MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC

Erratum to: CASPER plus (CollAborative care in screen-positive EldeRs with major depressive disorder): study protocol for a randomised controlled trial

Published onlinePUBLISHED ERRATUMThe original article is available at http://hdl.handle.net/10871/18985.n/

Identifying perinatal depression with case-finding instruments : a mixed-methods study (BaBY PaNDA – Born and Bred in Yorkshire PeriNatal Depression Diagnostic Accuracy)

Background: Perinatal depression is well recognised as a mental health condition but < 50% of cases are identified in routine practice. A case-finding strategy using the Whooley questions is currently recommended by the National Institute for Health and Care Excellence. Objectives: To determine the diagnostic accuracy, acceptability and cost-effectiveness of the Whooley questions and the Edinburgh Postnatal Depression Scale (EPDS) to identify perinatal depression. Design: A prospective diagnostic accuracy cohort study, with concurrent qualitative and economic evaluations. Setting: Maternity services in England. Participants: A total of 391 pregnant women. Main outcome measures: Women completed the Whooley questions, EPDS and a diagnostic reference standard (Clinical Interview Schedule – Revised) during pregnancy (20 weeks) and postnatally (3–4 months). Qualitative interviews were conducted with health professionals (HPs) and a subsample of women. Results: Diagnostic accuracy results: depression prevalence rates were 10.3% during pregnancy and 10.5% postnatally. The Whooley questions and EPDS (cut-off point of ≥ 10) performed reasonably well, with comparable sensitivity [pregnancy: Whooley questions 85.0%, 95% confidence interval (CI) 70.2% to 94.3%; EPDS 82.5%, 95% CI 67.2% to 92.7%; postnatally: Whooley questions 85.7%, 95% CI 69.7% to 95.2%; EPDS 82.9%, 95% CI 66.4% to 93.4%] and specificity (pregnancy: Whooley questions 83.7%, 95% CI 79.4% to 87.4%; EPDS 86.6%, 95% CI 82.5% to 90.0%; postnatally: Whooley questions 80.6%, 95% CI 75.7% to 84.9%; EPDS 87.6%, 95% CI 83.3% to 91.1%). Diagnostic accuracy of the EPDS (cut-off point of ≥ 13) was poor at both time points (pregnancy: sensitivity 45%, 95% CI 29.3% to 61.5%, and specificity 95.7%, 95% CI 93.0% to 97.6%; postnatally: sensitivity 62.9%, 95% CI 44.9% to 78.5%, and specificity 95.7%, 95% CI 92.7% to 97.7%). Qualitative evaluation: women and HPs were supportive of screening/case-finding for perinatal depression. The EPDS was preferred to the Whooley questions by women and HPs, mainly because of its ‘softer’ wording. Whooley question 1 was thought to be less acceptable, largely because of the terms ‘depressed’ and ‘hopeless’, leading to women not revealing their depressive symptoms. HPs identified a ‘patient-centred’ environment that focused on the mother and baby to promote discussion about mental health. Cost-effectiveness results: screening/case-finding using the Whooley questions or the EPDS alone was not the most cost-effective strategy. A two-stage strategy, ‘Whooley questions followed by the Patient Health Questionnaire’ (a measure assessing depression symptomatology), was the most cost-effective strategy in the range between £20,000 and £30,000 per quality-adjusted life-year in both the prenatal and postnatal decision models. Limitations: Perinatal depression diagnosis was not cross-referenced with women’s medical records so the proportion of new cases identified is unknown. The clinical effectiveness and cost-effectiveness of screening/case-finding strategies was not assessed as part of a randomised controlled trial. Conclusions: The Whooley questions and EPDS had acceptable sensitivity and specificity, but their use in practice might be limited by low predictive value and variation in their acceptability. A two-stage strategy was more cost-effective than single-stage strategies. Neither case-finding instrument met National Screening Committee criteria. Future work: The yield of screening/case-finding should be established with reference to health-care records. The clinical effectiveness and cost-effectiveness of screening/case-finding for perinatal depression needs to be tested in a randomised controlled trial. Funding: The National Institute for Health Research Health Services and Delivery Research programme

CollAborative care for Screen-Positive EldeRs with major depression (CASPER plus): a multicentred randomised controlled trial of clinical effectiveness and cost-effectiveness

Background: Depression in older adults is common and is associated with poor quality of life, increased morbidity and early mortality, and increased health and social care use. Collaborative care, a low-intensity intervention for depression that is shown to be effective in working-age adults, has not yet been evaluated in older people with depression who are managed in UK primary care. The CollAborative care for Screen-Positive EldeRs (CASPER) plus trial fills the evidence gap identified by the most recent guidelines on depression management. Objectives: To establish the clinical effectiveness and cost-effectiveness of collaborative care for older adults with major depressive disorder in primary care. Design: A pragmatic, multicentred, two-arm, parallel, individually randomised controlled trial with embedded qualitative study. Participants were automatically randomised by computer, by the York Trials Unit Randomisation Service, on a 1 : 1 basis using simple unstratified randomisation after informed consent and baseline measures were collected. Blinding was not possible. Setting: Sixty-nine general practices in the north of England. Participants: A total of 485 participants aged ≥ 65 years with major depressive disorder. Interventions: A low-intensity intervention of collaborative care, including behavioural activation, delivered by a case manager for an average of six sessions over 7–8 weeks, alongside usual general practitioner (GP) care. The control arm received only usual GP care. Main outcome measures: The primary outcome measure was Patient Health Questionnaire-9 items score at 4 months post randomisation. Secondary outcome measures included depression severity and caseness at 12 and 18 months, the EuroQol-5 Dimensions, Short Form questionnaire-12 items, Patient Health Questionnaire-15 items, Generalised Anxiety Disorder-7 items, Connor–Davidson Resilience Scale-2 items, a medication questionnaire, objective data and adverse events. Participants were followed up at 12 and 18 months. Results: In total, 485 participants were randomised (collaborative care, n = 249; usual care, n = 236), with 390 participants (80%: collaborative care, 75%; usual care, 86%) followed up at 4 months, 358 participants (74%: collaborative care, 70%; usual care, 78%) followed up at 12 months and 344 participants (71%: collaborative care, 67%; usual care, 75%) followed up at 18 months. A total of 415 participants were included in primary analysis (collaborative care, n = 198; usual care, n = 217), which revealed a statistically significant effect in favour of collaborative care at the primary end point at 4 months [8.98 vs. 10.90 score points, mean difference 1.92 score points, 95% confidence interval (CI) 0.85 to 2.99 score points; p < 0.001], equivalent to a standard effect size of 0.34. However, treatment differences were not maintained in the longer term (at 12 months: 0.19 score points, 95% CI –0.92 to 1.29 score points; p = 0.741; at 18 months: < 0.01 score points, 95% CI –1.12 to 1.12 score points; p = 0.997). The study recorded details of all serious adverse events (SAEs), which consisted of ‘unscheduled hospitalisation’, ‘other medically important condition’ and ‘death’. No SAEs were related to the intervention. Collaborative care showed a small but non-significant increase in quality-adjusted life-years (QALYs) over the 18-month period, with a higher cost. Overall, the mean cost per incremental QALY for collaborative care compared with usual care was £26,016; however, for participants attending six or more sessions, collaborative care appears to represent better value for money (£9876/QALY)

CollAborative care for Screen-Positive EldeRs with major depression (CASPER plus): a multicentred randomised controlled trial of clinical effectiveness and cost-effectiveness

BackgroundDepression in older adults is common and is associated with poor quality of life, increased morbidity and early mortality, and increased health and social care use. Collaborative care, a low-intensity intervention for depression that is shown to be effective in working-age adults, has not yet been evaluated in older people with depression who are managed in UK primary care. The CollAborative care for Screen-Positive EldeRs (CASPER) plus trial fills the evidence gap identified by the most recent guidelines on depression management.ObjectivesTo establish the clinical effectiveness and cost-effectiveness of collaborative care for older adults with major depressive disorder in primary care.DesignA pragmatic, multicentred, two-arm, parallel, individually randomised controlled trial with embedded qualitative study. Participants were automatically randomised by computer, by the York Trials Unit Randomisation Service, on a 1 : 1 basis using simple unstratified randomisation after informed consent and baseline measures were collected. Blinding was not possible.SettingSixty-nine general practices in the north of England.ParticipantsA total of 485 participants aged ≥ 65 years with major depressive disorder.InterventionsA low-intensity intervention of collaborative care, including behavioural activation, delivered by a case manager for an average of six sessions over 7–8 weeks, alongside usual general practitioner (GP) care. The control arm received only usual GP care.Main outcome measuresThe primary outcome measure was Patient Health Questionnaire-9 items score at 4 months post randomisation. Secondary outcome measures included depression severity and caseness at 12 and 18 months, the EuroQol-5 Dimensions, Short Form questionnaire-12 items, Patient Health Questionnaire-15 items, Generalised Anxiety Disorder-7 items, Connor–Davidson Resilience Scale-2 items, a medication questionnaire, objective data and adverse events. Participants were followed up at 12 and 18 months.ResultsIn total, 485 participants were randomised (collaborative care, n = 249; usual care, n = 236), with 390 participants (80%: collaborative care, 75%; usual care, 86%) followed up at 4 months, 358 participants (74%: collaborative care, 70%; usual care, 78%) followed up at 12 months and 344 participants (71%: collaborative care, 67%; usual care, 75%) followed up at 18 months. A total of 415 participants were included in primary analysis (collaborative care, n = 198; usual care, n = 217), which revealed a statistically significant effect in favour of collaborative care at the primary end point at 4 months [8.98 vs. 10.90 score points, mean difference 1.92 score points, 95% confidence interval (CI) 0.85 to 2.99 score points; p < 0.001], equivalent to a standard effect size of 0.34. However, treatment differences were not maintained in the longer term (at 12 months: 0.19 score points, 95% CI –0.92 to 1.29 score points; p = 0.741; at 18 months: < 0.01 score points, 95% CI –1.12 to 1.12 score points; p = 0.997). The study recorded details of all serious adverse events (SAEs), which consisted of ‘unscheduled hospitalisation’, ‘other medically important condition’ and ‘death’. No SAEs were related to the intervention. Collaborative care showed a small but non-significant increase in quality-adjusted life-years (QALYs) over the 18-month period, with a higher cost. Overall, the mean cost per incremental QALY for collaborative care compared with usual care was £26,016; however, for participants attending six or more sessions, collaborative care appears to represent better value for money (£9876/QALY).LimitationsStudy limitations are identified at different stages: design (blinding unfeasible, potential contamination), process (relatively low overall consent rate, differential attrition/retention rates) and analysis (no baseline health-care resource cost or secondary/social care data).ConclusionCollaborative care was effective for older people with case-level depression across a range of outcomes in the short term though the reduction in depression severity was not maintained over the longer term of 12 or 18 months. Participants who received six or more sessions of collaborative care did benefit substantially more than those who received fewer treatment sessions but this difference was not statistically significant.Future work recommendationsRecommendations for future research include investigating the longer-term effect of the intervention. Depression is a recurrent disorder and it would be useful to assess its impact on relapse and the prevention of future case-level depression