Darbe Plus IV Iron to Decrease Transfusions While Maintaining Iron Sufficiency in Preterm Infants (DIVI)

Trial of Darbepoetin Plus Slow-release Intravenous Iron to Decrease Transfusions and Improve Iron Status and Neurodevelopment in Preterm Infants

In this phase II trial, the investigators overarching goal is to demonstrate the feasibility and potential benefit of darbepoetin (Darbe) plus slow-release intravenous (IV) iron to decrease transfusions, maintain iron sufficiency and improve the neurodevelopmental outcomes of preterm infants.

Investigators hypothesize that in infants < 32 completed weeks of gestation, combined treatment with Darbe plus Ferumoxytol (FMX) or Darbe plus low molecular weight iron dextran (LMW-ID) will: 1) be safe, 2) decrease or eliminate transfusions, 3) maintain iron sufficiency, 4) result in higher hematocrit and 5) improve neurodevelopment. Investigators further hypothesize that when compared to oral iron supplementation (standard care), IV iron will be better tolerated, with less effect on the gastrointestinal (GI) microbiome

Study Overview

• Status: Recruiting
• Conditions: Iron-deficiency; Iron Deficiency Anemia; Prematurity; Iron Malabsorption
• Intervention / Treatment: Drug: Oral iron supplements; Drug: Darbepoetin Alfa; Drug: Low Molecular Weight Iron Dextran; Drug: Ferumoxytol injection

Detailed Description

Investigators hypothesize that in infants < 32 completed weeks of gestation, combined treatment with Darbe plus FMX or Darbe plus LMW-ID will: 1) be safe, 2) decrease or eliminate transfusions, 3) maintain iron sufficiency, 4) result in higher hematocrit and 5) improve neurodevelopment. Investigators further hypothesize that when compared to oral iron supplementation (standard care), IV iron will be better tolerated, with less effect on the gastrointestinal (GI) microbiome

Objectives:

1. To compare the safety, dose, and dosing interval for FMX and LMW-ID required for preterm infants receiving Darbe.

   Iron dosing will begin at 7 days after birth. Initial doses of 10 mg/kg/dose or 20 mg/kg/dose will be compared for each iron formulation (N=20 each).

2. To compare the safety, tolerance, and efficacy of IV iron (FMX or LMW-ID) plus Darbe (N=80) to standard care (oral ferrous sulfate (N=40). Adverse reactions to IV Iron will be documented, as will adverse responses to oral iron (feeding intolerance). Potential differences in the stool microbiome will be evaluated 3 weeks after the initial IV and oral iron doses.

3. Determine long-term outcomes:

   • 3.1 Neurodevelopmental outcomes of infants enrolled in Objectives 1 and 2 (N=120) will be sequentially assessed up to 2 years of age.
   • 3.2 The stool microbiome will be compared between study groups at 12 and 24 months to determine whether mode of iron delivery has long-term effects.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sandra E Juul, MD, PhD; Phone Number: 425 246-2536; Email: sjuul@uw.edu
• Study Contact Backup: Name: John Feltner, MS; Phone Number: 206 616-8021; Email: jfeltner@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington
      • Contact: John Feltner, MS; Phone Number: 206-616-8021; Email: jfeltner@uw.edu
      • Principal Investigator: Sandra E Juul, MD, PhD
      • Sub-Investigator: Kendell German, MD
      • Sub-Investigator: Mihai Puia-Dumitrescu, MD
      • Sub-Investigator: Dennis E Mayock, MD
      • Sub-Investigator: Sarah Kolnik, MD
      • Sub-Investigator: Sara Neches, MD
      • Sub-Investigator: Katie Strobel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• NICU patients (male and female) born at 24-0/7 to 31-6/7 weeks of gestation

All patients who meet inclusion criteria will be approached without regard to sex, race, ethnicity, parents' country of origin, or religious preferences.

Exclusion Criteria:

• Known fetal/infant anomalies of clinical significance (brain, cardiac, chromosomal anomalies)
• Parental consent unable to be obtained by 72 hours after birth
• Central hematocrit > 65%
• Evidence of high iron stores prior to enrollment (e.g. Ferritin >400 ng/mL with corresponding ZnPP/H of <30, Transferrin saturation >75%, iron > 200 mcg/dL, TIBC < 100 mcg/dL)
• Culture proven sepsis, meningitis, urinary tract infection, or other significant infection at the time of enrollment
• Mother under 18 years of age
• Unable to consent in English or Spanish

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1. Oral iron; Oral iron is started on day 7 of life if baby is feeding 100 mL/kg/day. Iron supplements of up to 12 mg/kg/day are given based on CBC, retic, ret-hgb, serum ferritin and zinc protoporphyrin to heme ratio (ZnPP/H). Iron supplements are adjusted every 2 weeks following iron studies.	Drug: Oral iron supplements; Infants in group 1 will receive standard care in the UW NICU with iron started on day 7 if tolerating 100 mL/kg/day enteral feeding. Iron supplements are adjusted every 2 weeks based on ferritin, zinc protoporphyrin to heme ratio and complete blood count (CBC).; Other Names: Ferr-in-sol
Experimental: Group 2; Infants randomized to this arm will receive Darbe 10 mcg/kg q week started on day 3 of life. In addition, beginning on day 7, they will receive LMW-ID: 10 mg/kg x 1, retreat if ferritin < 76 mcg/L	Drug: Darbepoetin Alfa; Infants in groups 2-5 will be started on Darbe 10 mcg/kg/week between 72 and 84 hours after birth.; Other Names: Aranesp; Darbe; Drug: Low Molecular Weight Iron Dextran; Infants in groups 2 and 3 will be given LMW-ID IV, 10 or 20 mg/kg/dose. They will be re-dosed if ferritin falls below 76. Iron parameters will be checked biweekly.; Other Names: INFeD; LMW-ID
Experimental: Group 3; Infants randomized to this arm will receive Darbe 10 mcg/kg q week started on day 3 of life. In addition, beginning on day 7, they will receive LMW-ID: 20 mg/kg x 1, retreat if ferritin < 76 mcg/L	Drug: Darbepoetin Alfa; Infants in groups 2-5 will be started on Darbe 10 mcg/kg/week between 72 and 84 hours after birth.; Other Names: Aranesp; Darbe; Drug: Low Molecular Weight Iron Dextran; Infants in groups 2 and 3 will be given LMW-ID IV, 10 or 20 mg/kg/dose. They will be re-dosed if ferritin falls below 76. Iron parameters will be checked biweekly.; Other Names: INFeD; LMW-ID
Experimental: Group 4; Infants randomized to this arm will receive Darbe 10 mcg/kg q week started on day 3 of life. In addition, beginning on day 7, they will receive FMX: 10 mg/kg x 1, retreat if ferritin < 76 mcg/L	Drug: Darbepoetin Alfa; Infants in groups 2-5 will be started on Darbe 10 mcg/kg/week between 72 and 84 hours after birth.; Other Names: Aranesp; Darbe; Drug: Ferumoxytol injection; Infants in groups 4 and 5 will be given FMX IV, 10 or 20 mg/kg/dose. They will be re-dosed if ferritin falls below 76. Iron parameters will be checked biweekly.; Other Names: Feraheme; FMX
Experimental: Group 5; Infants randomized to this arm will receive Darbe 10 mcg/kg q week started on day 3 of life. In addition, beginning on day 7, they will receive FMX: 20 mg/kg x 1, retreat if ferritin < 76 mcg/L	Drug: Darbepoetin Alfa; Infants in groups 2-5 will be started on Darbe 10 mcg/kg/week between 72 and 84 hours after birth.; Other Names: Aranesp; Darbe; Drug: Ferumoxytol injection; Infants in groups 4 and 5 will be given FMX IV, 10 or 20 mg/kg/dose. They will be re-dosed if ferritin falls below 76. Iron parameters will be checked biweekly.; Other Names: Feraheme; FMX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Ferritin at 35-36 weeks PMA	Plasma ferritin is measured every 2 weeks in the NICU. Ferritin at 35-36 weeks will be compared between the 5 treatment groups	birth to 36 weeks postmenstrual age
Number of IV iron doses required to maintain a ferritin level of > 75 ng/mL	Number of IV iron doses required to maintain a ferritin level of > 75 ng/mL will be compared in the 4 IV treatment arms	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Number of Blood transfusions	The number of blood transfusions received by infants in each group will be compared.	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Volume of blood transfusions	The volume of blood transfused to infants in each group will be compared	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and percent of patients per group that remain transfusion free	Number and percent of patients per group that remain transfusion free will be compared by group	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Early gut microbiome comparison between study groups	Stool samples will be collected for 16S amplicon sequencing and targeted culturomics. Organism types will be compared between groups prior to and 3 weeks after the first IV iron dose.	at 7 days (prior to iron supplementation) and 4 weeks after birth
Rate of referral for Brainstem auditory evoked response	Any latency in Brainstem auditory evoked response will be assessed and compared between study arms	at hospital discharge, near 36 weeks postmenstrual age
Rate of pass/fail the General Movements Assessments (GMA)	General Movements Assessments (GMA) will be assessed at 3 months corrected age, and results compared between study arms.	3 months corrected age
Late gut microbiome comparison between study groups	Stool samples will be collected for 16S amplicon sequencing and targeted culturomics. Organism types will be compared between groups. If differences in early microbiome (at 4 weeks of age) are noted, we will evaluate whether they persist at 1 and 2 years of age.	at 1 and 2 years corrected age.
Neurodevelopmental outcome as assessed by the Bayley Scales of Infant Development edition-IV (BSID-IV)	Bayley Scales of Infant Development edition-IV (BSID-IV) will be assessed in all enrolled patients at one and two years corrected age. Results for the treatment arms will be compared.	1 year and 2 years corrected age
Hematocrit	Hematocrit (lowest, highest, mean) by group to 35-36 weeks PMA	Birth to 36 weeks PMA
Safety of IV iron	Any evidence of anaphylaxis will be documented during and after the first IV infusion of iron	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Scores for the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be compared between groups	Parent questionnaire (WIDEA-FS) to assess neurodevelopment will be done at 6 months corrected age. Mean and median scores will be compared by treatment arm. The WIDEA includes 50 items with a maximum score of 200. Higher scores indicate more advanced neurodevelopmental functioning.	6 months corrected age
Scores for the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be compared between groups	Parent questionnaire (WIDEA-FS) to assess neurodevelopment will be done at 6 months corrected age. Mean and median scores will be compared by treatment arm. The WIDEA includes 50 items with a maximum score of 200. Higher scores indicate more advanced neurodevelopmental functioning.	18 months corrected age

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Sandra E Juul, MD, PhD, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2022
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: March 1, 2022
• First Submitted That Met QC Criteria: April 14, 2022
• First Posted (Actual): April 22, 2022

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: anemia; prematurity; iron deficiency; darbepoetin; IV Iron
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Hematologic Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Anemia, Iron-Deficiency; Premature Birth; Malabsorption Syndromes; Iron Deficiencies; Physiological Effects of Drugs; Trace Elements; Micronutrients; Anticoagulants; Hematinics; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Plasma Substitutes; Blood Substitutes; Darbepoetin alfa; Ferrosoferric Oxide; Dextrans; Iron; Iron-Dextran Complex
• Other Study ID Numbers: STUDY00015143; R01HD107003 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

We will comply with and share data in accordance with the definitions contained in the guidance document:

Data Element Definitions for Interventional and Observational Studies (https://prsinfo.clinicaltrials.gov/results_definitions.html) and the final rule (42 CFR Part 11) .

In addition, we will comply with NICHD requirements to release our de-identified data-set to the Data and Specimen Hub (DASH), a centralized resource for researchers to store and access data from studies funded by NICHD after the acceptance of publication of our main findings of the final data set (2 year outcomes) as per the NIH Data Sharing Policy: https://dash.nichd.nih.gov/. Biospecimens will not be available. Data will include study protocol, CRFs, and collected, de-identified data collected in REDCap.

• IPD Sharing Time Frame: Within 12 months of publication of our primary outcome, a final study data set will be accessible via a supervised private data enclave. Access will be limited to registered users who submit proposed specific questions or analysis plans and sign a data use agreement. "Supervised" indicates that individual requests are reviewed to protect the intellectual property rights of the project investigative team by restricting external development of manuscripts using the study data that substantially overlap with those that are already in development by study investigators. We will form a publications committee, with investigator representatives from the Clinical Coordinating Center and Data Coordinating Center at the University of Washington to establish manuscript development and publication guidelines.
• IPD Sharing Access Criteria: We will electronically document data requests through a web-based data portal at the University of Washington Center for Biomedical Statistics. The final research data set will be stored separately from the operational study database in a secure web-accessible REDCap database (at https://rcnut.iths.org), where access and downloads can be easily monitored and the data are downloadable in a variety of formats (Excel, R, SAS, Stata, SPSS). A comprehensive data dictionary will be available alongside the final research database. The data sharing plan will be executed within the final year of funding. The overhead required to support this data sharing plan is minimal and therefore no additional budget is requested to cover its costs.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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