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

Phase 2

Recruiting

• Conditions: Iron-deficiency; Prematurity; Iron Malabsorption; Iron Deficiency Anemia
• Interventions: Drug: Oral iron supplements; Drug: Darbepoetin Alfa; Drug: Ferumoxytol injection; Drug: Low Molecular Weight Iron Dextran

• Registration Number: NCT05340465
• Lead Sponsor: University of Washington

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:

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 Timeline

• Study First Submitted: 2022-03-01
• Study First Submitted QC: 2022-04-14
• Study First Posted: 2022-04-22
• Study Start: 2022-11-27
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-03
• Last Update Posted: 2024-12-06
• Primary Completion: 2025-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 5	Ferumoxytol injection	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
Group 2	Low Molecular Weight Iron Dextran	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
Group 3	Low Molecular Weight Iron Dextran	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
Group 4	Ferumoxytol injection	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
Group 1. Oral iron	Oral iron supplements	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.
Group 2	Darbepoetin Alfa	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
Group 3	Darbepoetin Alfa	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
Group 4	Darbepoetin Alfa	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
Group 5	Darbepoetin Alfa	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

Primary Outcome Measures

Name	Time	Method
Number of IV iron doses required to maintain a ferritin level of > 75 ng/mL	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)	Number of IV iron doses required to maintain a ferritin level of \> 75 ng/mL will be compared in the 4 IV treatment arms
Volume of blood transfusions	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)	The volume of blood transfused to infants in each group will be compared
Plasma Ferritin at 35-36 weeks PMA	birth to 36 weeks postmenstrual age	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 Blood transfusions	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)	The number of blood transfusions received by infants in each group will be compared.

Secondary Outcome Measures

Name	Time	Method
Rate of referral for Brainstem auditory evoked response	at hospital discharge, near 36 weeks postmenstrual age	Any latency in Brainstem auditory evoked response will be assessed and compared between study arms
Late gut microbiome comparison between study groups	at 1 and 2 years corrected age.	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.
Hematocrit	Birth to 36 weeks PMA	Hematocrit (lowest, highest, mean) by group to 35-36 weeks PMA
Neurodevelopmental outcome as assessed by the Bayley Scales of Infant Development edition-IV (BSID-IV)	1 year and 2 years corrected age	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.
Number and percent of patients per group that remain transfusion free	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)	Number and percent of patients per group that remain transfusion free will be compared by group
Early gut microbiome comparison between study groups	at 7 days (prior to iron supplementation) and 4 weeks after birth	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 pass/fail the General Movements Assessments (GMA)	3 months corrected age	General Movements Assessments (GMA) will be assessed at 3 months corrected age, and results compared between study arms.
Safety of IV iron	Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)	Any evidence of anaphylaxis will be documented during and after the first IV infusion of iron
Scores for the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be compared between groups	18 months corrected age	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.

Trial Locations

Locations (1)

University of Washington; 🇺🇸 Seattle, Washington, United States