Early Intervention Trials Research Articles

Modified Intensive Induction Treatment for Elderly Acute Myeloid Leukemia Patients Based on Peripheral Blast Clearance Rate: A Phase II Single-Arm Study

BackgroundOutcomes and prognosis of older patients with acute myeloid leukemia (AML) are fairly dismal and poor tolerance to regimens hinders treatment decision-making to expand to the greatest extent. Nevertheless, it is still indicated that a certain proportion of elder patients may benefit from intensive therapies [1], after which the insistent need for algorithms to select elder patients fit for intensive regimens has emerged. Based on the previous achievement, monitoring the peripheral blast clearance rate on the day 5 of induction chemotherapy (D5-PBCR) showed its promising value in younger patients [2]. Along with the increasingly important comprehensive geriatric assessment (CGA), we conducted this trial in fit elderly AML patients to confirm the non-inferior efficacy of modified intensive treatment on the basis of D5-PBCR.Materials and methodsThis multiple-center, single-arm, phase 2 trial of early intervention according to D5-PBCR results with modified “3+7” regimen was performed at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China) and the other two hospitals in Shanghai. Patients aged 60-75 years were assessed via CGA and required to be fit for intensive chemotherapy. Eligible patients had newly diagnosed AML with more than 0·5% blasts detected in the peripheral blood and adequate end-organ function. The initial induction included idarubicin (6 mg/m² for 3 days) and cytarabine (100 mg/m² for 7 days). Peripheral blood specimens were collected before and on day 5 of induction and analyzed by multi-parameter flow cytometry to calculate the D5-PBCR. D5-PRCR (+) patients received extra IDA (6 mg/m² for 2 days) starting from induction day 6 with the absence of contraindications. Responders received another “2+5” regimens and at least two cycles of mediate dose cytarabine or even allogeneic stem cell transplantation, if eligible. The primary endpoint was composite complete remission (CR/CRi), and secondary endpoints were overall survival, event-free survival, early mortality, minimal residual disease after one cycle of induction, drug toxicity, and safety. The trial was registered in the Chinese Clinical Trial Register (ChiCTR-OPC-16008955).ResultsBetween March 30, 2016, and June 30, 2021, a total of 120 eligible patients were enrolled in the trial (Fig.1). Fifty-nine (49.2%) patients were D5-PBCR (+), of which seventeen patients were ineligible for extra idarubicin due to severe infection or unstable hemodynamic parameters and one patient was lost to follow-up. None of the patients in the D5-PBCR (-) group discontinued induction due to adverse events, and three patients were lost to follow-up. The composite complete remission rate after one course of induction for all patients was 62.6% (62/99), with 65.5% (38/58) and 58.5% (24/41) for D5-PBCR (-) and D5-PBCR (+) groups, respectively (P=0.497). At a median follow-up of 24.3 months (95% CI 10.4-38.2), median overall survival (OS) was 20.0 months (95% CI 15.2-24.8) and 13.6 months (95% CI 9.8-17.4), and the median event-free survival (EFS) was 7.8 months (95% CI 2.5-13.1) and 6.6 months (95% CI 4.3-8.9), respectively (Fig.2). Neither the OS nor EFS showed significant differences between the two groups. The total 30-day mortality rate of the two cohorts was 6.8% (7/103). The median platelet recovery time (PLT>50×109/L) after induction therapy in CR/CRi was different between patients with D5-PBCR(-) and D5-PBCR(+) (22 days vs 26 days, P=0.000, Fig.2F). There was a trend but no significant difference in the recovery time of neutrophils (ANC>0.5×109/L) in two cohorts (21 days vs 23 days, P=0.025, Fig.2E). The incidence of adverse events during the first induction was comparable between the two groups and key adverse events of grade ≥3 included pneumonia(37%), sepsis (7%), and γ-glutamyl transpeptidase(GGT) increase (6%) in the entire cohort(Table.1).Conclusion:“3+7” regimen modified by the composition of D5-PBCR and CGA was safe and tolerable in fit older patients with AML. The efficacy and safety of induction were non-inferior compared with the results of existing trials, along with a relatively lower dose of IDA. We considered there may be reserved probability for combining other emerging drugs to challenge higher remission rate in fit AML with additional investigation.Keywords: acute myeloid leukemia; elderly; induction therapy; non-inferior; flow cytometry; D5-PBCR. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

General movement optimality score and general movements trajectories following early parent-administrated physiotherapy in the neonatal intensive care unit

BackgroundThe Prechtl General Movement Assessment (GMA) is a reliable tool for the functional assessment of the young nervous system. It is based on a global assessment of the quality of infants' movements. In addition, detailed steps of assessment have been developed – one for preterm and term age, and one for use between 3 and 5 months. One potential benefit of such a detailed analysis is the documentation of subtle changes in the infants' spontaneous movements caused by early intervention. AimTo present detailed scores of the infants' general movements (GMs) at preterm age, and of the infants' motor repertoire at 3 months' postterm age (PTA), for infants having participated in a randomized controlled trial (RCT) of early intervention, and to examine possible group differences. In addition, the aim is also to present the GMA from preterm to 3 months' PTA, comparing the intervention and the control group. Study designA retrospective study on infants who had participated in an RCT of parent-administered early intervention. Subjects141 infants born very preterm. Outcome measuresGMA, “Detailed Assessment of General Movements During Preterm and Term Age” and “Assessment of Motor Repertoire at 3 to 5 months”. ResultsThe GMA and the detailed assessments of GMs conducted at 36 weeks' post menstrual age (PMA) showed the same distribution of normal and abnormal movements in both the intervention and in the control group, as did the assessment of motor repertoire at 3 months' PTA. ConclusionNeither the GMA nor the detailed assessments of GMs at 36 weeks' PMA and of the motor repertoire at 13 weeks' PTA suggest that early intervention, performed before term, changes the GMs of very preterm-born infants.

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan

BackgroundControversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy.Methods/designThe BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24–72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent.The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data.Trial registrationClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.

Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women

ObjectivesTo compare the effect of oral estradiol (E2) plus vaginal progesterone (P4) against placebo on endometrial thickness, endometrial biopsy pathology, cervical cytology and total cancer incidence among healthy postmenopausal women. Study designThis study is a sub-analysis of the Early versus Late Intervention Trial with Estradiol (ELITE), a randomized, double-blinded, placebo-controlled trial that previously demonstrated that hormone therapy (HT) was associated with less progression of subclinical atherosclerosis than placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. This sub-analysis included only ELITE participants with an intact uterus, who were randomized to either daily oral micronized 17-beta-E2 1 mg/day with 4% vaginal micronized P4 gel 45 mg/day for 10 days each month or placebo. Main outcome measuresParticipants were evaluated at baseline and annually during a median follow-up of 4.8 years for endometrial thickness as determined by pelvic transvaginal ultrasound followed by an endometrial biopsy when indicated, and cervical cytology and cancer incidence. ResultsOver up to 80 months of follow-up, participants randomized to oral E2 plus vaginal P4 had progressive and statistically significant increases in endometrial thickness (p<0.001), underwent more endometrial biopsies and had a higher rate of endometrial hyperplasia on endometrial biopsy compared with the placebo group. Due to the close follow-up of participants in the trial protocol, these abnormal findings were effectively treated. ConclusionOur results suggest that 10 days of vaginal P4 45 mg/day is insufficient to completely oppose the effect of oral E2 1 mg/day on the endometrium. Further studies are needed to test alternative doses or frequencies of administration of vaginal P4 for adequate endometrial protection from E2 therapy among postmenopausal women.ClinicalTrials.gov registration NCT00114517

Very Preterm Early Motor Repertoire and Neurodevelopmental Outcomes at 8 Years.

Children born very preterm (<32 weeks' gestation) have more neurodevelopmental problems compared with term-born peers. Aberrant fidgety movements (FMs) are associated with adverse motor outcomes in children born very preterm. However, associations of aberrant FMs combined with additional movements and postures to give a motor optimality score-revised (MOS-R) with school-aged cognitive and motor outcomes are unclear. Our aim with this study was to determine those associations. Of 118 infants born <30 weeks' gestation recruited into a randomized controlled trial of early intervention, 97 had a general movements assessment at 3 months' corrected age and were eligible for this study. Early motor repertoire including FMs and MOS-R were scored from videos of infant's spontaneous movement at 3 months' corrected age. At 8 years' corrected age, cognitive and motor performances were evaluated. Associations of early FMs and MOS-R with outcomes at 8 years were determined using linear regression. Seventy-eight (80%) infants with early motor repertoire data had neurodevelopmental assessments at 8 years. A higher MOS-R, and favorable components of the individual subscales of the MOS-R, including the presence of normal FMs, were associated with better performance for general cognition, attention, working memory, executive function and motor function at 8 years; eg, presence of normal FMs was associated with a 21.6 points higher general conceptual ability score (95% confidence interval: 12.8-30.5; P < .001) compared with absent FMs. Favorable early motor repertoire of infants born <30 weeks is strongly associated with improved cognitive and motor performance at 8 years.

Magnetic Resonance Imaging Findings Among Individuals With Olfactory and Cognitive Impairment

The underlying mechanism of the association between olfactory impairment and dementia may be explained by neurodegenerative changes detected on magnetic resonance imaging (MRI). The purpose of this systematic review is to describe neurodegenerative changes on MRI in patients with olfactory impairment and mild cognitive impairment (MCI) or dementia. Systematic review. A literature search encompassing PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Google Scholar for studies with MRI and olfactory testing among participants diagnosed with MCI or dementia was performed. Sample size, study design, cognitive impairment type, olfactory testing, and MRI findings were abstracted. Two investigators independently reviewed all articles. The search yielded 556 nonduplicate abstracts, from which 86 articles were reviewed and 24 were included. Seventeen (71%) of 24 studies reported hippocampal volume findings, with 14 studies reporting a relationship between hippocampal volume and olfactory performance. Two (50%) of four prospective studies reported the potential utility of baseline hippocampal volume as a marker of dementia conversion from MCI. Five (21%) of 24 studies reporting olfactory functional MRI (fMRI) findings highlighted the utility of olfactory fMRI to identify individuals in the early stages of cognitive decline. Current evidence suggests hippocampal volume correlates with olfactory performance in individuals with cognitive impairment, and that olfactory fMRI may improve early detection of AD. However, the predictive utility of these imaging markers is limited in prospective studies. MRI may be a useful modality for selecting patients at high risk of future cognitive decline for enrollment in early treatment trials. Laryngoscope, 132:177-187, 2022.

A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy.

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

A Phase 2 Trial of Early Intervention with Ibrutinib in Patients with Asymptomatic, High-Risk CLL

▪Introduction:The current IWCLL guidelines recommend initiation of therapy for progressive, symptomatic disease since studies have yet to demonstrate improved survival with early treatment with chemotherapy. However, available therapeutic options have recently increased significantly, including the development of Bruton's tyrosine kinase inhibitors such as ibrutinib (IB). IB is now approved for both previously untreated and relapsed patients requiring therapy. While IB achieves complete remissions in the minority of relapsed/refractory cases, the drug effects sustained responses, including >20% complete responses in frontline patients, hence providing a rationale for its use earlier in the disease course. Because CLL is associated with profound cellular, humoral and innate immune suppression that worsens with disease progression even in the absence of treatment, patients with CLL respond poorly to routine vaccinations. IB has been shown to reverse disease mediated immune dysfunction partly through Th1 skewing. We sought two test two hypotheses in this study: 1) the safety and efficacy of a defined period of therapy (2 years) of ibrutinib in early stage high risk disease and 2) ability of ibrutinib to improve the efficacy of routine vaccines administered to patients undergoing IB therapy.Methods:This is a single-stage phase II study of IB in previously untreated asymptomatic, genetically high-risk patients with CLL, who did not meet IWCLL treatment criteria. High risk genomics were defined as del(11)(q22.3), del(17)(p13.1), unmutated IGHV, and/or complex karyotype (≥3 cytogenetic abnormalities). Patients were randomized to receive IB 420mg PO daily in 4-week cycles either with the pneumococcal, influenza and TdaP vaccines (Arm A, concurrent) or following vaccination (Arm B, sequential)(see Fig 1). The primary objective of the study is to determine the safety and 2-year progression-free survival of asymptomatic, high-risk CLL patients treated with IB. Secondary objectives include determination of safety and immune responses to vaccines in relation to IB administration along with response characteristics, resistance development and quality-of-life outcomes.Results:Forty-four patients (66% male) have been enrolled on the trial. All patients are high-risk; 91% with unmutated IGHV, 86% with del17p, 66% with del11q, and 76% with complex karyotype. Two patients who progressed on arm B prior to starting therapy with IB are not included in the primary endpoint analysis, and one discontinued because of lung cancer diagnosis 8 months after starting IB. Patients on arms A and B have completed a median of 17 and 15.5 cycles of treatment respectively. Vaccinations in patients with CLL were generally safe and well-tolerated with only 3 patients in Arm B experiencing 5 grade 1 AEs (injection site reactions). There have been no grade 4 toxicities related to IB, and 2 patients have experienced 4 occurrences of grade 3 atrial fibrillation related to IB. Two additional patients experienced 1 episode of grade 3 fever and grade 3 chest pain respectively, which were deemed to be unrelated to IB. No hematologic grade 3 or 4 adverse events were observed. All 41 remaining patients continue IB without evidence of progressive disease. Early treatment with IB was associated with reduction in cancer related stress (p<0.01), anxiety (p=0.004) and improvement in sleep (p=0.02). Patients in Arm A reported a higher decline in anxiety levels as compared to patients in the sequential treatment arm (p=0.04).Conclusion:Treatment of early stage, high risk CLL patients with ibrutinib demonstrates no unexpected safety signals and all patients remain progression free (at median 16 months of follow-up) providing support that this treatment approach is feasible. Earlier IB treatment also results in a decline in stress and anxiety and improvements in sleep compared to patients awaiting treatment. The study is ongoing and updated clinical and vaccine response data will be reported. [Display omitted] DisclosuresJones:Sunesis: Other: Institutional research funding; Abbvie, Pharmacyclics, Genentech, Gilead, Janssen, Merck, and Acerta: Other: Institutional research funding; Genentech, Abbvie, Pharmacyclics, Gilead, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrd:Janssen: Research Funding; Genentech: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

Revisiting Cytochemical Myeloperoxidase (MPO) Stain for Early Diagnosis of Acute Promyelocytic Leukemia (APML) in Areas with Limited Resources: An Experience from a Tertiary Care Center in India

Introduction- Acute Promyelocytic leukemia (APML) needs to be suspected early so that All-Trans Retinoic Acid (ATRA) therapy can be started as soon as possible. Flow cytometry shows absence of CD34 and HLADR in most cases and so can aid in diagnosis along with the usual morphological clues. However, it may have confusing patterns as in hypogranular APML and sometimes may be positive for HLA- DR and CD34. RT-PCR for detection of characteristic APML translocations (t(15;17),t(17;17) and others) is gold standard for APML diagnosis which is time consuming and often not possible especially in resource limited areas. Cytochemical MPO stain is a robust laboratory test that can be a valuable aid to morphology in early diagnosis of APML. In this study, the role of cytochemical MPO was evaluated for early diagnosis of APML.Method- This study included all the cases of APML that were diagnosed in a tertiary care center in India from May 2011 to May 2014. Cytochemical stains (MPO, Non- specific Esterase (NSE), Periodic- acid Schiff (PAS) stains were performed on peripheral smear and bone marrow aspirates. Flow cytometry was performed on peripheral blood/bone marrow aspirate in EDTA on Beckman Coulter Flow Cytometer (FC500) using a panel of markers. RT-PCR was not available. However, all the above cases responded immediately to trial of ATRA (diagnosis confirmed by response to treatment trial with ATRA). The study was approved by Institutional Ethics committee.Results & Discussion- 13 cases of APML (6 males, 7 females) were identified with age ranging from 2-36 years. On flow cytometry, side scatter was moderate in 4 cases and high in 9 cases. The former were AML M3v (hypogranular variant) whereas the latter were classic APML. CD13 was heterogeneously dim to moderate positive in 12/13 cases .CD 33 was homogenously positive in all 13 cases (dim positive in 3; moderate positive in 10). CD34 was positive in 1/13 case and HLA-DR was positive in 2/13cases. All cases showed 3+ cytochemical MPO positivity, diffuse flush PAS positivity and NSE positivity. All cases went into immediate remission on treatment with ATRA.Thus even though flow cytometry was helpful in diagnosing APML, there were still some variations in the patterns. It is concluded that, though flow cytometric pattern of APML is often characteristic, occasionally it may have moderate side scatter and positive HLA-DR and CD34. In such situations and also in places with limited availability of flow cytometry/ RT PCR , strong (3+) cytochemical MPO staining in addition to characteristic morphologic features helps in the quick suspicion of APML and early treatment trial with ATRA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Stratification of Smoldering Multiple Myeloma in the Light of the Revised IMWG Diagnostic Criteria

Introduction: The 2014 revised International Myeloma Working Group (IMWG) definition of multiple myeloma (MM) and smoldering MM (SMM), reclassified high risk patients with SMM who had one or more of bone marrow plasma cell percentage (BMPC) ≥ 60%, involved to uninvolved free light chain ratio (FLCr)≥100 and >1 focal lesion on magnetic resonance imaging as MM. A previous model developed at our institution to predict progression of SMM to MM or systemic amyloidosis included serum-M spike ≥3 g/dL, BMPC≥10% and FLCr >8 as predictors and was devised before 2014 (Dispenzieri et al. Blood; 2008). We aimed to devise a simple scoring system, using routinely used parameters, to risk stratify patients with SMM as defined by the current diagnostic criteria.Methods: We retrospectively reviewed electronic medical records to identify patients who satisfied the 2014 revised IMWG criteria for SMM, who were seen at our institution between 2001 and 2015. We collected data regarding baseline characteristics, date of progression, myeloma defining event, and first treatment. Time to progression (TTP) was defined as time duration from diagnosis of SMM to initiation of therapy for MM/amyloidosis. Patients were censored in TTP analysis if they did not progress at last follow-up, started cancer chemotherapy or steroids for other indications, or if they enrolled in a treatment trial of SMM. We used receiver operating characteristics (ROC) analysis to identify best cut-offs for continuous variables like serum M-spike, BMPC and FLCr in predicting progression at 3 years from diagnosis of SMM. We used Cox proportional hazards model to identify the effect of predictors on TTP and estimate their hazard ratios (HRs). TTP was estimated using Kaplan Meier method.Results: We included 433 patients in the final analysis. The estimated median follow-up duration was 6.0 years (95%CI, 5.4-6.8). Using ROC curve analysis, we identified M-spike of 2g/dL, BMPC of 20%, and FLCr of 20 as cut-offs to predict progression at 3 years. Apart from the above variables, we also included immunoglobulin isotype (IgG vs non-IgG) and presence of immunoparesis in the univariate analysis. The results of univariate analysis are shown in Table 1 . M-spike >2 g/dL, BMPC>20%, and FLCr>20 were significant in the univariate model and were included in the multivariate Cox proportional hazards model which included 419 patients. M-spike [HR: 1.67 (CI, 1.18-2.38); p=0.003], BMPC [HR: 2.02 (CI, 1.44-2.84); p<0.0001] and FLCr [HR: 1.88 (CI, 1.37-2.57); p=0.0001] predicted reduced TTP in the multivariate model. Depending on the presence of M-spike>2 g/dL, BMPC>20% and FLCr>20, we divided patients into three groups- low risk (none of the three risk factors; n=143), intermediate risk (one of the three risk factors; n=121) and high risk (two or more of the risk factors; n=155). The estimated median TTP for the low, intermediate and high risk groups were 9.1 years (CI, 5.4-not reached), 3.7 years (CI, 2.8-6.9) and 1.6 years (CI, 1.1-2.5) respectively (p<0.0001; Figure 1). There was no difference in TTP between patients who had two or three of the above risk factors at diagnosis. The 5-year estimated risk of progression in the low, intermediate and high risk groups were 26.5%, 57.1% and 81.0% respectively.Conclusions: M-spike >2 g/dL, BMPC>20% and FLCr>20 at diagnosis are routinely measured parameters which can be used to risk stratify patients meeting current diagnostic criteria for SMM. Presence of 2 or more of these risk factors identifies a high risk group with shorter TTP. These patients might benefit from clinical trials of early intervention to prevent/ delay progression to MM/amyloidosis. [Display omitted] DisclosuresDispenzieri:Celgene, Millenium, Pfizer, Janssen: Research Funding. Gertz:Millennium: Consultancy, Honoraria; Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria. Dingli:Karyopharm Therapeutics: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Alexion Pharmaceuticals: Consultancy. Russell:Imanis Life Sciences: Equity Ownership; Vyriad: Equity Ownership. Kapoor:Takeda, Celgene and Amgen: Research Funding. Kumar:Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Skyline: Honoraria.

Baby-OSCAR: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies\u2014a statistical analysis plan for short-term outcomes

BackgroundThe Baby-OSCAR trial is a multi-centre, randomised, placebo-controlled parallel group trial of early treatment of large patent ductus arteriosus (PDA) with ibuprofen in extremely preterm infants. This paper describes the statistical analysis plan for the short-term health outcomes of the Baby-OSCAR trial.Methods and designThis is a randomised controlled trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies improves short and long-term health and economic outcomes. Infants born between 23+0 and 28+6 weeks of gestation, confirmed by echocardiography as having a large PDA (with a diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern), with parental informed consent, were randomly allocated to receive either ibuprofen or placebo within 72 h of birth. The primary outcome is a composite of death by 36 weeks’ postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age.ResultsBaseline demographic and clinical characteristics will be described by randomised group. The primary analysis will be on the modified intention to treat (ITT) population. Counts and percentages will be presented for binary and categorical variables, and mean and standard deviation or median and interquartile range will be presented for continuous variables. For binary outcomes, risk ratios and confidence intervals will be calculated using log binomial or Poisson regression with a robust variance estimator. Continuous outcomes will be analysed using linear regression models, or quantile regression models if skewed. Analyses will be adjusted for all minimisation factors where technically possible, and correlation between siblings from multiple births will be accounted for by nesting the clusters as a random effect. Both crude and adjusted effect estimates will be presented, with the primary inference based on the adjusted estimates. Ninety-five per cent confidence intervals will be used for all pre-specified outcome comparisons.ConclusionThis paper describes the statistical analysis plan for short-term health outcomes of the trial, including the analysis principles, definitions of important outcomes, methods for primary analysis, pre-specified subgroup analysis, and secondary analysis. The plan was finalised prior to completion of short-term follow-up.Trial registrationISRCTN registry ISRCTN84264977. Registered on 15 September 2010.

A feasibility randomised controlled trial of a brief early intervention for adolescent depression that targets emotional mental images and memory specificity (IMAGINE)

Brief, evidence-based interventions for adolescent depression are urgently required, particularly for school-settings. Cognitive mechanisms research suggests dysfunctional mental imagery and overgeneral memory could be promising targets to improve mood. This feasibility randomised controlled trial with parallel symptomatic groups (n = 56) compared a novel imagery-based cognitive behavioural intervention (ICBI) to non-directive supportive therapy (NDST) in school settings. Blind assessments (of clinical symptoms and cognitive mechanisms) took place pre-intervention, post-intervention and follow-up three months later. The trial aimed to evaluate the feasibility and acceptability of the methodology and interventions, and estimate the likely range of effects of the intervention on self-reported depression. The pre-defined criteria for proceeding to a definitive RCT were met: full recruitment occurred within eleven months; retention was 89%; ICBI acceptability was above satisfactory; and no harm was indicated. Intention-to-treat analysis found large effects in favour of ICBI (relative to NDST) at post-intervention in reducing depressive symptoms (d = −1.34, 95% CI [-1.87, −0.80]) and improving memory specificity (d = 0.79 [0.35, 1.23]), a key cognitive target. The findings suggest that ICBI may not only improve mood but also strengthen abilities associated with imagining and planning the future, critical skills at this life stage. A fully powered evaluation of ICBI is warranted.Trial Registration: https://www.isrctn.com/; ISRCTN85369879.

Natural history of incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration

ObjectiveTo assess the time course and risk factors for conversion of incomplete retinal pigment epithelium and outer retina atrophy (iRORA) to complete retinal pigment epithelium and outer retina atrophy (cRORA) in eyes with non-neovascular intermediate age-related macular degeneration (iAMD), using optical coherence tomography (OCT) analysis. DesignRetrospective survival study. ParticipantsTracked structural Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) volume datasets from 2 retinal specialists at the University of California–Los Angeles were retrospectively screened to identify consecutive participants with non-neovascular iAMD without signs of atrophy or macular neovascularization in either eye at baseline. MethodsIn the first stage of selection, 321 consecutive iAMD eyes were screened for onset of iRORA. Eyes that developed iRORA within the first 24 months were followed for an additional 24 months to assess the rate of conversion to cRORA. A Kaplan-Meier survival curve was formulated to illustrate the conversion from iRORA to cRORA. ResultsAmong 321 baseline participants with iAMD, 87 incident iRORA lesions (50 eyes, 42 participants) were included in the conversion analysis. Eighty-one iRORA lesions (93.1%) converted to cRORA within 24 months (median 14 months). Multivariate binary logistic regression analysis indicated that intraretinal hyperreflective foci and extrafoveal iRORA location at baseline were associated with a faster rate of progression to cRORA (model R2 = 0.816, p < 0.05). ConclusionsThe majority of incident iRORA lesions progress to cRORA within a 24-month period. These findings may be of value in the design of early intervention trials for risk stratification and prognostication but need to be validated with a prospective analysis.

Multifaceted pattern of longitudinal imaging changes in cognitively normal midlife adults: The PREVENT‐Dementia study

AbstractBackgroundFirst‐degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Identifying preclinical brain changes would facilitate both early quantifiable longitudinal disease monitoring and interventional trials. However, the literature of imaging changes in FH+ remains highly controversial. We aim to investigate “estimated years to onset of dementia” (EYOD) as a surrogate marker of preclinical progression and assessed whether FH+ approaching the onset of dementia would express more severe patterns of longitudinal brain changes.Method89 FH+ persons underwent serial 3T‐MRI with T1‐MPRAGE, DWI and ASL (mean interval: 2 years). The longitudinal Freesurfer pipeline was used to segment hippocampal subfields and early‐AD regions. Partial‐volume corrected ASL data and DWI data were processed with FSL‐BASIL4 and DTI‐TK5. Small vessel disease was indexed with white matter hyperintensities (WMHs) (Figure 1). We applied linear mixed effects models with random intercepts to predict MRI changes relative to baseline EYOD, accounting for baseline age, gender, education and time from baseline. Secondary analyses examined the interaction of APOE‐ε4+ on proximity‐related brain changes.ResultA shorter EYOD was associated with progressive decrease in FA, increase in MD/RD and atrophy of the fusiform gyrus over time (Figure 2). Interaction analyses revealed that APOE‐ε4+ carriers showed significant longitudinal atrophy of the hippocampal subfields with shorter EYOD. In contrast, cortical perfusion increased before plateauing ∼10 years before estimated onset. There were no associations of EYOD with mean cortical thickness or WMHs (See Figure 3 for a summary of main findings).ConclusionOur findings represent an extensive characterisation of longitudinal brain changes associated with proximity to dementia in FH+. Individuals who are approaching their parental age of dementia onset may be showing incipient brain abnormalities, particularly amongst APOE‐ε4 carriers. The involvement of early‐AD regions also confer support to the biological validity of EYOD as a stage marker of preclinical progression. Further clinical follow‐up of our sample would provide critical validation of these findings.

Multi‐faceted brain changes associated with proximity to dementia onset: The PREVENT‐Dementia study

AbstractBackgroundFirst‐degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Identifying preclinical brain changes would facilitate both early quantifiable longitudinal disease monitoring and interventional trials. However, the literature of imaging changes in FH+ remains highly controversial. We aim to investigate “estimated years to onset of dementia” (EYOD) as a surrogate marker of preclinical progression and assessed whether FH+ approaching the parental age of dementia onset would express more severe patterns of longitudinal brain changes.Method89 FH+ persons underwent serial 3T‐MRI with T1‐MPRAGE, DWI and ASL (mean interval: 2 years). The longitudinal Freesurfer pipeline was used to segment hippocampal subfields and early‐AD regions. Partial‐volume corrected ASL data and DWI data were processed with FSL‐BASIL4 and DTI‐TK5. Small vessel disease was indexed with white matter hyperintensities (WMHs) (Figure 1). We applied linear mixed effects models to predict MRI changes relative to EYOD, accounting for age, gender, education and time from baseline. Secondary analyses examined the interaction of APOE‐ε4+ on proximity‐related brain changes.ResultA shorter EYOD was associated with progressive decrease in FA, increase in MD/RD and atrophy of the fusiform gyrus over time (Figure 2). Interaction analyses revealed that APOE‐ε4+ carriers showed significant longitudinal atrophy of the hippocampal subfields with shorter EYOD. In contrast, cortical perfusion increased before plateauing ∼10 years before estimated onset. There were no associations of EYOD with mean cortical thickness or WMHs (See Figure 3 for a summary of main findings).ConclusionOur findings represent the first extensive characterisation of longitudinal brain changes associated with proximity to dementia in FH+. Individuals who are approaching their parental age of dementia onset may be showing incipient brain abnormalities, particularly amongst APOE‐ε4 carriers. The specificity our findings in early‐AD regions also confer support to biological validity of EYOD as a stage marker of preclinical progression. Further ongoing clinical follow‐up of our sample would provide critical validation of these findings.

Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19.

BackgroundUse of hydroxychloroquine in hospitalized patients with coronavirus disease 2019 (COVID-19), especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from 3 outpatient randomized clinical trials.MethodsWe conducted 3 randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, postexposure prophylaxis, and early treatment for COVID-19 using an internet-based design. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings.ResultsWe enrolled 2795 participants. The median age of research participants (interquartile range) was 40 (34–49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2544 (91%) participants reported side effect data, and 748 (29%) reported at least 1 medication side effect. Side effects were reported in 40% with once-daily, 36% with twice-weekly, 31% with once-weekly hydroxychloroquine, compared with 19% with placebo. The most common side effects were upset stomach or nausea (25% with once-daily, 19% with twice-weekly, and 18% with once-weekly hydroxychloroquine, vs 11% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for once-daily, 17% twice-weekly, and 13% once-weekly hydroxychloroquine, vs 7% for placebo). Two individuals were hospitalized for atrial arrhythmias, 1 on placebo and 1 on twice-weekly hydroxychloroquine. No sudden deaths occurred.ConclusionsData from 3 outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials, in cohorts of healthy outpatients, can safely investigate whether hydroxychloroquine is efficacious for COVID-19.ClinicalTrials.gov IdentifierNCT04308668 for postexposure prophylaxis and early treatment trials; NCT04328467 for pre-exposure prophylaxis trial.

Early Treatment of COVID-19 Disease: A Missed Opportunity.

Antivirals have demonstrated efficacy in treating other infectious diseases in early stages of disease, reducing morbidity, mortality, and the likelihood of onward transmission. At the time of writing, more than 1900 clinical trials are registered globally to assess the efficacy and safety of candidate therapeutics for COVID-19. The majority of these trials are designed to evaluate the comparative efficacy and safety of candidate therapeutics for the treatment of COVID-19 to prevent death among populations of hospitalized patients with advanced disease. Yet, emerging epidemiological evidence now indicates that the majority of those infected with the SARS-CoV-2, while still infectious, experience minimal or mild disease symptomology. Like HIV and hepatitis C that pioneered treatment as prevention, there is a missed opportunity for trials of early pharmaceutical intervention for COVID-19 disease evaluating not only reductions in morbidity and mortality but also transmissibility. We discuss this clinical research gap within an historical context of viral treatment as prevention for HIV and hepatitis C, and comment on the challenges and opportunities for clinical research of candidate therapeutics for early COVID-19 disease.

Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.

Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy.

To identify factors associated with serum estradiol (E2) levels among healthy postmenopausal women using hormone therapy (HT). This is an unplanned post hoc analysis of data from ELITE (Early versus Late Intervention Trial with Estradiol), a randomized controlled trial of 1 mg oral E2 with or without vaginal progesterone in healthy early compared with late (<6 years compared with 10 or more years since menopause) postmenopausal women. We included results from visits when women reported at least 80% compliance with HT. Mixed-effects linear models identified factors associated with serum E2 levels while participants were taking HT, assessed every 6 months over a median follow-up of 4.8 years and adjusted for baseline E2 level, visit, and reduced E2 dose. Possible correlates evaluated included demographics, clinical characteristics, medication use, and biomarkers of liver and kidney metabolic function. The analysis included 2,160 E2 measurements in 275 postmenopausal women. Mean±SD age was 55.4±3.9 vs 64.4±5.5 years, and mean±SD time since menopause was 3.6±1.8 vs 16.0±5.6 years for early vs late postmenopausal women. Adjusted for pretreatment E2 level, visit, and reduced dose indicator, higher serum E2 levels were associated with higher body mass index (BMI), higher weight, surgical menopause, alcohol use, and antihypertensive medication use. Current and past smoking and antifungal medication use were associated with lower serum E2 levels. In the multivariable model, higher BMI and alcohol use were associated with higher serum E2 levels, whereas current and past smoking were associated with lower serum E2 levels. These factors were similar between early and late postmenopausal women. Factors associated with serum E2 levels among postmenopausal women taking HT include BMI, alcohol use, and smoking. As serum E2 levels relate to HT effect, achievement of desirable E2 levels may be maximized through personalized intervention. ClinicalTrials.gov, NCT00114517.

Time from diagnosis to 2nd treatment is a promising surrogate for overall survival in patients with advanced stage follicular lymphoma

It is difficult to demonstrate an overall survival (OS) benefit in trials of immediate therapy vs observation in follicular lymphoma (FL). Time to 2nd treatment (TT2T) may be a preferred endpoint. We identified 584 consecutive patients at our institution with advanced stage FL grade 1–3 A for whom intention was observation (n = 248) or therapy (n = 338). Median time to 1st treatment (TT1T), TT2T, and OS were estimated (subdistribution function). Modified Kendall's tau (mKτ) was used to assess correlation between survival endpoints. Among initially observed patients, median TT1T was 3.3 years, TT2T was 12.1 years, 10-year treatment-free survival was 23%, and 10-year OS was 82%. TT2T was strongly correlated with OS following initial observation (mKτ 0.46, p = .004) or therapy (mKτ 0.53, p < .0001), while duration of observation was not. TT2T is a potential surrogate for OS. Given the outstanding survival in this population, early intervention trials should focus on identifying high risk patients.