Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Defining estimands for efficacy assessment in single arm phase 1b or phase 2 clinical trials in oncology early development.

The addendum of the ICH E9 guideline on the statistical principles for clinical trials introduced the estimand framework. The framework is designed to strengthen the dialog between different stakeholders, to introduce greater clarity in the clinical trial objectives and to provide alignment between the estimand and statistical analysis. Estimand framework related publications thus far have mainly focused on randomized clinical trials. The intention of the Early Development Estimand Nexus (EDEN), a task force of the cross-industry Oncology Estimand Working Group (www.oncoestimand.org), is to apply it to single arms Phase 1b or Phase 2 trials designed to detect a treatment-related efficacy signal, typically measured by objective response rate. Key recommendations regarding the estimand attributes include that in a single arm early clinical trial, the treatment attribute should start when the first dose is received by the participant. Focusing on the estimation of an absolute effect, the population-level summary measure should reflect only the property used for the estimation. Another major component introduced in the ICH E9 addendum is the definition of intercurrent events and the associated possible ways to handle them. Different strategies reflect different clinical questions of interest that can be answered based on the journeys an individual subject can take during a trial. We provide detailed strategy recommendations for intercurrent events typically seen in early-stage oncology. We highlight where implicit assumptions should be made transparent as whenever follow-up is suspended, a while-on-treatment strategy is implied.

Why estimands are needed to define treatment effects in clinical trials.

BACKGROUND: The estimand for a clinical trial is a precise definition of the treatment effect to be estimated. Traditionally, estimates of treatment effects are based on either an ITT analysis or a per-protocol analysis. However, there are important clinical questions which are not addressed by either of these analyses. For example, consider a trial where patients take a rescue medication. The ITT analysis includes data after use of rescue, while the per-protocol analysis excludes these patients altogether. Neither of these analyses addresses the important question of what the treatment effect would have been if patients did not take rescue medication. MAIN TEXT: Trial estimands provide a broader perspective compared to the limitations of ITT and per-protocol analysis. Trial treatment effects depend on how events occurring after treatment initiation such as use of alternative medication or discontinuation of the intervention are included in the definition. These events can be accounted for in different ways, depending on the clinical question of interest. CONCLUSION: The estimand framework is an important step forward in improving the clarity and transparency of clinical trials. The centrality of estimands to clinical trials is currently not reflected in methods recommended by the Cochrane group or the CONSORT statement, the current standard for reporting clinical trials in medical journals. We encourage revisions to these guidelines.

Association of Baseline and Pharmacodynamic Biomarkers With Outcomes in Patients Treated With the PD-1 Inhibitor Budigalimab.

Budigalimab, a novel anti-PD-1 monoclonal antibody, demonstrated efficacy and biomarker pharmacodynamics in patients with head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC) consistent with those reported by other PD-1 inhibitors. Herein are presented additional outcomes of biomarker analyses from the phase 1 study of budigalimab monotherapy in patients with HNSCC and NSCLC (NCT03000257). PD-1 inhibitor naive patients with advanced HNSCC (n=41) or NSCLC (n=40) received budigalimab intravenously at 250 mg every 2 weeks (Q2W) or 500 mg Q4W until progression. Archival tumor specimens were evaluated by immunohistochemistry for CD8 and tumor PD-1 ligand 1 (PD-L1) expression, RNA, and whole-exome sequencing. Serum and whole blood samples were acquired at baseline and at select on-treatment time points. As of October 2019, best overall response of 15% in HNSCC and 18% in NSCLC was observed in all treated patients; both cohorts reported responses in PD-L1+ and PD-L1- tumors. Treatment with budigalimab was associated with increases in multiple soluble biomarkers including interferon gamma-induced chemokines. Expanded overall T-cell counts, total CD8 T-cell counts, and percentages of CD8+CD45RA-CD62L- effector memory T cells were observed at cycle 1, day 15 in responders. Univariate analysis demonstrated an association between prolonged progression-free survival and higher tumor mutational burden/neoantigen load, smaller tumor size, lower platelet-lymphocyte ratios, lower CCL23, lower colony-stimulating factor 1, and lower interleukin-6 levels at baseline. The biomarker analysis presented herein identified additional early pharmacodynamic biomarkers associated with anti-PD-1 activity and improved clinical responses to budigalimab in patients with advanced HNSCC and NSCLC.

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

BACKGROUND: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016). PATIENTS AND METHODS: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments. RESULTS: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts. CONCLUSIONS: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.

Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer.

BACKGROUND: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC. MATERIALS AND METHODS: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle. RESULTS: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months. CONCLUSION: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing. CLINICAL TRIAL REGISTRATION NUMBER: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.

Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181).

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD-1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body-weight-based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune-related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD-1 targeting agents. No treatment-related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD-1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure-safety analyses did not indicate any trends. Observed PK and PD-1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.

Mismatch of Subjective and Objective Risk of Falling in Patients with Dementia.

BACKGROUND: Match or mismatch of objective physiological and subjectively perceived fall risk may have serious consequences in patients with dementia (PwD) while research is lacking. OBJECTIVE: To analyze mismatch of objective and subjective fall risk and associated factors in PwD. METHOD: Cohort study in a geriatric rehabilitation center. Objective and subjective risk of falling were operationalized by Tinetti's Performance Oriented Mobility Assessment and the Falls Efficacy Scale-International. Four sub-groups according to objective and subjective fall risk were classified. Subgroups were compared for differences in clinical, cognitive, psychological, and behavioral variables. RESULTS: In geriatric rehab patients with mild to moderate dementia (n = 173), two-thirds showed a mismatch of subjective versus objective risk of falling, independently associated with previous falls. Underestimation of objective fall risk (37.6%) was determined by lower activity avoidance (OR 0.39), less concerns about falling due to previous falls (OR 0.25), and higher quality of life (OR 1.10), while overestimation (28.9%) was determined by higher rate of support seeking strategies (OR 50.3), activity avoidance (OR 15.2), better executive (OR 21.0) and memory functions (OR 21.5), and lower quality of life (OR.75) in multivariate logistic regression. CONCLUSION: The majority of patients showed a mismatch between objective and subjective falls risk. Underestimation as well as overestimation of fall risk was associated with specific profiles based on cognitive- and psychological status, falls and fall-related behavioral consequences which should be included in the comprehensive assessment of fall risk, and planning of individualized fall prevention programs for this population.

Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19 Pandemic.

Abstract-The COVID-19 pandemic has had and continues to have major impacts on planned and ongoing clinical trials. Its effects on trial data create multiple potential statistical issues. The scale of impact is unprecedented, but when viewed individually, many of the issues are well defined and feasible to address. A number of strategies and recommendations are put forward to assess and address issues related to estimands, missing data, validity and modifications of statistical analysis methods, need for additional analyses, ability to meet objectives and overall trial interpretability.

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials-Application of the Estimand Framework.

Abstract-Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

Disseminated Tumor Cells in the Bone Marrow of Patients with Operable Primary Breast Cancer: Prognostic Impact in Immunophenotypic Subgroups and Clinical Implication for Bisphosphonate Treatment.

BACKGROUND: Disseminated tumor cells (DTC) in the bone marrow (BM) of primary breast cancer (BC) patients are a promising surrogate marker of micrometastatic spread and an independent predictor of poor prognosis for disease-free survival (DFS) and overall survival (OS). The present study aims to analyze DTCs as an independent prognostic factor for DFS/OS in tumor biology and bisphosphonate treatment. METHODS: A total of 504 patients with operable primary BC and a median observation time of 72.3 months [lower quartile (LQ) 58.1; upper quartile (UQ) 82.8] have been included. DTCs were detected via immunohistochemistry as MUC-1 positive cells in the BM of 59.13 % (298 of 504) of the patients. The immunophenotyping of cancer cells was achieved immunohistochemically as well. RESULTS: For luminal A/B carcinoma patients, we observed a significant benefit of BM DTC negativity with respect to DFS (luminal A, P = 0.0498; luminal B, P = 0.0224). In triple-negative patients, DTC-negative BM was associated with a longer OS (P = 0.0326). In a multivariate Cox survival analysis relating to DFS and OS, the DTC status was identified as an independent prognostic factor for DFS in luminal A/B BC (P = 0.0071). A multivariate Cox survival analysis among DTC-positive patients with luminal immunophenotype showed bisphosphonate application (P = 0.0326) to be an independent prognostic factor for DFS. CONCLUSIONS: The findings of our multivariate analyses reveal BM DTC positivity as an independent risk factor for DFS particularly in luminal A/B BC patients. This might be a novel criterion for the identification of candidates most likely to benefit from additional adjuvant therapy possibly including bisphosphonates.

Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease.

BACKGROUND & AIMS: It is well known that inflammation increases liver stiffness (LS) in patients with chronic hepatitis C (HCV) and alcoholic liver disease (ALD) independent of fibrosis stage, but no inflammation-adapted cut-off values have been settled so far. An early identification of rapid fibrosers, however, is essential to decide whom to treat first with the novel but expensive antiviral drugs. METHODS: Liver stiffness, biopsy-proven fibrosis stages F0-F4 (METAVIR or Kleiner score) and routine laboratory parameters were studied in 2068 patients with HCV (n = 1391) and ALD (n = 677). RESULTS: Among the routine parameters for liver damage, AST correlated best with LS (HCV: r = 0.54, P < 0.0001 and ALD: r = 0.34, P < 0.0001). In the absence of elevated transaminases, cut-off values were almost identical between HCV and ALD for F1-2, F3 and F4 (HCV: 5.1, 9.0 and 11.9 kPa vs ALD: 4.9, 8.1 and 10.5 kPa). These cut-off values increased exponentially as a function of median AST level. The impact of AST on LS was higher in lobular-pronounced ALD as compared to portal tract-localized HCV. Most notably, Cohen's weighted Kappa displayed an improved agreement of the novel AST-dependent cut-off values with histological fibrosis stage both for HCV (0.68 vs 0.65) and ALD (0.80 vs 0.76). CONCLUSIONS: The novel AST-adapted cut-off values improve non-invasive fibrosis staging in HCV and ALD and may be also applied to other liver diseases. Especially in HCV, they could help to decide whom to treat first with the novel but expensive antiviral drugs.

Methods for proper handling of overrunning and underrunning in phase II designs for oncology trials.

Phase II studies in oncology are frequently conducted as two-stage single-arm trials with a binary endpoint indicating tumor response. As a common feature of these designs, the sample sizes of the two stages and the decision rules for the interim and the final analysis have to be pre-specified and adhered to strictly during the course of the trial in order to assure control of the type I error rate. In practice, however, the attained sample sizes often deviate from the planned ones leading to the situation of overrunning or underrunning. The currently available approaches to deal with this problem are either based on assumptions that are rarely met in practice or do not guarantee that the significance level is kept. However, strict control of the type I error rate plays an important role also for single-arm cancer trials, as they are frequently a fundamental part of the registration information. We propose a general methodology that allows handling both unintentional and intentional overrunning and underrunning while strictly controlling the type I error rate. Application of the proposed procedure and some of its characteristics are illustrated with a real phase II oncology trial.

Performance of adaptive designs for single-armed phase II oncology trials.

When planning a single-armed clinical trial with binary endpoint, the sample size is determined such that the desired power is achieved for a single value of the target rate. However, there is usually some uncertainty with respect to the true treatment effect. It is therefore more realistic to specify an interval for the possible true rate to accommodate this uncertainty. For this situation, we examine comprehensively the overall performance of various Phase II oncology designs and sample size recalculation strategies. The methods and results of our investigations can be used to identify the most appropriate approach for a specific clinical trial situation at hand. Application is illustrated with a clinical trial in rectal cancer.

Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study.

BACKGROUND: Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups. METHODS: 55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months. RESULTS: HbA1c at baseline was, 7.3+/-0.7% in the oral group, 7.3+/-0.9% and 7.5+/-0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/-0.8%, 6.6+/-0.7% and 6.7+/-0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/-6.4 and 29.4+/- 6.7 units respectively) compared to the group on oral medication (23.2+/-6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/-0.14) at baseline to 0.76mm (+/-0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74). CONCLUSION: The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus. TRIAL REGISTRATION: (Clinical Trials Identifier: NCT00523393).

Sensor-derived physical activity parameters can predict future falls in people with dementia.

BACKGROUND: There is a need for simple clinical tools that can objectively assess the fall risk in people with dementia. Wearable sensors seem to have the potential for fall prediction; however, there has been limited work performed in this important area. OBJECTIVE: To explore the validity of sensor-derived physical activity (PA) parameters for predicting future falls in people with dementia. To compare sensor-based fall risk assessment with conventional fall risk measures. METHODS: This was a cohort study of people with confirmed dementia discharged from a geriatric rehabilitation ward. PA was quantified using 24-hour motion-sensor monitoring at the beginning of the study. PA parameters (percentage of walking, standing, sitting, and lying; duration of single walking, standing, and sitting bouts) were extracted using specific algorithms. Conventional assessment included performance-based tests (Timed Up and Go Test, Performance-Oriented Mobility Assessment, 5-chair stand) and questionnaires (cognition, ADL status, fear of falling, depression, previous faller). Outcome measures were fallers (at least one fall in the 3-month follow-up period) versus non-fallers. RESULTS: 77 people were included in the study (age 81.8 ± 6.3; community-dwelling 88%, institutionalized 12%). Surprisingly, fallers and non-fallers did not differ on any conventional assessment (p = 0.069-0.991), except for 'previous faller' (p = 0.006). Interestingly, several PA parameters discriminated between the groups. The 'walking bout average duration', 'longest walking bout duration' and 'walking bout duration variability' were lower in fallers, compared to non-fallers (p = 0.008-0.027). The 'standing bout average duration' was higher in fallers (p = 0.050). Two variables, 'walking bout average duration' [odds ratio (OR) 0.79, p = 0.012] and 'previous faller' (OR 4.44, p = 0.007) were identified as independent predictors for falls. The OR for a 'walking bout average duration' <15 s for predicting fallers was 6.30 (p = 0.020). Combining 'walking bout average duration' and 'previous faller' improved fall prediction (OR 7.71, p < 0.001, sensitivity/specificity 72%/76%). DISCUSSION: RESULTS demonstrate that sensor-derived PA parameters are independent predictors of the fall risk and may have higher diagnostic accuracy in persons with dementia compared to conventional fall risk measures. Our findings highlight the potential of telemonitoring technology for estimating the fall risk. RESULTS should be confirmed in a larger study and by measuring PA over a longer period of time.

Improvements in gait characteristics after intensive resistance and functional training in people with dementia: a randomised controlled trial.

BACKGROUND: Preventing and rehabilitating gait disorders in people with dementia during early disease stage is of high importance for staying independent and ambulating safely. However, the evidence gathered in randomized controlled trials (RCTs) on the effectiveness of exercise training for improving spatio-temporal gait parameters in people with dementia is scarce. The aim of the present study was to determine whether a specific, standardized training regimen can improve gait characteristics in people with dementia. METHODS: Sixty-one individuals (mean age: 81.9 years) with confirmed mild to moderate stage dementia took part in a 3-month double-blinded outpatient RCT. Subjects in the intervention group (IG) received supervised, progressive resistance and functional group training for 3 months (2 times per week for two hours) specifically developed for people with dementia. Subjects in the control group (CG) conducted a low-intensity motor placebo activity program. Gait characteristics were measured before and after the intervention period using a computerized gait analysis system (GAITRite®). RESULTS: Adherence to the intervention was excellent, averaging 91.9% in the IG and 94.4% in the CG. The exercise training significantly improved gait speed (P < 0.001), cadence (P = 0.002), stride length (P = 0.008), stride time (P = 0.001), and double support (P = 0.001) in the IG compared to the CG. Effect sizes were large for all gait parameters that improved significantly (Cohen's d: 0.80-1.27). No improvements were found for step width (P = 0.999), step time variability (P = 0.425) and Walk-Ratio (P = 0.554). Interestingly, low baseline motor status, but not cognitive status, predicted positive training response (relative change in gait speed from baseline). CONCLUSION: The intensive, dementia-adjusted training was feasible and improved clinically meaningful gait variables in people with dementia. The exercise program may represent a model for preventing and rehabilitating gait deficits in the target group. Further research is required for improving specific gait characteristics such as gait variability in people with dementia. TRIAL REGISTRATION: ISRCTN49243245.

An intensive exercise program improves motor performances in patients with dementia: translational model of geriatric rehabilitation.

BACKGROUND: Translation of intensive exercise programs developed specifically for patients with dementia into clinical settings is lacking. OBJECTIVE: To determine if a progressive resistance and functional training program, previously evaluated in dementia outpatients, can be implemented in a geriatric inpatient setting in order to improve motor performances in patients with dementia. METHODS: Eligible patients in one ward of a German geriatric hospital were assigned to the intervention group (IG, n = 74) and received intensive exercise training specifically designed for patients with dementia. Patients in the second ward were observed as a control group (CG, n = 74). All patients received usual care treatment. Primary endpoints were maximal lower extremity strength measured by a leg-press device and duration of the 5-chair-stand test for functional performance. Secondary outcomes included a number of parameters for strength and function. RESULTS: The rehabilitation period averaged 18.1 ± 6.8 days. The IG significantly improved in both primary endpoints (change: maximal strength, IG: +51.9 ± 42.3% versus CG: +13.5 ± 51.8%, p < 0.001; functional performance, IG: -19.2 ± 22.3% versus CG: -3.8 ± 32.2% s, p = 0.037). Secondary outcomes confirmed effects for strength and some, but not all, functional parameters. Interestingly, low baseline motor status, but not cognitive status, predicted positive training response. CONCLUSION: An intensive exercise program can be implemented in a geriatric rehabilitation setting to improve motor performances in patients with dementia. Results suggest that an intensification of training is feasible in the target group and substantially increases the benefits in comparison to receiving usual care exercise only.

Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases.

BACKGROUND: Post-stroke immune depression contributes to the development of infections which are major complications after stroke. Previous experimental and clinical studies suggested that humoral stress mediators induce immune dysfunction. However, prospective clinical studies testing this concept are missing and no data exists for other cerebrovascular diseases including intracerebral hemorrhage (ICH) and TIA. METHODS: We performed a prospective clinical study investigating 166 patients with TIA, ischemic and hemorrhagic stroke. We measured a broad panel of stress mediators, leukocyte subpopulations, cytokines and infection markers from hospital admission to day 7 and on follow-up after 2-3 months. Multivariate regression analyses detected independent predictors of immune dysfunction and bacterial infections. ROC curves were used to test the diagnostic value of these parameters. RESULTS: Only severe ischemic strokes and ICH increased some catecholamine metabolites, ACTH and cortisol levels. Immunodysfunction was eminent already on hospital admission after large brain lesions with lymphocytopenia as a key feature. None of the stress mediators was an independent predictor of lymphocytopenia or infections. However, lymphocytopenia on hospital admission was detected as an independent explanatory variable of later infections. NIHSSS and lymphocytopenia on admission were excellent predictors of infection. CONCLUSIONS: Our results question the present pathophysiological concept of stress-hormone mediated immunodysfunction after stroke. Early lymphocytopenia was identified as an early independent predictor of post-stroke infections. Absence of lymphocytopenia may serve as a negative predictive marker for stratification for early antibiotic treatment.