Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. METHODS: Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0-23), maintenance (Weeks 24-52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24-36). RESULTS: A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. CONCLUSIONS: The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.

COCCIDIOSIS IN GREEN TURTLES (CHELONIA MYDAS) IN AUSTRALIA: PATHOGENESIS, SPATIAL AND TEMPORAL DISTRIBUTION, AND CLIMATE-RELATED DETERMINANTS OF DISEASE OUTBREAKS.

An epizootic of coccidiosis in free-ranging green turtles (Chelonia mydas) occurred in Australia in 1991 and the parasites were thought to be Caryospora cheloniae. Recurring outbreaks over an increased geographic range followed. We used medical records and temporal and spatial data of turtles diagnosed with coccidiosis between 1991 and 2014 to characterize the disease and factors associated with outbreaks. Most affected animals were subadults or older. Neurologic signs with intralesional cerebral coccidia were observed. Coccidia associated with inflammation and necrosis were predominantly found in the intestine, brain, kidney, and thyroid. Cases occurred in the spring and summer. Three major outbreaks (1991, 2002, and 2014) were concentrated in Port Stephens, New South Wales (NSW) and Moreton Bay, Queensland, but cases occurred as far south as Sydney, NSW. Coccidiosis cases were more likely during, or 1 mo prior to, El Niño-like events. Molecular characterization of the 18S rRNA locus of coccidia from tissues of 10 green turtles collected in 2002 and 2004 in Port Stevens and Sydney imply that they were Schellackia-like organisms. Two genotypes were identified. The Genotype 3 sequence was most common (in eight of 10 turtles), with 98.8% similarity to the 18S sequence of Schellackia orientalis. The Genotype 4 sequence was less common (in two of 10 turtles) with 99.7% similarity to the 18S sequence of the most common genotype (Genotype 1) detected in turtles from the 2014 Moreton Bay outbreak. Our study will help with the identification and management of future outbreaks and provide tools for identification of additional disease patterns in green turtles.

The kappa-opioid receptor antagonist nor-BNI inhibits cocaine and amphetamine, but not cannabinoid (WIN 52212-2), abstinence-induced withdrawal in planarians: an instance of 'pharmacologic congruence'.

The broad applicability of receptor theory to diverse species, from invertebrates to mammals, provides evidence for the evolution in complexity of pharmacologic receptor diversification and of receptor-effector signal transduction mechanisms. However, pre-mammalian species have less receptor subtype differentiation, and thus, might share signal transduction pathways to a greater extent than do mammals, a phenomenon that we term 'pharmacologic congruence'. We have demonstrated previously that the lowest species considered to have a centralized nervous system, planarians, display both abstinence-induced and antagonist-precipitated withdrawal signs, indicative of the development of physical dependence. We report here: (1) amphetamine abstinence-induced withdrawal, and (2) the attenuation of cocaine and amphetamine, but not cannabinoid agonist (WIN 52212-2), abstinence-induced withdrawal by the opioid receptor antagonist naloxone and by the selective kappa-opioid receptor subtype antagonist nor-BNI (nor-Binaltorphimine), but not by the selective mu-opioid or the delta-opioid receptor subtype antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) and naltrindole. These results provide evidence that the withdrawal from cocaine and amphetamine, but not cannabinoids, in planarians is mediated through a common nor-BNI-sensitive (kappa-opioid receptor-like) pathway.