DISCLOSURE FUNDING BRONCHOPULMONARY DYPLASIA (BPD) UCSF. Preventing BPD: Is Inhaled Nitric Oxide the Answer? March, 2009

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1 Preventing BPD: Is Inhaled Nitric Oxide the Answer? March, 2009 Roberta A. Ballard Professor of Pediatrics UCSF DISCLOSURE INO THERAPEUTICS (IKARIA) has provided: * Inhaled Nitric Oxide (INOmax) * Delivery system (INOvent) * Support for completion of follow-up * Support for ongoing database analysis The company was not and is not involved in: * design of study * safety monitoring * data analysis or interpretation * manuscript preparation FUNDING NHLBI funded the RCT and SCOR (U01 HL 62514, P50 HL56401) GCRC Program (MO1 RR00240, MO1 RR00084, MO1RR00425, MO1 RR001271, MO1 RR00064, MO1 RR00080) Additional NIH support - (P30 HD26979, MRDDRC) BRONCHOPULMONARY DYPLASIA (BPD) Chronic Lung Disease (CLD) in Preterm infant 1 st described 1967 by Northway Associated with Mechanical Ventilation and High Oxygen Exposure Infants were weeks gestation The New BPD involves week GA Infants Pathology has changed 1

2 BPD PATHOBIOLOGY BPD PATHOBIOLOGY Susceptible Host Immature, undeveloped lung Deficient immune and antioxidant defenses Surfactant deficiency and dysfunction Genetic predisposition Lung Injury Disturbed intrauterine environment Hypoxia, hyperoxia, mechanical ventilation Inflammation Pulmonary edema Oxidative stress BPD PATHOBIOLOGY Epidemiology of BPD Resulting in Decreased compliance Increased airway resistance Increased pulmonary vascular resistance Disrupted angiogenesis and alveolarization Abnormal repair and growth 29,000 infants gm BW per year in US VON DATA 2006 (for survivors) BW (g) CLD 36 Discharged O % 42% % 25% 2

3 BPD: A CLINICALLY IMPORTANT PROBLEM! Prolonged Hospitalization/Ventilation Poor Nutrition and Growth Long term Pulmonary complications including Asthma BPD associated with poor neurodevelopmental outcome BPD Therapies MULTIFACTORIAL DISEASE No One Answer COMBINED THERAPY *Gentle Ventilation *Caffeine IS INO A COMPONENT? INO to Prevent BPD? Mechanism with Biological Plausibility Treatment makes a Significant Difference Therapy is Safe: Short Term Benefit is Sustained Therapy is Safe: Long Term Therapy is Cost Effective BIOLOGICAL PLAUSIBILITY SUMMARY BPD ANIMAL MODELS RX with INO * Decreased airway muscle and resistance * Improved Compliance * Decreased Inflammation * Improved surfactant function * Protection against hyperoxic injury * Beneficial effect on Lung Growth * Beneficial effect on Angiogenesis * Beneficial effect on Alveolarization 3

4 ino Improves Lung Growth After VEGFR Inhibition Tang, et al 2005 PROPOSED EFFECTS OF NO ON DEVELOPMENT OF THE RESPIRATORY SYSTEM (Martin and Walsh New Engl J Med 2005) INO to Prevent BPD? Mechanism with Biological Plausibility Treatment makes a Significant Difference Therapy is Safe: Short Term Benefit is Sustained Therapy is Safe: Long Term Therapy is Cost Effective CLINICAL TRIALS BACKGROUND 1998 Inhaled NO studies in the preterm infant * for respiratory failure at birth * for established CLD (>28 days) 4

5 CLINICAL TRIALS BACKGROUND 1998 Inhaled NO studies in the preterm infant * for respiratory failure at birth * for established CLD (>28 days) BPD and IVH Trials for Respiratory Failure at Birth Kinsella 1999 trend toward less BPD OI ~25 no increase in IVH Schreiber 2003 less BPD and less IVH OI ~ 7 Mestan 2005 (Schreiber study) -improved outcome at age 2 (better than IVH effect) BPD and IVH Trials for Respiratory Failure at Birth Van Meurs 2005 OI = 21 Increased Mortality, BPD and IVH in <1000 gm Decreased BPD in > 1000 gm BPD and IVH Trials for Respiratory Failure at Birth Kinsella 2006 OI = 5.5 No Difference in BPD for <1000 Gm Decreased BPD in > 1000 gm Decreased abnormalities on HUS 5

6 CLINICAL TRIALS BACKGROUND 1998 Inhaled NO studies in the preterm infant * for respiratory failure at birth * for established CLD (>28 days) ino in CLD - Pilot Study Rationale For Initial Study (10/95) Severe CLD - mortality of > 40% Pulmonary hypertension -- known to be responsive to ino in the term newborn - - a component of severe CLD Banks et al: Pediatrics 1999 ino in CLD - Pilot Study Change in FIO2 After 3 Days ino F i O Pre-iNO 3 days ino 20 decrease 7 no change 1 increase >15% reduction in F i O 2 in 20/28 trials of ino (p<.01 by Wilcoxon Sign Rank Test) 6

7 ino (ppm) ino Administration in 4 Trials (Truog) Ballard (180) Kinsella (~70) Schreiber (~40) Van Meurs (~15) NO CLD TRIAL May, 2000 to April, infants g born 21 US hospitals 9% mortality Days of Life 1555 eligible (vent support 7-21 days) 587 (38%) enrolled (5 withdrawn) TRIAL DESIGN STUDY HYPOTHESES TREATMENT REGIMEN Minimum duration - 24 days 10 to 12 days at > 10ppm Study gas continued when extubated Study gas continued by nasal canula even if off NCPAP EFFICACY Primary Outcome: Improve survival without CLD Secondary Outcomes: Decrease length of ventilation, hospitalization and oxygen supplementation Improve outcome at 40 and 44 weeks PMA SAFETY Co-morbidities of prematurity 2-year neurodevelopmental outcome Biomarkers in tracheal aspirate and plasma 7

8 NO CLD TRIAL CHARACTERISTICS AT BASELINE* INO Control P N=294 N=288 Mean BW (g) % 68% % 32% Mean GA (wk) 26 +/ / Male (%) 53% 56% 0.46 * corrected 7/07 NO CLD TRIAL STATUS AT ENTRY* Co-Morbidities INO PBO P N=294 N=288 Sepsis 24% 20% 0.38 PDA 65% 67% 0.92 NEC 4% 4% 1.00 GR III/IV IVH 12% 16% 0.17 (unilateral) *corrected 7/07 PRIMARY OUTCOME BY BIRTH WEIGHT PRIMARY OUTCOME BY AGE AT ENTRY All g g d d Survival without CLD (%) Survival without CLD (%) n=294 n=197 n=97 n=288 n=197 n=91 n=112 n=182 n=115 n=173 0 ino-treated Treatment Placebo 0 ino-treated Treatment Placebo 8

9 OUTCOME AT 40 WEEKS PMA FOR EARLY ENTRY INFANTS All g NO CLD TRIAL CONCLUSIONS * Increases survival w/o CLD at 36 wk PMA Discharge or off Support (%) n=103 n=70 n=33 n=111 n=82 n=29 * Improves outcome at 40 and 44 weeks PMA * Infants < 800 g appear to share in the benefits * Early (7-14 d) Rx appears more effective than later (15-21 d) NNT = 4 0 ino-treated Treatment Placebo INO to Prevent BPD? Mechanism with Biological Plausibility Treatment makes a Significant Difference Therapy is Safe: Short Term Benefit is Sustained Therapy is Safe: Long Term Therapy is Cost Effective NO CLD TRIAL CO-MORBIDITIES AFTER ENTRY INO PBO P N=294 N=288 Sepsis 41% 41% 0.91 PDA treated 18% 19% 0.85 NEC 8% 7% 0.63 with surgery 3% 3% 0.84 ROP 84% 82% 1.00 with surgery 24% 24%

10 LABORATORY STUDIES: SAFETY OF INHALED NITRIC OXIDE IN THE NO CLD STUDY Nitric oxide metabolites (nitrate/nitrite) Biomarkers of oxidative stress (carbonyls/3nt) Biomarkers of lung inflammation Effects on surfactant Elastin metabolism (desmosine) NO CLD LABORATORY STUDIES Goals Investigate safety of ino treatment Insights into mechanism of beneficial effects Samples 539 tracheal aspirate samples collected from 99 intubated infants in Philadelphia, Kansas City and Westchester 881 plasma samples collected from 107 infants 402 urine samples collected from 52 infants Sample collected at study entry and 1-2, 4, 11, 18, and 25 d on study gas 21 different assays in tracheal aspirate; 4 assays in plasma; 2 in urine Truog (Kansas City) and P. Ballard (Philadelphia) laboratories Starcher Laboratory (Tyler) for desmosine assay SUMMARY No evidence of adverse effects of ino on biomarkers or surfactant---safety of therapy Plasma NO metabolites reflect dose of ino Carbonyls (oxidative stress) and low TA nitrogen oxides associated with adverse outcome Implications for effects of ino therapy (per NO CLD protocol) ino not decrease level of oxidative/nitrative stress No impact on levels of inflammatory biomarkers Improves surfactant function only transiently Consistent with NO effects primarily on alveolarization and airway tone INO to Prevent BPD? Mechanism with Biological Plausibility Treatment makes a Significant Difference Therapy is Safe: Short Term Benefit is Sustained Therapy is Safe: Long Term Therapy is Cost Effective 10

11 Impact of ino on Pulmonary Outcome at 1 Year* Hibbs,2007 MEDICAL HISTORY: Wheezing or whistling in chest ino (%) Placebo (%) Bronchodilators Inhaled Steroids Systemic Steroids RR (95% CI) 0.70 ( ) 0.53 ( ) 0.50 ( ) 0.56 ( ) NNT (95% CI) ( ) 7.5 ( ) 14.1 ( ) Other Markers of Respiratory Status* * by GEE MEDICAL HISTORY: ino (%) Placebo (%) Any Hospitalization 46.5% 50.4% Respiratory Hospitalization 22.6% 21.9% Diuretic use 18.6% 28.4% Any Home O 2 Use 38.4% 49.5% Persistent O 2 at Follow-up 3.0% 9.4% RR 0.83 ( ) 1.03 ( ) 0.54 ( ) 0.65 ( ) 0.30 ( ) NNT ( ) 9.4 ( ) 15.9 ( ) INO to Prevent BPD INO (%) Placebo (%) Odds Ratio* (95% CI) White ( ) Minority ( ) Female ( ) Male ( ) Study Entry: 7-14 days old Study Entry: days old Birth Weight g Birth Weight g ( ) ( ) ( ) ( ) Mechanism with Biological Plausibility Treatment makes a Significant Difference Therapy is Safe: Short Term Benefit is Sustained Therapy is Safe: Long Term Therapy is Cost Effective *Odds Ratio, calculated by GEE. 11

12 Neurodevelopmental Outcomes at 2 Years in the NO CLD Trial of Inhaled Nitric Oxide (ino) M Walsh, AM Hibbs, C Martin, L Palermo, A Cnaan, R Keller, E Vittinghoff, R Ballard for the NO CLD Study Investigators. Follow-up Hypothesis: Inhaled nitric oxide will be safe with no significant detrimental impact on neurodevelopmental impairment at 24 months corrected age. NO CLD 24-Month Follow-Up months adjusted age Bayley Scales of Infant Development II by certified examiner Followup on 496 infants (93%) 411 (83%) complete information at 24 months 85 incomplete information adjudicated 19 with suspect outcome 90% of treated and 88% of placebo analyzed Neurodevelopment at 24 months ino N=243 Placebo N=234 P or RR (95% CI) Mental Dev Index Psychomotor Dev Index Bilateral Blind (%) (0.40, 2.40) Deaf with amplification (%) (0.68, 9.52) Disabling Cerebral Palsy (%) (0.59, 2.55) Neurodevelopment Impaired (%) (0.75, 1.12) 12

13 CONCLUSIONS: ino reduced BPD and was safe as used in the NO CLD Trial. There was no evidence of harm on neurologic, developmental or growth outcomes. We did not see neuroprotection with the ino strategy of this study which was initiated at a median of 16 days and provided prolonged dosing. INO to Prevent BPD Mechanism with Biological Plausibility Treatment makes a Significant Difference Therapy is Safe: Short Term Benefit is Sustained Therapy is Safe: Long Term Therapy is Cost Effective Economic Evaluation of Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation John A. F. Zupancic Anna Maria Hibbs Lisa Palermo Richard J. Martin William E. Truog Avital Cnaan Dennis Black Phillip L. Ballard Jeffrey D. Merrill Xianqun Luan Sandra R. Wadlinger Roberta A. Ballard and the NO CLD Study Group HEALTH SERVICE RESOURCE USE NICU Costs Driven By: * Personnel intensity up to 70% of cost * Surgical Procedures * Blood product transfusions * Parenteral nutrition * Radiological Procedures * Selected laboratory tests * Selected medications (e.g. surfactant) Zupancic J et al. Int J Tech Assess Health Care 2003;19(2):330 13

14 HEALTH SERVICE RESOURCE USE NICU Costs Driven By: * Personnel intensity up to 70% of cost * Surgical Procedures * Radiological Procedures * Parenteral nutrition * Blood product transfusions * Selected laboratory tests * Selected medications (e.g. surfactant) Duration of hospitalization & ventilation Proxies for above Zupancic J et al. Int J Tech Assess Health Care 2003;19(2):330 NO CLD TRIAL HEALTH SERVICES RESOURCE USE (entered 7 to 14 days, N=211)* INO Control Difference (mean number of days) Hospitalization Ventilation *by GEE NO CLD TRIAL Outcome after Discharge (whole group) INO Control Home on O2 36% 46% Analysis Cost-Effectiveness = ino Costs Placebo Costs ino Effects Placebo Effects Home on Vent (1) 0.4% (5) 2.0% 14

15 Cost per survivor without BPD All Infants Cost per survivor without BPD Infants enrolled 7 14 days Study Arm Cost Cost Survivor w/o BPD Survivor w/o BPD Placebo 193, ino 194,702 1, ,197 Cost/ Survivor w/o BPD Study Arm Cost Cost Survivor w/o BPD Survivor w/o BPD Placebo 187, Cost/ Survivor w/o BPD ino 181,525-5, DOMINANT Distribution of Costs and Effects Infants enrolled at 7 to 14 days Putting it into perspective Incremental Costs $40,000 $30,000 $20,000 $10,000 -$10,000 -$20,000 -$30,000 -$40,000 Higher costs, worse outcome: DOMINATED $ Lower costs, better outcome: DOMINANT ECMO (Pediatrics 2006; 117: 1640) 13,385 per life year saved ino for PPHN (Pediatrics 2004; 114: 417) $33,200 per survivor Universal hearing screening (Pediatrics 2002; 110: 855) $44,000 per case of deafness detected -$50,000 Incremental Survivors without BPD 15

16 Conclusions Nitric oxide therapy for prevention of death and BPD in high risk infants < 1250 grams, using the NO-CLD protocol, is economically appealing Results sensitive to daily cost of nitric oxide Response to inhaled nitric oxide (INO): Further analysis of the NO CLD trial Keller RL 1, Vittinghoff E 2, Palermo L 2, Ballard RA 1, Ballard PL 1, Truog W 3 1 Pediatrics/Neonatology, UCSF, San Francisco CA, 2 Epi/Biostats, UCSF, San Francisco CA, 3 Pediatrics, University of MO, Kansas City MO Aims To identify which infants most likely to respond to ino To compare the 36 week (CLD 36) and 40 week (CLD 40) respiratory outcomes in NO CLD To evaluate predictors of 1 year pulmonary outcome NO CLD trial: secondary outcomes 40 weeks PMA - Discharged or hospitalized off respiratory support - Improved from 52% to 62% (RR 1.20; CI 1.04, 1.39) 1 year corrected age Hibbs 2008 Decreased respiratory medications and oxygen supplementation Decreased use of bronchodilators in all subgroups 16

17 Conclusions No significant differential benefit of inhaled NO at 40 weeks by baseline characteristics These findings differ from the analysis of the 36 week outcome (CLD 36) The 40 week outcome is a stronger predictor of pulmonary health in the first year of life than the 36 week outcome NO CLD TRIAL SPECULATION Used in infants at high risk of BPD, the mechanism of INO is likely to be to decrease airway resistance, improve compliance, surfactant function, angiogenesis, alveolarization and lung growth as in animal models FUTURE DIRECTIONS Potential for other therapies combined with ino to prevent a multifactorial disease? Gentler ventilation strategies (eg., NCPAP) Anti-inflammatory and antioxidant therapies Late surfactant treatment THANKS TO - Dr. Cnaan and the DCC staff at CHOP - All the Site Investigators and Coordinators - The RN, RRT and MD staffs at all sites - The Parents and Families - Lisa Palermo and Dennis Black at UCSF 17

18 NO CLD TRIAL INVESTIGATORS Philadelphia J Merrill, J Bernbaum Cleveland R Martin, D Wilson-Costello Kansas City W Truog, H Kilbride Seattle D Mayock, FC Bennet Utah D Null, A Bodnar Oakland D Durand, A Espinoza Boston E Eichenwald, C Martin Jacksonville M Hudak, D Childers Cedar s LA A Puri, S Sehgal Columbus S Welty, C Timan Westchester SGolombek, J Kase Long Is Jewish SCourtney, A Adesman Louisville DStewart, S Wilkerson 18