Adding a treatment arm to an ongoing clinical trial: a review of methodology and practice

Incorporating an emerging therapy as a new randomisation arm in a clinical trial that is open to recruitment would be desirable to researchers, regulators and patients to ensure that the trial remains current, new treatments are evaluated as quickly as possible, and the time and cost for determining optimal therapies is minimised. It may take many years to run a clinical trial from concept to reporting within a rapidly changing drug development environment; hence, in order for trials to be most useful to inform policy and practice, it is advantageous for them to be able to adapt to emerging therapeutic developments. This paper reports a comprehensive literature review on methodologies for, and practical examples of, amending an ongoing clinical trial by adding a new treatment arm. Relevant methodological literature describing statistical considerations required when making this specific type of amendment is identified, and the key statistical concepts when planning the addition of a new treatment arm are extracted, assessed and summarised. For completeness, this includes an assessment of statistical recommendations within general adaptive design guidance documents. Examples of confirmatory ongoing trials designed within the frequentist framework that have added an arm in practice are reported; and the details of the amendment are reviewed. An assessment is made as to how well the relevant statistical considerations were addressed in practice, and the related implications. The literature review confirmed that there is currently no clear methodological guidance on this topic, but that guidance would be advantageous to help this efficient design amendment to be used more frequently and appropriately in practice. Eight confirmatory trials were identified to have added a treatment arm, suggesting that trials can benefit from this amendment and that it can be practically feasible; however, the trials were not always able to address the key statistical considerations, often leading to uninterpretable or invalid outcomes. If the statistical concepts identified within this review are considered and addressed during the design of a trial amendment, it is possible to effectively assess a new treatment arm within an ongoing trial without compromising the original trial outcomes

Adhesive capsulitis of the hip: three case reports.

PURPOSE: To describe the diagnosis and treatment of adhesive capsulitis of the hip (ACH). METHOD: A literature review and consideration of three case reports. DISCUSSION: Adhesive capsulitis of the hip is a supposedly rare but probably underestimated condition which predominantly affects middle-aged women. Clinical assessment reveals a painful limitation of joint mobility. The diagnosis is confirmed by arthrography, where the crucial factor is a joint capacity below 12ml. Osteoarthritis and complex regional pain syndrome type 1 are the two main differential diagnoses. Whether the treatment is pharmacological, physical or surgical depends on the aetiology of the condition. Physiotherapy is essential for limiting residual deficits and functional impairments. CONCLUSION: Adhesive capsulitis of the hip is probably more common than suggested by the limited medical literature. The condition is frequently idiopathic but can be secondary to another joint pathology. The first-line treatment consists of sustained-release corticosteroid intra-articular injections and physical therapy. Arthroscopy and manipulation under anaesthesia may be useful in cases of ACH which are refractory to treatment

Nail Involvement as a Predictor of Differential Treatment Effects of Secukinumab Versus Ustekinumab in Patients with Moderate to Severe Psoriasis.

Patients with plaque psoriasis may experience varying levels of treatment response to different biologics, based on phenotypic characteristics and underlying genetic factors. Nail psoriasis is a common manifestation of psoriasis (approx. 50% of patients) and has been linked to the human leukocyte antigen-C*0602 (HLA-C*0602) allele, which in turn has been associated with differential treatment responses to certain drugs. Here we investigate whether nail involvement in patients with psoriasis can predict differential skin responses to two biologics with different modes of action, namely secukinumab (anti-interleukin-17A) and ustekinumab (anti-interleukin-12/23), to ultimately guide treatment choice. Data were pooled from the CLEAR and CLARITY studies and stratified post hoc by nail involvement status at baseline. Psoriasis Area and Severity Index (PASI) 75 and 90 responses over 52 weeks and absolute PASI ≤ 3, ≤ 1, and 0 values at weeks 16 and 52, were assessed. Based on the medical history, 30.4% (269/886) of the patients in the secukinumab arm and 29.7% (265/891) of patients in the ustekinumab arm presented with nail involvement. Nail involvement status had little to no impact on the efficacy of secukinumab, as comparable responses were achieved for patients with and without nail involvement in terms of PASI 75/90, ≤ 3, and 0 responses; slightly lower PASI ≤ 1 reponses were achieved in patients with nail involvement. In the ustekinumab arm, patients with nail involvement achieved lower responses across all endpoints. These findings indicate that nail involvement can serve as an observable prognostic factor for efficacy in skin psoriasis treatment and guide the choice between secukinumab and ustekinumab. CLEAR: NCT02074982; CLARITY: NCT02826603

Vibrio fortis sp nov and Vibrio hepatarius sp nov., isolated from aquatic animals and the marine environment

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Neural Networks for High-Storage ContentAddressable Memory: VLSI Circuit and Learning Algorithm

Abstract —Neural networks used as content-addressable memories show unequaled retrieval and speed capabilities in problems srreh as vision and pattern recognition. We propose a new implementation of a VLSI fully interconnected neural network with only two binary memory points per synapse. The small area of single synaptic cells allows implementation of neural networks with hundreds of neurons. Classical learning algorithms like the Hebb’s rule show a poor storage capacity, especially in VLSI neural networks where the range of the synapse weights is limited by the number of memory points contained in each connectiorq we propose a new algorithm for programming a Hopfield neuraf network as a high-storage content-addressable memory. The storage capacity obtained with this algorithm is very promising for pattern recognition applications. I