Mixed-effects Model For Repeated Measures Research Articles

Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights From DAPA-HF.

Background:In a post hoc analysis, the frequency of occurrence of an early decline (dip) in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin and its association with outcomes were evaluated in patients with heart failure and reduced ejection fraction randomized in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial.Methods:Patients with heart failure with reduced ejection fraction with or without type 2 diabetes and an eGFR ≥30 mL·min−1·1.73 m−2 were randomized to placebo or dapagliflozin 10 mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed with repeated-measures mixed-effect models.Results:The mean change in eGFR between day 0 and 14 was −1.1 mL·min−1·1.73 m−2 (95% CI, −1.5 to −0.7) with placebo and −4.2 mL·min−1·1.73 m−2 (95% CI, −4.6 to −3.9) with dapagliflozin, giving a between-treatment difference of 3.1 mL·min−1·1.73 m−2 (95% CI, 2.6–3.7). The proportions of patients randomized to dapagliflozin experiencing a >10%, >20%, and >30% decline in eGFR were 38.2%, 12.6%, and 3.4%, respectively; for placebo, they were 21.0%, 6.4%, and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin compared with placebo was 2.36 (95% CI, 2.07–2.69; P<0.001). Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19–1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI, 0.59–0.91; Pinteraction<0.001). A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events.Conclusions:The average dip in eGFR after dapagliflozin was started was small and associated with better clinical outcomes compared with a similar decline on placebo in patients with heart failure with reduced ejection fraction. Large declines in eGFR were uncommon with dapagliflozin.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

First-line nivolumab plus ipilimumab versus chemotherapy for the treatment of unresectable malignant pleural mesothelioma: patient-reported outcomes in CheckMate 743

ObjectiveIn CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient-reported outcomes (PROs). Materials and MethodsPatients (N = 605) were randomized to nivolumab + ipilimumab or chemotherapy. Changes in disease-related symptom burden and health-related quality of life (HRQoL) were evaluated descriptively using the Lung Cancer Symptom Scale (LCSS)-Mesothelioma (Meso) average symptom burden index (ASBI), LCSS-Meso 3-item global index (3-IGI), 3-level EuroQol 5-dimensional (EQ-5D-3L) visual analog score (VAS), and EQ-5D-3L utility index. PROs were assessed at baseline and every 2 (nivolumab + ipilimumab) or 3 weeks (chemotherapy) through 12 weeks, every 6 weeks through 12 months, every 12 weeks thereafter, and at specified follow-ups. Mixed-effect model repeated measures (MMRM) and time to deterioration analyses were conducted. ResultsCompletion rates were generally >80%. LCSS-Meso ASBI mean changes from baseline trended to improve over time with nivolumab + ipilimumab and deteriorate with chemotherapy, but did not meet clinically important difference thresholds [±10 score change]. EQ-5D-3L VAS mean scores improved over time with nivolumab + ipilimumab; by week 60, patients had scores consistent with United Kingdom normal population values. MMRM analyses favored nivolumab + ipilimumab for all individual symptoms except cough. Nivolumab + ipilimumab delayed time to definitive deterioration in HRQoL (hazard ratio 0.52 [95% confidence interval 0.36–0.74]) and showed a trend in symptom delay versus chemotherapy. ConclusionsNivolumab + ipilimumab decreased the risk of deterioration in disease-related symptoms and HRQoL versus chemotherapy and maintained QoL in patients with unresectable MPM.

The association of C-reactive protein with responses to escitalopram antidepressant treatment in patients with major depressive disorder

BackgroundThe effects of escitalopram vary markedly among MDD patients, and approximately one-third of patients fail to respond. A poor antidepressant response might be associated with excessively high C-reactive protein (CRP) levels, but the impact is not clear. We hypothesized that in adults with major depressive disorder, the peripheral biomarker, CRP, was associated with the response to escitalopram (SSRI). MethodsThis was a prospective follow-up study. All 71 patients were treated with escitalopram for 12 weeks. Blood samples were collected at baseline and week 12. Remission was defined as a score of 7 or less on the HAMD-17 scale at week 12. Spearman correlations and multiple linear regressions were used to explore the relationship between continuous CRP levels and the HAMD-17 scores. Logistic regression was used to determine the predictors for remission. The restricted maximum likelihood (REML)-based mixed-effect model for repeated measures (MMRM) was used to examine the change of the HAMD-17 total scores between high and low CRP groups. ResultsCompared with the high CRP group (≥0.8 mg/l), the low baseline CRP group had a higher remission rate (22.73% vs. 48.89%, χ2 = 4.2, p = 0.0403). Logistic regression revealed that patients with lower CRPs were 3.920 times (95% CI: 1.142, 13.460) more likely to experience remission (p = 0.0300). The multiple linear regression model showed that the HAMD-17 total score reduction (baseline to week 12) was negatively correlated with the baseline CRP level (t = −2.00, p = 0.0494). ConclusionsWe observed a predictive role of CRP for remission and symptomatic improvement after escitalopram treatment of MDD patients based on continuous or categorical CRP levels.

A219 AMINOTRANSFERASE IMPROVEMENTS IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS ARE ASSOCIATED WITH FIBROSIS REGRESSION IN THE REGENERATE STUDY

Abstract Background The interim analysis of the REGENERATE study showed obeticholic acid (OCA) 25 mg treatment significantly improved liver histology in patients with nonalcoholic steatohepatitis (NASH) and fibrosis. Elevations in aminotransferases are associated with adverse liver-related outcomes in NASH. Aims Here, we evaluate the utility of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of treatment response to OCA in patients with NASH. Methods Changes in ALT (upper limit of normal [ULN] = 55 U/L) and AST (ULN = 34 U/L) were assessed systematically at 1, 3, 6, 12, and 18 months in 931 NASH patients with stage 2 or 3 fibrosis randomized 1:1:1 to placebo (PBO), OCA 10 mg, or OCA 25 mg in REGENERATE (intent-to-treat population). Least-square mean (LSM) and 95% confidence intervals (CIs) of percentage change from baseline in ALT and AST were analyzed using a mixed-effect repeated-measures model. Results Baseline characteristics were well-balanced across treatment arms: ALT 79±53 U/L; AST 58±36 U/L; 44% F2, 56% F3. Aminotransferase values were &amp;gt; ULN for ALT in 60% (7% &amp;gt; 3xULN), and for AST in 74% (9% &amp;gt; 3xULN) of patients. Rapid, progressive, and dose-dependent improvement in ALT and AST was seen across PBO, OCA 10 mg, and OCA 25 mg arms, which at Month 18 was: ALT LSM change (95% CI), respectively, -4.9% (-10.7–0.9), -23.2% (-28.9– -17.4) and -31.9% (-37.7– -26.1) and in AST, -8.7% (-12.1– -5.2), -13.4% (-16.8– -9.9), and -19.4 (-22.8– -15.9). ALT and AST LSM reductions in OCA arms vs PBO were seen regardless of patient ULN status at baseline. In all patients, ALT/AST reduction was associated with probability of fibrosis regression at Month 18, ranging from approximately 20%, 95% CI (14–27) to 45% (37–54) with any reduction in ALT (&amp;gt; 0%–100%) and between approximately 20%, 95% CI (25–38) to 43% (35–57) with any reduction in AST (&amp;gt; 0%–100%). Interestingly, even with increases of ≤ 40% in AST or ALT there was still a small probability of fibrosis regression (&amp;lt; 20%). Analysis of changes in ALT and AST in individual patients showed that more patients had improvements on OCA than PBO at Month 18 (FIG 1). Conclusions OCA resulted in consistent dose-dependent improvement of ALT and AST. Patients with reductions in ALT or AST were up to twice as likely to have fibrosis improvement than those whose ALT or AST increased. The REGENERATE study is ongoing and will continue through clinical outcomes for verification and description of clinical benefits of OCA in treatment of NASH. Funding Agencies None

Abstract P5-16-01: Assessment of health-related quality of life by clinical response from the phase 3 ASCENT study in metastatic triple-negative breast cancer (mTNBC)

Abstract Background: In ASCENT, patients with mTNBC refractory to or relapsing after ≥2 prior chemotherapies (at least one in the metastatic setting) were randomized 1:1 to receive sacituzumab govitecan (SG) or single-agent treatment of physician’s choice (TPC) (capecitabine, eribulin, vinorelbine, or gemcitabine). Primary endpoint was progression free survival. Secondary endpoints included overall survival, objective response rate, clinical benefit rate, and safety. Here we examined whether health-related quality of life (HRQoL) differed by clinical response. Methods: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQC30) version 3 was used to assess HRQoL at baseline and on day 1 of each treatment cycle. This analysis included intention-to-treat patients who had a completed at least one of the 15 domains/scales at baseline and at least one evaluable assessment at post-baseline visits based on EORTC QLQ-C30. Patients were classified as responders (partial or complete disease response) or non-responders (stable or progressive disease or not evaluable) based on best overall response (RECIST). A mixed-effect model for repeated measures (MMRM) was used to estimate leastsquare (LS) mean EORTC QLQC30 score changes from baseline using all HRQoL data assessed during Cycle 2 Day 1 (C2D1) to C6D1 (where n was ≥25 in both treatment arms) for responders and nonresponders within each treatment group. Results: Mean QLQ-C30 subscale scores at baseline were similar between treatment arms. The analysis included 236 patients in the SG arm of the full trial population, of whom 82 (35%) were clinical responders; and 183 in the TPC arm, of whom 11 (6%) were clinical responders. Due to the small number of TPC responders, inferential statistical testing to compare between-group difference was not performed.Irrespective of their clinical response status, patients treated with SG showed more favorable LS mean changes than patients who received TPC in all EORTC QLQ-C30 domains, except for nausea/vomiting and diarrhea (Table). Overall, LS mean changes in EORTC QLQ-C30 scores in SG nonresponders were less favorable than those in SG responders, but more favorable than those in TPC responders and TPC nonresponders for most EORTC QLQ-C30 domains. Conclusions: The analysis demonstrates that regardless of response status, SG responders and non-responders showed a better trend in HRQoL changes than TPC. Patients who achieved a tumor response to SG may benefit most in HRQoL. Although patients treated with SG reported higher rates of diarrhea, this did not generate a negative impact on their overall quality of life or functioning. Table: Mixed effects model least-square mean EORTC QLQ-C30 score changes from baselineLeast-square mean change from baseline (95% confidence interval)SG responders(N=82)SG nonresponders(N=154)TPC responders(N=11)TPC non-responders(N=172)Global health status/QoL2.46 (-1.52, 6.43)-0.57 (-3.68, 2.54)-1.64 (-10.22, 6.95)-2.29 (-5.63, 1.05)FunctioningPhysical2.93 (-0.92, 6.79)0.22 (-2.71, 3.15)-3.47 (-11.93, 4.99)-3.75 (-6.87, -0.63)Role-0.35 (-5.74, 5.04)-3.23 (-7.45, 0.99)-8.40 (-19.93, 3.13)-7.33 (-11.88, -2.78)Emotional6.20 (2.23, 10.18)1.97 (-1.12, 5.06)4.87 (-3.70, 13.44)0.08 (-3.24, 3.40)Cognitive0.90 (-2.99, 4.79)-2.25 (-5.26, 0.76)-4.46 (-12.87, 3.95)-1.26 (-4.49, 1.98)Social2.06 (-3.50, 7.61)-3.35 (-7.65, 0.95)-5.79 (-18.29, 6.72)-4.36 (-8.99, 0.27)SymptomsFatigue0.90 (-3.49, 5.28)2.84 (-0.60, 6.29)4.15 (-5.34, 13.65)6.65 (2.93, 10.38)Nausea/vomiting4.68 (1.42, 7.95)4.03 (1.42, 6.64)1.38 (-5.53, 8.29)2.62 (-0.21, 5.45)Pain-11.40 (-16.43, -6.36)-8.57 (-12.48, -4.66)-11.99 (-22.85, -1.13)-0.24 (-4.47, 3.99)Dyspnea-7.88 (-13.09, -2.67)-1.90 (-5.93, 2.13)1.97 (-9.33, 13.27)3.86 (-0.47, 8.18)Insomnia-6.12 (-11.99, -0.26)-3.51 (-8.04, 1.02)4.83 (-7.85, 17.51)-0.98 (-5.86, 3.90)Appetite loss0.22 (-5.25, 5.70)5.45 (1.15, 9.75)8.67 (-3.05, 20.40)4.60 (-0.05, 9.26)Constipation0.93 (-4.57, 6.43)2.20 (-2.09, 6.49)3.87 (-7.96, 15.70)3.52 (-1.12, 8.16)Diarrhea16.03 (10.32, 21.74)13.65 (9.19, 18.11)2.46 (-9.88, 14.80)-1.53 (-6.34, 3.29)Financial difficulties-3.57 (-8.54, 1.39)-2.44 (-6.21, 1.34)-4.41 (-15.27, 6.46)0.61 (-3.42, 4.64)A higher score for a functional domain represents a higher or healthier level of functioning; a higher score for the global health status/QoL represents a higher overall HRQoL; but a higher score for a symptom domain represents a higher level of symptomatology or problems Citation Format: Sibylle Loibl, Sara M. Tolaney, Kevin Punie, Mafalda Oliveira, Hope S. Rugo, Aditya Bardia, Sara A. Hurvitz, Adam Brufsky, Kevin M Kalinsky, Javier Cortes, Joyce O’Shaughnessy, Lisa A. Carey, Luca Gianni, Véronique Diéras, Ling Shi, Mahdi Gharaibeh, Luciana Preger, Lee Moore, See Phan, Martine Piccart. Assessment of health-related quality of life by clinical response from the phase 3 ASCENT study in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-01.

Abstract OT1-12-08: Randomized study comparing electronic patient reported outcomes (ePROs) monitoring with routine follow up during trastuzumab deruxtecan treatment in patients with inoperable or metastatic breast cancer (PRO-DUCE study)

Abstract Background: Trastuzumab Deruxtecan (T-DXd) is a novel antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) with a DNA topoisomerase I inhibitor payload and has demonstrated antitumor activity in clinical trials. Based on the results of a global Phase II clinical trial (DESTINY-Breast01, NCT03248492), T-DXd was conditionally approved for the treatment of patients with HER2+ unresectable or metastatic breast cancer who had received ≥2 prior anti-HER2 based therapies (US, EU, UK, etc) or after prior chemotherapy (Japan). With regards to the safety profile, the incidence of cumulative toxicities such as peripheral neuropathy and edema was lower with T-DXd as compared to what has been observed with taxanes. However, chemotherapy-induced nausea and vomiting (CINV), fatigue, and neutrophil count decrease were observed as treatment emergent adverse events (TEAE). Interstitial lung disease (ILD)/pneumonitis was especially observed in 15.2% of patients treated with T-DXd, leading to death in 2.7% of patients. These adverse events need appropriate monitoring and management in daily clinical practice. We hypothesized that electronic patient-reported outcomes (ePROs) monitoring would allow early detection of adverse events due to T-DXd and thus improve patient safety and quality of life (QoL). Study design: This is an open-label, multicenter, randomized controlled study comparing ePRO monitoring with routine follow-up of patients with HER2+ advanced or metastatic breast cancer who receive T-DXd in routine clinical practice. Patients randomized to the ePRO group are monitored through weekly PRO-CTCAE assessment as well as daily temperature and SpO2 measurement using the ePRO application on the patient's mobile device. Changes in symptoms are monitored by the attending physician using an electronic chart. In addition, an e-mail alert is sent to the site medical staff if any symptoms exceed a predetermined threshold. The primary endpoint of the study is the change from baseline in the EORTC QLQ-C30 (Global QoL) score at 24 weeks. Secondary endpoints include time to deterioration of Global QoL, EORTC FA12 score change, overall survival, progression-free survival, and adherence to the ePRO monitoring as assessed by the proportion of patients completing the questionnaires. Analysis of primary endpoint will be done using mixed effects models for repeated measures (MMRM) and sample size will be estimated based on the Wald test for differences between groups in mean parameters at 24 weeks. To detect 10-points score difference between the groups with a standard deviation of 24, with a two-sided alpha level of 10%, and a power of 87%, 55 patients would be required in each group. Enrollment started in March 2021. Clinical trial identification: jRCTs031200387 Citation Format: Takafumi Sangai, Yuichiro Kikawa, Mitsuchika Hosoda, Yohei Hamanaka, Yuko Tanabe, Tatsuya Yoshida, Kaori Tane, Daisuke Takabatake, Tetsuhiko Taira, Kazuhiro Araki, Takayuki Iwamoto, Mamoru Takada, Kazutaka Narui, Takeshi Yamaguchi, Akimitsu Yamada, Tomoko Miura, Yukari Uemura, Tomohiko Aihara, Hirofumi Mukai, Naruto Taira. Randomized study comparing electronic patient reported outcomes (ePROs) monitoring with routine follow up during trastuzumab deruxtecan treatment in patients with inoperable or metastatic breast cancer (PRO-DUCE study) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-08.

Abstract P4-10-04: Health-related quality of life (HRQoL) in hormone receptor-positive, HER2-negative, luminal B breast cancer patients treated with ribociclib plus letrozole or chemotherapy

Abstract Background: Neoadjuvant ribociclib plus letrozole (R+L), was evaluated in the phase II Coralleen study (NCT03248427) in comparison with poli-chemotherapy (CT) in women with hormone receptor-positive (HR+), HER2-negative, luminal B breast cancer. In the primary efficacy analysis, both groups showed a similar proportion of pts with PAM50 low-risk risk of recurrence at surgery (46.9% vs 46.1%) (Prat. Lancet Oncol. 2020). Now we present patients (pts)-reported HRQoL results. Methods: In the CORALLEEN study, 106 postmenopausal women with stage I-IIIA HR+/HER2-negative Luminal B breast cancer by PAM50 were randomized 1:1 to receive six 28-days cycles of R+L (n=52) or four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel (n=54). The primary efficacy endpoint was the proportion of patients with PAM50 Risk of Recurrence (ROR) low disease at surgery in each arm. Pts-reported HRQoL was evaluated at baseline (bl), day 1 of each subsequent cycle and before surgery, using i) the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) and ii) the breast cancer-specific EORTC QLQ-BR23 questionnaires. On-treatment comparison of mean change from bl in global health status (GHS), functioning and symptom scales was performed. Longitudinal linear mixed-effect models using a random intercept and random slope were fitted to estimated least squares (LS) mean change. The proportion of patients with clinically meaningful (10-point thereshold) deterioration was estimated in each group. Results: Completion and compliance rates of HRQoL questionaries at bl was 100% for R+L group and 98% for CT group, at week 12 completion rate was 92% and 87% and before surgery 80% in both groups. At bl, EORTC QLQ-C30 GHS scores were similar between R+L and CT groups (median 80.4 and 79.4, respectively). Before surgery, GHS scores presented a slight decrease in the R+L group while it considerably decreased in the CL group (mean change -5.2 vs. -23.6). The between-group difference in mean change from bl was 18.4 points (95% CI 9.8 - 26.9) showing a worsening in patients receiving CT. Overall, at the end of treatment 38% of patients in the R+L and 68% of patients in the CT group reported a clinically meaningful deterioration. R+L group presented better results in the mean change from bl in all functioning and symptom scales, specially in terms of fatigue and appetite loss (28.7 and 24 points difference between groups, respectively) (Table). Conclusions: R+L provided better outcomes in GHS HRQoL, functioning and symptoms in comparison with CT for the treatment of patient with high-risk breast cancer in the pre-operative setting. Together with the similar clinical efficacy and manageable safety profile, these results provide additional support for the development of clinical trials evaluating R+L in this patient population. Estimated mean change from baseline to before surgery (95% CI)Estimated mean change from baseline to before surgery (95% CI)Difference in the mean change in R+L vs. CTR+LCTGlobal health status 1-5.2 (-11.3 ; 0.9)-23.6 (-29.6 ; -17.6)18.4 (9.8 ; 26.9)Functional scales• Physical1-4.3 ( -9.5 ; 0.8)-20.3 (-25.5 ; -15.1)16 (8.7 ; 23.2)• Social1-6.3 (-13 ; 0.4)-19.7 (-26.1 ; -13.4)13.4 (4.2 ; 22.6)• Emotional1-0.7 (-7.4 ; 6.0)-6.8 (-13.3 ; -0.2)6.1 (-3.3 ; 15.4)• Role1-4.8 (-11.8 ; 2.2)-26.7 (-33.7 ; -19.7)21.9 (12 ; 31.8)• Body imagine2-3.2 (-8.9 ; 2.5)-12.9 (-18.5 ; -7.3)9.7 (1.7 ; 17.7)• Sexual enjoymnet2-5.3 (-20.4 ; 9.9)-36.1 (-54.4 ; -17.8)30.8 (7.2 ; 54.5)Symptom scales• Fatigue15.7 (0.7 ; 10.9)35.1 (26.6 ; 43.7)-28.7 (-38.2 ; -19.1)• Pain15.5 (-1.2 ; 12.1)15.5 (9 ; 22.1)-10.1 (-19.4 ; -0.8)• Insomnia14.8 (-2.7 ; 12.4)10.6 (3.2 ; 18.0)-5.8 (-16.2 ; 4.6)• Appetite loss12.5 (-5.8 ; 10.8)26.5 (18.2 ; 34.9)-24 (-35.8 ; -12.3)• Upset by hair loss28.8 (-10.4 ; 27.9)27.7 (8.3 ; 47.2)-18.9 (-45.6 ; 7.7)• Breast symptoms2-2.6 (-6.3 ; 1.2)0.7 (-3.0 ; 4.3)-3.3 (-8.5 ; 1.9)Positive values favour R+L except for symptom scale where negative values favour R+L. Changes from baseline were estimated using a repeated-measures mixed-effect model. CI, confidence interval. 1 EORTC QLQ-C30, 2EORTC QLQ-BR23 questionnaires. Citation Format: Guillermo Villacampa, Laia Paré, Cristina Hernando, Miriam Arumí, Montserrat Muñoz, Miguel Gil-Gil, Yann Izarzugaza, Neus Ferrer, Alvaro Montaño, Eva Ciruelos, Santiago González-Santiago, Claudette Falato, Patricia Villagrasa, Joaquín Gavilá, Aleix Prat, Tomás Pascual. Health-related quality of life (HRQoL) in hormone receptor-positive, HER2-negative, luminal B breast cancer patients treated with ribociclib plus letrozole or chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-04.

QoL analysis: A randomized phase 3 study of sequential versus combination treatment in first-line chemotherapy for metastatic colorectal cancer—The C-cubed study.

102 Background: The C-cubed (C3) study demonstrated a sequential approach start from fluoropyrimidines (FP) plus bevacizumab (Bmab) followed by oxaliplatin (OX) adding significantly improved a median Treatment failure of strategy (TFS) for a combination approach start from FP+OX+Bmab [15.2 months vs. 7.6 months, HR, 0.475; 95% CI, 0.362 to 0.623; p &lt; 0.0001] in first-line metastatic colorectal cancer (mCRC). In this congress, we focus on the quality of life (QOL) assessments as a pre-planned analysis. (Study information: UMIN000015405). Methods: The C3 study was a randomized phase III study which evaluated the time to discontinuation of OX-containing therapy (sequential approach [Capecitabine/5-FU (FP)+Bmab followed by OX-FP+Bmab] vs. combination approach [OX-FP+Bmab]. The primary endpoint was TFS and secondary endpoints were ORR, OS, PFS, Safety and QoL. QOL assessments included European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) (EORTC QLQ C-30), EuroQol 5D 5L (EQ5D) and the Patient Neurotoxicity Questionnaire (PNQ) in both arm as a pre-planned analysis. Each questionnaire was collected at the time of enrolment, 6, 12, 18 months and end of treatment. QOL scores were compared using a mixed-effects models for repeated measures (MMRM). Results: A total 292 patients participated in QoL part (arm A: n =148; arm B: n =144). The returned questionnaire sheets were 292 (reply rate: 97%), 206 (68%), 199 (65%), 61 (20%) at baseline, 6, 12, 18 months, respectively. Sequential approach was statistically improved than combination approach as follows: Physical functioning (p&lt;0.001), Cognitive functioning (p=0.012), Social functioning (p=0.0004), and Fatigue (p=0.013) in EORTC QLQ C-30. In addition, at 6 months (after which attrition in the combination arm was more than 50%) after randomization, the mean change rate from baseline of EQ5D score in the sequential approach versus combination approach were: –1.91 (SD 27.57) versus –9.62 (29.60). In contract, PNQ sensory score showed that sequential approach was not statistically improved for combination approach (0.22 [SD: 0.89] vs. 0.61 [SD: 0.95], p=0.115). Conclusions: The further clarification of patients’ characteristics are needed, but this sequential approach can be advocated as a valuable treatment option in first-line mCRC for current guideline based on these QoLs and main efficacy data.

Early- and subsequent- response of cognitive functioning in Alzheimer's disease: Individual-participant data from five pivotal randomized clinical trials of donepezil

The association between early improvement and subsequent change in cognition is unexamined in antidementia clinical trials. We aimed to examine the consequences of early-response to antidementia medication in Alzheimer's disease. Participant-level data were analyzed from five pivotal clinical trials of donepezil for Alzheimer's disease lasting up to 24 weeks (N = 1917). Early-response was based on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change scores under minus four from baseline to week six, otherwise classified non-response; then subgrouped by donepezil or placebo. The primary analysis tested the group differences in ADAS-Cog change from baseline for the interval after week six up to 24, based on a three-level mixed-effects model repeated measures (MMRM) model. Four models of increasing complexity were tested, and the most parsimonious model was examined in the primary analysis. The remaining models were tested in sensitivity analysis. In the analytic sample, 32.09% (N = 396/1234) of donepezil and 24.01% (N = 164/683) of placebo participants were classified as early responders, and 67.91% donepezil (N = 838/1234), 75.99% (N = 519/683) placebo participants were not. MMRM identified a statistically significant (P < 0.05) responder group effect. Marginal means (MM) demonstrated more improvement for the early responders (donepezil: MM = −4.13, 95% CI = -5.93, −2.32; placebo MM = 1.81, 95% CI = −4.12, 0.50), compared to non-early responders (donepezil MM = 0.05, 95% CI = -1.40, 1.51; placebo MM = 2.59, 95% CI = 0.99, 4.19). Results replicated in sensitivity analysis. Our results inform clinicians regarding the extent and consequences of early improvement in cognitive functioning and potentially contribute to treatment monitoring and the design of clinical trials for Alzheimer's disease.

P468 Evaluation of work productivity and activity impairment in moderate-to-severe ulcerative colitis participants treated with ozanimod in the phase 3 True North study

Abstract Background Ulcerative Colitis (UC) is an autoimmune disease which negatively impacts patients’ quality of life including work performance. This study examined the effect of ozanimod on work productivity and activity impairment (WPAI) in participants with moderate-to-severe UC in the phase 3 True North study. Methods Participants who received 1 mg QD ozanimod during a 10-week Induction Period (IP) and were clinical responders from both placebo-controlled and open-label cohorts were randomised to ozanimod (n=230) or placebo (n=227) for a 42-week Maintenance Period (MP). Work productivity was measured with the WPAI-UC patient-reported outcome instrument that assesses absenteeism, presenteeism, work productivity loss, and activity impairment due to UC over the previous week. The WPAI-UC was administered at Weeks 10, 28, 40, and 52. Differences in WPAI-UC domain scores at the end of the IP were evaluated using t tests. Mixed-effects models for repeated measures (MMRMs) were fit to estimate least-squares mean WPAI-UC scores adjusted for treatment, time (categorical), clinical variables, and corticosteroid use at Week 10. MMRMs were also applied to evaluate differences in WPAI domain scores between groups defined by clinical response, clinical remission, and endoscopy score. Generalised estimating equation (GEE) models were applied to estimate the odds of improving or remaining stable (using a ≥7% change threshold) on WPAI-UC domains for those on ozanimod versus placebo. Missing values were multiply imputed using a placebo-based imputation model; estimates were combined using Rubin’s rules. Results At the end of the IP, the ozanimod group had significantly lower impairment of work productivity and activity (WPA) than the placebo group (Tab 1). During MP, the ozanimod group reported significantly lower levels of impairment for presenteeism (14.0% vs 20.2%; P=.003), work productivity loss (15.9% vs. 22.4%; P=.005), and activity impairment (15.4% vs 22.3%; P=.0001) compared to the placebo group (Tab 2). At Week 52, participants with improved endoscopy score, in clinical remission, or in clinical response had significantly lower impairment in all WPAI-UC domains (Tab 3). Participants in the ozanimod group showed increased odds of improving or remaining stable compared to those in the placebo group for all WPAI-UC domains (Fig 1). Conclusion Participants in the ozanimod arm had significantly better work productivity at the end of induction. Among participants who received ozanimod and achieved response in IP, ozanimod maintenance treatment was associated with improvements in WPA. These improvements were greater among participants who achieved clinical response or remission or improved endoscopic score.

Little evidence for a reduced late positive potential to unpleasant stimuli in major depressive disorder

BackgroundIndividuals with major depressive disorder (MDD) present with deficits in emotional reactivity. Conflicting models have been proposed to explain this effect. We sought to confirm reports of blunted reactivity to negatively-valanced emotional stimuli, in line with the emotional context insensitivity hypothesis of depression, in a preregistered study. MethodsForty-one depressed participants and 41 age- and gender-matched healthy controls were presented a series of unpleasant and neutrally-valanced pictures in a passive view paradigm while acquiring electroencephalography (EEG). The late positive potential (LPP), an EEG correlate of emotional reactivity, was compared between groups using mixed-effects repeated-measures models and exploratory cluster-based permutation tests. A sensitivity analysis was performed to assess the robustness of LPP findings by reanalysing the LPPs using 24 EEG pipelines from studies identified in the literature. ResultsWe found no difference in LPP amplitudes between MDD and healthy individuals using the preregistered analysis pipeline. The sensitivity analysis revealed that the magnitude and direction of LPP effect sizes were affected by the analysis pipeline. Exploratory permutation analysis revealed an electrode cluster that showed a significant reduction in the LPP for MDD participants while viewing unpleasant pictures. ConclusionsThese results do not provide evidence in support of the emotional context insensitivity hypothesis, except for the exploratory data-driven approach. Methodological differences, in particular in the analysis pipeline, contribute to the heterogeneity of LPP modulation in depression. A standardised approach to quantify EEG correlates of emotional reactivity is needed to evaluate alternative models of emotional reactivity in depression.

Real World Adherence to a Severely Energy Restricted Meal Replacement Diet in Participants with Class II and III Obesity

Severely energy-restricted diets (SERDs) are an effective treatment for obesity, however, adherence to such diets is often perceived as poor by healthcare professionals. This investigation evaluated adherence to a 12-week SERD in participants with class II and III obesity. Reported food consumption was compared against individualised SERD prescriptions. Body weight measures were obtained at baseline, 12 and 52 weeks. The data were analysed in three groups (i) the entire cohort (n = 26), (ii) completers (n = 13) and (iii) non-completers (n = 13). SERD prescription elements included (i) the number of meal replacement products; (ii) total protein; (iii) total energy intake; (iv) level of dietary energy restriction; (v) vegetable serves; (vi) water serves, and (vii) how much physical activity was performed. A generalised repeated-measures mixed-effects model was used to investigate if adherence to the program elements individually, or collectively, influenced weight loss. Completers had an average (± SD) of 4549 ± 748 kJ energy intake per day, resulting in a mean energy restriction of 62% compared to the 69% prescribed, indicating a degree of non-adherence. The percent weight changes for completers and non-completers were −7.8 ± 4.7% and −1.6 ± 2.6% at 12 weeks, and −12.2 ± 12.1% and −1.8 ± 3.2% at 52 weeks, respectively. Complete dietary adherence to a SERD may not be necessary to achieve a clinically relevant weight loss of 12% at 52 weeks, if energy is restricted by at least 62% (~4600 kJ per day) relative to requirements.

Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer's disease: A randomized, double-blind, phase 2, proof-of-concept study.

IntroductionThis study explored the efficacy and safety of a serotonin‐6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine.MethodsThe effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty‐seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization. After a 2‐ to 4‐week screening period, the study consisted of a 26‐week double‐blind treatment period, and a 4‐week washout period. The primary efficacy measure was the 11‐item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐Cog 11). Secondary efficacy measures were Clinical Dementia Rating Scale–Sum of Boxes, Mini‐Mental State Examination, 23‐item Alzheimer's Disease Co‐operative Study Activities of Daily Living, and 12‐item Neuropsychiatric Inventory. Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). A total of 564 patients were randomized to receive either daily masupirdine 50 mg (190 patients), masupirdine 100 mg (185 patients), or placebo (189 patients). The study is registered at ClinicalTrials.gov (NCT02580305).ResultsThe MMRM results showed statistically non‐significant treatment differences in change from baseline in ADAS‐Cog 11 scores at week 26, comparing each masupirdine dose arm to the placebo arm. No significant treatment effects were observed in the secondary evaluations.DiscussionMasupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed.Highlights Masupirdine was evaluated in moderate Alzheimer's disease patients.First trial in class with background treatment of donepezil and memantine.Masupirdine was generally safe and well tolerated.Possible reasons for the observed trial results are discussed.

Relationship between baseline clinical characteristics and efficacy of lusutrombopag in thrombocytopenic patients with chronic liver disease: post hoc analysis of two placebo-controlled phase 3 trials

Objective Lusutrombopag is a thrombopoietin receptor agonist approved to treat thrombocytopenia in patients with chronic liver disease (CLD). This post hoc analysis of the Japanese L-PLUS 1 and global L-PLUS 2 trials aimed to clarify factors related to platelet count increase after lusutrombopag treatment. Methods In L-PLUS 1, Pearson’s correlation coefficients were used to evaluate correlations between platelet count and spleen index, thrombopoietin concentration, white blood cell (WBC) counts, and red blood cell counts (intent-to-treat [ITT] population). Associations between platelet count increase after lusutrombopag treatment and each parameter were assessed by regression analysis and mixed-effect model for repeated measures (MMRM). Associations between time-dependent changes in platelet count increase and each parameter were also examined in the L-PLUS 2 lusutrombopag ITT population by MMRM. Results In L-PLUS 1, the baseline platelet count was correlated with pretreatment spleen index (r = −0.23, 95% confidence interval [CI] −0.41 to −0.03) and WBC count (r = 0.26, 95% CI 0.06 to 0.43). No selected parameters were associated with the maximum platelet count increase from baseline. Patients with WBC counts below the normal range showed smaller platelet count increases after lusutrombopag treatment than patients with WBC counts within the normal range (p = .0028). In L-PLUS 2 (p = .0533), findings were similar and confirmed by larger pooled data of L-PLUS 1/L-PLUS 2 (p = .0021). Conclusions This post hoc analysis revealed a possible association between baseline WBC count and platelet count increase after lusutrombopag treatment. WBC count could be a relevant factor for lusutrombopag efficacy.

Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19.

RationaleAlveolar and endothelial injury may be differentially associated with coronavirus disease (COVID-19) severity over time.ObjectivesTo describe alveolar and endothelial injury dynamics and associations with COVID-19 severity, cardiorenovascular injury, and outcomes.MethodsThis single-center observational study enrolled patients with COVID-19 requiring respiratory support at emergency department presentation. More than 40 markers of alveolar (including receptor for advanced glycation endproducts [RAGE]), endothelial (including angiopoietin-2), and cardiorenovascular injury (including renin, kidney injury molecule-1, and troponin-I) were serially compared between invasively and spontaneously ventilated patients using mixed-effects repeated-measures models. Ventilatory ratios were calculated for intubated patients. Associations of biomarkers with modified World Health Organization scale at Day 28 were determined with multivariable proportional-odds regression.Measurements and Main ResultsOf 225 patients, 74 (33%) received invasive ventilation at Day 0. RAGE was 1.80-fold higher in invasive ventilation patients at Day 0 (95% confidence interval [CI], 1.50–2.17) versus spontaneous ventilation, but decreased over time in all patients. Changes in alveolar markers did not correlate with changes in endothelial, cardiac, or renal injury markers. In contrast, endothelial markers were similar to lower at Day 0 for invasive ventilation versus spontaneous ventilation, but then increased over time only among intubated patients. In intubated patients, angiopoietin-2 was similar (fold difference, 1.02; 95% CI, 0.89–1.17) to nonintubated patients at Day 0 but 1.80-fold higher (95% CI, 1.56–2.06) at Day 3; cardiorenovascular injury markers showed similar patterns. Endothelial markers were not consistently associated with ventilatory ratios. Endothelial markers were more often significantly associated with 28-day outcomes than alveolar markers.ConclusionsAlveolar injury markers increase early. Endothelial injury markers increase later and are associated with cardiorenovascular injury and 28-day outcome. Alveolar and endothelial injury likely contribute at different times to disease progression in severe COVID-19.

Bone mineral density, kidney function and participant-reported outcome measures in women who switch from tenofovir disoproxil emtricitabine and a nonnucleoside reverse transcriptase inhibitor to abacavir, lamivudine and dolutegravir.

Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). We conducted a randomized controlled trial in which women aged ≥40years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy. Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively]. Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.

Mobile Text Messaging for Tobacco Risk Communication Among Young Adult Community College Students: Randomized Trial of Project Debunk.

BackgroundThe use of new and emerging tobacco products (NETPs) and conventional tobacco products (CTPs) has been linked to several alarming medical conditions among young adults (YAs). Considering that 96% of YAs own mobile phones, SMS text messaging may be an effective strategy for tobacco risk communication.ObjectiveProject Debunk is a community-based randomized trial aiming to identify specific types of messages that effectively improve perceived NETP and CTP risk among YAs in community colleges.MethodsWith YAs recruited offline from 3 campuses at the Houston Community College (September 2016 to July 2017), we conducted a 6-month randomized trial with 8 arms based on the combination of 3 message categories: framing (gain-framed vs loss-framed), depth (simple vs complex), and appeal (emotional vs rational). Participants received fully automated web-based SMS text messages in two 30-day campaigns (2 messages per day). We conducted repeated-measures mixed-effect models stratified by message type received, predicting perceived CTP and NETP risks. Owing to multiple testing with 7 models, an association was deemed significant for P<.007 (.05 divided by 7).ResultsA total of 636 participants completed the baseline survey, were randomized to 1 of 8 conditions (between 73 and 86 participants per condition), and received messages from both campaigns. By the 2-month post campaign 2 assessment point, 70.1% (446/636) completed all outcome measures. By the end of both campaigns, participants had a significant increase in perceived NETP risk over time (P<.001); however, participants had a marginal increase in perceived CTP risk (P=.008). Separately for each group, there was a significant increase in perceived NETP risk among participants who received rational messages (P=.005), those who received emotional messages (P=.006), those who received simple messages (P=.003), and those who received gain-framed messages (P=.003).ConclusionsIn this trial, YAs had an increase in perceived NETP risk. However, with stratification, we observed a significant increase in perceived NETP risk upon exposure to rational, emotional, simple, and gain-framed messages. In addition, YAs generally had an increase in perceived CTP risk and presented nonsignificant but observable improvement upon exposure to emotional, complex, and loss-framed messages. With the results of this study, researchers and practitioners implementing mobile health programs may take advantage of our tailored messages through larger technology-based programs such as smartphone apps and social media campaigns.Trial RegistrationClinicalTrials.gov NCT03457480; https://clinicaltrials.gov/ct2/show/NCT03457480International Registered Report Identifier (IRRID)RR2-10.2196/10977

Microdermabrasion facilitates direct current stimulation by lowering skin resistance.

BackgroundTranscranial direct current stimulation (tDCS) is reported to induce irritating skin sensations and occasional skin injuries, which limits the applied tDCS dose. Additionally, tDCS hardware safety profile prevents high current delivery when skin resistance is high.ObjectiveTo test if decreasing skin resistance can enable high‐dose tDCS delivery without increasing tDCS‐related skin sensations or device hardware limits.MethodsWe compared the effect of microdermabrasion and sonication on 2 mA direct current stimulation (DCS) through forearm skin for 2–3 min on 20 subjects. We also surveyed the subjects using a questionnaire throughout the procedure. We used a linear mixed‐effects model for repeated‐measures and multiple logistic regression, with adjustments for age, race, gender and visit.ResultsMicrodermabrasion, with/out sonication, led to significant decrease in skin resistance (1.6 ± 0.1 kΩ or ∼32% decrease, p < 0.0001). The decrease with sonication alone (0.4 ± 0.1 kΩ or ∼7% decrease, p = 0.0016) was comparable to that of sham (0.3 ± 0.1 kΩ or ∼5% decrease, p = 0.0414). There was no increase in the skin–electrode interface temperature. The perceived DCS‐related sensations did not differ across skin preparation procedures (p > 0.16), but microdermabrasion (when not combined with sonication) led to increased perceived sensation (p < 0.01).ConclusionsMicrodermabrasion (with/out sonication) resulted in reduced skin resistance without increase in perceived skin sensations with DCS. Higher current can be delivered with microdermabrasion‐pre‐treated skin without changing the device hardware while reducing, otherwise higher voltage required to deliver the same amount of current.

An intervention to improve teacher well-being support and training to support students in UK high schools (the WISE study): A cluster randomised controlled trial.

Teachers are at heightened risk of poor mental health and well-being, which is likely to impact on the support they provide to students, and student outcomes. We conducted a cluster randomised controlled trial, to test whether an intervention to improve mental health support and training for high school teachers led to improved mental health and well-being for teachers and students, compared to usual practice. We also conducted a cost evaluation of the intervention. The intervention comprised (i) Mental Health First Aid training for teachers to support students; (ii) a mental health awareness session; and (iii) a confidential staff peer support service. In total 25 mainstream, non-fee-paying secondary schools stratified by geographical area and free school meal entitlement were randomly allocated to intervention (n = 12) or control group (n = 13) after collection of baseline measures. We analysed data using mixed-effects repeated measures models in the intention-to-treat population, adjusted for stratification variables, sex, and years of experience. The primary outcome was teacher well-being (Warwick-Edinburgh Mental Well-being Scale). Secondary outcomes were teacher depression, absence, and presenteeism, and student well-being, mental health difficulties, attendance, and attainment. Follow-up was at months 12 (T1) and 24 (T2). We collected process data to test the logic model underpinning the intervention, to aid interpretation of the findings. A total of 1,722 teachers were included in the primary analysis. Teacher well-being did not differ between groups at T2 (intervention mean well-being score 47.5, control group mean well-being score 48.4, adjusted mean difference -0.90, 95% CI -2.07 to 0.27, p = 0.130). The only effect on secondary outcomes was higher teacher-reported absence among the intervention group at T2 (intervention group median number of days absent 0, control group median number of days absent 0, ratio of geometric means 1.04, 95% CI 1.00 to 1.09, p = 0.042). Process measures indicated little change in perceived mental health support, quality of relationships, and work-related stress. The average cost of the intervention was £9,103 per school. The study's main limitations were a lack of blinding of research participants and the self-report nature of the outcome measures. In this study, we observed no improvements to teacher or student mental health following the intervention, possibly due to a lack of impact on key drivers of poor mental health within the school environment. Future research should focus on structural and cultural changes to the school environment, which may be more effective at improving teacher and student mental health and well-being. www.isrctn.com ISRCTN95909211.

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial