarni VM; HALF-PINT Study Investigators and the PALISI Network. Tight Glycemic Control in Critically Ill Children. N Engl J Med. 2017 Feb 23;376(8):729-741. doi: 10.1056/NEJMoa1612348. Epub 2017 Jan 24.

  PMID: 28118549 DERIVED

MeSH Terms

Conditions

Heart Failure; Respiratory Insufficiency; Insulin Resistance

Interventions

Insulin

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Respiration Disorders; Respiratory Tract Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Michael Agus
• Organization: Boston Children's Hospital

michael.agus@childrens.harvard.edu

617-355-5849

Study Officials

• Michael SD Agus, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

• Vinay M Nadkarni, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pediatrics, Harvard Medical School

Study Record Dates

• First Submitted: March 21, 2012
• First Posted: March 29, 2012
• Study Start: April 1, 2012
• Primary Completion: September 1, 2016
• Study Completion: February 1, 2018
• Last Updated: July 25, 2022
• Results First Posted: December 11, 2017

Record last verified: 2022-07

Locations

US (33); AU (1); CA (1)