Poractant alfa 120mg/1.5ml endotracheopulmonary suspension vials

Introduction The availability and use of surfactant replacement therapy (SRT) for respiratory distress syndrome (RDS) in low- and middle-income countries (LMICs) is variable with unclear impact on infant outcomes. This review evaluates the published evidence on SRT in the management of preterm neonates with RDS in LMICs, with a focus on SRT availability, administration, timing, type, and cost. Methods A systematic scoping review of seven databases was conducted, following the Preferred Items for Systematic Reviews and Meta-Analysis guidelines extension for Scoping Reviews. English language systematic reviews and observational and experimental studies, published between January 2010 and July 2023, were eligible for this review. Case reports, small case series, and qualitative studies were excluded. Titles and abstracts were screened by one reviewer and full text by two independent researchers. Sufficiently homogeneous randomized controlled trials (RCTs) were synthesized using random-effects meta-analyses, while other results were synthesized narratively. Primary outcomes for meta-analyses were (1) need for invasive mechanical ventilation (IMV), (2) development of bronchopulmonary dysplasia (BPD), and (3) in-hospital mortality. Results After screening 483 titles/abstracts and 266 full texts, 113 articles were included in the final review (52 RCTs, 50 observational studies, and 11 systematic reviews). Studies reported both INtubation-SURfactant-Extubation (INSURE) and Less/Minimal Invasive Surfactant Administration/Treatment (LISA/MIST) methods of SRT, with different threshold criteria for implementation. There was moderate certainty evidence that using LISA/MIST reduced the need for IMV [risk difference (RD): 0.10 (95% confidence interval, CI: 0.04–0.17); p = 0.001] compared with INSURE, with a borderline effect on BPD [RD: 0.04 (95% CI: 0.00–0.08); p = 0.05] and no significant effect on mortality [RD: 0.01 (95% CI: −0.02 to 0.04; p = 0.5)]. There was low certainty evidence that poractant alfa (200 mg/kg) was associated with a reduced need for mechanical ventilation compared with beractant (100 mg/kg) (RD 0.10 (95% CI: 0.02–0.18); p = 0.01), with a similar reduction in mortality [RD: 0.07 (95% CI: 0.01–0.13); p = 0.02]. No cost-effectiveness studies were identified. Conclusion LISA/MIST should be used in preference to INSURE. Poractant alfa (200 mg/kg) is conditionally recommended in preference to beractant (100 mg/kg). Regionally relevant cost-effectiveness studies are needed.

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Findings from previous meta-analyses of randomized clinical trials (RCTs) in premature infants with respiratory distress syndrome (RDS) varied as to whether clinical outcomes differed by type of animal-derived pulmonary surfactant; real-world evidence (RWE) was excluded. We extracted study characteristics and outcomes from full-text articles from a systematic search for studies that compared beractant with poractant alfa for RDS in preterm infants. RWE data were tabulated; RCT data were subjected to meta-analyses. Designs, patient characteristics, and follow-up durations varied widely among studies (4 RWE, 15 RCT). RWE studies with adjusted odds ratios (ORs) found no statistically significant between-treatment differences in outcomes. In RCT meta-analyses, no statistically significant between-treatment differences were observed for death (OR [95% confidence interval], 1.35 [0.98-1.86]), bronchopulmonary dysplasia (1.25 [0.96-1.62]), pneumothorax (1.21 [0.72-2.05]), and air leak syndrome (2.28 [0.82-6.39]). Collectively, outcomes were similar with beractant and poractant alfa in RWE studies and pooled RCTs.

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BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). STATISTICAL ANALYSIS PLAN: A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA.

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Randomized controlled trial (RCT) data are analyzed by two challengeable adjusted and non-adjusted approaches. Performing appropriate adjusted analysis leads to a more interpretable and efficient estimation of treatment effects. Semiparametric adjustment approach modifies the estimating equations solved by the marginal treatment effect estimator by adding an augmentation function, which makes use of the baseline covariates and estimate the unbiased marginal treatment effect with improved precision. The effect of the intervention obtained using the semi-parametric adjustment method, similar to the unadjusted method and contrary to the adjusted parametric method, is marginal, resulting in better interpretability. Moreover, due to leveraging baseline covariates, it is more efficient compared to the unadjusted models. This study aimed to estimate the effect of beractant (Beraksurf™, Tekzima Company), compared with the Poractant alfa (Curosurf®, Chiesi Pharmaceuticals), as surfactant replacement therapy, on the need for Intermittent Positive Pressure Ventilation (IPPV) in Neonatal Respiratory Distress Syndrome (NRDS) more precisely by fitting a semi-parametric efficient model adjusted for appropriate covariates. This study is secondary and we re-analyzing data of a published RCT. This RCT was conducted in the NICU of Alzahra Hospital in Tabriz, Iran for eight months, and 200 infants were assigned to two groups receiving either 100 mg/kg BeraksurfTM (n = 99) or 200 mg/kg Curosurf® (n = 101). The effect of the treatments was evaluated regarding the need for IPPV by fitting semi-parametric logistic regression models, adjusted for the best subset of covariates selected by the forward variable selection algorithm and confounders identified by the expert panel. IPPV in our study was administered via an endotracheal tube, as per the protocol followed in the primary trial. The need for IPPV was determined based on the clinical judgment of neonatologists, considering the infants' respiratory distress levels, oxygen saturation, and arterial blood gas measurements. The decision was made within the first 72 h after surfactant administration. The proportions of the required IPPV outcome were 29.3% and 59.4% in the BeraksurfTM group and Curosurf®, respectively. While the unadjusted comparison between the two treatments was significant (OR = .283, 95% CI: (.157, .509), P-value < .001), adjusted OR in semi-parametric logistic regression by adjusting for the best subset of covariates selected by forward method including steroids, Apgar score at min1, and initial Fio2 wasn’t significant (OR = .751, 95% CI: (.510, 1.111), P-value = .151). The efficacy of this semi-parametric model over the unadjusted model was 1.81. The results of the expert-based adjusted model, adjusting for the gestational age, birth weight, and initial FiO2, were consistent with those derived from the R2-based selection, supporting the robustness of our findings (OR = .685, 95% CI: (.449, 1.529), P-value = .078). Fitting a semi-parametric model adjusted for the baseline covariates resulted in a marginal, unbiased, more efficient and interpretable estimation of BeraksurfTM versus Curosurf® effects. Although the crude model showed that BeraksurfTM was more effective than Curosurf®, the results of the efficient semi-parametric model with adjustment for the best subset of covariates revealed no statistically significant difference between the two drugs regarding their effects. We hope that the use of this method and its findings will contribute to a better understanding of covariate adjustment.

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BACKGROUND: Bronchiolitis is a common viral respiratory disease of infants, with severity ranging from mild symptoms, such as coryza and feeding difficulties, to fulminant respiratory failure. Endotracheal administration of exogenous surfactant has been shown in small studies to improve gas exchange in critically ill infants with bronchiolitis. We aimed to investigate the safety and efficacy of endotracheal poractant alfa for treating critical bronchiolitis compared with a sham procedure. METHODS: BESS was a multicentre, blinded, randomised, sham-controlled, parallel-group, phase 2, superiority trial with exploratory mechanism evaluation studies. The trial was done in 15 paediatric intensive care units in the devolved National Health Service (NHS) of England, Scotland, and Northern Ireland. Preterm and term-born infants younger than 26 weeks of gestationally corrected age admitted to hospitals with bronchiolitis requiring invasive mechanical ventilation (IMV) were randomly assigned (1:1) to receive up to three doses of endotracheal poractant alfa (Curosurf) or sham intervention, allocated through web-based randomisation. Randomisation was stratified by duration of IMV before randomisation (<24 h and ≥24 h) and by site. The infants and their families, clinical care staff, Liverpool Clinical Trial Centre staff, and members of the site research teams were masked to treatment allocations. Endotracheal poractant alfa was given initially at 200 mg/kg, followed by 100 mg/kg at 12 h intervals. The primary endpoint was the duration of IMV from randomisation to final successful extubation. All infants who were successfully extubated were included in the intention-to-treat analysis. Safety outcomes were analysed in infants who had received at least one trial intervention. This trial was registered prospectively with ISRCTN (ISRCTN11746266) and EudraCT (2018-001169-18), and is completed. FINDINGS: The trial was completed after six recruitment seasons. Between Dec 18, 2018, to March 31, 2024, 1009 infants were assessed for eligibility, 232 of whom were randomly assigned to receive either endotracheal poractant alfa (n=115) or a sham intervention (n=117). 130 (56%) of 232 infants were male and 102 (44%) were female. Three infants were withdrawn from the study. None were lost to follow-up. The median duration of IMV was 64·9 h (IQR 43·2-92·1) in the endotracheal poractant alfa group and 62·0 h (39·3-95·1) in the sham intervention group. The geometric mean ratio was 1·02 (95% CI 0·84-1·24; t-test p=0·86). No clinically significant safety issues were associated with endotracheal poractant alfa and there were no deaths. INTERPRETATION: Poractant alfa, administered endotracheally to infants with early critical bronchiolitis, although safe, did not reduce the duration of IMV compared with the sham intervention. Therefore, our findings suggest that it should not be used for this indication at this dose and administration method. FUNDING: UK National Institute for Health and Care Research, UK Research and Innovation Medical Research Council, Chief Scientist Office Scotland, Health and Social Care Research and Development Division Northern Ireland, and Chiesi Farmaceutici, Italy.

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We would like to commend the authors for executing a study we wish we had done. Surfactant replacement therapy for preterm infants with respiratory distress syndrome (RDS) has been shown to reduce mortality and associated complications. Bovine lipid extract surfactant (BLES) was developed in Canada in the early 1980s and has been the most widely used preparation in the country for decades. Production and distribution costs are relatively low and BLES remains one of the most economical of the commercially available surfactant preparations. Poractant alfa (Curosurf) is the most widely used surfactant in most other countries and European guidelines recommend that it be used to treat intubated babies with confirmed RDS [1]. Comparative studies with various bovine surfactant preparations suggest that there may be an advantage to using Curosurf at the recommended initial high dose of 200 mg/kg [2]. Curosurf was introduced into Canada in 2017 and clinicians were uncertain as to whether a change to routine practice might be indicated. We did not have the resources to conduct a large randomized trial comparing the two surfactants, so our group conducted a small RCT at three centers [3] and followed it with a comparative effectiveness trial involving most of the NICUs in Canada [4]. In both studies, BLES and Curosurf seemed to have similar efficacy and safety profiles when treating intubated premature infants with RDS. However, few infants were treated using LISA/MIST which has since become the recommended standard approach for babies with RDS initially managed with noninvasive respiratory support. While poractant alfa has been used in most trials assessing LISA, a small trial from Canada showed that BLES could be used for LISA with good treatment success in spite of the larger volume instilled and lower total phospholipid dosing provided when compared to poractant alfa [5]. RDS is the most common cause of neonatal death in preterm infants born in low and middle-income countries (LMICs). Treatments for these infants include provision of basic supportive care, application of continuous positive airway pressure, administration of exogenous surfactant and in some cases, use of mechanical ventilation [6]. Each of these therapeutic measures is expected to improve survival incrementally when applied to the management of preterm infants in healthcare settings. While basic supportive care and CPAP have become standard in most LMICs, surfactant is not universally available, and when available, may not be used because of prohibitive cost. Costs are not usually covered by government health authorities, and families may be required to pay for it out of pocket or forego treatment if they cannot afford it. One vial of surfactant can cost as much as a month's salary in some settings. An affordable surfactant preparation for use in LMICs is required for optimal uptake and benefit to be appreciated. This study from Zamal et al. reports on a study designed to answer a clinically very pertinent question: what is the comparative efficacy and cost-effectiveness of BLES versus poractant alfa when administered via the LISA technique in moderately preterm infants with RDS [7]. The authors performed a well-designed, single-center, randomized controlled trial, which included 282 moderately (28−34 weeks) preterm infants, who were less than 6 h post-birth with respiratory distress requiring noninvasive respiratory support and at least 30% oxygen. They observed no clinically significant differences in the need for intubation or time on invasive or noninvasive respiratory support, nor for any usual prematurity-related predischarge complications or mortality. The total surfactant cost was 30% lower in the BLES group: the authors conclude that “BLES's significant cost advantage makes it a compelling choice for resource-limited settings.” While the results of this study should make clinicians comfortable in choosing BLES to treat preterm babies when using the LISA technique, we suggest the next step to be a multicenter, international study examining this question. Such a study should include extremely preterm infants, where the LISA technique is being used more and more. Ultimately, an effective synthetic surfactant preparation that can be mass-produced at low cost would be expected to be the best solution to the limited access currently impacting preterm babies with RDS in resource-limited settings. Brigitte Lemyre: writing – review and editing. Michael Dunn: writing – review and editing. The authors declare no conflicts of interest. The authors have nothing to report.

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Background: Neonatal respiratory distress syndrome (NRDS) affects approximately up to 7% of all term newborns. This study aimed to assess the efficacy and safety of investigational beractant (BeraksurfTM, Tekzima Company) in comparison with poractant alfa (Curosurf®, Chiesi Pharmaceuticals) as surfactant replacement therapy in NRDS. Methods: This trial was a randomized, controlled, single-blind, phase III study of two natural surfactants which was conducted in NICU of Alzahra hospital in Tabriz for 8 months. 220 infants were enrolled in 2 groups to receive either 100 mg/kg BeraksurfTM or 200 mg/kg Curosurf® as an initial dose endotracheally. Additional doses were given if needed. Infants’ gestational age, birth weight, discharge weight and other demographic information were recorded. Efficacy outcomes were changes of fraction of inspired oxygen (FiO2) and the number of infants who reached FiO2 less than 0.3 (treatment success rate) which were compared between both groups with analysis of covariance (ANCOVA). Results: The results showed that the treatment success rate was 92% and 72% in BeraksurfTM and Curosurf® groups, respectively (Pvalue&lt; 0.001). In addition, no difference was observed in the efficacy of these two treatments in terms of binary outcomes and incidence of complications such as mortality. Conclusion: The result analysis of current study implies BeraksurfTM has same beneficial impact on clinical management of RDS as Curosurf® among infants below 32 weeks. However, larger studies are needed to evaluate further efficacy and safety outcomes of this surfactant in comparison with the reference products in other subgroups.

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Abstract Objective: Exogenous surfactant therapy is vital in managing respiratory distress syndrome (RDS) in preterm infants, with less invasive surfactant administration (LISA) gaining popularity. This study aimed to assess the efficacy and short-term outcomes of LISA using beractant and poractant alfa. Study Design: In a randomized controlled trial , we enrolled preterm infants (28-33 +6 weeks) with RDS requiring surfactant. LISA was employed, with beractant at 100 mg/kg or poractant-alfa at 200 mg/kg. Primary outcome was the need for intubation within 72 hours. Results: Among 120 infants, 3.3% in both groups required intubation within 72 hours (p value 1.00, 95% CI 0.14 - 6.86). No significant differences in secondary outcomes were noted, except a trend towards increased necrotizing enterocolitis with beractant . Beractant was significantly more economical. Conclusion: Beractant and poractant-alfa exhibit similar efficacy in LISA for preterm infants with RDS. Economic considerations, especially in LMICs, favour beractant. The trial is registered in the clinical trial registry of India (CTRI/2023/03/050375).

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