Explore the vast range of titles available.

Background Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare the relative efficacy of Test to Control by reference to a clinically important margin, M . Main text Non-inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M ; and (b) superiority if Test is slightly better than Control even if it is by less than M . From Control’s perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials. Conclusion Rules for interpretation should not favor one treatment over another. Claims of statistical or clinical superiority should depend on whether or not the null margin or the clinically relevant margin is exceeded.

Background: All the processes leading to neurodegeneration cannot be addressed with just one medication. Combinations of drugs affecting various disease mechanisms concurrently could demonstrate improved effect in slowing the course of Parkinson’s disease (PD). Objective: This was a drug-repurposing experiment designed to assess several combinations of nine drugs for possible added or synergistic efficacy using in vitro models of PD. Methods: We evaluated 44 combinations of the nine medications (sodium phenylbutyrate, terazosin, exenatide, ambroxol, deferiprone, coenzyme-Q10, creatine, dasatinib and tauroursodeoxycholic acid) selected for their previously demonstrated evidence of their impact on different targets, showing neuroprotective properties in preclinical models of PD. We utilized wild-type induced pluripotent stem-cell-derived human dopaminergic neurons treated with 1-methyl-4-phenylpyridinium for initial screening. We retested some combinations using an idiopathic PD patient-derived induced pluripotent stem cell line and alpha-synuclein triplication line. We assessed anti-neuroinflammatory effects using human microglia cells. As metrics, we evaluated neurite length, number of branch points per mm2, the number of live neurons, neurofilament heavy chain and pro-inflammatory cytokines. Results: We have identified four combinations of two to three drugs that showed an additive protective effect in some endpoints. Only the combination of sodium phenylbutyrate, exenatide and tauroursodeoxycholic acid showed improvement in four endpoints studied. Conclusions: We demonstrated that some of the medications, used in combination, can exert an additive neuroprotective effect in preclinical models of PD that is superior to that of each of the compounds individually. This project can lead to the development of the first treatment for PD that can slow or prevent its progression.

Cultural background may influence the perception of psychiatric symptoms. We examined the effects of cultural biases on the identification of manic symptoms using the Young Mania Rating Scale. Two video interviews, each with an American person with mania, were shown to psychiatrists from three countries (US, UK and India). Total scores on the scale differed significantly between the US and UK (P < 0.001) and between India and UK (P < 0.001) rater groups. Overall, differences between India and US rater groups were less marked (P=0.28). These differences suggest that cultural biases influence the interpretation of manic symptoms.

Current therapies for osteoarthritis have limitations. LEVI-04 is a p75 neurotrophin receptor (p75NTR) fusion protein that inhibits neurotrophin-3. We assessed the efficacy and safety of LEVI-04 in individuals with knee osteoarthritis. This randomised, placebo-controlled, double-blind, phase 2 trial enrolled participants from Denmark, Hong Kong, Poland, Moldova, and the Czech Republic with painful (≥4/10 Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain scores) and radiographic knee osteoarthritis. Participants were randomised 1:1:1:1 to receive a monthly intravenous placebo or LEVI-04 0·3 mg/kg, 1·0 mg/kg, or 2·0 mg/kg through to week 16, with safety follow-up to week 30. The primary endpoint was change in WOMAC pain from randomisation to week 17 in the intention-to treat population. Safety analyses included all participants who received the study drug. This trial is registered with ClinicalTrials.gov, NCT05618782, and EU Clinical Trials database, EudraCT 2021-006540-28. Between Oct 19, 2022, and Oct 23, 2023, of 1598 participants screened, 518 (292 female and 226 male; mean age 64·0 years [SD 8·07]) were randomly assigned to receive LEVI-04 0·3 mg/kg (n=130), 1·0 mg/kg (n=130), or 2·0 mg/kg (n=129) or placebo (n=129). One person who did not receive the study treatment was excluded from the safety analysis. At week 17, least squares mean difference in WOMAC pain versus placebo were −0·51 (95% CI −0·96 to −0·07), p=0·023; −0·62 (−1·07 to −0·17), p=0·015; and −0·79 (−1·24 to −0·35) p=0·0024 in the LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively. Effect sizes (standardised mean difference) at week 17 were 0·28 (95% CI 0·52 to 0·04), 0·33 (0·58 to 0·09), and 0·43 (0·68 to 0·19) for the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively. LEVI-04 showed no increased incidence in serious adverse events, treatment-emergent adverse events (75 [58%], 86 [66%], 83 [64%] in the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg dose groups, respectively, and 87 [67%] placebo), or joint pathologies, including rapidly progressive osteoarthritis. LEVI-04 was well tolerated and showed significant improvements in pain and function. These results support supplementing endogenous p75NTR in treating osteoarthritis. Levicept.

Objective Our objective was to demonstrate the safety, tolerability, and efficacy of a minocycline foam, FMX103, in the treatment of moderate-to-severe facial papulopustular rosacea. Methods This was a phase II, randomized, double-blind, multicenter study. Healthy subjects aged ≥ 18 years with moderate-to-severe rosacea that had been diagnosed ≥ 6 months previously and with ≥ 12 inflammatory facial lesions were randomized (1:1:1) to receive once-daily 1.5% FMX103, 3% FMX103, or vehicle for 12 weeks. The primary endpoint was the absolute change in inflammatory lesion count at week 12. Other assessments included grade 2 or higher Investigator’s Global Assessment (IGA) improvement, IGA “clear” or “almost clear” (IGA 0/1), clinical erythema, and safety/tolerability. Safety and efficacy were evaluated at weeks 2, 4, 8, and 12, with a safety follow-up at week 16. Results A total of 232 subjects were randomized; 213 completed the study. At week 12, inflammatory lesion count reduction was significantly greater for the 1.5 and 3% FMX103 doses than for vehicle (21.1 and 19.1 vs. 7.8, respectively; both p  < 0.001). Both doses were significantly better than vehicle for achieving grade 2 or higher IGA improvement and assessment of “clear” or “almost clear.” Both doses appeared generally safe and well tolerated. In total, 11 (4.7%) subjects reported treatment-related treatment-emergent adverse events (TEAEs); all but one (eye discharge) were dermal related, and all resolved by study end. No treatment-related systemic TEAEs were reported. Four subjects discontinued the study because of TEAEs (3% FMX103, n  = 3; vehicle, n  = 1). Conclusion Topical minocycline foam, FMX103, appeared to be an effective, safe, and well tolerated treatment for moderate-to-severe papulopustular rosacea. These results support further investigation in larger clinical trials. Clinicaltrials.gov identifier NCT02601963.

In this paper we derive a new p-value based multiple testing procedure that improves upon the Hommel procedure by gaining power as well as having a simpler step-up structure similar to the Hochberg procedure. The key to this improvement is that the Hommel procedure can be improved by a consonant procedure. Exact critical constants of this new procedure can be numerically determined. The zeroth-order approximations to the exact critical constants, albeit slightly conservative, are simple to use and need no tabling, and hence are recommended in practice. The proposed procedure is shown to control the familywise error rate under independence among the p-values. Simulations empirically demonstrate familywise error rate control under positive and negative dependence. Power superiority of the proposed procedure over competing ones is also empirically demonstrated. Illustrative examples are given.

Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, is important for eye and brain development and ongoing visual, cognitive, and cardiovascular health. Unlike fish-sourced oils, the bioavailability of DHA from vegetarian-sourced (algal) oils has not been formally assessed. We assessed bioequivalence of DHA oils in capsules from two different algal strains versus bioavailability from an algal-DHA-fortified food. Our 28-day randomized, placebo-controlled, parallel group study compared bioavailability of (a) two different algal DHA oils in capsules (“DHASCO-T” and “DHASCO-S”) at doses of 200, 600, and 1,000 mg DHA per day (n = 12 per group) and of (b) an algal-DHA-fortified food (n = 12). Bioequivalence was based on changes in plasma phospholipid and erythrocyte DHA levels. Effects on arachidonic acid (ARA), docosapentaenoic acid-n-6 (DPAn-6), and eicosapentaenoic acid (EPA) were also determined. Both DHASCO-T and DHASCO-S capsules produced equivalent DHA levels in plasma phospholipids and erythrocytes. DHA response was dose-dependent and linear over the dose range, plasma phospholipid DHA increased by 1.17, 2.28 and 3.03 g per 100 g fatty acid at 200, 600, and 1,000 mg dose, respectively. Snack bars fortified with DHASCO-S oil also delivered equivalent amounts of DHA on a DHA dose basis. Adverse event monitoring revealed an excellent safety and tolerability profile. Two different algal oil capsule supplements and an algal oil-fortified food represent bioequivalent and safe sources of DHA.

A sharper Bonferroni procedure for multiple tests of significance is derived. This procedure is an improvement of Hochberg's (1988) procedure which contrasts the individual P-values with corresponding critical points. It is shown that Hochberg's original procedure is conservative, and can be made more powerful by enlarging the rejection region so that the type-one error is exactly at the nominal level. It is also shown that the modified procedure retains all the desired properties of the original procedure.