Background:
While the efficacy and safety of deferiprone (DFP) in adult patients with transfusion‐dependent hemoglobinopathies (TDH) has been extensively studied, data in children are sparse.
Aims:
...We report results of DEferiprone Evaluation in Pediatrics‐2 (DEEP‐2), (EudraCT Number 2012‐000353‐31), a Phase III multicentre, randomized, open label study funded by the EU FP7 Research Program, to compare the efficacy of DFP liquid formulation versus deferasirox dispersible tablets (DFX).
Methods:
DEEP‐2 was a non‐inferiority, 12‐months, active‐controlled trial that included TDH patients, including sickle cell disease (SCD), of 1 month to < 18 years of age. The primary composite efficacy endpoint was treatment success rate based on changes in serum ferritin (SF) levels (all patients) and cardiac iron concentration (MRI‐T2∗) (patients >10 years able to undergo MRI). Predefined criteria (Figure) were used to determine treatment success for the per protocol (PP) population. The secondary endpoints were changes in SF level, cardiac MRI‐T2∗, liver iron concentration‐R2 (LIC‐R2) and safety profile. Non‐inferiority (NI) was based on the 2‐sided 95% confidence interval (CIL, CIU) of the difference in the success rate between the two arms and was established if CIL was greater than −0.125. In the intention‐to‐treat (ITT) analysis, treatment failure was strictly assigned to patients who withdrew from the study, irrespective of the ferritin response observed at the time of the study suspension.
Results:
21 sites from 7 countries participated in the trial between 3/2014 and 9/2017. 393 patients were randomized (1:1 DFP vs. DFX) and included 117 patients < 6 years of age (30%), 38 with non β‐thalassemia TDH (mainly SCD) and 54 chelation‐naïve. DFP was non‐inferior to DFX based on the PP population (n = 271) while the NI criterion was not met for the ITT population (n = 390) due mainly to more patient withdrawals in the DFP arm, which were not mandated by the protocol (Figure). After 1year treatment (PP population) SF changed from 2468 to 2120 ng/ml in DFP arm and from 2822 to 2328 ng/ml in the DFX arm. Cardiac MRI T2∗ values changed from 31.3 to 32.4ms and from 30.8 to 32.0ms in DFP and DFX arm, respectively. Statistical analysis of the change in SF at the end of treatment also showed NI of DFP for the PP population (δ = −20, CIU = 317 ng/ml; NI criterion: <400 ng/ml), but not for the ITT population when missing SF levels were not analyzed. No significant differences were seen between treatment arms for changes in MRI‐T2∗ and LIC. Overall, there were no statistically significant differences between the two arms in serious adverse events (SAEs) and drug‐related SAEs. 18 (9.3%) DFP and 11 (5.5%) DFX‐treated patients were reported with neutropenia, 3 reversible cases of agranulocytosis were detected in DFP arm, and 2 reversible renal failures in DFX arm.
Summary/Conclusion:
This FP7‐sponsored trial on chelation therapy in pediatric patients with TDH is the largest in this age group and the only one comparing the two oral chelating agents. The results of the study show that 1) oral iron chelation treatment is effective even in very young ages, 2) treatment with DFP was not inferior to DFX in patients who received 12 months treatment, 3) NI was not shown in the ITT analysis partially due to a different rate of withdrawal not necessarily mandated by the protocol, 4) the overall safety profile of both DFP and DFX was acceptable. The results of the DEEP‐2 trial provide evidence to support the use of DFP in pediatric patients.
A new class of selective FXIIIa inhibitors with a bicyclic 1,2,4-thiadiazole pharmacophore is described. At 160 μM, compound 8 caused 50% reduction in fibrin γ-chain cross-linking and suppressed the ...polymerization of α chains in platelet-depleted human plasma clots. Fibrinolysis rates in response to tissue plasminogen activator were directly proportional to the concentration of 8 in plasma at the time of clotting.
The elastic constants of doped UO2 simulating a burn-up in the reactor of up to 200 GWd/tM (#~20% U-atoms replaced by fission products) were measured by synchrotron diffraction under high pressure ...and by Knoop indentation. As a complement, also the corresponding thermal expansion was determined by X-ray diffraction at high temperature. It is shown that the elastic constants of the simulated fuels are increased with burn-up, while the thermal expansion is decreased, satisfying the Gruneisen equation. An increasing Gruneisen constant *g with burn-up is also suggested. The results are, however, in contradiction with empirical bulk modulus estimates and previous data from ultrasonic measurements indicating either slightly decreasing or unchanged to strongly decreasing stiffness with burn-up. The need to perform detailed cohesive energy calculations of the doped fuel (ab initio or empirical potential methods), as well as to review the role of microstructure heterogeneities in the ultrasonic E-modulus determinations are therefore suggested.
Indoor air quality in restaurants was studied in two cities in northwest Ohio after clean indoor air ordinances had been enacted. Carbon dioxide and ultrafine particles were measured in two ...restaurants in Toledo and two restaurants in Bowling Green. One restaurant in each city was smoke free, and one restaurant in each city contained a dedicated smoking room. A smoke free office space was also assessed as a reference site. Measurements were collected with datalogging instrumentation simultaneously in both the designated smoking room, if present, and in the nonsmoking section. For smoke free establishments, datalogging instrumentation was also used. Carbon dioxide levels were elevated in all four restaurants, with only 32% of the measurements meeting the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE) criterion level of 1000 ppm. Ultrafine particles currently do not have any formal standard or guideline. Statistically significant differences were evident between all four restaurants and the reference site. The largest differences were found between the two designated smoking rooms and the reference site (p < 0.001), with the mean levels in the smoking rooms up to 43 times higher than in the reference site. The results from this study indicate inadequate fresh air supply in all four restaurants, particularly in the designated smoking rooms, and the possibility that the designated smoking rooms were not containing the environment tobacco smoke, based on the ultrafine particle concentrations measured in the nonsmoking areas of the smoking restaurants.
Summary
The emergence of practice‐based research networks (PBRN) has facilitated the execution of multifaceted community‐based studies. As study complexity increases, so does the number of ...methodological barriers encountered. This paper's goal was to delineate methodological barriers and to evaluate the effectiveness of selected strategies and approaches developed and implemented in allowing a prospective, national PBRN cohort study to succeed in enrolling geographically dispersed mother/healthy term infant dyads (n = 4300) on the day of post‐partum discharge. Specific methodological barriers included: (1) obtaining multiple Institutional Review Board (IRB) approvals; (2) gathering longitudinal data from multiple individuals; (3) soliciting multiple perspectives on discharge decision making; and (4) bolstering minority enrolment. The most effective strategies and approaches we employed to address these methodological challenges were: (1) preparing and distributing the ‘IRB Packet’; (2) recruiting multiple practices covered by the same IRB; and (3) obtaining supplemental funding for increasing minority enrolment. We expect that other PBRN investigators can benefit from our experience and solutions in the successful conduct of this multifaceted community‐based study.
For the assessment of bioequivalence it is assumed that drug clearance in each subject on each of the study days is the same and any observed differences in AUC and/or Cmax between a brand and ...generic formulation are due to differences in bioavailability. We hypothesized that this assumption was invalid for highly variable drugs such as verapamil and tested it by comparing bioavailability for the brand vs itself.
To avoid any contribution from potential formulation differences, we evaluated bioavailability for isoptin SR 240 mg tablets in 9 healthy volunteers on 2 occasions separated by 1 week as part of a larger study. A validated HPLC assay was used to measure serial blood samples over 36 hours.
The AUC0-1 varied 3.8 fold among subjects and 5/9 subjects had > 30% difference in AUC0-1 on the 2 days. After log transformation, the mean AUC0-1 +/- %cv (ng.h/mL) on Occasion 1 (878 +/- 38) was 23% greater (p = 0.031) than on Occasion 2 (713 +/- 41). The 90% confidence interval of Occasion 1/Occasion 2 was 106-143%. The Cmax varied > 9 fold (30-278 ng/mL) among subjects. The intrasubject difference between days ranged from -46% to +298%. The 90% confidence interval was 72-152% for Cmax. Since the same lot of Isoptin was used in the same subjects on 2 occasions, the observed differences must be due to biological variability in verapamil pharmacokinetics, not formulation differences.
The intra-subject biological variability complicates bio-equivalence assessment and can lead to an erroneous assumption of bioinequivalence.
The WHO List of International Comparator Pharmaceutical Products (CPP) For Equivalence Assessment of Interchangeable Multi-Source (Generic) Products will address an important issue in developing new ...generic drugs because it will identify the 'correct' reference product. This list will reduce unnecessary clinical studies in jurisdictions requiring new generics to be compared with brand products sold locally. Eventually, by employing the CPP, there will be a world-wide standard for brand and generic drugs, assuring the same level of quality internationally. The strategy of a single global reference is meritorious, but there are several hurdles to overcome. Most important is that the same brand may differ in dissolution and/or bioavailability in various jurisdictions, including some drugs with a narrow therapeutic index like phenytoin. Several examples are provided in this manuscript. This issue of regional differences has relevance, not only to the WHO list, but also to the matter of how safety and efficacy was established for that product in the first place. Normally, phase III clinical studies are conducted on a product manufactured in a single site, set to one standard. If the product differs in bioavailability in different jurisdictions, one is left with the question: 'which product has remained true to the original formulation?' Alternatively, if safety and efficacy is maintained with all formulations, then one is faced with the question: 'are the criteria currently employed for bioequivalence unnecessarily restrictive?'
Several clinical studies demonstrate reduced serum concentrations of renally excreted drugs in patients with cystic fibrosis (CF). To explain this phenomenon, we propose a model supporting increased ...proximal tubular secretion of certain drugs in individuals with CF. We hypothesize that the chloride channel located on the apical surface of renal proximal tubular cells and controlled by the cystic fibrosis transmembrane conductance regulator (CFTR) operates suboptimally in CF patients, and that the abnormal CFTR decreases Cl
− reabsorption, resulting in an increased concentration of CI
− in the tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal CI
− moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secretion by the renal tubule. Hence, due to enhanced tubular secretion, individuals with CF demonstrate increased tubular clearance of organic anion drugs, resulting in lower steady state serum concentrations.
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