How Often Do Safety Signals Occur by Chance in First-in-Human Trials?

Clinicians working on first-in-human clinical studies need to be able to judge whether safety signals observed on an investigational drug were more likely to have occurred by chance or to have been caused by the drug. We retrospectively reviewed 84 Novartis studies including 1234 healthy volunteers receiving placebo, to determine the expected incidence of changes in commonly measured laboratory parameters and vital signs, in the absence of any active agent. We calculated the frequency of random incidence of safety signals, focusing on the liver, cardiovascular system, kidney and pancreas. Using the liver enzyme alanine aminotransferase (ALT) as an example, we illustrate how a predictive model can be used to determine the probability of a given subject to experience an elevation of ALT above the upper limit of the normal range under placebo, conditional on the characteristics of this subject and the study

Targeted Therapies: Adaptive Sequential Designs For Subgroup Selection In Clinical Trials

A critical part of clinical trials in drug development is the analysis of treatment efficacy in patient subgroups (subpopulations). Due to multiplicity and the small sample sizes involved, this analysis presents substantial statistical challenges and can lead to misleading conclusions. In this thesis, we develop methodology for statistically valid subgroup analysis in a variety of settings. First, we consider a number of trial designs of varying flexibility for the case of one subgroup of interest. Some procedures are novel, while others are adapted from the literature. Included is data-driven consideration of adaptive change of subject eligibility criteria-known as adaptive enrichment-whereby apparently nonresponsive patient populations are not recruited after data has been unblinded for an interim analysis. We conduct an extensive numerical study to investigate design operating characteristics, as well as sensitivity to subgroup prevalence and interim analysis timing. We observe that power gains can be substantial when a treatment is only effective in the subgroup of interest. Following this example, selected procedures are generalized to allow for analysis of an arbitrary number of subgroups. Next, we propose a K -stage group sequential design that can be applied as a confirmatory seamless Phase II/III design. The design is specified through upper and lower spending functions, defined in terms of calendar times. After the first stage, poorly performing subgroups are eliminated and the remaining population is pooled for the duration of the trial. This procedure combines the elimination of non-sensitive subgroups with the definitive assessment of treatment efficacy associated with traditional group sequential designs. Numerical examples show that the procedure has high power to detect subgroup-specific effects, and the use of multiple interim analysis points can lead to substantial sample size savings. We address the challenges of adjusting for selection bias, and protecting the familywise error rate in the strong sense. All designs are presented either in terms of standardized test statistics or the efficient score, making the analysis of normal, binary, or time-to-event data straightforward

Study protocol CKAF156X2201: A proof-of-concept, open label study to assess efficacy, safety, tolerability and pharmacokinetics of KAF156 in adult patients with acute, uncomplicated Plasmodium falciparum or vivax malaria mono-infection

This is a redacted study protocol (CKAF156X2201) for inclusion with our manuscript 'The novel imidazolopiperazine KAF156 clears parasitemia rapidly in falciparum and vivax malaria', currently being reviewed by the New England Journal of Medicine for publication. The original manuscript was approved through OAK (07 Jan 2016 Article 28035). The New England Journal has requested inclusion of the study protocol with our manuscript, and will publish the protocol online under the supplementary materials section associated with the manuscript. There is precedent for this - the KAE609X2201 protocol was published with redactions in the same journal in 2014, following review and approval by NIBR legal and patents. Consequently, Richard Janovjak (NITD legal) has been added as a reviewer at the request of Priya Mannum. We have redacted personal names and information of people not associated with the this publication, as well as the sections on biomarkers and pharmacogenomics, and most of the exploratory objectives, except for those mentioned in the manuscript

Protocol No. CKAE609X2201 A proof-of-concept open label, 3-day repeated dose study to assess efficacy, safety, tolerability and pharmacokinetics of KAE609 in adult patients with acute, uncomplicated Plasmodium falciparum or vivax malaria mono-infection

Not applicable. This is a redacted protocol for inclusion in the online supplementary materials accompanying the manuscript entitled 'The novel spiroindolone KAE609 clears parasitemia rapidly in Falciparum and Vivax malaria

Regenerative and Antibacterial Properties of Acellular Fish Skin Grafts and Human Amnion/Chorion Membrane: Implications for Tissue Preservation in Combat Casualty Care.

To access publisher's full text version of this article click on the hyperlink belowImprovised explosive devices and new directed energy weapons are changing warfare injuries from penetrating wounds to large surface area thermal and blast injuries. Acellular fish skin is used for tissue repair and during manufacturing subjected to gentle processing compared to biologic materials derived from mammals. This is due to the absence of viral and prion disease transmission risk, preserving natural structure and composition of the fish skin graft.The aim of this study was to assess properties of acellular fish skin relevant for severe battlefield injuries and to compare those properties with those of dehydrated human amnion/chorion membrane.We evaluated cell ingrowth capabilities of the biological materials with microscopy techniques. Bacterial barrier properties were tested with a 2-chamber model.The microstructure of the acellular fish skin is highly porous, whereas the microstructure of dehydrated human amnion/chorion membrane is mostly nonporous. The fish skin grafts show superior ability to support 3-dimensional ingrowth of cells compared to dehydrated human amnion/chorion membrane (p < 0.0001) and the fish skin is a bacterial barrier for 24 to 48 hours.The unique biomechanical properties of the acellular fish skin graft make it ideal to be used as a conformal cover for severe trauma and burn wounds in the battlefield.Office of Naval Research and Kerecis Limited, Eyrargata,Isafjordur, Icelan

A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel imidazolopiperazine KAF156, to assess safety, tolerability and pharmacokinetics in healthy adult volunteers

KAF156 belongs to a new class of antimalarial, imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single and multiple ascending dose study in 70 healthy male volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults, and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single dose cohorts (10-1200 mg, including one 400 mg food effect cohort; (4-10 subjects/cohort); and in multiple dose cohorts (60-600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6-14 days post last dose. KAF156 was tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (N=4, 11.1%), diarrhea (N=3, 8.3%), dizziness (N=3, 8.3%) and abdominal pain (N=2, 5.6%) were the commonest adverse events. Headache (N=4, 16.7%), nausea (N=3, 12.5%), upper respiratory tract infection (N=3, 12.5%), and dizziness (N=2, 8.3%) were the commonest adverse events following multiple doses. KAF156 Tmax was between 1.0-6.0 hours. Both AUC and Cmax increased more than dose-proportionally in both single and multiple ascending dose cohorts (terminal half-life 42.5-70.7 hours). There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while mean Cmax decreased from 778 ng/mL to 627 ng/mL and Tmax was delayed from a median of 3.0 hours under fasted conditions to 6.0 hours under fed conditions. Renal elimination is a minor route