Lelia Duley

An interim analysis of progression-free survival in this trial showed that ibrutinib-venetoclax was superior to fludarabine-cyclophosphamide-rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib-venetoclax is more effective than ibrutinib alone is unclear. In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib-venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival. A total of 172 of the 260 participants (66.2%) in the ibrutinib-venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib-venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib-venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib-venetoclax, ibrutinib-alone, and FCR groups, respectively. With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib-venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Background Chronic lymphocytic leukemia (CLL) is a common adult blood cancer. There is no cure, but a third of people never require treatment and new targeted drugs have improved outcome. Understanding the experience of living with CLL is important for clinicians, health care providers and researchers. Methods This was an open internet-based survey of people with CLL, conducted by people with CLL. It was advertised via email and social media. Findings 1,009 people completed the survey. Respondents were more likely to be women (526, 52% female; 482, 48% male) and were younger at diagnosis (574, 57% Conclusions Fatigue is a key problem for people with CLL. CLL impacts on the physical and emotional aspects of quality of life.

The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac severe adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Background: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. Methods: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. Results: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38–93) minutes for doctor consent, 55 (37–95) minutes for 2-stage patient, 69 (43–110) minutes for 2-stage relative, 75 (48–124) minutes for 1-stage patient, and 90 (56–155) minutes for 1-stage relative consents ( P <0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5–2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5–3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03–0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up. Conclusions: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. Registration: URL: https://www.isrctn.com ; Unique identifier: ISRCTN93732214.

Background: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo.Objective: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo.Design: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up.Setting: Sixteen UK hospitals – participants were recruited from primary and secondary care and the community.Participants: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area.Interventions: Topical corticosteroids [mometasone furoate 0.1% (Elocon^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based.Main outcome measures: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment (‘a lot less noticeable’ or ‘no longer noticeable’ on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment).Results: In total, 517 participants were randomised (adults,n = 398; and children,n = 119; 52% male; 57% paler skin types I–III, 43% darker skin types IV–VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment ‘success’ was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%;p = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval –4.4% to 14.9%;p = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective).Limitations: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase.Conclusion: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed.Future work: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed.Trial registration: Current Controlled Trials ISRCTN17160087.Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.

Background Economic evidence for vitiligo treatments is absent. Objective To determine the cost‐effectiveness of (a) hand‐held narrowband‐UVB (NB‐UVB) and (b) combination of topical corticosteroid (TCS) and NB‐UVB compared to TCS for localised vitiligo. Methods Cost‐effectiveness analysis alongside a pragmatic, 3‐arm, placebo‐controlled RCT with 9 months’ treatment. 517 Adults and children (aged ≥5 years) with active vitiligo affecting <10% of skin recruited from secondary care and community were randomised 1:1:1 to receive: TCS; NB‐UVB; or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost‐utility analyses measured QALYs using the EQ‐5D‐5L for those aged 11+ and CHU‐9D for those aged 5 to <18. Results Mean (SD) cost per participant was £774.4 (83.71) for NB‐UVB, £813.38 (111.39) for combination treatment and £599.98 (96.18) for TCS. In analyses adjusted for age and target patch location, incremental difference in cost for combination treatment compared to TCS was £211.46 (95% CI 188.10 to 234.81), corresponding to a risk difference of 10.94% (Number‐Needed‐To‐Treat (NNT= 9). Incremental cost was £1,932.35 per successful treatment. The incremental difference in cost for NB‐UVB compared to TCS was £173.44 (95% CI 150.55 to 196.32) with a risk difference of 5.20% (NNT=19). Incremental cost was £3,335.74 per successful treatment. Conclusion Combination treatment, compared to TCS alone, has a lower incremental cost per additional successful treatment than NB‐UVB only. Combination treatment would be considered cost effective if decision makers are willing to pay £1,932 per additional treatment success.

Purpose: The purpose of this study is to assess the feasibility of conducting a large, multicentre randomised controlled trial (RCT) comparing needle fasciotomy with limited fasciectomy for treatment of Dupuytren’s contractures. Design: The design of this study is a parallel, two-arm, multicentre, randomised feasibility trial with embedded QuinteT Recruitment Intervention. Participants: Patients aged 18 years or over who were referred from primary to secondary care for treatment of a hand with Dupuytren’s contractures of one or more fingers of more than 30° at the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints and well-defined cord(s). Patients were excluded if they had undergone previous Dupuytren’s contracture surgery on the same hand. Methods: Potential participants were screened for eligibility. Recruited participants randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy and followed-up for up to 6 months after treatment. Data on recruitment rates, completion of follow-up, and procedure costs were collected. Four patient reported outcome measures (PROMs) and objective outcome measures were collected before intervention and 6 weeks and 6 months afterwards. Results: One hundred and fifty-three of 267 (57%) primary-care referrals for Dupuytren’s contractures met the eligibility criteria for the study. Seventy-one of the 153 (46%) agreed to participate and were randomly allocated to treatment with needle fasciotomy or limited fasciectomy. Sixty-seven of these underwent their allocated treatment, two were crossovers from limited fasciectomy to needle fasciotomy, and two (both allocated limited fasciectomy) received no treatment. Fifty-nine participants (85%) completed 6-month follow-up PROMs. Participants felt the MYMOP, PEM and URAM PROMs allowed them to better describe how their treatment affected their hand function than the DASH PROM. The estimated costs of limited fasciectomy (in an operating theatre) and needle fasciotomy (in a clinic room) were £777 and £111 respectively. Conclusion: A large RCT comparing treatment of Dupuytren’s contractures by needle fasciotomy and limited fasciectomy is feasible. Data from this study will help determine the number of sites and duration of recruitment required to complete an adequately powered RCT and will assist the selection of PROMs in future studies on the treatment of Dupuytren’s contractures. (Level 1 feasibility study). Trial registration: Trial registered with ISRCTN (registration number: ISRCTN11164292), date assigned - 28/08/2015.

Background: We report a process to identify and prioritise research questions in preterm birth that are most important to people affected by preterm birth and healthcare practitioners in the United Kingdom and Republic of Ireland. Methods: Using consensus development methods established by the James Lind Alliance, unanswered research questions were identified using an online survey, a paper survey distributed in NHS preterm birth clinics and neonatal units, and through searching published systematic reviews and guidelines. Prioritisation of these questions was by online voting, with paper copies at the same NHS clinics and units, followed by a decision-making workshop of people affected by preterm birth and healthcare professionals. Results: Overall 26 organisations participated. Three hundred and eighty six people responded to the survey, and 636 systematic reviews and 12 clinical guidelines were inspected for research recommendations. From this, a list of 122 uncertainties about the effects of treatment was collated: 70 from the survey, 28 from systematic reviews, and 24 from guidelines. After removing 18 duplicates, the 104 remaining questions went to a public online vote on the top 10. Five hundred and seven people voted; 231 (45%) people affected by preterm birth, 216 (43%) health professionals, and 55 (11%) affected by preterm birth who were also a health professional. Although the top priority was the same for all types of voter, there was variation in how other questions were ranked. Following review by the Steering Group, the top 30 questions were then taken to the prioritisation workshop. A list of top 15 questions was agreed, but with some clear differences in priorities between people affected by preterm birth and healthcare professionals. Conclusions: These research questions prioritised by a partnership process between service users and healthcare professionals should inform the decisions of those who plan to fund research. Priorities of people affected by preterm birth were sometimes different from those of healthcare professionals, and future priority setting partnerships should consider reporting these separately, as well as in total.

Background Pre‐eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low‐dose aspirin in particular, might prevent or delay development of pre‐eclampsia. Objectives To assess the effectiveness and safety of antiplatelet agents, such as aspirin and dipyridamole, when given to women at risk of developing pre‐eclampsia. Search methods For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (30 March 2018), and reference lists of retrieved studies. We updated the search in September 2019 and added the results to the awaiting classification section of the review. Selection criteria All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Studies only published in abstract format were eligible for inclusion if sufficient information was available. We would have included cluster‐randomised trials in the analyses along with individually‐randomised trials, if any had been identified in our search strategy. Quasi‐random studies were excluded. Participants were pregnant women at risk of developing pre‐eclampsia. Interventions were administration of an antiplatelet agent (such as low‐dose aspirin or dipyridamole), comparisons were either placebo or no antiplatelet. Data collection and analysis Two review authors assessed trials for inclusion and extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention‐to‐treat basis. For this update we incorporated individual participant data (IPD) from trials with this available, alongside aggregate data (AD) from trials where it was not, in order to enable reliable subgroup analyses and inclusion of two key new outcomes. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. Main results Seventy‐seven trials (40,249 women, and their babies) were included, although three trials (relating to 233 women) did not contribute data to the meta‐analysis. Nine of the trials contributing data were large (> 1000 women recruited), accounting for 80% of women recruited. Although the trials took place in a wide range of countries, all of the nine large trials involved only women in high‐income and/or upper middle‐income countries. IPD were available for 36 trials (34,514 women), including all but one of the large trials. Low‐dose aspirin alone was the intervention in all the large trials, and most trials overall. Dose in the large trials was 50 mg (1 trial, 1106 women), 60 mg (5 trials, 22,322 women), 75mg (1 trial, 3697 women) 100 mg (1 trial, 3294 women) and 150 mg (1 trial, 1776 women). Most studies were either low risk of bias or unclear risk of bias; and the large trials were all low risk of bas. Antiplatelet agents versus placebo/no treatment The use of antiplatelet agents reduced the risk of proteinuric pre‐eclampsia by 18% (36,716 women, 60 trials, RR 0.82, 95% CI 0.77 to 0.88; high‐quality evidence), number needed to treat for one women to benefit (NNTB) 61 (95% CI 45 to 92). There was a small (9%) reduction in the RR for preterm birth 500 mL (23,769 women, 19 trials; RR 1.06, 95% CI 1.00 to 1.12; moderate‐quality evidence due to clinical heterogeneity), and they probably marginally increase the risk of placental abruption, although for this outcome the evidence was downgraded due to a wide confidence interval including the possibility of no effect (30,775 women; 29 trials; RR 1.21, 95% CI 0.95 to 1.54; moderate‐quality evidence). Data from two large trials which assessed children at aged 18 months (including results from over 5000 children), did not identify clear differences in development between the two groups. Authors' conclusions Administering low‐dose aspirin to pregnant women led to small‐to‐moderate benefits, including reductions in pre‐eclampsia (16 fewer per 1000 women treated), preterm birth (16 fewer per 1000 treated), the baby being born small‐for‐gestational age (seven fewer per 1000 treated) and fetal or neonatal death (five fewer per 1000 treated). Overall, administering antiplatelet agents to 1000 women led to 20 fewer pregnancies with serious adverse outcomes. The quality of evidence for all these outcomes was high. Aspirin probably slightly increased the risk of postpartum haemorrhage of more than 500 mL, however, the quality of evidence for this outcome was downgraded to moderate, due to concerns of clinical heterogeneity in measurements of blood loss. Antiplatelet agents probably marginally increase placental abruption, but the quality of the evidence was downgraded to moderate due to low event numbers and...

Introduction: Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups such as those who usually receive immediate neonatal care. Previous and current trials compare various policies, including immediate cord clamping, time- or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enables exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. Objectives: 1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis; and 2) to evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. Methods and analysis: We will conduct a systematic search of Medline, Embase, clinical trial registries, and other sources for all planned, ongoing and completed randomised controlled trials comparing alternative cord management strategies at preterm birth (before 37 weeks’ gestation). IPD will be sought for all trials. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for pre-specified subgroups of participants. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes intraventricular haemorrhage (any grade) and infant blood transfusions (any). Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. Ethics and dissemination: Approved by University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline-developers and policy-makers, and will be disseminated via publications, presentations, and media releases. Registration: Australian New Zealand Clinical Trials Registry: ACTRN12619001305112. STRENGTH AND LIMITATIONS OF THIS STUDY: This will be the most comprehensive review to date of interventions for umbilical cord management in preterm infants and the findings will be highly relevant to clinicians and guideline developers The use of individual participant data will allow assessment of the best treatment option for key subgroups of participants Network meta-analysis will enable the comparison and ranking of all available treatment options using direct and indirect evidence For some of the trials it will not be possible to obtain individual participant data, so published aggregate results will be used instead Risk of bias in the primary trials will be assessed using Cochrane criteria, and certainty of evidence for the meta-analyses will be appraised using the GRADE approach for the pairwise comparisons, and the CINeMA approach for the network meta-analysis