Fetal weight estimation by ultrasound: development of Indian population-based models.

PURPOSE: Existing ultrasound-based fetal weight estimation models have been shown to have high errors when used in the Indian population. Therefore, the primary objective of this study was to develop Indian population-based models for fetal weight estimation, and the secondary objective was to compare their performance against established models. METHODS: Retrospectively collected data from 173 cases were used in this study. The inclusion criteria were a live singleton pregnancy and an interval from the ultrasound scan to delivery of ≤7 days. Multiple stepwise regression (MSR) and lasso regression methods were used to derive fetal weight estimation models using a randomly selected training group (n=137) with cross-products of abdominal circumference (AC), biparietal diameter (BPD), head circumference (HC), and femur length (FL) as independent variables. In the validation group (n=36), the bootstrap method was used to compare the performance of the new models against 12 existing models. RESULTS: The equations for the best-fit models obtained using the MSR and lasso methods were as follows: log10(EFW)=2.7843700+0.0004197(HC×AC)+0.0008545(AC×FL) and log10(EFW)=2.38 70211110+0.0074323216(HC)+0.0186555940(AC)+0.0013463735(BPD×FL)+0.0004519715 (HC×FL), respectively. In the training group, both models had very low systematic errors of 0.01% (±7.74%) and -0.03% (±7.70%), respectively. In the validation group, the performance of these models was found to be significantly better than that of the existing models. CONCLUSION: The models presented in this study were found to be superior to existing models of ultrasound-based fetal weight estimation in the Indian population. We recommend a thorough evaluation of these models in independent studies.

A Phase I study to determine safety, pharmacokinetics, and pharmacodynamics of ANF-RHO™, a novel PEGylated granulocyte colony-stimulating factor, in healthy volunteers.

Patients receiving pegfilgrastim (Neulasta®) for the treatment of neutropenia can experience bone pain following the injections required to achieve effective neutrophil levels. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of ANF-RHO™, a novel pegylated granulocyte colony stimulating factor, were assessed in a randomized, controlled, double-blind Phase 1 clinical study in healthy volunteers. Subjects received a single subcutaneous dose of ANF-RHO over a range of 6 doses (5-50 µg/kg), placebo (saline), or the recommended clinical dose of pegfilgrastim administered at the labeled fixed 6 mg dosage (equivalent to 80-100 µg/kg). The primary outcome measure was safety and tolerability. Secondary outcomes included PK and PD effects on absolute neutrophil count (ANC) and number of CD34+ progenitor cells. Severity of bone pain was also assessed. In healthy volunteers, ANF-RHO was administered at ascending doses up to 50 µg/kg without significant adverse effects; appeared to be better (5 to 30 µg/kg) or equally well (50 µg/kg) tolerated, and had lower mean bone pain scores as compared to pegfilgrastim. ANF-RHO achieved CD34+ and ANC numbers at significantly lower doses, and had a significantly longer circulating half-life than pegfilgrastim. These results suggest that ANF-RHO can be provided less frequently, at a lower dose, and with fewer side effects. ANF-RHO had unique, prolonged PK/PD attributes as compared to marketed pegfilgrastim, suggesting that it may provide an improved clinical benefit in further clinical studies in patients with chemotherapy-induced or chronic idiopathic neutropenia.

A phase Ib, open-label, single arm study to assess the safety, pharmacokinetics, and impact on humoral sensitization of SANGUINATE infusion in patients with end-stage renal disease.

The endeavor to study desensitization in kidney transplantation has not been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization, and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive three weekly infusions of SG (320 mg/kg). The study was stopped after five subjects were enrolled, and their data were analyzed after completing a follow-up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean (SD) Cmax , Tmax , AUC, and half-life of 4.39 (0.69) mg/mL, 2.42 (0.91) hours, 171.86 (52.35) mg h/mL, and 40.60 (11.96) hours, respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals.

SANGUINATE™ (PEGylated Carboxyhemoglobin Bovine) Improves Cerebral Blood Flow to Vulnerable Brain Regions at Risk of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been linked to focal reductions in cerebral blood flow (CBF) and microvascular impairments in oxygen delivery. Effective therapies that restore flow and oxygen transport to vulnerable brain regions are currently lacking. SANGUINATE is a dual-action carbon monoxide-releasing and hemoglobin-based oxygen transfer agent with efficacy in animal models of focal brain ischemia and tolerability in patients with sickle cell disease. METHODS: We performed a safety and proof-of-principle study in 12 SAH patients at risk of DCI across three escalating doses (160, 240, and 320 mg/kg). We used 15O-PET (performed at baseline, after SANGUINATE and at 24 h) to evaluate efficacy for improving CBF and restoring flow-metabolism balance (assessed by oxygen extraction fraction [OEF]) to vulnerable regions (defined as baseline OEF ≥ 0.50). RESULTS: SANGUINATE resulted in a transient rise in mean arterial pressure (116 ± 15-127 ± 13 mm Hg, p = 0.001) that normalized by 24 h and allowed three patients with DCI to be weaned off vasopressors. No adverse events were noted during infusion. Global CBF did not rise (43 ± 8-46 ± 9 ml/100 g/min) although a trend was seen at the highest dose (45 ± 7-51 ± 9, p = 0.044). However, a significant 16% rise in regional CBF associated with reduction in OEF was seen in vulnerable regions, but did not persist at 24 h. CONCLUSIONS: We demonstrated that this novel agent can improve regional CBF and may improve oxygen supply-demand balance. Clinical studies (likely with repeat dosing) are required to evaluate whether this effect can prevent DCI or cerebral infarction.

A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia.

BACKGROUND: Treatment of sickle cell anemia is a challenging task and despite the well understood genetic and biochemical pathway of sickle hemoglobin, current therapy continues to be limited to the symptomatic treatment of pain, supplemental oxygen, antibiotics, red blood cell transfusions and hydroxyurea. SANGUINATE is a carbon monoxide releasing molecule and oxygen transfer agent under clinical development for the treatment of sickle cell anemia and comorbidities. METHODS: An open-label randomized Phase Ib study was performed in adult sickle cell anemia patients. Two dose levels of SANGUINATE were compared to hydroxyurea in 24 homozygotes for Hb SS. Twelve subjects received either a low dose (160mg/kg) of SANGUINATE or 15mg/kg hydroxyurea. Another 12 subjects received either a high dose (320mg/kg) of SANGUINATE or 15mg/kg hydroxyurea. The primary endpoint was the safety of SANGUINATE versus hydroxyurea in sickle cell anemia patients. Secondary endpoints included determination of the plasma pharmacokinetics and assessment of hematologic measurements. RESULTS: Musculoskeletal related adverse events were the most common. Transient troponin I levels increased in three patients, one of whom had an increase in tricuspid regurgitant velocity; however, no clinical signs were noted. Following an assessment of vital signs, tricuspid regurgitant velocity, electrocardiogram, serum biochemistry, hematology, urinalysis, and analysis of reported adverse events, SANGUINATE was found to be safe in stable sickle cell anemia patients. CONCLUSIONS: The clinical trial met its primary objective of demonstrating an acceptable safety profile for SANGUINATE in patients with sickle cell anemia. This trial established the safety of SANGUINATE at both dose levels and permitted its advance to Phase II trials.

A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia

Abstract Background: Treatment of sickle cell anemia is a challenging task and despite the well understood genetic and biochemical pathway of sickle hemoglobin, current therapy continues to be limited to the symptomatic treatment of pain, supplemental oxygen, antibiotics, red blood cell transfusions and hydroxyurea. SANGUINATE is a carbon monoxide releasing molecule and oxygen transfer agent under clinical development for the treatment of sickle cell anemia and comorbidities. Methods: An open-label randomized Phase Ib study was performed in adult sickle cell anemia patients. Two dose levels of SANGUINATE were compared to hydroxyurea in 24 homozygotes for Hb SS. Twelve subjects received either a low dose (160 mg/kg) of SANGUINATE or 15 mg/kg hydroxyurea. Another 12 subjects received either a high dose (320 mg/kg) of SANGUINATE or 15 mg/kg hydroxyurea. The primary endpoint was the safety of SANGUINATE versus hydroxyurea in sickle cell anemia patients. Secondary endpoints included determination of the plasma pharmacokinetics and assessment of hematologic measurements. Results: Musculoskeletal related adverse events were the most common. Transient troponin I levels increased in three patients, one of whom had an increase in tricuspid regurgitant velocity; however, no clinical signs were noted. Following an assessment of vital signs, tricuspid regurgitant velocity, electrocardiogram, serum biochemistry, hematology, urinalysis, and analysis of reported adverse events, SANGUINATE was found to be safe in stable sickle cell anemia patients. Conclusions: The clinical trial met its primary objective of demonstrating an acceptable safety profile for SANGUINATE in patients with sickle cell anemia. This trial established the safety of SANGUINATE at both dose levels and permitted its advance to Phase II trials.

Ultrasonography-based Fetal Weight Estimation: Finding an Appropriate Model for an Indian Population.

BACKGROUND: Very limited information is available regarding the accuracy and applicability of various ultrasonography parameters [abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), and head circumference (HC)]-based fetal weight estimation models for Indian population. The objective of this study was to systematically evaluate commonly used fetal weight estimation models to determine their appropriateness for an Indian population. METHODS: Retrospective data of 300 pregnant women was collected from a tertiary care center in Bengaluru, India. The inclusion criteria were a live singleton pregnancy, gestational age ≥ 34 weeks, and last ultrasound scan to delivery duration ≤ 7 days. Cases with suspected fetal growth restriction or malformation were excluded. For each case, fetal weight was estimated using 34 different models. The models specifically designed for low birth weight, small for gestation age, or macrosomic babies were excluded. The models were ranked based on their mean percentage error (MPE) and its standard deviation (random error). A model with the least MPE and random error ranking was considered as the best model. RESULTS: In total, 149 cases were found suitable for the study. Out of 34, only 12 models had MPE within ± 10% and only seven models had random error < 10%. Most of the Western population-based models had a tendency to overestimate the fetal weight. Based on MPE and random error ranking, the Woo's (AC-BPD) model was found to be the best, followed by Jordaan (AC), Combs (AC-HC-FL), Hadlock (AC-HC), and Hadlock-3 (AC-HC-FL) models. It was observed that the models based on just AC and AC-BPD combinations had statistically significant lesser MPE than the models based on all other combinations (p < 0.05). CONCLUSION: It was observed that the existing models have higher errors on Indian population than on their native populations. This points toward limitations in direct application of these models on Indian population without due consideration. Therefore, it is recommended that clinicians should exert caution in interpretation of fetal weight estimations based on these models. Moreover, this study highlights a need of models based on native Indian population.

PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial.

PEGylated carboxyhemoglobin bovine (SANGUINATE) is a dual action carbon monoxide releasing (CO)/oxygen (O2 ) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE's efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients.