A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to he stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase H and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail. Copyright (C) 2008 John Wiley & Sons, Ltd.

Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study

Background: Osteoarthritis (OA) of the knee is the most prevalent joint disorder. Previous studies suggest that bromelain, a pineapple extract, may be a safer alternative/adjunctive treatment for knee OA than current conventional treatment. Aim: To assess the efficacy of bromelain in treating OA of the knee. Design: Randomized, double-blind placebo-controlled trial. Methods: Subjects (n=47) with a confirmed diagnosis of moderate to severe knee OA were randomized to 12 weeks of bromelain 800 mg/day or placebo, with a 4-week follow-up. Knee (pain, stiffness and function) and quality-of-life symptoms were reported monthly in the WOMAC and SF36 questionnaires, respectively. Adverse events were also recorded. The primary outcome measure was the change in total WOMAC score from baseline to the end of treatment at week 12. Longitudinal models were used to evaluate outcome. Results: Thirty-one patients completed the trial (14 bromelain, 17 placebo). No statistically significant differences were observed between groups for the primary outcome (coefficient 11.16, p=0.27, 95%CI-8.86 to 31.18), nor the WOMAC subscales or SF36. Both treatment groups showed clinically relevant improvement in the WOMAC disability subscale only. Adverse events were generally mild in nature. Discussion: This study suggests that bromelain is not efficacious as an adjunctive treatment of moderate to severe OA, but its limitations support the need for a follow-up study.

HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain

Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. The aim of this study was to determine whether these compounds could also affect neuropathic pain. Different class I HDACIs were delivered intrathecally into rat spinal cord in models of traumatic nerve injury and antiretroviral drug-induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40% to 50% as a result of HDACI treatment, but only if started before any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence of neuropathic pain.