Novel study designs to investigate the placebo response

<p>Abstract</p> <p>Background</p> <p>Investigating the size and mechanisms of the placebo response in clinical trials have relied on experimental procedures that simulate the double-blind randomized placebo-controlled design. However, as the conventional design is thought to elucidate drug rather than placebo actions, different methodological procedures are needed for the placebo response.</p> <p>Methods</p> <p>We reviewed the respective literature for trials designs that may be used to elucidate the size of the placebo response and the mechanisms associated with it.</p> <p>Results</p> <p>In general, this can be done by either manipulation the information provided to the subjects, or by manipulation the timing of the drug applied. Two examples of each strategy are discussed: the "balanced placebo design" (BDP) and the "balanced cross-over design" (BCD) and their variants are based on false information, while the "hidden treatment" (HT) and the ""delayed response test" (DRT) are based on manipulating the time of drug action. Since most such approaches include deception or incomplete information of the subjects they are suitable for patient only with authorized deception.</p> <p>Conclusion</p> <p>Both manipulating the information provided to subjects (BDP, DCD) or manipulating the timing of drug application (HT, DRT) allows overcoming some of the restrictions of conventional drug trials in the assessment of the placebo response, but they are feasible mostly in healthy subjects for ethical reasons.</p

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

The ethical desirability of moral bioenhancement: A review of reasons

Background: The debate on the ethical aspects of moral bioenhancement focuses on the desirability of using biomedical as opposed to traditional means to achieve moral betterment. The aim of this paper is to systematically review the ethical reasons presented in the literature for and against moral bioenhancement. Discussion: A review was performed and resulted in the inclusion of 85 articles. We classified the arguments used in those articles in the following six clusters: (1) why we (don't) need moral bioenhancement, (2) it will (not) be possible to reach consensus on what moral bioenhancement should involve, (3) the feasibility of moral bioenhancement and the status of current scientific research, (4) means and processes of arriving at moral improvement matter ethically, (5) arguments related to the freedom, identity and autonomy of the individual, and (6) arguments related to social/group effects and dynamics. We discuss each argument separately, and assess the debate as a whole. First, there is little discussion on what distinguishes moral bioenhancement from treatment of pathological deficiencies in morality. Furthermore, remarkably little attention has been paid so far to the safety, risks and side-effects of moral enhancement, including the risk of identity changes. Finally, many authors overestimate the scientific as well as the practical feasibility of the interventions they discuss, rendering the debate too speculative. Summary: Based on our discussion of the arguments used in the debate on moral enhancement, and our assessment of this debate, we advocate a shift in focus. Instead of speculating about non-realistic hypothetical scenarios such as the genetic engineering of morality, or morally enhancing 'the whole of humanity', we call for a more focused debate on realistic options of biomedical treatment of moral pathologies and the concrete moral questions these treatments raise