Iron-deficiency, Iron Deficiency Anemia, Iron Malabsorption, Prematurity
Conditions
Keywords
prematurity, iron deficiency, anemia, darbepoetin, IV Iron
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.
Interventions
DRUGDarbepoetin Alfa
Infants in groups 2-5 will be started on Darbe 10 mcg/kg/week between 72 and 84 hours after birth.
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.
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.
DRUGOral 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).
Sponsors
University of Washington
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
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/L
Eligibility
Sex/Gender
ALL
Age
No minimum to 3 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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. |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Hematocrit | Birth to 36 weeks PMA | Hematocrit (lowest, highest, mean) by group to 35-36 weeks PMA |
| 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 |
| 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 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. |
| 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. |
Countries
United States
Contacts
CONTACTKendell R German, MD
CONTACTJohn Feltner, MS
PRINCIPAL_INVESTIGATORKendell R German, MD
University of Washington
Outcome results
None listed