Darbepoetin for Ischemic Neonatal Stroke to Augment Regeneration (DINOSAUR)

• ClinicalTrials.gov Identifier: NCT03171818
• Recruitment Status: Recruiting
• First Posted: May 31, 2017
• Last Update Posted: November 13, 2020
• Sponsor: UMC Utrecht
• Collaborators: Alberta Children's Hospital; The Hospital for Sick Children
• Information provided by (Responsible Party): dr. M.J.N.L. Benders, UMC Utrecht

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
PAIS; Neonatal Stroke; Perinatal Stroke	Drug: Darbepoetin Alfa; Drug: Saline	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: An international multicenter, randomized placebo controlled intervention study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: This will be a double-blinded study, meaning that both the patient (and his/her parents) and the health care providers, including neonatologist, pediatrician, nurses, physiotherapists, etc, are not allowed to know what treatment the patient has been given. Those that collect outcome parameters, such as MRI data and neurodevelopmental outcome, are also unaware of treatment allocation, meaning that blinding will be maintained during the full study-period of 18 months.
• Primary Purpose: Treatment
• Official Title: Darbepoetin for Ischemic Neonatal Stroke to Augment Regeneration
• Actual Study Start Date: July 1, 2017
• Estimated Primary Completion Date: October 1, 2021
• Estimated Study Completion Date: April 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Darbepoetin; Darbepoetin alfa (Aranesp, Amgen)	Drug: Darbepoetin Alfa; Darbepoetin alfa (Aranesp, Amgen) 2 doses of 10 microgram/kg i.v.; Other Name: Aranesp
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 Name: Sodium Chloride

Outcome Measures

Primary Outcome Measures :

1. Change in stroke tissue loss [ Time Frame: 6-8 weeks of age ]
   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.

Secondary Outcome Measures :

1. Reorganization of corticospinal connectivity [ Time Frame: 6-8 weeks of age ]
   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.
2. Neurodevelopment [ Time Frame: 18 months of age ]
   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).
3. Neurological assessment [ Time Frame: 18 months of age ]
   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.
4. Development of Cerebral Palsy [ Time Frame: 18 months of age ]
   Development of Unilateral Spastic Cerebral Palsy (USCP) using the Gross Motor Function Classification system (GMFCS) and compare this between groups (darbepoetin vs placebo).

Eligibility Criteria

• Ages Eligible for Study: up to 7 Days (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Manon Benders, MD PhD; +31 88 755 5555; m.benders@umcutrecht.nl

Contact: Nienke Wagenaar, MD; +31 88 755 5555; n.wagenaar@umcutrecht.nl

Locations

Netherlands

Wilhelmina Childrens Hostpital/University Medical Center Utrecht; Recruiting

Utrecht, Netherlands, 3584 EA

Contact: Manon Benders, MD, PhD +31(0)887554545

Contact: Nienke Wagenaar, MD +31(0)887554545 ext 63630 n.wagenaar@umcutrecht.nl

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

Sponsors and Collaborators

UMC Utrecht

Alberta Children's Hospital

The Hospital for Sick Children

Investigators

• Principal Investigator: Manon Benders, MD PhD; UMC Utrecht

More Information

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.

• Responsible Party: dr. M.J.N.L. Benders, Principal Investigator UMC Utrecht, UMC Utrecht
• ClinicalTrials.gov Identifier: NCT03171818
• Other Study ID Numbers: NL53975.041.16
• First Posted: May 31, 2017
• Last Update Posted: November 13, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Darbepoetin alfa; Hematinics