Trial Outcomes & Findings for Preterm Erythropoietin Neuroprotection Trial (PENUT Trial) (NCT NCT01378273)

Last Updated: 2020-08-26

Results Overview

Severe NDI was defined as Bayley Scales of infant Development, 3rd edition composite motor score or composite cognitive score \<70. This instrument is normed at 100 with standard deviation of 15. Cerebral palsy was classified as hemiplegia, diplegia, or quadriplegia, and severity was determined according to the Gross Motor Function Classification System (GMFCS) (levels range from 0 \[no impairment\] to 5 \[most severe impairment\]). Severe cerebral palsy was defined as a GMFCS level higher than 2.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

941 participants

Primary outcome timeframe

22-26 months corrected age

Results posted on

2020-08-26

Participant Flow

Participant milestones

Participant milestones
Measure	Control Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age. Control: Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.	Epo 1000 U/kg Followed by 400 U/kg Subjects will receive 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects will receive subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age. Epo: Enrollment will occur within 24 hours of birth. Study drug will be administered intravenously for the first 6 doses. Subjects in the Epo arm will then receive 400 U/kg/dose three times a week until they reach 32-6/7 weeks postmenstrual age. Control infants will receive sham injections.
Overall Study STARTED	464	477
Overall Study COMPLETED	460	476
Overall Study NOT COMPLETED	4	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Gestational age at birth

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Control n=460 Participants Enrollment will occur within 24 hours of birth. Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age. Subjects are then followed until 22-26 months for neurodevelopmental testing.	Epo 1000 U/kg Followed by 400 U/kg n=476 Participants Enrollment will occur within 24 hours of birth. Epo 1000 U/kg/dose will be administered intravenously for the first 6 doses. Subjects in the Epo arm will then receive 400 U/kg/dose three times a week until they reach 32-6/7 weeks postmenstrual age. Subjects are then followed until 22-26 months for neurodevelopmental testing.	Total n=936 Participants Total of all reporting groups
Age, Customized 24 weeks of gestation	119 Participants n=5 Participants • Gestational age at birth	113 Participants n=7 Participants • Gestational age at birth	232 Participants n=5 Participants • Gestational age at birth
Age, Customized 25 weeks of gestation	124 Participants n=5 Participants • Gestational age at birth	121 Participants n=7 Participants • Gestational age at birth	245 Participants n=5 Participants • Gestational age at birth
Age, Customized 26 weeks of gestation	118 Participants n=5 Participants • Gestational age at birth	103 Participants n=7 Participants • Gestational age at birth	221 Participants n=5 Participants • Gestational age at birth
Age, Customized 27 weeks of gestation	99 Participants n=5 Participants • Gestational age at birth	139 Participants n=7 Participants • Gestational age at birth	238 Participants n=5 Participants • Gestational age at birth
Sex: Female, Male Female	218 Participants n=5 Participants	232 Participants n=7 Participants	450 Participants n=5 Participants
Sex: Female, Male Male	242 Participants n=5 Participants	244 Participants n=7 Participants	486 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	85 Participants n=5 Participants	115 Participants n=7 Participants	200 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	370 Participants n=5 Participants	354 Participants n=7 Participants	724 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	7 Participants n=5 Participants	9 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) Asian	18 Participants n=5 Participants	10 Participants n=7 Participants	28 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) Black or African American	120 Participants n=5 Participants	120 Participants n=7 Participants	240 Participants n=5 Participants
Race (NIH/OMB) White	293 Participants n=5 Participants	317 Participants n=7 Participants	610 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Region of Enrollment United States	460 participants n=5 Participants	476 participants n=7 Participants	936 participants n=5 Participants
Consented and received first study drug dose	460 Participants n=5 Participants	476 Participants n=7 Participants	936 Participants n=5 Participants

PRIMARY outcome

Timeframe: 22-26 months corrected age

Population: 936 subjects 24-0/7 to 27-6/7 weeks' gestation were randomized and received Epo (n=476) or placebo (n=460) in a double-blinded manner. Survivors who were fully evaluated at 2 years of age are included in the analysis.

Outcome measures

Outcome measures
Measure	Control n=365 Participants Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age.	Epo 1000 U/kg Followed by 400 U/kg n=376 Participants Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 22-26 Months Corrected Age	94 Participants	97 Participants

SECONDARY outcome

Timeframe: From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)

Population: All subjects who received at least one dose of study drug.

Serious adverse events were prespecified. These included any symptomatic thrombosis involving a major vessel, unrelated to an infusion catheter requiring anticoagulation therapy, hematocrit level \>65% or an increase of ≥15% in hematocrit in the absence of a preceding blood transfusion, hypertension (defined by receipt of antihypertensive therapy for more than 1 month, discharge with medication, or both), severe pulmonary hemorrhage, severe necrotizing enterocolitis (defined as Bell's stage 2b or 3), severe retinopathy of prematurity resulting in laser surgery or bevacizumab therapy, severe sepsis (defined as culture-proven bacterial or fungal sepsis resulting in blood-pressure support or substantive new respiratory support), grade 3 or 4 intracranial hemorrhage, cardiac arrest that did not result in death, and death.

Outcome measures

Outcome measures
Measure	Control n=460 Participants Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age.	Epo 1000 U/kg Followed by 400 U/kg n=476 Participants Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
Number of Participants With a Serious Adverse Events (SAE)	284 Participants	282 Participants

SECONDARY outcome

Timeframe: 36 weeks postmenstrual age

Population: Patients who survived to 36 weeks postmenstrual age at 9 preselected sites

Brain MRI at 36 weeks PMA. Injury scoring was done using a modified scoring system of Kidokoro, with higher scores indicating greater brain injury. Scoring Range: 0-39

Outcome measures

Outcome measures
Measure	Control n=101 Participants Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age.	Epo 1000 U/kg Followed by 400 U/kg n=93 Participants Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
Imaging	4.1 score on a scale Standard Deviation 2.6	3.8 score on a scale Standard Deviation 2.1

SECONDARY outcome

Timeframe: Baseline (first 24 hours after birth), days 7, 9 and 14 after birth

Population: Patients who had a baseline Epo level drawn

Plasma Epo concentrations were measured in both groups within the first 24 h after birth before study drug administration (baseline), 30 minutes after study drug administration on day 7 (peak Epo concentration) and 30 minutes before study drug on day 9 (trough Epo) and a random level on day 14 after transition to subcutaneous dosing.

Outcome measures

Outcome measures
Measure	Control n=384 Participants Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age.	Epo 1000 U/kg Followed by 400 U/kg n=391 Participants Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
Biomarkers Peak Epo	2.2 mU/mL Interval 1.1 to 4.8	2,907 mU/mL Interval to 6998.0
Biomarkers Baseline	7.6 mU/mL Interval 3.4 to 20.5	7 mU/mL Interval 3.9 to 21.4
Biomarkers Trough Epo	5.1 mU/mL Interval 1.7 to 8.9	15.3 mU/mL Interval 7.4 to 28.9
Biomarkers Random (day 14)	4.6 mU/mL Interval 2.1 to 8.6	25 mU/mL Interval 9.6 to 66.5

Adverse Events

Control

Serious events: 284 serious events

Other events: 460 other events

Deaths: 45 deaths

Epo 1000 U/kg Followed by 400 U/kg

Serious events: 282 serious events

Other events: 476 other events

Deaths: 53 deaths

Serious adverse events

Serious adverse events
Measure	Control n=460 participants at risk Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age (PMA)	Epo 1000 U/kg Followed by 400 U/kg n=476 participants at risk Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age (PMA).
Blood and lymphatic system disorders Polycythemia	0.22% 1/460 • Number of events 1 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	0.42% 2/476 • Number of events 2 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Blood and lymphatic system disorders Major Thrombosis	0.43% 2/460 • Number of events 2 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	1.1% 5/476 • Number of events 5 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Respiratory, thoracic and mediastinal disorders Severe pulmonary hemorrhage	4.1% 19/460 • Number of events 19 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	6.3% 30/476 • Number of events 30 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Gastrointestinal disorders Necrotizing enterocolitis	7.8% 36/460 • Number of events 36 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	5.9% 28/476 • Number of events 28 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Infections and infestations Severe sepsis	8.3% 38/460 • Number of events 38 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	7.4% 35/476 • Number of events 35 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Nervous system disorders Severe intracranial hemorrhage	13.9% 64/460 • Number of events 64 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	12.0% 57/476 • Number of events 57 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Eye disorders Severe retinopathy of prematurity	6.5% 30/460 • Number of events 30 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	6.3% 30/476 • Number of events 30 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Cardiac disorders Hypertension	2.2% 10/460 • Number of events 10 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	1.3% 6/476 • Number of events 6 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
General disorders Nonfatal cardiac arrest	1.7% 8/460 • Number of events 8 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	1.9% 9/476 • Number of events 9 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
General disorders Other unexpected life-threatening events	6.7% 31/460 • Number of events 31 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	5.7% 27/476 • Number of events 27 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
General disorders Death	9.8% 45/460 • Number of events 45 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	11.1% 53/476 • Number of events 53 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)

Other adverse events

Other adverse events
Measure	Control n=460 participants at risk Subjects received 6 doses of vehicle intravenously during the first 2 weeks of life. Doses were administered at 48 hour intervals from the time of enrollment. Following high dose administration, sham subcutaneous injections were given three times a week through to 32-6/7 weeks postmenstrual age (PMA)	Epo 1000 U/kg Followed by 400 U/kg n=476 participants at risk Subjects received 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Following the high dose period, subjects received subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age (PMA).
Respiratory, thoracic and mediastinal disorders Bronchopulmonary dysplasia	35.0% 161/460 • Number of events 161 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	36.1% 172/476 • Number of events 172 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Cardiac disorders Treated patent ductus arteriosus	37.4% 172/460 • Number of events 172 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	37.4% 178/476 • Number of events 178 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Gastrointestinal disorders Necrotizing enterocolitis	11.5% 53/460 • Number of events 53 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	9.7% 46/476 • Number of events 46 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Nervous system disorders Intracranial hemorrhage (all grades)	39.3% 181/460 • Number of events 181 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	35.3% 168/476 • Number of events 168 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Nervous system disorders Periventricular leukomalasia	9.3% 43/460 • Number of events 43 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	8.6% 41/476 • Number of events 41 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Nervous system disorders Cerebellar hemorrhage	2.2% 10/460 • Number of events 10 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	1.7% 8/476 • Number of events 8 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Eye disorders Retinopathy of Prematurity (all grades)	56.1% 258/460 • Number of events 258 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	51.3% 244/476 • Number of events 244 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)
Blood and lymphatic system disorders Blood transfusion	87.2% 401/460 • Number of events 401 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)	71.6% 341/476 • Number of events 341 • Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth)

Additional Information

Sandra Juul MD, PhD

University of Washington

Phone: 2062216814

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place