Darbepoetin for Ischemic Neonatal Stroke to Augment Regeneration (DINOSAUR)

The aim of the study is to perform a randomized double-blind placebo controlled prospective study in newborn infants with MRI confirmed Middle Cerebral Artery (MCA) Perinatal Arterial Ischemic Stroke (PAIS) with darbepoetin. It will be investigated whether intravenous administered darbepoetin can induce the formation of neuronal tissue and restore brain function in neonates who suffered from PAIS compared to placebo treated controls. The ultimate goal of this study is therefore to develop a therapy using erythropoiesis-stimulating agents (ESA) such as darbepoetin to reduce or even prevent lifelong consequences of PAIS-related brain injury in this group of term newborns.

Study Overview

• Status: Recruiting
• Conditions: Perinatal Stroke; Neonatal Stroke; PAIS
• Intervention / Treatment: Drug: Darbepoetin Alfa; Drug: Saline

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Manon Benders, MD PhD; Phone Number: +31 88 755 5555; Email: m.benders@umcutrecht.nl
• Study Contact Backup: Name: Lisanne M Baak, MD; Phone Number: +31 88 755 5555; Email: l.m.baak-3@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584 EA
    • Recruiting
    • Wilhelmina Childrens Hostpital/University Medical Center Utrecht
    • Contact: Manon Benders, MD, PhD; Phone Number: +31(0)887554545
    • Principal Investigator: Linda S de Vries, MD, PhD
    • Principal Investigator: Manon JN Benders, MD, PhD
    • Sub-Investigator: Nienke Wagenaar, MD
    • Sub-Investigator: Floris Groenendaal, MD, PhD
    • Sub-Investigator: Jeroen Dudink, MD, PhD
    • Contact: Lisanne M Baak, MD; Phone Number: +31(0)887554545; Email: L.M.Baak-3@umcutrecht.nl
    • Sub-Investigator: Lisanne M Baak, MD
    • Principal Investigator: Niek E van der Aa, MD, PhD
    • Principal Investigator: Adam Kirton, MD, PhD
    • Principal Investigator: Nomazulu Dlamini, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newborns ≥ 36+0 weeks of gestation, both male and female
• MRI confirmed diagnosis of acute PAIS, in the MCA region with involvement of the cortical spinal tract (e.g. Posterior Limb of Internal Capsule [PLIC] or peduncles) within one week after birth
• Written informed consent from custodial parent(s)

Exclusion Criteria:

• Moderate -severe Hypoxic-Ischemic Encephalopathy (HIE) with or without hypothermia therapy
• Any proven or suspected major congenital anomaly, chromosomal disorder, metabolic disorder;
• Presence of a serious infection of the central nervous system;
• No realistic prospect of survival, (e.g. severe brain injury), at the discretion of the attending physician.
• Infant for whom withdrawal of supportive care is being considered.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Saline	Drug: Saline; The placebo will consist of saline, containing 9.0 g of salt per liter (0.90%) i.v.; Other Names: Sodium Chloride
Experimental: Darbepoetin; Darbepoetin alfa (Aranesp, Amgen)	Drug: Darbepoetin Alfa; Darbepoetin alfa (Aranesp, Amgen) 2 doses of 10 microgram/kg i.v.; Other Names: Aranesp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in stroke tissue loss	The primary objective is to determine whether there is a difference in the degree in stroke tissue loss between darbepoetin and placebo treatment, which will be measured by the change in lesion size between the time of onset of the insult and 6-8 weeks of age. The primary endpoint will be estimated using advanced volumetric magnetic resonance (MRI) techniques, performed within one week after clinical presentation and at 6-8 weeks of age.	6-8 weeks of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reorganization of corticospinal connectivity	To assess whether there are differences between darbepoetin and placebo treatment in Diffusion Tensor Imaging (DTI) parameters of selected regions of interest. DTI-MRI techniques are performed at 6-8 weeks of age.	6-8 weeks of age
Neurodevelopment	To assess cognitive and motor development at 18 months of age using the Bayley Scales of Infants and Toddler Development (BSITD)-III scores compare them between groups (darbepoetin vs placebo).	18 months of age
Neurological assessment	To assess neurological deficit and function using the Pediatric Stroke Outcome Measure (PSOM) and compare this score between groups (darbepoetin vs placebo). The PSOM is performed at 18 months of age.	18 months of age
Development of Cerebral Palsy	Development of Unilateral Spastic Cerebral Palsy (USCP) using the Gross Motor Function Classification system (GMFCS) and compare this between groups (darbepoetin vs placebo).	18 months of age

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: The Hospital for Sick Children; Alberta Children's Hospital
• Investigators: Principal Investigator: Manon Benders, MD PhD, UMC Utrecht

Publications and helpful links

General Publications

• Benders MJ, van der Aa NE, Roks M, van Straaten HL, Isgum I, Viergever MA, Groenendaal F, de Vries LS, van Bel F. Feasibility and safety of erythropoietin for neuroprotection after perinatal arterial ischemic stroke. J Pediatr. 2014 Mar;164(3):481-6.e1-2. doi: 10.1016/j.jpeds.2013.10.084. Epub 2013 Dec 8.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2017
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: May 24, 2017
• First Submitted That Met QC Criteria: May 30, 2017
• First Posted (Actual): May 31, 2017

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Hematinics; Darbepoetin alfa
• Other Study ID Numbers: NL53975.041.16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes