Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies

E-Consent-a guide to maintain recruitment in clinical trials during the COVID-19 pandemic

BACKGROUND: The COVID-19 pandemic has posed daunting challenges when conducting clinical research. Adopting new technologies such as remote electronic consent (e-Consent) can help overcome them. However, guidelines for e-Consent implementation in ongoing clinical trials are currently lacking. The NeuroSAFE PROOF trial is a randomized clinical trial evaluating the role of frozen section analysis during RARP for prostate cancer. In response to the COVID-19 crisis, recruitment was halted, and a remote e-Consent solution was designed. The aim of this paper is to describe the process of implementation, impact on recruitment rate, and patients' experience using e-Consent. METHODS: A substantial amendment of the protocol granted the creation of a remote e-Consent framework based on the REDCap environment, following the structure and content of the already approved paper consent form. Although e-Consent obviated the need for in-person meeting, there was nonetheless counselling sessions performed interactively online. This new pathway offered continuous support to patients through remote consultations. The whole process was judged to be compliant with regulatory requirements before implementation. RESULTS: Before the first recruitment suspension, NeuroSAFE PROOF was recruiting an average of 9 patients per month. After e-Consent implementation, 63 new patients (4/month) have been enrolled despite a second lockdown, none of whom would have been recruited using the old methods given restrictions on face-to-face consultations. Patients have given positive feedback on the use of the platform. Limited troubleshooting has been required after implementation. CONCLUSION: Remote e-Consent-based recruitment was critical for the continuation of the NeuroSAFE PROOF trial during the COVID-19 pandemic. The described pathway complies with ethical and regulatory guidelines for informed consent, while minimizing face-to-face interactions that increase the risk of COVID-19 transmission. This guide will help researchers integrate e-Consent to ongoing or planned clinical trials while uncertainty about the course of the pandemic continues. TRIAL REGISTRATION: NeuroSAFE PROOF trial NCT03317990 . Registered on 23 October 2017. Regional Ethics Committee reference 17/LO/1978

Single Sample Expression-Anchored Mechanisms Predict Survival in Head and Neck Cancer

Gene expression signatures that are predictive of therapeutic response or prognosis are increasingly useful in clinical care; however, mechanistic (and intuitive) interpretation of expression arrays remains an unmet challenge. Additionally, there is surprisingly little gene overlap among distinct clinically validated expression signatures. These “causality challenges” hinder the adoption of signatures as compared to functionally well-characterized single gene biomarkers. To increase the utility of multi-gene signatures in survival studies, we developed a novel approach to generate “personal mechanism signatures” of molecular pathways and functions from gene expression arrays. FAIME, the Functional Analysis of Individual Microarray Expression, computes mechanism scores using rank-weighted gene expression of an individual sample. By comparing head and neck squamous cell carcinoma (HNSCC) samples with non-tumor control tissues, the precision and recall of deregulated FAIME-derived mechanisms of pathways and molecular functions are comparable to those produced by conventional cohort-wide methods (e.g. GSEA). The overlap of “Oncogenic FAIME Features of HNSCC” (statistically significant and differentially regulated FAIME-derived genesets representing GO functions or KEGG pathways derived from HNSCC tissue) among three distinct HNSCC datasets (pathways:46%, p<0.001) is more significant than the gene overlap (genes:4%). These Oncogenic FAIME Features of HNSCC can accurately discriminate tumors from control tissues in two additional HNSCC datasets (n = 35 and 91, F-accuracy = 100% and 97%, empirical p<0.001, area under the receiver operating characteristic curves = 99% and 92%), and stratify recurrence-free survival in patients from two independent studies (p = 0.0018 and p = 0.032, log-rank). Previous approaches depending on group assignment of individual samples before selecting features or learning a classifier are limited by design to discrete-class prediction. In contrast, FAIME calculates mechanism profiles for individual patients without requiring group assignment in validation sets. FAIME is more amenable for clinical deployment since it translates the gene-level measurements of each given sample into pathways and molecular function profiles that can be applied to analyze continuous phenotypes in clinical outcome studies (e.g. survival time, tumor volume)

Single Sample Expression-Anchored Mechanisms Predict Survival in Head and Neck Cancer

Gene expression signatures that are predictive of therapeutic response or prognosis are increasingly useful in clinical care; however, mechanistic (and intuitive) interpretation of expression arrays remains an unmet challenge. Additionally, there is surprisingly little gene overlap among distinct clinically validated expression signatures. These “causality challenges” hinder the adoption of signatures as compared to functionally well-characterized single gene biomarkers. To increase the utility of multi-gene signatures in survival studies, we developed a novel approach to generate “personal mechanism signatures” of molecular pathways and functions from gene expression arrays. FAIME, the Functional Analysis of Individual Microarray Expression, computes mechanism scores using rank-weighted gene expression of an individual sample. By comparing head and neck squamous cell carcinoma (HNSCC) samples with non-tumor control tissues, the precision and recall of deregulated FAIME-derived mechanisms of pathways and molecular functions are comparable to those produced by conventional cohort-wide methods (e.g. GSEA). The overlap of “Oncogenic FAIME Features of HNSCC” (statistically significant and differentially regulated FAIME-derived genesets representing GO functions or KEGG pathways derived from HNSCC tissue) among three distinct HNSCC datasets (pathways:46%, pOncogenic FAIME Features of HNSCC can accurately discriminate tumors from control tissues in two additional HNSCC datasets (n = 35 and 91, F-accuracy = 100% and 97%, empirical pp = 0.0018 and p = 0.032, log-rank). Previous approaches depending on group assignment of individual samples before selecting features or learning a classifier are limited by design to discrete-class prediction. In contrast, FAIME calculates mechanism profiles for individual patients without requiring group assignment in validation sets. FAIME is more amenable for clinical deployment since it translates the gene-level measurements of each given sample into pathways and molecular function profiles that can be applied to analyze continuous phenotypes in clinical outcome studies (e.g. survival time, tumor volume).</p