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The Importance of New Definitions for BPD: The Case for Primary Prevention and

Early Biomarker Discovery

X Simpósio Internacional de Neonatologia

Rio de Janeiro, Brasil

June 23, 2016

BPD: Lung injury during a critical window of lung development

• Impaired lung growth – Reduction of lung surface area →

abnormal gas exchange

• Impaired Blood Vessel Growth – Pulmonary hypertension

• Abnormalities of lung structure can persist into adulthood

Control BPD

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So many studies, so little progress…..

• Despite decades of promising research, primary prevention of BPD has proven elusive.

• There is an alarming lack of evidence to support the use of any pharmacologic agent in the management of infants at risk of developing or with established BPD… with the exception of caffeine and vitamin A.

• Little change in the incidence of BPD in the past 20 years.

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Courtesy of Steven Donn

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Why have clinical trials of (name your favorite therapy) yielded negative or inconsistent results,

despite promising preclinical studies?

• BPD is a non-specific diagnosis based on a supplemental oxygen requirement at 36 weeks

• BPD has a more complex pathogenesis in human infants, i.e. multiple endotypes – Infection/inflammation

– Intermittent hypoxia and hyperoxia

– Free radicals/oxidant injury

– Nutrition

– Genetics

• Variable approach to the intervention

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• Primary prevention of neonatal lung

diseases

Biomarkers: early diagnosis/early

interventions

• Precision medicine

Requires precision definitions

Future Priorities

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• Barriers to primary prevention of BPD

• Promising areas for research – normal and aberrant lung development

– BPD endotypes

– biomarkers for more targeted therapeutic approaches

• Research recommendations and priorities to accelerate discovery and promote lung health in infants born preterm

Ann Am Thorac Soc Vol 11, Supplement 3, pp S146–S153, Apr 2014

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embryonic

pseudoglandular

alveolar

PRETERM BIRTH

week

Stages of lung

development saccular

canalicular

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40……3 years

Genetic Makeup Epigenetics Fetal

Programming Predisease State Lung Disease

Gene mutations Susceptibility genes Pharmacogenetic

response to drugs

Prenatal, perinatal and intergenerational exposures to toxins, stress, smoke, diet

IUGR, nutrition, placental function, maternal illness, antenatal steroids

Structurally & biochemically immature lung, infection/ inflammation, oxidant injury, volutrauma, apnea, poor nutrition

Altered alveolar, vascular & airway structure and function; enhanced susceptibility to childhood and adult lung disease

Healthy Newborn

Lung

Lifelong Lung Health

Primary BPD Prevention Blocking One or More Factors

Figure 1. Primary prevention for BPD: Windows of opportunities

Highest BPD risk

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Modulating and Host Response Factors

• Responses of individual patients to these insults are modulated by genetic, epigenetic and antenatal factors

9

BPD structurally & biochemically immature lung

hyperoxia and oxidant injury

volutrauma infection &

inflammation

poor nutrition

poor respiratory drive and apnea

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Challenges to Primary Prevention Research

• BPD - rare disease with different phenotypes, necessitating multi-institutional collaborations

• Ethical challenges - balancing risks and benefits of preventive strategies

– Some premature infants not destined to develop BPD will be exposed to experimental therapies with potential adverse effects

• Pharmaceutical companies - reluctant to study a critically ill pediatric population with high mortality and long statute of limitations.

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Challenges to Primary Prevention Research

• The optimal timing for primary prevention interventions is unclear.

– Does BPD start in utero, at the time of delivery, or in the early postnatal period?

– How do interactions between antenatal exposures and postnatal events modulate the risk or severity of disease?

• Lack validated biomarkers that predict later disease and can serve as surrogates for long-term respiratory outcomes.

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BPD Endotypes

• It is likely that distinct causal factors dominate in different patients.

• Failure to identify subpopulations with distinct mechanisms of disease (endotypes) contributes to:

– exposures to therapies unlikely to benefit individual patients

– negative trials

– skepticism about biologically plausible therapies that may benefit a subset of at-risk infants

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Precision Medicine in the NICU: The Potential Value of Validated Biomarkers of Disease

• Facilitate the development of tailored, personalized therapeutic approaches

• Reduce healthcare costs and the risks of broadly applying ineffective therapies.

• Improved patient endotyping prior to randomization may enhance safety and efficacy of RCTs of novel therapies

• May increase screening costs and result in fewer eligible babies requiring larger multi-center collaborative efforts

Science at the heart of medicine 13

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The Hallmarks of a Good Biomarker

• Practical and affordable

• Predicts later disease or serves as surrogates for long-term respiratory outcomes

• Elucidates underlying pathophysiologic mechanisms: i.e. allows us to refine BPD risk by endotypes

• Validated in replication cohorts

Science at the heart of medicine 14

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Challenges of Biomarker Research for BPD

• Source of biomarker

– DNA, miRNA, amniotic fluid, TA, blood, urine, stool

– Normalization

• Timing of collection

– Birth, first hours, days, weeks?

– Pattern of biomarker expression

– GA and postnatal age-dependent patterns of normal

15

0

10

20

1 3 7 14 28Days of life

Bio

mark

er

level

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Challenges of Biomarker Research for BPD

• Appropriate control group

• Multiple confounders (need a great biostatistician)

• Absolute value versus change over time

– Continuous variable, cutoff or quartiles?

• Interactions among various biomarkers

– Balance of inflammatory and anti-inflammatory cytokines; pro- and antioxidants; alpha and gamma tocopherol

16

Antioxidant defenses

Oxidant stress

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BPD: We have a definition problem

• Inherent shortcoming of defining a disease by how we treat it!

• Current definition of BPD provides no information about pathophysiology, disease progression or phenotype variability

– Multiple definitions: Shennon, NIH workshop, Physiologic

• Relatively poor correlation between a diagnosis of BPD, as currently defined, and later childhood respiratory morbidity

Science at the heart of medicine 17

McEvoy, Jain, Schmidt, Abman, Bancalari, Aschner, Annals ATS 2014

Limitations of Existing Definitions of BPD

• Do not account for recent changes in clinical practice

– Room-air–high flow NC (to provide positive airway pressure)

– Extremely low flow with 100% oxygen

– Unclassifiable and misclassified babies

• Relevance of 36 weeks as the outcome time point

– Lung development continues through childhood

Prematurity and Respiratory Outcomes Program

A multi-center study funded by the NIH

RFA-HL-10-007

PROP U01

PURPOSE:

Promote collaborative, innovative research to identify

mechanisms and associated functional and molecular

biomarkers of respiratory disease risk of premature

infants

PROP Structure

Data Coordinating Center (DCC) Univ. of PA

Multi-center

Database

Pro

spectiv

e B

iore

pository

Sponsor: NHLBI and NICHD (BPCA)

Washington

University

Cincinnati

Children's

UCSF

Univ Rochester

Univ Buffalo

Vanderbilt

Duke

Indiana

Subject Characteristics of Survivors to 36 weeks

n = 765

Gestational age, mean (SD), wk 26.7 (1.4)

Birth weight, mean (SD), g 917 (236)

Antenatal Corticosteroids 85.6%

Female, n (%) 48.6%

Multiple births 25.4%

Surfactant in DR 60.4%

835 infants < 29 weeks were enrolled; Survival to 36 weeks was 91.6%

Frequency of BPD in PROP Cohort using Strict Definitions without Imputation and Modified Definitions

1Modified Shennan by assigning infants discharged before 36 wks in room-air as no BPD 2Modified Workshop by omitting need for 28 days of supplemental oxygen; without

consideration of receipt of supplemental oxygen prior to 36 wks, the category of mild BPD

is eliminated

Examples of Potential Misclassification

At 36 wks PMA: Workshop Shennan Physiologic

1/16 LPM NC – 100% severe Yes ?

5 cm CPAP - RA severe No Yes*

*Not eligible for RA/flow reduction challenge

Distribution of Flow and FiO2 among Infants on Nasal Cannula at 36 Weeks PMA or Discharge

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Does a diagnosis of BPD at 36 weeks predict respiratory morbidity after hospital discharge and throughout the first year of life?

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Unresolved Issues

• Lower GA infants remain on support longer and stay in the hospital longer – is a 36 wk outcome still relevant?

• In era of targeted oxygen saturations, does the physiologic definition/RA challenge add any useful information?

• Need for earlier diagnosis of those most likely to have a poor outcome.

• Should a diagnosis of BPD be assigned based on respiratory status on a single day?

• Need for refined definition at 36-40 wks that predicts childhood and perhaps adulthood pulmonary outcomes.

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Audacious Goals of PROP Writing Group

• Develop a score for assessing severity of respiratory disease at term/discharge based on use of respiratory support (flow and O2) and medications.

• Assess the relationship between severity score and known at-birth risk factors for adverse respiratory outcome: GA, BW, gender, race, delivery mode, antenatal corticosteroids, etc.

• Assess the relationship between severity score and assignment of BPD by current definitions.

• Validate key findings in a separate infant cohort.

• Examine relationship between severity score and first year respiratory outcome.

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Develop definitions for “adequate respiratory function” in ELGAN

• Identifies infants whose respiratory function is appropriate for their developmental age and with the least likelihood of respiratory morbidity in early childhood.

• Encompasses the various compartments of the respiratory system: the upper airway, the lower airway and the parenchymal gas exchange units

• Ideally will take into account physiology, immunology, structure and function, central control of breathing, host defenses

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Adequate respiratory function

• Respiratory stability with no form of support (FiO2 or flow) for 1 week before 40 weeks or discharge if before 40 weeks.

• Off respiratory medications including diuretics, bronchodilators, caffeine, steroids (any), pulmonary vasodilators for 1 week before 40 weeks or discharge

– Absence of respiratory support and absence of caffeine as indirect markers of adequate control of breathing and ability to nipple feed.

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Relationship between O2 concentration and flow rate and how many passed or failed the RAC as a function of their flow rate

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Inadequate Respiratory Function 1. Death between 2 weeks and 40 weeks or discharge due to respiratory

illness

2. Invasive respiratory support (Intubated) and any O2 > 0.21 at 40 weeks

3. Non-invasive respiratory support (CPAP, Vapotherm, high flow humidified system such as Fisher Paykel, high flow NC for alveolar disease, upper airway support, control of breathing issues) and supplemental O2

4. Non-invasive respiratory support as above without supplemental O2

5. Low flow nasal cannula with FiO2 = 1.0 at 40 weeks

6. Low flow nasal cannula with blended oxygen at 40 weeks

7. Nasal cannula flow with FiO2 = 0.21

8. Room air at 40 weeks but for less than 7 days or with respiratory medications

9. Off medications and respiratory support at 40 weeks but for less than 7 days

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Discharge-day status for babies discharged before 40 0/7 PMA weeks (n=428 )

PRD: positive response in ≥ 2 separate questionnaires for at least 1 of the following domains: home technology

dependence, respiratory medications, hospitalization for respiratory cause or wheeze/cough without a cold >1x per week

RMSS: severe, if there were ≥2 respiratory hospitalizations, home oxygen after 3 months or any home mechanical ventilation,

systemic steroid exposure or pulmonary vasodilators at any time, or symptoms despite concurrent inhaled corticosteroids in

≥2 questionnaires;

moderate/mild, if one hospitalization, home oxygen <3 months or tracheostomy without ventilation, any inhaled corticosteroid

exposure, or bronchodilator or symptoms in ≥2 questionnaires; minimal/none for all other cases.

PROP – Consort Diagram

835 infants <29 weeks GA enrolled

765 36 week survivors

684 in study hospital at 36 weeks

316 in study hospital at 40 weeks

Before 36 weeks 63 deaths 7 withdrawals

Before 36 weeks 68 discharged home 15 transferred

Between 36-40 weeks 360 discharged home 3 deaths 1 withdrawals 3 transferred

Status of babies still hospitalized at 40 weeks

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The Frustration of Negative Trials: Ineffective therapies or ineffective trial design?

• “Statistically negative trials” or “indeterminate trials,” cannot prove that a therapy is ineffective

• Alternative explanations for negative trials

– Insufficient sample size

– Small effect size: timing, dose, duration of therapy not optimized

– Too much noise (variation) in the outcome

• Each strategy to improve the likelihood of a positive clinical trial poses a potential tradeoff in generalizability, cost, sample size, signal, or noise.

Rubenfeld, GD "Confronting the Frustrations of Negative Clinical Trials in Acute Respiratory

Distress Syndrome", Annals of the American Thoracic Society, Vol. 12, No. Supplement 1 (2015), pp. S58-S63.

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The Frustration of Negative Trials: Improving the signal to noise ratio

• The ability of a clinical trial of a given size (power) to identify a statistically significant effect is related to the magnitude of the effect of the therapy (signal) and the variation (noise) in that outcome in the study:

• Noise can be introduced by heterogeneous patient populations, heterogeneous centers, clinical care, and medical co-interventions.

Gordon D. Rubenfeld "Confronting the Frustrations of Negative Clinical Trials in Acute Respiratory

Distress Syndrome", Annals of the American Thoracic Society, Vol. 12, No. Supplement 1 (2015), pp. S58-S63.

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Potential Strategies and Alternative Trial Designs

• Other than optimizing the dose and duration of therapy, the most important concept for magnifying the effect of the therapy is that the patient’s disease should have the pathophysiology that the treatment targets: i.e. endotypes are important.

• The real problem is our limited fundamental understanding of the biology of BPD.

Gordon D. Rubenfeld "Confronting the Frustrations of Negative Clinical Trials in Acute Respiratory

Distress Syndrome", Annals of the American Thoracic Society, Vol. 12, No. Supplement 1 (2015), pp. S58-S63.

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Future enhancements to trial design of targeted therapies

• Identification of

Physiologic or biochemical markers of disease susceptibility

Genetic or biochemical markers of response to therapy

Good surrogate endpoints that correlate with long-term outcomes