Incorporating the sample correlation into the testing of two endpoints in clinical trials.

We introduce an improved Bonferroni method for testing two primary endpoints in clinical trial settings using a new data-adaptive critical value that explicitly incorporates the sample correlation coefficient. Our methodology is developed for the usual Student's t-test statistics for testing the means under normal distributional setting with unknown population correlation and variances. Specifically, we construct a confidence interval for the unknown population correlation and show that the estimated type-1 error rate of the Bonferroni method with the population correlation being estimated by its lower confidence limit can be bounded from above less conservatively than using the traditional Bonferroni upper bound. We also compare the new procedure with other procedures commonly used for the multiple testing problem addressed in this paper.

Exact critical values for group sequential designs with small sample sizes.

Group sequential clinical trial designs allow the sequential hypothesis testing as data is accumulated over time, while ensuring the control of type-1 error rate. These designs vary in how they split the overall type-1 error among analyses, but practically, all assume that: 1. The underlying data is normal or approximately so, and 2. the sample sizes are large, so the individual test statistics are sufficiently normal rather than Student's t. These two assumptions lead to the reliance on the multivariate normal distribution for calculation of the critical values. Several publications have pointed out that for small sample sizes, such an approach leads to an inflated type-1 error and proposed different sets of critical values from either simulations or by an ad-hoc adjustment to the asymptotic critical values. In this paper, we develop the exact joint distribution of the test statistics for any sample size. We show how to calculate exact critical values that conform to some well-known alpha-spending functions, such as the O'Brien-Fleming and Pocock critical values. We also compare the resulting type-1 error of these critical values with the asymptotic, as well as with other methods that have been proposed for small sample sizes.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.

Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline.

BACKGROUND: Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimer's disease. Higher DHA intake is inversely correlated with relative risk of Alzheimer's disease. The potential benefits of DHA supplementation in age-related cognitive decline (ARCD) have not been fully examined. OBJECTIVE: Determine effects of DHA administration on improving cognitive functions in healthy older adults with ARCD. METHODS: Randomized, double-blind, placebo-controlled, clinical study was conducted at 19 U.S. clinical sites. A total of 485 healthy subjects, aged ≥55 with Mini-Mental State Examination >26 and a Logical Memory (Wechsler Memory Scale III) baseline score ≥1 standard deviation below younger adults, were randomly assigned to 900 mg/d of DHA orally or matching placebo for 24 weeks. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. RESULTS: Intention-to-treat analysis demonstrated significantly fewer PAL six pattern errors with DHA versus placebo at 24 weeks (difference score, -1.63 ± 0.76 [-3.1, -0.14, 95% CI], P = .03). DHA supplementation was also associated with improved immediate and delayed Verbal Recognition Memory scores (P < .02), but not working memory or executive function tests. Plasma DHA levels doubled and correlated with improved PAL scores (P < .02) in the DHA group. DHA was well tolerated with no reported treatment-related serious adverse events. CONCLUSIONS: Twenty-four week supplementation with 900 mg/d DHA improved learning and memory function in ARCD and is a beneficial supplement that supports cognitive health with aging. TRIAL REGISTRATION: Clinicaltrials.gov, Identifier: NCT0027813.

A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea.

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.

Bioequivalence of Docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food.

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.

Non-inferiority versus superiority drug claims: the (not so) subtle distinction.

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.

Five-day study to judge the short-term effect of a benzoyl peroxide 3% gel on acne lesions.

INTRODUCTION: Acne is a common, chronic skin disease that has both physical and psychological consequences. Over-the-counter products are a treatment option frequently chosen by dermatologists and acne sufferers for reasons of cost or convenience. There are reports that such products can effect rapid resolution in certain lesion parameters. AIMS: To evaluate the short-term effect of a benzoyl peroxide 3% gel on acne lesions. METHODS: A 5-day, double-blind, randomized clinical trial was conducted among subjects with mild-to-moderate acne. Subjects applied the benzoyl peroxide 3% gel, a salicylic acid 2% gel, or a vehicle gel under supervision once daily for 4 days. Target lesion parameters of swelling, diameter, and erythema were evaluated at various times after the first and subsequent applications. RESULTS: Although target lesion parameters showed overall improvement from baseline, the effects of the active treatment gels were not significantly different from those of the vehicle gel at any evaluation. The assessed parameters showed marked variability in target lesion behavior at the subject level over the course of the study. CONCLUSIONS: The results of this study illustrate the unpredictability of individual acne lesion's responses to therapy and the challenge associated with using these responses to judge short-term treatment efficacy. While rapid acne resolution is desired by patients and consumers, setting realistic expectations for treatment response is critical to encourage compliance and avoid disappointment.

An improved Hochberg procedure for multiple tests of significance.

We propose a simple modification of Hochberg's step-up Bonferroni procedure for multiple tests of significance. The proposed procedure is always more powerful than Hochberg's procedure for more than two tests, and is more powerful than Hommel's procedure for three and four tests. A numerical analysis of the new procedure indicates that its Type I error is controlled under independence of the test statistics, at a level equal to or just below the nominal Type I error. Examination of various non-null configurations of hypotheses shows that the modified procedure has a power advantage over Hochberg's procedure which increases in relationship to the number of false hypotheses.

Validation of a photonumeric wrinkle assessment scale for assessing nasolabial fold wrinkles.

BACKGROUND: Reliable clinical assessment tools are needed to evaluate the effects of injectable devices and fillers. This study was designed to validate a new photonumeric wrinkle assessment scale using standardized photographic methodology to obtain reference photographs. METHODS: Multiple photographs (test set) from approximately 78 volunteer subjects with varying degrees of severity of the left/right nasolabial fold wrinkles were examined. Photographs of 18 subjects representing the full spectrum of nasolabial fold wrinkle severity were selected from the test set by a study team of three independent physicians and were classified using a six-point scale (0 = no wrinkles; 5 = very deep wrinkle, redundant fold). One representative photograph was identified by study team consensus for each of the six scale points. Photographs were randomly arranged in booklets for a second, independent, group of five physician raters to grade both left/right nasolabial fold wrinkles twice over a 2-week interval. The scale was considered valid if interevaluator reliability, as measured by intraclass correlation coefficient, was greater than or equal to 80 percent. RESULTS: Intrarater reliability was significant (p < 0.001) for all five physicians and overall, with Pearson correlation coefficients greater than 92 percent in all cases. The overall weighted kappa coefficient for intrarater reliability for all five raters was 0.598 (range, 0.433 to 0.684). The overall interrater reliability kappa value was 0.525, and a high degree of interrater reliability was observed at week 1 and week 2 time points (intraclass correlation coefficient = 0.890 and 0.880, p < 0.001 for both), validating the new wrinkle assessment scale. CONCLUSION: This study validates the new wrinkle assessment scale, which provides a reliable clinical tool for use in nasolabial fold wrinkle evaluation.

Culture and assessment of manic symptoms.

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.