Wolvehampton, United Kingdom

The Biomechanical Outcomes of Autologous Chondrocyte Implantation

Knee joint articular cartilage is a primary load-bearing surface that endures repetitive high impact loading during activities of daily living. Individuals of any age can injure the knee's articular cartilage. However, as cartilage has an innate limited capacity to regenerate, surgical interventions that adopt tissue engineering techniques are often necessary to repair cartilage and preserve the joint. Autologous chondrocyte implantation (ACI) is a surgical procedure that is offered to some patients with focal cartilage injuries of the knee. The first pilot study on the use of ACI in humans was published by Brittberg and colleagues in 1994. By 2010 35,000 ACI procedures had been performed worldwide. Patient-reported outcomes and survivorship of ACI have been well reported in current literature. However, objective biomechanical and functional outcomes of ACI patients are not well understood. This knowledge is essential for optimising treatment, because poor functional outcome is known to worsen quality of life. This is particularly true for patients of working age who wish to return to an active and independent lifestyle. The applicant recently conducted and published a systematic review on the functional outcome of ACI. The review identified only 19 eligible articles of 20 ACI cohorts. The data showed that the average range of motion (ROM) improved with clinical (>5˚) and statistical significance (p < 0.05) postoperatively: 130.5± 14.8˚ to 136.1±10.2º, however only 7 studies reported both pre- and post-operative RoM. Knee strength significantly improved within the first two postoperative years but remained poorer than control groups at final follow-up (n=11). The review also found no statistical differences between ACI and control groups in their ability to perform functional activities like the 6-minute walk and hop tests post-operatively (n = 8). Only two papers had published on the kinematics of gait post-operatively. Both papers reported the outcomes of the same cohort, stating that there were no significant differences in spatio-temporal parameters between ACI patients and controls post-operatively. However, kinematic differences were observed during two specific phases of the gait cycle. Differences were also reported in peak knee adduction and peak knee extension moments. The limited literature identified by this review highlighted the urgent need for research into the functional outcomes of joint preservation surgeries like ACI to optimise functional outcome.

A Study of Zasocitinib in Adults With Psoriatic Arthritis Who Have or Have Not Been Treated With Biologic Medicines

Safety, Effectiveness, and Pharmacokinetics of BNT327 in Combination With Chemotherapy and Other Investigational Agents for Lung Cancer

Each substudy contains a Phase 2 part followed by a Phase 3 part. Participants will be randomized to one of two dose levels of BNT327 plus chemotherapy for the Phase 2 part of each substudy. After the analysis of the Phase 2 data (efficacy, safety, and exposure-response), an internal review committee (IRC) will decide whether participants will be treated with BNT327 at dose level 1 or 2 in the Phase 3 part of the substudies. After dose selection, the selected dose will be used for all participants in the study. For the Phase 3 parts of both substudies, an independent data monitoring committee (IDMC) will be established as needed to provide independent review of the data during the study. The sponsor may decide not to perform or stop recruiting participants in the Phase 2 part of the study depending on data generated in the BNT327-01 (NCT06449209) and BNT327-02 (NCT06449222) studies. The sponsor may also choose not to continue all substudies.

Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML

Intensive Weight Loss Intervention Versus Usual Care for Adults With Obesity

In the LightCARE trial, an intensive weight loss (IWL) intervention will compared with usual care. The IWL lasts two years, and includes total dietary replacements, behavioural support, and weight loss medication in three phases: - Induction' phase (week 0-12 after randomisation): total dietary replacement (TDR) programme and behavioural support with weight loss medication (WLM) if rate of weight loss is insufficient. - Weight loss continuation' phase (week 13-32 after randomisation): progression of dietary programme including reduction in use of TDR products, reintroduction of healthy foods, with behavioural support, introduction of physical activity, WLM (as required). - Maintenance' phase (week 33-104 after randomisation): Continued healthy diet and physical activity with WLM (if required), with return to induction phase if weight regain occurs induction, weight loss continuation, maintenance. Usual care will differ between the two countries (Denmark and the United Kingdom). In Denmark, participants will receive a pamphlet on current obesity management guidelines from the Danish National Board of Health, and will be advised to contact their GP for potential referral to local municipality-based obesity management programmes. Furthermore, a notification will be sent to the participant's GP, informing that the participant has been enrolled in the trial and is randomised to usual care. The availability and structure of current obesity programmes varies between municipalities. In the United Kingdom, participants will be offered to discuss weight management programmes available in their area with their GP practice; the programmes available referral routes vary slightly from place to place. Tier 2 weight management services are mostly commissioned by local authority, and therefore differ slightly across the 333 local authorities in England. These local community-based weight management services provide diet, nutrition, behavioural advice.

ARTEMIS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With a Heart Attack

The Clinical Utility of BioEP in Diagnostic Decision Making in Epilepsy

Neuronostics will conduct a two-arm randomised control trial with two groups: (i) Usual Care, (ii) Usual Care + BioEP score and report. In this context, usual care involves clinical/ patient history, eye-witness accounts and any standard tests ordered (electroencephalogram (EEG), Magnetic Resonance Imaging (MRI), blood tests etc.). Investigators will recruit adults attending first seizure clinics where there is a suspicion that epilepsy is the causing symptoms and so a first EEG is recommended. Participants will be sourced from 10 sites. The trial duration will be 1 year recruitment, and 2 year follow up period. Randomisation: Consenting individual patients will be randomly assigned to either Usual Care or Usual Care + BioEP in a 1:1 ratio. Randomisation will be stratified by centre, with eligible and consenting participants allocated in random blocks. The allocation schedule will be generated by the trial statistician, and concealed from the clinicians assessing eligibility and recruiting patients.

Transforming Ovarian Cancer Diagnostic Pathways

A woman's chances of surviving 5 years after Ovarian Cancer (OC) diagnosis drops from 90% if diagnosed at Stage 1 to 15% at Stage 4. Currently, GPs use a blood test called CA125 and ultrasound scan to decide whether to refer a woman to hospital for suspected OC. CA125 misses 50% of early-stage cancers (Stage 1 and 2); both tests cause unnecessary referrals. Recently, a blood test called Human epididymis protein 4 (HE4) in combination with CA125 in a formula called ROMA (Risk of Malignancy Algorithm) has been developed. ROMA is used by doctors in the US and Europe to guide referrals and recommended by the American College of Obstetrics and Gynaecology. A large Cochrane systematic review of 30,000+ patients across 50 papers shows ROMA detects more cancers at earlier stage than a combination of CA125 and ultrasound. All included studies were conducted in hospital where OC rates are high, however a model at 3% OC rate shows that ROMA is superior. Before the test can be introduced in NHS, it is necessary to confirm this evidence in a large primary care study and establish cost effectiveness. The wider NHS cancer programme funded SONATA project evaluates an integrated pathway from community to cancer specialists using ROMA. It includes National Health Service (NHS) pilots in primary and secondary care to establish how practice can be supported to change, evaluates facilitators and barriers to change as well as a community campaign to promote OC awareness. This study is one component of the SONATA project. In it, two large NHS labs will additionally test 41,000 blood samples from women whose GPs requested CA125 testing for suspected OC with ROMA to accurately identify the number of patients who can be detected earlier. This will enable the investigators to establish cost effectiveness of ROMA and definitive data on accuracy in primary care.

Axillary Management in Breast Cancer Patients with Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy

Background: The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no evidence of residual nodal disease. Aim: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years. Methods: Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years. Outcomes: The co-primary outcomes are disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years. Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness. Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years. Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated. Timelines for delivery: Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination.

Comparison of the Outcomes of Single vs Multiple Arterial Grafts in Women

ROMA:Women will leverage the infrastructure and the existing women population of the ROMA trial. ROMA:Women has two key Aims. In Aim 1, the investigators will compare major adverse cardiac and cerebrovascular events (death, stroke, non-procedural myocardial infarction, repeat revascularization and hospital readmission for acute coronary syndrome or heart failure) in a cohort of 2,000 women randomized 1:1 to MAG or SAG (690 from the parent ROMA trial + 1,310 from ROMA:Women). In Aim 2, the investigators will compare generic (SF-12, EQ-5D) and disease-specific (Seattle Angina Questionnaire) QOL and physical and mental health symptoms (PROMIS-29) in a sub-cohort of 500 women randomized 1:1 to MAG or SAG. Differences by important subgroups (patients younger or older than 70 years, diabetics, racial and ethnic minorities, on vs off pump CABG, type of arterial grafts used) will also be evaluated. ROMA:Women is a two-arm, international, multi-center, randomized clinical trial nested in the ROMA trial. ROMA:Women will include all the women enrolled in the parent ROMA trial and will leverage the existing ROMA infrastructure including clinical trial unit, database, case report forms (CRF), randomization system, site training resources, informed consent forms (ICF), regulatory approvals, Central Events Review Committee (CEC) processes/personnel, network of participating sites, site PIs, and study coordinators. The planned randomization procedure, interventions and treatment arms, outcome assessments and follow-up protocol of ROMA:Women are identical to those of the currently ongoing parent ROMA trial. The sites participating in ROMA will continue enrollment of women after the completion of the ROMA trial and additional sites will also be opened to reach the target sample size of ROMA:Women.