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

Primary Purpose

Prematurity, Iron-deficiency, Iron Deficiency Anemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Darbepoetin Alfa
Low Molecular Weight Iron Dextran
Ferumoxytol injection
Oral iron supplements
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prematurity focused on measuring prematurity, iron deficiency, anemia, darbepoetin, IV Iron

Eligibility Criteria

undefined - 3 Days (Child)All SexesDoes not accept healthy volunteers

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, polycythemia, twin-twin transfusion, etc.)
  • 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

Sites / Locations

  • University of WashingtonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Experimental

Experimental

Experimental

Experimental

Arm Label

Group 1. Oral iron

Group 2

Group 3

Group 4

Group 5

Arm Description

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.

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

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

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

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

Outcomes

Primary Outcome Measures

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
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
Number of Blood transfusions
The number of blood transfusions received by infants in each group will be compared.
Volume of blood transfusions
The volume of blood transfused to infants in each group will be compared

Secondary Outcome Measures

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
Hematocrit
Hematocrit (lowest, highest, mean) by group to 35-36 weeks PMA
Safety of IV iron
Any evidence of anaphylaxis will be documented during and after the first IV infusion of iron
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.
Rate of referral for Brainstem auditory evoked response
Any latency in Brainstem auditory evoked response will be assessed and compared between study arms
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.
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.
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.
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.
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.

Full Information

First Posted
March 1, 2022
Last Updated
June 22, 2023
Sponsor
University of Washington
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT05340465
Brief Title
Darbe Plus IV Iron to Decrease Transfusions While Maintaining Iron Sufficiency in Preterm Infants
Acronym
DIVI
Official Title
Trial of Darbepoetin Plus Slow-release Intravenous Iron to Decrease Transfusions and Improve Iron Status and Neurodevelopment in Preterm Infants
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 27, 2022 (Actual)
Primary Completion Date
June 30, 2025 (Anticipated)
Study Completion Date
June 30, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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: 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). 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prematurity, Iron-deficiency, Iron Deficiency Anemia, Iron Malabsorption
Keywords
prematurity, iron deficiency, anemia, darbepoetin, IV Iron

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Group 1 Control, oral iron up to 12 mg/kg/day per Unit protocol Group 2 Darbe 10 mcg/kg q week plus LMW-ID: 10 mg/kg x 1, retreat if ferritin < 76 mcg/L Group 3 Darbe 10 mcg/kg q week plus LMW-ID: 20 mg/kg x 1, retreat if ferritin < 76 mcg/L Group 4 Darbe 10 mcg/kg q week plus FMX 10 mg/kg x 1, retreat if ferritin < 76 mcg/L Group 5 Darbe 10 mcg/kg q week plus FMX 20 mg/kg x 1, retreat if ferritin < 76 mcg/L
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Group 1 will be unblinded. In Groups 2-5 all infants will receive Darbe, and the iron preparation and dose will be blinded.
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1. Oral iron
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Group 2
Arm Type
Experimental
Arm Description
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
Arm Title
Group 3
Arm Type
Experimental
Arm Description
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
Arm Title
Group 4
Arm Type
Experimental
Arm Description
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
Arm Title
Group 5
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Darbepoetin Alfa
Other Intervention Name(s)
Aranesp, Darbe
Intervention Description
Infants in groups 2-5 will be started on Darbe 10 mcg/kg/week between 72 and 84 hours after birth.
Intervention Type
Drug
Intervention Name(s)
Low Molecular Weight Iron Dextran
Other Intervention Name(s)
INFeD, LMW-ID
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ferumoxytol injection
Other Intervention Name(s)
Feraheme, FMX
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Oral iron supplements
Other Intervention Name(s)
Ferr-in-sol
Intervention Description
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).
Primary Outcome Measure Information:
Title
Plasma Ferritin at 35-36 weeks PMA
Description
Plasma ferritin is measured every 2 weeks in the NICU. Ferritin at 35-36 weeks will be compared between the 5 treatment groups
Time Frame
birth to 36 weeks postmenstrual age
Title
Number of IV iron doses required to maintain a ferritin level of > 75 ng/mL
Description
Number of IV iron doses required to maintain a ferritin level of > 75 ng/mL will be compared in the 4 IV treatment arms
Time Frame
Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Title
Number of Blood transfusions
Description
The number of blood transfusions received by infants in each group will be compared.
Time Frame
Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Title
Volume of blood transfusions
Description
The volume of blood transfused to infants in each group will be compared
Time Frame
Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Secondary Outcome Measure Information:
Title
Number and percent of patients per group that remain transfusion free
Description
Number and percent of patients per group that remain transfusion free will be compared by group
Time Frame
Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Title
Hematocrit
Description
Hematocrit (lowest, highest, mean) by group to 35-36 weeks PMA
Time Frame
Birth to 36 weeks PMA
Title
Safety of IV iron
Description
Any evidence of anaphylaxis will be documented during and after the first IV infusion of iron
Time Frame
Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)
Title
Early gut microbiome comparison between study groups
Description
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.
Time Frame
at 7 days (prior to iron supplementation) and 4 weeks after birth
Title
Rate of referral for Brainstem auditory evoked response
Description
Any latency in Brainstem auditory evoked response will be assessed and compared between study arms
Time Frame
at hospital discharge, near 36 weeks postmenstrual age
Title
Rate of pass/fail the General Movements Assessments (GMA)
Description
General Movements Assessments (GMA) will be assessed at 3 months corrected age, and results compared between study arms.
Time Frame
3 months corrected age
Title
Scores for the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be compared between groups
Description
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.
Time Frame
6 months corrected age
Title
Scores for the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be compared between groups
Description
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.
Time Frame
18 months corrected age
Title
Late gut microbiome comparison between study groups
Description
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.
Time Frame
at 1 and 2 years corrected age.
Title
Neurodevelopmental outcome as assessed by the Bayley Scales of Infant Development edition-IV (BSID-IV)
Description
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.
Time Frame
1 year and 2 years corrected age

10. Eligibility

Sex
All
Maximum Age & Unit of Time
3 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sandra E Juul, MD, PhD
Phone
425 246-2536
Email
sjuul@uw.edu
First Name & Middle Initial & Last Name or Official Title & Degree
John Feltner, MS
Phone
206 616-8021
Email
jfeltner@uw.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sandra E Juul, MD, PhD
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Feltner, MS
Phone
206-616-8021
Email
jfeltner@uw.edu
First Name & Middle Initial & Last Name & Degree
Sandra E Juul, MD, PhD
First Name & Middle Initial & Last Name & Degree
Kendell German, MD
First Name & Middle Initial & Last Name & Degree
Mihai Puia-Dumitrescu, MD
First Name & Middle Initial & Last Name & Degree
Dennis E Mayock, MD
First Name & Middle Initial & Last Name & Degree
Sarah Kolnik, MD
First Name & Middle Initial & Last Name & Degree
Sara Neches, MD
First Name & Middle Initial & Last Name & Degree
Katie Strobel, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

Learn more about this trial

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

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