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

Sponsor

University of Washington (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05340465

Collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

120

Enrollment

Location

Arms

57.5

Anticipated Duration (Months)

2.1

Patients Per Site Per Month

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
Prematurity Iron-deficiency Iron Deficiency Anemia Iron Malabsorption	Drug: Darbepoetin Alfa Drug: Low Molecular Weight Iron Dextran Drug: Ferumoxytol injection Drug: Oral iron supplements	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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/LGroup 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:

Quadruple (Participant, Care Provider, Investigator, Outcomes 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.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 15, 2022

Anticipated Primary Completion Date :

Jun 30, 2025

Anticipated Study Completion Date :

Jun 30, 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Rate of anaphylaxis will be compared between treatment groups [Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)]
Serious adverse reactions to IV iron will be documented including hypotension, hypertension, bradycardia, rash or other noted vital sign / clinical change within 60 minutes of receiving an IV dose of iron.
Number of doses of IV iron required to maintain serum ferritin > 75 microgram/L will be compared between IV iron groups [birth to 36 weeks postmenstrual age]
The number of doses of FMX and LMW-ID will be compared in the 4 IV iron treatment arms. Patients will be re-dosed if ferritin falls below 76 mcgm/L.
Cumulative transfusion volume (mL/kg) [Birth to 36 weeks postmenstrual age (or prior to discharge if this occurs prior to 36 weeks)]
Cumulative transfusion volume (median (IQR)) from birth to 36 weeks PMA will be compared between study arms

Secondary Outcome Measures

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 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
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.
Scores for the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be compared between groups [6 months and 18 months corrected age]
Parent questionnaire (WIDEA-FS) to assess neurodevelopment will be done at 6 and 18 months corrected age. Mean and median scores will be compared by treatment arm
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 3 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

NICU patients (male and female) born at 24-0/7 to 31-6/7 weeks of gestation
Parental consent obtained by 72 hours after birth
English or Spanish speaking parents
All patients who meet inclusion criteria will be approached without regard to sex, race, ethnicity, parents' country of origin, or religious preferences.