Issues, challenges, and the way forward in conducting clinical trials among neonates: investigators' perspective.

Clinical trials are essential to test the safety and efficacy of new treatments in any population. The paucity of drug trials especially in the neonatal population has led to the widespread use of unlicensed or off-label medications, exposing them to the risks of drug toxicity and ineffective treatment. Ethical and operational challenges are no longer considered valid excuses for not conducting drug trials in neonates. We recently participated in a combined phase-2 and phase-3 trial investigating a new indigenous goat lung surfactant extract (GLSE) for the treatment of respiratory distress syndrome (RDS) in preterm neonates. In this article, we share pertinent challenges faced by us during the trial to better inform and foster-positive discussion among drug developers, administrators, regulatory authorities, patient advocacy groups, and researchers. Also, we provide many tools developed for the GLSE trial that can be modified and used by prospective trialists.

Goat lung surfactant for treatment of respiratory distress syndrome among preterm neonates: a multi-site randomized non-inferiority trial.

OBJECTIVE: To investigate the safety and efficacy of goat lung surfactant extract (GLSE) compared with bovine surfactant extract (beractant; Survanta®, AbbVie, USA) for the treatment of neonatal respiratory distress syndrome (RDS). STUDY DESIGN: We conducted a double-blind, non-inferiority, randomized trial in seven Indian centers between June 22, 2016 and January 11, 2018. Preterm neonates of 26 to 32 weeks gestation with clinical diagnosis of RDS were randomized to receive either GLSE or beractant. Repeat dose, if required, was open-label beractant in both the groups. The primary outcome was a composite of death or bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA). Interim analyses were done by an independent data and safety monitoring board (DSMB). RESULT: After the first interim analyses on 5% enrolment, the "need for repeat dose(s) of surfactant" was added as an additional primary outcome and enrolment restricted to intramural births at five of the seven participating centers. Following second interim analysis after 98 (10% of 900 planned) neonates were enroled, DSMB recommended closure of study in view of inferior efficacy of GLSE in comparison to beractant. There was no significant difference in the primary outcome of death or BPD between GLSE group (n = 52) and beractant group (n = 46) (50.0 vs. 39.1%; OR 1.5; 95% CI 0.7-3.5; p = 0.28). The need for repeat dose of surfactant was significantly higher in GLSE group (65.4 vs. 17.4%; OR 9.0; 95% CI 3.5-23.3; p < 0.001). CONCLUSIONS: Goat lung surfactant was less efficacious than beractant (Survanta®) for treatment of RDS in preterm infants. Reasons to ascertain inferior efficacy of goat lung surfactant requires investigation and possible mitigating strategies in order to develop a low-cost and effective surfactant.

Internal energy flows of coma-affected singular beams in low-numerical-aperture systems.

The circulating phase gradient component of a singular beam gets modified when focused by a low-numerical-aperature system suffering from coma aberration. The gradient due to this coma aberration splits the higher charge vortex into elementary vortices and distributes them spatially. This splitting depends on the charge and polarity of the incident singular beam as well as the sign and magnitude of the aberration coefficient. The transverse component of the Poynting vector field distribution at the focal plane is decomposed into the curl or solenoidal component and divergence or irrotational component using the Helmholtz-Hodge decomposition technique. The solenoidal component that relates to the orbital angular momentum carries the circulating energy, while the irrotational component shows the sources and sinks of the energy. Intriguing results of the study of energy flow around the edge dislocations apart from the point phase defects in the irrotational components are also presented.

Young's experiment with waves near zeros.

We report an interesting observation in the formation of Young's fringes from a two pinhole arrangement illuminated by waves from the neighborhood of a zero of an optical phase singularity. Spacing of the Young's fringes appears to defy the dependence of pin-hole separation. But for larger pinhole separation such an anomalous phenomenon is not discernible. The experiments show that the fringe spacing is governed by the stronger local phase gradient near the vortex core that also has a radial part. Many diffraction experiments reported so far have missed this aspect as the phase gradient in a vortex beam is normally considered to have only azimuthal and longitudinal components. This work reveals the vortex core structure and is the first experimental evidence to the existence of a radial component of this phase gradient.

Focal plane internal energy flows of singular beams in astigmatically aberrated low numerical aperture systems.

Singular beams have circulating energy components. When such beams are focused by low numerical aperture systems suffering from astigmatic aberration, these circulating energy components get modified. The phase gradient introduced by this type of aberration splits the higher charge vortices. The dependence of the charge, the aberration coefficient, and the size of the aperture on the nature of the splitting process are reported in this paper. The transverse components of the Poynting vector fields that can be derived from the phase gradient vector field distributions are further decomposed into solenoidal and irrotational components using the Helmholtz-Hodge decomposition method. The solenoidal components relate to the orbital angular momentum of the beams, and the irrotational components are useful in the transport of intensity equations for phase retrieval.

Helmholtz Hodge decomposition of scalar optical fields.

It is shown that the vector field decomposition method, namely, the Helmholtz Hodge decomposition, can also be applied to analyze scalar optical fields that are ubiquitously present in interference and diffraction optics. A phase gradient field that depicts the propagation and Poynting vector directions can hence be separated into solenoidal and irrotational components.