Darbe + IV Iron for Premature Infants

(DIVI Trial)

Overseen By Kendell R German, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Disqualifiers: Anomalies, High hematocrit, High iron, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Birth to 36 weeks postmenstrual age

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining darbepoetin (Darbe) with intravenous (IV) iron can improve outcomes for premature infants born before 32 weeks of gestation. Researchers aim to determine if this treatment reduces the need for blood transfusions, maintains stable iron levels, and supports better brain development compared to standard oral iron. The trial includes several treatment groups, testing different doses and types of IV iron alongside Darbe. Ideal candidates are preterm infants in the NICU, born between 24 and 31 weeks of gestation. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in neonatal care.

Will I have to stop taking my current medications?

The trial protocol does not specify whether participants must stop taking their current medications. It is best to discuss this with the trial coordinators or your healthcare provider.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that darbepoetin alfa (Darbe) is safe for both premature and full-term babies. Studies have confirmed its safety, with no major harmful effects found. Evidence indicates that the iron treatments being tested, ferumoxytol (FMX) and low molecular weight iron dextran (LMW-ID), can have side effects, but specific safety information for newborns is still being collected.

The trial is in Phase 2, indicating that the treatment has already been tested for safety in adults. Scientists are now assessing its safety and effectiveness in a specific group, such as premature babies. This phase provides insights into how well the treatment is tolerated. The goal of using darbepoetin with either FMX or LMW-ID is to reduce the need for blood transfusions and improve health outcomes for premature babies while maintaining safe iron levels. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for premature infants because they explore the use of Darbepoetin Alfa combined with intravenous iron, which could offer new hope for better anemia management in these vulnerable babies. Unlike the standard oral iron supplements, which rely on the baby's digestive system to absorb iron, the investigational treatment delivers iron directly into the bloodstream, potentially offering a faster and more efficient iron replenishment. Additionally, Darbepoetin Alfa stimulates red blood cell production, which could enhance recovery and growth in premature infants. This dual approach might significantly improve outcomes by quickly addressing iron deficiency and supporting overall blood health.

What evidence suggests that this trial's treatments could be effective for preterm infants?

Research has shown that using darbepoetin (Darbe) with intravenous (IV) iron can help preterm infants by reducing the need for blood transfusions and improving iron levels. In this trial, some infants will receive Darbe combined with Ferumoxytol (FMX) to maintain sufficient iron levels and support brain development. Other infants will receive Darbe with low molecular weight iron dextran (LMW-ID), which has also shown promise in achieving these goals. The trial tests both combinations for safety and whether they are gentler on infants' stomachs compared to standard oral iron supplements. ^{2 3 6 7 8}

Who Is on the Research Team?

Kendell R German, MD

Principal Investigator

University of Washington

Are You a Good Fit for This Trial?

This trial is for preterm infants born between 24 and almost 32 weeks of gestation. It's open to all eligible NICU patients regardless of sex, race, or ethnicity. Infants with high iron levels, infections at enrollment, significant clinical anomalies, or whose parents cannot consent within 72 hours after birth are excluded.

Inclusion Criteria

I understand that eligibility is not based on my sex, race, ethnicity, background, or religion.

My baby was born between 24 and 31 weeks of pregnancy.

Exclusion Criteria

Your blood thickness is higher than normal.

Your blood tests show that you have a lot of iron in your body.

My baby has been diagnosed with a significant health condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Infants receive Darbepoetin and intravenous iron starting from day 3 and day 7 of life respectively, with doses adjusted based on iron studies

Birth to 36 weeks postmenstrual age

Weekly visits for dose adjustments and monitoring

Follow-up

Participants are monitored for neurodevelopmental outcomes and gut microbiome changes up to 2 years of age

Up to 2 years corrected age

Assessments at 1 year and 2 years corrected age

Long-term Follow-up

Long-term monitoring of neurodevelopmental outcomes and gut microbiome

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Darbepoetin Alfa
• Ferumoxytol injection
• Low Molecular Weight Iron Dextran
• Oral iron supplements

Trial Overview The study tests if Darbepoetin (Darbe) combined with IV iron (Ferumoxytol or low molecular weight iron dextran) can reduce the need for blood transfusions while maintaining sufficient iron levels and improving neurodevelopment in premature infants compared to oral iron supplements.

How Is the Trial Designed?

Group I: Group 5 Experimental Treatment 2 Interventions

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 II: Group 4 Experimental Treatment 2 Interventions

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 III: Group 3 Experimental Treatment 2 Interventions

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 IV: Group 2 Experimental Treatment 2 Interventions

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 V: Group 1. Oral iron Active Control 1 Intervention

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.

Darbepoetin Alfa is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Aranesp for:

• Anemia associated with chronic kidney disease
• Anemia in adult cancer patients with non-myeloid malignancies

Approved in United States as Aranesp for:

• Anemia associated with chronic kidney disease
• Anemia in patients with non-myeloid malignancies where anemia is due to concomitantly administered chemotherapy

Approved in Canada as Aranesp for:

• Anemia associated with chronic kidney disease
• Anemia in patients with non-myeloid malignancies where anemia is due to concomitantly administered chemotherapy

Approved in Japan as Aranesp for:

• Anemia associated with chronic kidney disease
• Anemia in patients with non-myeloid malignancies where anemia is due to concomitantly administered chemotherapy

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

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

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

In a study of 396 patients with chemotherapy-induced anemia, the combination of darbepoetin alpha and intravenous (IV) iron resulted in a significantly higher hematopoietic response rate (86% vs. 73%) compared to standard practice, which included oral iron or no iron.

The addition of IV iron also led to fewer red blood cell transfusions (9% vs. 20%) during treatment, indicating improved efficacy without compromising safety, as both treatment regimens were well tolerated with similar adverse event profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Bastit, L., Vandebroek, A., Altintas, S., et al.[2015]

A total of 197 adverse events (AEs) were reported among patients using various intravenous iron products, with ferumoxytol showing the highest rate of AEs at 746 per million units sold, compared to iron sucrose at 5.25 per million.

Ferumoxytol was associated with significantly higher risks of death and serious nonfatal AEs compared to iron sucrose and sodium ferric gluconate, indicating a need for caution when using this newer iron product.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of rates of reported adverse events associated with i.v. iron products in the United States. Bailie, GR.[2022]

Over a 38-month period, drug therapy was linked to an average of 243 reported deaths annually in infants and young children under 2 years old, with a significant number occurring in the first month and year of life.

A substantial portion of adverse events (24%) were associated with drug exposure from the mother during pregnancy, delivery, or lactation, highlighting the need for careful consideration of medication risks during this critical period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reported adverse drug events in infants and children under 2 years of age. Moore, TJ., Weiss, SR., Kaplan, S., et al.[2022]

In a study of 240 pediatric inpatients at a Brazilian hospital, 18.8% experienced at least one adverse drug event, with a total of 62 events identified, indicating a significant concern for patient safety.

The study found that cardiovascular drugs were most frequently associated with these adverse events, highlighting the need for careful monitoring and management of these medications in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of adverse drug events identified by trigger in Brazilian pediatric inpatients. Silva, LT., Modesto, ACF., Martins, RR., et al.[2022]

Darbepoetin, a long-acting erythropoiesis-stimulating agent (ESA), has shown significant effectiveness in promoting red blood cell production in both term and preterm infants, potentially reducing the need for blood transfusions.

In addition to its erythropoietic effects, darbepoetin may also offer neuroprotective benefits, helping to prevent and treat brain injuries in infants, which highlights its dual role in neonatal care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darbepoetin Administration in Term and Preterm Neonates. Patel, S., Ohls, RK.[2018]

The study assessed the safety and feasibility of administering a single dose of Darbepoetin alpha (Darbe) to 21 neonates with mild neonatal encephalopathy, and found no adverse events reported in either the Darbe or placebo groups.

Both groups showed average developmental scores on the Bayley Scales of Infant and Toddler Development, indicating that while the treatment was safe, further large-scale trials are needed to evaluate the efficacy of Darbe in improving outcomes for these infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darbepoetin as a neuroprotective agent in mild neonatal encephalopathy: a randomized, placebo-controlled, feasibility trial. DuPont, TL., Baserga, M., Lowe, J., et al.[2023]

Darbepoetin alfa (DA) was safely administered to 3 neonates with Rhesus isoimmunization to treat late-onset anemia, with no adverse effects reported.

The treatment with DA reduced the need for packed red blood cell transfusions, indicating its efficacy in managing anemia in these infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darbepoetin Alfa for Late-onset Anemia in Neonates with Rhesus Hemolytic Disease. Rv, S., S, R.[2023]

In a phase III study involving 320 anemic lung cancer patients, darbepoetin alfa significantly reduced the need for blood transfusions (27% vs. 52%) and increased hemoglobin levels compared to placebo, demonstrating its efficacy in treating chemotherapy-associated anemia.

Darbepoetin alfa also improved fatigue levels in patients, with a higher percentage showing significant improvement in fatigue scores compared to those receiving placebo, while maintaining a similar safety profile with no adverse effects on disease outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. Vansteenkiste, J., Pirker, R., Massuti, B., et al.[2022]

In a study of 579 hospitalized children, 28% experienced adverse drug events (ADEs), with the highest rates among those treated for cancer and with anti-infective drugs, indicating a significant concern for drug safety in pediatric care.

The most common ADEs were gastrointestinal, central nervous system (CNS), and skin reactions, with 19% classified as serious; importantly, parental observations contributed valuable information about these reactions, especially CNS-related events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events in children during hospitalization and after discharge in a Norwegian university hospital. Buajordet, I., Wesenberg, F., Brørs, O., et al.[2019]

In a study involving 90 preterm neonates (45 treated with darbepoetin alfa and 45 controls), the administration of darbepoetin alfa did not significantly affect neutrophil counts or the rates of neutropenia compared to the control group.

There were no differences in the occurrence of neutropenia (ANC ≤1000/μL) or severe neutropenia (ANC ≤500/μL) between the darbe-treated and control neonates, indicating that darbepoetin alfa does not impact neutrophil levels in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of Neutropenia in Preterm Neonates Following Administration of Darbepoetin Alfa. Andrews, N., Friedman, S., Dunham, M., et al.[2023]

In a study involving 17 patients on peritoneal dialysis, darbepoetin alfa was found to maintain hemoglobin levels effectively and safely when administered every other week, demonstrating its potential as a less frequent alternative to rHuEPO.

The change in hemoglobin levels was minimal and not statistically significant, indicating that while darbepoetin alfa is safe, its efficacy in terms of hemoglobin improvement is comparable to rHuEPO, even with reduced dosing frequency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A trial of subcutaneous administration of darbepoetin alfa once every other week for the treatment of anemia in peritoneal dialysis patients. Mahajan, S., Boulton, H., Gokal, R.[2015]

In a study of 102 preterm infants, those treated with darbepoetin alfa (Darbe) or erythropoietin (Epo) required significantly fewer blood transfusions compared to the placebo group, indicating effective management of anemia.

Darbe, administered once a week, was as effective as Epo, which was given three times a week, suggesting that less frequent dosing with Darbe can help maintain red blood cell levels without increasing the risk of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Ohls, RK., Christensen, RD., Kamath-Rayne, BD., et al.[2021]

In a study of 683 acutely admitted pediatric patients, 2.4% were admitted due to adverse drug reactions (ADRs), with a significantly higher incidence (68.1%) among those exposed to cancer chemotherapy.

A concerning 84% of ADRs in chemotherapy patients were linked to unlicensed or off-label drugs, highlighting the need for careful monitoring and regulation of these medications in pediatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reaction-related admissions in paediatrics, a prospective single-centre study. Posthumus, AA., Alingh, CC., Zwaan, CC., et al.[2021]

Darbepoetin alfa administered every 3 weeks at doses of 300 μg or 500 μg was effective in treating anemia in chemotherapy patients, with similar success rates in achieving target hemoglobin levels (75% for 300 μg and 78% for 500 μg).

Adding intravenous (IV) iron improved the response rate, with 82% of patients receiving IV iron reaching the target hemoglobin compared to 72% without it, indicating that IV iron can enhance the efficacy of darbepoetin alfa in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darbepoetin alfa 300 or 500 μg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Auerbach, M., Silberstein, PT., Webb, RT., et al.[2015]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05340465

Darbe Plus IV Iron to Decrease Transfusions While ... Trial of darbepoetin plus slow-release intravenous iron to decrease transfusions and improve iron status and neurodevelopment in preterm infants.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4529960/

Darbepoetin administration in Term and Preterm Neonates Darbe shows great promise in decreasing or eliminating transfusions in neonates, and in preventing and treating brain injury in term and preterm infants.

3. withpower.com withpower.com/trial/phase-2-anemia-iron-deficiency-5-2022-96c7d

Darbe + IV Iron for Premature Infants (DIVI Trial) This trial uses Darbepoetin and slow-release IV iron to help preterm infants. The treatment aims to reduce the need for blood transfusions, keep iron levels ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05340465/darbe-plus-iv-iron-to-decrease-transfusions-while-maintaining-iron-sufficiency-in-preterm-infants

Darbe Plus IV Iron to Decrease Transfusions While ... Darbepoetin (Darbe) plus slow-release intravenous (IV) iron to decrease transfusions, maintain iron sufficiency and improve the neurodevelopmental outcomes of ...

5. hopkinsmedicine.org hopkinsmedicine.org/-/media/files/allchildrens/clinical-pathways/darbepoetin-use-in-the-management-of-anemia-of-prematurity.pdf

darbepoetin-use-in-the-management-of-anemia-of- ... Early administration of EPO has been shown to reduce the number of transfusions required in preterm infants, though the small reduction is ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2011/103951orig1s5173_103951orig1s5258lbl.pdf

Aranesp (Darbepoetin alfa) Label - accessdata.fda.gov This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/ ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05340465?term=DEXTRAN%2075&rank=8

Darbe Plus IV Iron to Decrease Transfusions While ... 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 ...

8. aranesp.com aranesp.com/professional/oncology/efficacy_safety

Aranesp® (darbepoetin alfa) | Efficacy and Safety Adverse reactions were based on data from a randomized, double-blind, placebo-controlled study of Aranesp in 597 patients (Aranesp 301, placebo 296) with ...