Summarising salient information on historical controls: A structured assessment of validity and comparability across studies

BACKGROUND: While placebo-controlled randomised controlled trials remain the standard way to evaluate drugs for efficacy, historical data are used extensively across the development cycle. This ranges from supplementing contemporary data to increase the power of trials to cross-trial comparisons in estimating comparative efficacy. In many cases, these approaches are performed without in-depth review of the context of data, which may lead to bias and incorrect conclusions. METHODS: We discuss the original 'Pocock' criteria for the use of historical data and how the use of historical data has evolved over time. Based on these factors and personal experience, we created a series of questions that may be asked of historical data, prior to their use. Based on the answers to these questions, various statistical approaches are recommended. The strategy is illustrated with a case study in colorectal cancer. RESULTS: A number of areas need to be considered with historical data, which we split into three categories: outcome measurement, study/patient characteristics (including setting and inclusion/exclusion criteria), and disease process/intervention effects. Each of these areas may introduce issues if not appropriately handled, while some may preclude the use of historical data entirely. We present a tool (in the form of a table) for highlighting any such issues. Application of the tool to a colorectal cancer data set demonstrates under what conditions historical data could be used and what the limitations of such an analysis would be. CONCLUSION: Historical data can be a powerful tool to augment or compare with contemporary trial data, though caution is required. We present some of the issues that may be considered when involving historical data and what (if any) statistical approaches may account for differences between studies. We recommend that, where historical data are to be used in analyses, potential differences between studies are addressed explicitly

Measuring Health and Broader Well-Being Benefits in the Context of Opiate Dependence: The Psychometric Performance of the ICECAP-A and the EQ-5D-5L

BACKGROUND: Measuring outcomes in economic evaluations of social care interventions is challenging because both health and well-being benefits are evident. The ICEpop CAPability instrument for adults (ICECAP-A) and the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) are measures potentially suitable for the economic evaluation of treatments for substance use disorders. Evidence for their validity in this context is, however, lacking. OBJECTIVES: To assess the construct validity of the ICECAP-A and the EQ-5D-5L in terms of convergent and discriminative validity and sensitivity to change on the basis of standard clinical measures (Clinical Outcomes in Routine Evaluation-Outcome Measure, Treatment Outcomes Profile, Interpersonal Support Evaluation List, Leeds Dependence Questionnaire, and Social Satisfaction Questionnaire). METHODS: A secondary analysis of pilot trial data for heroin users in opiate substitution treatment was conducted. Baseline convergence with clinical measures was assessed using the Pearson correlation coefficient. Discriminative validity was assessed using one-way analysis of variance and stepwise regressions. Sensitivity to changes in clinical indicators was assessed at 3 and 12 months using the standardized response mean statistic and parametric and nonparametric testing. RESULTS: Both measures had the same level of construct validity, except for clinical indicators of well-being, for which the ICECAP-A performed better. The ICECAP-A was sensitive to changes in both health and well-being indicators. The EQ-5D-5L had lower levels of sensitivity to change, and a ceiling effect (27%), particularly evident in the dimensions of self-care (89%), mobility (75%), and usual activities (72%). CONCLUSIONS: The findings support the construct validity of both measures, but the ICECAP-A gives more attention to broader impacts and is more sensitive to change. The ICECAP-A shows promise in evaluating treatments for substance use disorders for which recovery is the desired outcome

Targeted Albumin Therapy Does Not Improve Short-Term Outcome in Hyponatremic Patients Hospitalized With Complications of Cirrhosis: Data From the ATTIRE Trial

INTRODUCTION: Patients with decompensated cirrhosis and hyponatremia have a poor prognosis. We investigated Albumin to Prevent Infection in Chronic Liver Failure trial data to determine whether targeted albumin infusions improved outcome in patients with hyponatremia at baseline. METHODS: We examined the interaction between targeted albumin and standard care for the composite primary end point, stratifying by baseline sodium ≥ and <130 mmol/L. RESULTS: Randomization to albumin was associated with a significant increase in sodium; however, there was no interaction between sodium category and treatment for the trial primary end point. DISCUSSION: Targeted intravenous albumin infusions increased serum sodium level in hospitalized hyponatremic patients with cirrhosis, but this did not improve outcome

Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial

Background: Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. Methods: In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. Findings: There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3–15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p = 0.006), lower white cell counts throughout hospital stay (p < 0.001) and reduced plasma procalcitonin (p = 0.009) and interlukin-8 levels (p = 0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. Interpretations: Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. Funding: Wellcome Trust and Department of Health and Social Care

Autism and the U.K. secondary school experience

This research investigated the self-reported mainstream school experiences of those diagnosed on the autistic spectrum compared with the typically developing school population. Existing literature identifies four key areas that affect the quality of the school experience for students with autism: social skills, perceived relationships with teaching staff, general school functioning, and interpersonal strengths of the young person. These areas were explored in a mainstream U.K. secondary school with 14 students with autism and 14 age and gender matched students without autism, using self-report questionnaires and semi-structured interviews. Quantitative analyses showed consistent school experiences for both groups, although content analysis of interview data highlighted some differences in the ways in which the groups perceive group work, peers, and teaching staff within school. Implications for school inclusion are discussed, drawing attention to how staff awareness of autism could improve school experience and success for students with autism attending mainstream schools

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial

BACKGROUND: Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. METHODS: In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. FINDINGS: Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. INTERPRETATIONS: Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. FUNDING: Wellcome Trust and Department of Health and Social Care

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.Peer reviewe

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Summarising salient information on historical controls: A structured assessment of validity and comparability across studies

Background While placebo-controlled randomised controlled trials remain the standard way to evaluate drugs for efficacy, historical data are used extensively across the development cycle. This ranges from supplementing contemporary data to increase the power of trials to cross-trial comparisons in estimating comparative efficacy. In many cases, these approaches are performed without in-depth review of the context of data, which may lead to bias and incorrect conclusions. Methods We discuss the original ‘Pocock’ criteria for the use of historical data and how the use of historical data has evolved over time. Based on these factors and personal experience, we created a series of questions that may be asked of historical data, prior to their use. Based on the answers to these questions, various statistical approaches are recommended. The strategy is illustrated with a case study in colorectal cancer. Results A number of areas need to be considered with historical data, which we split into three categories: outcome measurement, study/patient characteristics (including setting and inclusion/exclusion criteria), and disease process/intervention effects. Each of these areas may introduce issues if not appropriately handled, while some may preclude the use of historical data entirely. We present a tool (in the form of a table) for highlighting any such issues. Application of the tool to a colorectal cancer data set demonstrates under what conditions historical data could be used and what the limitations of such an analysis would be. Conclusion Historical data can be a powerful tool to augment or compare with contemporary trial data, though caution is required. We present some of the issues that may be considered when involving historical data and what (if any) statistical approaches may account for differences between studies. We recommend that, where historical data are to be used in analyses, potential di

Repression of cyclin D1 as a target for germ cell tumors

Metastatic germ cell tumors (GCT) are curable, however GCTs refractory to cisplatin-based chemotherapy have a poor prognosis. This study explores D-type cyclins as molecular targets in GCTs because all-trans-retinoic acid (RA)-mediated differentiation of the human embryonal carcinoma (EC) cell line NT2/D1 is associated with G1 cell cycle arrest and proteasomal degradation of cyclin D1. RA effects on D-type cyclins are compared in human EC cells that are RA sensitive or dually RA and cisplatin resistant (NT2/D1-R1) and in clinical GCTs that have both EC and mature teratoma components. Notably, GCT differentiation was associated with reduced cyclin D1 but increased cyclin D3 expression. RA was shown here to repress cyclin D1 through a transcriptional mechanism in addition to causing its degradation. The siRNA-mediated repression of individual cyclin D species resulted in growth inhibition in both RA sensitive and resistant EC cells. Only repression of cyclin D1 occurred in vitro and when clinical GCTs mature, implicating cyclin D1 as a molecular therapeutic target. To confirm this, the EGFR-tyrosine kinase inhibitor, Erlotinib, was used to repress cyclin D1. This inhibited proliferation in RA and cisplatin sensitive and resistant EC cells. Taken together, these findings implicate cyclin D1 targeting agents for the treatment of GCTs