title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
3.4. Domain scores of the RQLQ | fever | DLE | After 11 weeks of DLE treatment, the mean daily activity score improved from 3.62 ± 1.3 to 2.09 ± 1.25, The mean sleep symptom score improved from 3.1 ± 1.51 to 1.52 ± 1.33, Clinical improvement was seen in non-hay fever symptoms, and the mean score improved from 2.77 ± 1.67 to 1.6 ± 1.25, Practical problems mean score improved from 4.43 ± 1.46 to 2.23 ± 1.4, The mean nasal symptom score improved from 4.1 ± 1.5 to 2.08 ± 1.24, The mean score for ocular symptoms improved from 3.2 ± 1.66 to 1.6 ± 1.32, Emotional symptoms improved from 3.48 ± 1.52 to 1.59 ± 1.11, The scores for each domain before and after 11 weeks of adjuvant DLE are shown in Figure Individual scores per domain in the RQLQ(S) questionnaire. (A, C, E, G, I, K, M) Scores per group of items in the RQLQ(S) before and after adding DLE for 11 weeks, depicting the mean and standard deviation. A 2-tailed paired | PMC10328667 |
3.5. Individual RQLQ Items | DLE, RHINOCONJUNCTIVITIS | Each individual item in the RQLQ questionnaire showed clinical (MID ≥ 0.5) and statistical improvements with the use of DLE (Fig. RQLQ score per item on the questionnaire before and after 11 weeks of DLE.Probability CI = confidence interval, DLE = dialyzable leukocyte extract, RQLQ = Standardized version (Spanish-Mexico) of the Rhinoconjunctivitis Quality of Life Questionnaire. | PMC10328667 | |
3.6. Adverse events | headache | DLE, ADVERSE EVENT | None of the patients presented with serious AE. Four patients presented with non-serious AE, 1 patient presented with headache related to the first 2 doses of DLE, and 3 patients showed overall worsened AR symptoms. Table Adverse events during the study period. | PMC10328667 |
4. Discussion | DLE, fever, fatigue, rash, pruritus, nasal congestion, allergic disease, nose symptoms | DLE, RARE HEADACHE, DISEASE | AR is the most common allergic disease, and treatment options for this persistent disease are limited; therefore, there is a continuous search for new and safe treatment options.Owing to its mechanism of action that diminishes the Th2-inflammatory response,The total RQLQ scores in our study showed clinically significant improvements, surpassing the minimal required 0.5-point change in score, aside from showing statistical significance after 11 weeks of DLE treatment. The QoL improvement observed in this study was well above the required MID and exceeded that of other immunomodulators, such as specific immunotherapy and probiotics. A real-world clinical study of sublingual and subcutaneous immunotherapy that used RQLQ as a primary endpoint reported MID after 6 months of subcutaneous immunotherapy.As each patient was compared with her/himself, the type of standard treatment was irrelevant even if it remained unchanged. Despite the differences in the number of AR medications taken, we found no difference in QoL improvement between patients taking one, two, three, or four different AR medications. According to the guidelines, patients with persistent symptoms of AR require one or two medications (nasal steroids with or without oral antihistamines), not including immunotherapy. A third medication (leukotriene antagonist) may benefit pediatric patients with AR, and some may occasionally use local vasoconstrictors.All 7 domains (daily activity limitation, sleep problems, nose symptoms, eye symptoms, non-hay fever symptoms, practical problems, and emotional function) in the RQLQ questionnaire showed statistical and clinical improvements during DLE treatment. Each of the 28 individual items in the questionnaire also showed statistical and clinical improvement. Bousquet et alThe main symptoms of AR are sneezing, nasal congestion, pruritus, and nasal secretion.Despite the DLE dose reduction in each phase, we observed a significant improvement in the RQLQ scores over time, suggesting that DLE dosing once a week may be adequate for most patients. However, we cannot exclude the possibility that a higher initial dose is beneficial. Additional studies comparing the efficacies of different doses are required to resolve this issue.The most common AE associated with the use of DLE are headache, increased disease symptoms, rash, and fatigue, which are present in less than 2% of DLE users.The limitations of this study include the small number of subjects, lack of a control group, and the fact that only QoL was evaluated. Due to the sample size and lack of a control group, no definite conclusions can be made regarding efficacy of DLE until larger, controlled, multicenter studies involving different populations are done. Nonetheless, this study provides encouraging results in favor of continuing the study of DLE as a possible treatment option for AR. QoL is one of the many tools available for assessing patients with AR. | PMC10328667 |
5. Conclusions | DLE | DLE | DLE may be beneficial as adjuvant treatment for AR. Our results provide preliminary data for future research. Interestingly, the patients showed additional improvement with increased treatment time, and dose reduction did not have a worsening effect. | PMC10328667 |
Acknowledgments | The authors wish to thank Elizabeth Juniper and her team for allowing us to use the RQLQ questionnaire. | PMC10328667 | ||
Supplementary Material | PMC10328667 | |||
Abbreviations: | ICH | ALLERGIC RHINITIS | adverse eventsallergic rhinitisconfidence intervaldialyzable leukocyte extractminimal important differencequality of lifeRhinoconjunctivitis Quality of Life QuestionnaireThis work was supported by the Instituto Politécnico Nacional, a public university and producer of the Dialyzable Leukocyte Extract used in this study. Their role was to supply medication without any role in the study design, protocol preparation, data collection, data analysis, interpretation of data, manuscript preparation, or the decision to submit the manuscript for publication.This research was designed, approved, and conducted ethically in accordance with the World Medical Association Declaration of Helsinki and the principles of Good Clinical Practice by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Written informed consent was obtained from all the trial participants before all trial-related procedures were initiated. The study protocol was approved by an independent Ethics Committee (IC 13-001).SMP-T was involved in the development of Transferon OralAll data generated or analyzed during this study are included in this published article [and its supplementary information files].Supplemental Digital Content is available for this article.How to cite this article: Homberg TA, Lara I, Andaluz C, Cervantes-Trujano E, Hernández-Martínez PM, Pérez-Tapia SM, Jiménez-Martínez MC. Quality of life in adult patients using dialyzable leukocyte extract for allergic rhinitis. Medicine 2023;102:27(e34186). | PMC10328667 |
References | PMC10328667 | |||
Abstract | PMC10638544 | |||
Methods | intermittent claudication, claudication | INTERMITTENT CLAUDICATION | This was an open, multicentre, randomized controlled trial. Patients with intermittent claudication attending vascular surgery outpatient clinics were randomized (1:1) to receive either neuromuscular electrical stimulation (NMES) or not in addition to local standard care available at study centres (best medical therapy alone or plus supervised exercise therapy (SET)). The objective of this trial was to investigate the clinical efficacy of an NMES device in addition to local standard care in improving walking distances in patients with claudication. The primary outcome was change in absolute walking distance, measured by a standardized treadmill test at 3 months. Secondary outcomes included intermittent claudication (IC) distance, adherence, quality of life, and haemodynamic changes. | PMC10638544 |
Results | REGRESSION | Of 200 participants randomized, 160 were included in the primary analysis (intention to treat, Tobit regression model). The square root of absolute walking distance was analysed (due to a right-skewed distribution) and, although adjunctive NMES improved it at 3 months, no statistically significant effect was observed. SET as local standard care seemed to improve distance compared to best medical therapy at 3 months (3.29 units; 95 per cent c.i., 1.77 to 4.82; | PMC10638544 | |
Conclusion | INTERMITTENT CLAUDICATION | Supervised exercise therapy is effective and NMES may provide further benefit in mild IC.This trial was supported by a grant from the Efficacy and Mechanism Evaluation Program, a Medical Research Council and National Institute for Health and Care Research partnership. Trial registration: ISRCTN18242823.Supervised exercise therapy is an effective treatment for patients with intermittent claudication. Neuromuscular electrical stimulation as an adjunct to local standard care may benefit patients with mild intermittent claudication. | PMC10638544 | |
Introduction | limbIntermittent claudication, atherosclerotic arterial stenosis, resultant reduction, PAD | PAD, PERIPHERAL ARTERIAL DISEASE | Peripheral arterial disease (PAD) is a common condition caused predominantly by atherosclerotic arterial stenosis or occlusion, with resultant reduction in blood flow to the affected limbIntermittent claudication (IC) is the commonest symptom of PAD, affecting 5–10 per cent of people over 50 years of ageThe UK National Institute for Health and Care Excellence (NICE)Neuromuscular electrical stimulation (NMES) devices are an emerging technology that may benefit patients with IC by increasing the distance walked before symptomatic limitation and thus improving QoLTechnological advances have allowed the development of portable, inexpensive and safe NMES units suitable for domiciliary use | PMC10638544 |
Methods | PMC10638544 | |||
Design | The trial design has been published previously | PMC10638544 | ||
Participants | Claudication | CLAUDICATION, CRITICAL LIMB ISCHAEMIA | Patients with IC attending vascular surgery outpatient clinics were screened. Patients aged 18 years or older were eligible if they had a positive Edinburgh Claudication Questionnaire, and an ankle–brachial pressure index (ABPI) of <0.9 or positive stress test (fall in ankle pressure greater than 30 mmHg, 40 seconds post 1-minute treadmill at 10 per cent gradient, 4 km/h). Exclusion criteria included pregnancy, inability to complete the treadmill test or SET, severe IC requiring surgery, critical limb ischaemia as defined by the European Consensus Document | PMC10638544 |
Randomization | RECRUITMENT | Participants were randomly allocated 1:1, using random block sizes and stratified by recruitment site. Those sites with SET ( | PMC10638544 | |
Interventions | PMC10638544 | |||
Best medical therapy | hypertension | DIABETES MELLITUS, HYPERTENSION | All participants received BMT including exercise advice, smoking cessation, statin, antiplatelet and management of hypertension and diabetes mellitus, according to local standard care. | PMC10638544 |
Supervised exercise therapy | Participants at SET centres were enrolled into the local SET programme; the number of weekly sessions and duration varied between centres ( | PMC10638544 | ||
Neuromuscular electrical stimulation | diabetic | Participants randomly assigned to the NMES group were given the RevitiveThe device was to be used for at least one 30-minute session daily (up to a maximum of six sessions daily) for 3 months (treatment period); diabetic patients were encouraged to use NMES for a minimum of two 30-minute sessions daily.Participants in both groups were followed up at 3 months (end of treatment period), 6 and 12 months post-randomization (end of study participation). | PMC10638544 | |
Follow up | ADVERSE EVENTS | Assessments at these time points included the standardized treadmill test, ABPI, peripheral pulse examination, quality-of-life questionnaires, haemodynamic assessments, review of patient diaries, assessment of adverse events and concomitant medications.The 12-month follow-up appointment marked the end of study participation ( | PMC10638544 | |
Outcomes | claudication pain, AWD | DISEASE, INTERMITTENT CLAUDICATION | The primary outcome measure was AWD at 3 months using the standardized Gardner–Skinner treadmill test; beginning at 3.2 km/h at a 0 per cent incline with the incline increasing by 2 per cent every 2 minutes, for a total of 15 minutes. Patients indicated when they first experienced claudication pain (ICD) and the test would finish when this prevented continuation (AWD). To prevent bias, patients were blinded to the AWD.Secondary outcomes included ICD, compliance to interventions, QoL and haemodynamic changes. ICD was assessed by the Gardner–Skinner treadmill test at randomization, 3, 6 and 12 months. Device compliance during the treatment period was assessed by self-report patient diaries, cross-checked with voltage/current data loggers. Patients were able to continue to use the device following the 3-month treatment period.The generic EuroQoL Five Dimensions Five-Level (EQ-5D-5L), the Medical Outcomes Study 36-Item Short-Form (SF-36) Health Survey and the disease e-specific Intermittent Claudication Questionnaire (ICQ) (Due to the COVID-19 pandemic, study sites replaced on-site visits with telephone calls (A health economic analysis was prespecified in the trial protocol, but the results are not reported in the current article. | PMC10638544 |
Statistical analysis | AWDs, AWD | REGRESSION, SECONDARY | The sample size was estimated assuming the mean AWD in the control group would be 200 m at 3 monthsThe AWDs of participants who walked more than 15 minutes on the treadmill at 3 months were censored at 790 m. We hypothesized that there would be an improvement in AWD at 3 months in the treatment group compared to the control group in patients with IC by using a prespecified Tobit regression model to incorporate the right-censored data. The model included the AWD baseline measurement, a treatment indicator and the type of centre (SET A predefined statistical analysis plan (SAP) was written. Any analysis not in the SAP is defined as post hoc.The secondary outcome of ICD was analysed using a multilevel Tobit regression at 3, 6 and 12 months to incorporate the right-censored distribution of data. For ABPI, mixed models were used. As the ABPI data showed a skewed distribution, log transformation was used for the analyses.Mixed models for each of the quality-of-life scores were performed to investigate changes in QoL over time, treating patient and centre as random effects, and QoL scores at baseline, time, treatment and interaction of treatment and time as fixed effects.Subgroup analysis to investigate the effect of the intervention among NMES + SET + BMT, NMES + BMT, SET + BMT and BMT was performed. Seven subgroup analyses were performed in the intention-to-treat (ITT) population for the primary outcome (AWD), measured at 3 months using Tobit regression models, five were originally described in the SAP and two were added later as post-hoc analyses.A post-hoc analysis was performed with baseline AWD divided into short, medium and long distances (<25 per cent, 25–75 per cent and >75 per cent, respectively). For each stratum a Tobit regression for the transformed right-censored AWD at 3 months was performed.All analyses were performed on an ITT basis with STATA software, version 17 (StataCorp), with statistical significance set at a two-sided alpha level of 5 per cent. | PMC10638544 |
Results | PMC10638544 | |||
Screening | From 2 February 2018 until 31 March 2020, a total of 1410 patients were screened, and 200 consented and were subsequently randomized into the trial at 11 participating centres. However, 10 patients were removed from the analysis after randomization as they were identified as screening failures (Cumulative numbers of patients who had been lost to follow-up and had died by each follow-up time pointTen patients were excluded post-randomization. Patients at SET centres attended their first SET class within 2 weeks from randomization. Treatment protocol violations occurred in 6 patients in the control group (SET and non-SET groups) and in 5 patients in the SET intervention group.Baseline characteristics were similar in both groups (Baseline characteristics of trial participantsABPI, ankle–brachial pressure index; BMT, best medical therapy; NMES, neuromuscular electrical stimulation; SET, supervised exercise therapy. Percentages may not total to 100 because of rounding. *Information on ABPI was missing for 2 patients in the treatment group (left and right ABPI) and 2 and 1 patient(s) in the control group (right and left ABPI), respectively. | PMC10638544 | ||
Primary outcome | AWD | REGRESSION | The Tobit regression model indicated that there was no statistically significant difference in the AWD at 3 months between the two study groups (NMES + SET + BMT and NMES + BMT
AWD: absolute walking distance; ITT: intention-to-treat; SET: supervised exercise therapy. Tobit regression model: square root of AWD at 3 months = intercept + square root of AWD (baseline) + Treatment + Type of centre. *The square root transformation of AWD was used for baseline and 3 months measurements. Square root transformation variables satisfy the assumptions of the Tobit model. However, there was a significant increase in the AWD at 3 months (square root; 3.29 units; 95 per cent c.i., 1.77 to 4.82; | PMC10638544 |
Secondary outcomes | ±, SAEs, AWD | INTERMITTENT CLAUDICATION, REGRESSION, ADVERSE EVENTS | When considering the repeated measures of ICD in time, and adjusting for age, gender, BMI, smoking status, treatment by time interaction and ICD at baseline using a multilevel Tobit model for ICD at 3, 6, and 12 months, we found that there was no statistically significant difference between treatment and control groups (Participants’ right ABPI (log-transformed for normality) significantly increased over the follow-up period, irrespective of treatment group, by 0.07 (95 per cent c.i., 0.02 to 0.12; Quality-of-life outcomes are summarized in Summary of disease-specific and generic patient-reported quality of life outcomes*BMT: best medical therapy; ICQ: intermittent claudication questionnaire; EQ-5D-5L: EuroQol Group 5-Dimension 5-Level questionnaire; NMES: neuromuscular electrical stimulation; SET: supervised exercise therapy; SF-36: medical outcomes study 36-item short-form health survey. *Plus–minus values are means ± SD. †The between-group differences were estimated by a mixed model adjusted for each baseline quality of life score, time, treatment and the interaction term of time and treatment as fixed effects and centre and patients as random effects. The control group was the reference group. The widths of the confidence intervals were not adjusted for multiple comparisons and should not be used for formal reference. ‡Scores on the ICQ range from 0 to 100, with higher scores indicating worse health related to intermittent claudication. §Scores on the EQ-5D-5L health scale (a visual analogue scale) range from 0 to 100, with higher scores indicating better health. ¶Scores on the EQ-5D-5L health index range from 0 to 1, with higher scores indicating better health. The EQ-5D-5L health index was calculated with the value set for EnglandSerious adverse events (SAEs; Subgroup analyses are summarized in
AWD: absolute walking distance; BMT: best medical therapy; ITT: intention-to-treat; NMES: neuromuscular electrical stimulation; SET: supervised exercise therapy. *Indicates the reference category. †Right censoring set up at (28.106939) square root of AWD at 790 m. ‡Tobit regression model: square root of AWD at 3 months = intercept + square root of AWD (baseline) + Subgroup + residual. §Subgroup 1: Non-SET Compliance was measured for all interventions. Participants at SET centres were deemed compliant if they attended 50 per cent or more sessions, and if participants completed at least 75 per cent of their recommended level of NMES usage. Of 99 participants that attended SET, 69 were compliant (69.7 per cent) with data missing for 11 patients (11.1 per cent). Of 92 participants using the device, 68 were compliant (73.9 per cent), with data missing for 12 patients (13.0 per cent). Patients reported good tolerability to device use; 87.5 per cent stated it was ‘very easy’ to use as reported in the device experience questionnaire. | PMC10638544 |
Post-hoc analysis | AWD | A post-hoc analysis was performed looking at stratification of baseline AWD. The AWD at baseline was divided into three strata: short, medium and long distances (set at <25 per cent, 25–75 per cent and >75 per cent, respectively) using the descriptive statistics in For patients that could not walk further than 100 m at baseline, there was no clear statistical difference between the two treatment arms, or between type of centre (SET | PMC10638544 | |
Discussion | PMC10638544 | |||
Principal findings | AWD | This trial showed that SET is an effective treatment for patients with IC. The addition of NMES may have an adjuvant benefit on AWD, particularly in patients with mild IC. From the subgroup analysis we can conclude that SET has a greater impact in the improvement of AWD both alone or in combination with NMES. Exercise advice alone has the lowest impact on the improvement of AWD. | PMC10638544 | |
Strengths and weaknesses of the study | AWD | SECONDARY, CONTRACTIONS | Our trial has several limitations. First, the AWD that was used as the primary outcome measure showed a large range in both groups at baseline, with a right-skewed distribution. We did not stratify by baseline AWD for the primary outcome analysis. Second, only 160 participants had analysable primary outcome data due to missing treadmill data at baseline and/or 3 months. The number of participants lost to follow-up was higher than first anticipated. Additionally, the COVID-19 pandemic resulted in local centre policy, at some participating centres, dictating that participants were not permitted to attend study appointments face to face. Instead, remote visits were performed with physical assessments, such as the treadmill test, being missed. Certain secondary outcomes, such as haemodynamic measures, were not adjusted for centre effects and thus may not account for centre–centre variability. Finally, there was the absence of a sham device comparator. This was considered during the protocol design but was deemed impractical to implement due to the patient setting the stimulation level to a threshold where calf contractions are visible (the IsoRocker feature allows the device to tilt back and forth).The main strength of the NESIC trial is that this is the first moderately sized RCT looking at the adjuvant benefit of NMES in patients with IC. The results of this trial are generalizable across vascular units that provide SET and those that provide BMT only. A further strength is that compliance data were collected separately for NMES, SET and exercise advice, with clear definitions on what is deemed as compliant. | PMC10638544 |
Comparisons with other studies | PAD | PAD | The primary analysis suggests NMES has no additional benefit overall in individuals with IC receiving local standard care. This finding is divergent from the RCT by Babber Compliance with intervention is an important consideration when managing patients with PAD. In this trial, 69.7 per cent of patients with access to SET met the definition of compliance (50 per cent or more classes held by the site). Current data on patient adherence to SET programmes is problematic due to differences in defining compliance among studies and the large variation in SET programme duration. Harwood Compliance with NMES in this study was 73.9 per cent, which was less than what was observed in the 6-week pilot study (97 per cent) and subsequent RCT (96 per cent)A sensitivity analysis, using only the compliance rules for SET and NMES, with all patients receiving exercise advice, showed no clear statistical differences to the main analysis (including all seven subgroup analyses). | PMC10638544 |
Meaning of the study | The results of our study add to the growing body of evidence that SET has a significant benefit on walking distances of patients with ICIn the current trial we found that there was no overall significant improvement in walking distances in those patients using NMES as an adjunctive treatment to SET. No statistically significant effect was observed, but there was a trend suggesting a potential advantage to combined treatment. Interestingly, our post-hoc analysis suggests the response to SET and NMES appears to be dependent on baseline walking ability, and that these treatment options may be better for patients with IC able to walk longer distances. This, taken with the previous body of evidence of improved walking distancesIn conclusion, this multicentre, randomized trial demonstrates the clear benefit of SET for patients with IC. NMES appears to be beneficial both as an adjunct to SET and on its own in patients with longer baseline walking distances. This is of particular importance for patients with mild IC and in vulnerable groups that may feel unable to travel or feel uncomfortable attending SET and/or commercial gyms in light of the COVID-19 pandemic, as NMES devices are widely available and can be used in a home setting. | PMC10638544 | ||
Unanswered questions and future research | Further studies are needed to confirm the effectiveness of NMES in combination with SET, and in patients with IC who have good baseline walking distances in a larger sample size. | PMC10638544 | ||
Supplementary Material | Click here for additional data file. | PMC10638544 | ||
Acknowledgements | This trial is registered as ISRCTN18242823. We thank all the trial participants. We thank Actegy Ltd for providing the NMES devices for the study. We also thank the members of the trial management group, trial steering committee, and independent data monitoring committee for their ongoing advice and support for the trial, and the principal investigators and their colleagues for recruiting and monitoring trial participants and for their hard work and commitment (A complete list of NESIC Trial Investigators is provided in the | PMC10638544 | ||
Funding | This trial was supported by a grant from the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). Neuromuscular electrical stimulation (NMES) devices were provided by Actegy Ltd (Bracknell, UK) and laser Doppler flowmetry (LDF) devices were provided by Moor Instruments Ltd (Axminster, UK). | PMC10638544 | ||
Disclosure | P., Stroke | HEART, STROKE | All authors have completed the copyright transfer agreement and declare: Professor Alun H. Davies and Mr Joseph Shalhoub received financial support from the National Institute for Health and Care Research Efficacy and Mechanism Evaluation (NIHR EME) Programme and Imperial College London for the submitted work; Professor Alun H. Davies reports grants from NIHR, The Stroke Association, The Graham-Dixon Charitable Trust, The J. P. Moulton Charitable Foundation, Laboratoires Urgo, Actegy Ltd, the Royal College of Surgeons and Imperial College Healthcare NHS Trust during the conduct of the study, none of which is related to the submitted work; Mr Joseph Shalhoub reports grants from NIHR and British Heart Foundation during the conduct of this study, consulting fees from Oxford Healthtech Ltd unrelated to the present submission, and membership of the Circulation Foundation (charity) committee, Vascular Society Research Special Interest Groups and Research Committee, Surgical Research Society Council & Vascular and Endovascular Research Network Committee; Miss Sasha Smith reports grants from Actegy Ltd; Mr Manjit Gohel reports personal fees and other from Medtronic, personal fees and other from Cook Medical unrelated to the present submission; Ian Chetter reports membership of the HTA Prioritisation Committee B (in hospital) from 2021 to 2025. | PMC10638544 |
Supplementary material | PMC10638544 | |||
Data availability | All data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review. Data-access requests are handled on a case-by-case basis and will be reviewed by the corresponding author, Trial Management Group and sponsor (Imperial College London). A record of all access to data will be maintained by the Imperial College Archive team. | PMC10638544 | ||
References | PMC10638544 | |||
Abstract | PMC10166935 | |||
Background | NSCLC, Nab‐paclitaxel, tumor | LUNG CANCER, TUMOR, NSCLC | Nab‐paclitaxel (nab‐PTX) has better transfer to tumor tissue than cremophor‐based paclitaxel. It suggests that the optimum dose of nab‐PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab‐PTX in patients with previously treated advanced non‐small cell lung cancer (NSCLC). | PMC10166935 |
Methods | Patients were randomly allocated (1:1) to receive nab‐PTX monotherapy at 100 mg/m | PMC10166935 | ||
Results | Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. | PMC10166935 | ||
Conclusion | NSCLC, stage IIIB/IV or postoperative | ONCOLOGY, NSCLC | Both standard dose and low dose of nab‐PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab‐PTX 70 mg/mIn this phase 2 randomized clinical trial to examine activity and safety, and to determine optimum dose of nab‐PTX in patients with previously treated stage IIIB/IV or postoperative relapsed NSCLC, both 100 and 70 mg/m2 of nab‐PTX monotherapy were active in patients with previously treated advanced NSCLC. Since the 70 mg/m2 dose has a better safety profile and numerically favored median overall survival, 70 mg/m2 on days 1, 8, and 15 every 4 weeks would be the optimal dose and schedule for nab‐PTX during treatment of NSCLC.
Previous presentations: Portions of this study were presented at the European Society for Medical Oncology Congress, 16‐21 September, 2021. | PMC10166935 |
INTRODUCTION | toxicity, tumor, NSCLC | TUMOR, NSCLC | Traditionally, the dose of anti‐cancer agents has been decided based on the incidence of dose‐limiting toxicity (DLT) in a phase I clinical trial. Ideally, however, the optimum dose should be decided based on efficacy and toxicity. This is because following a dose recommendation based on DLT alone, rather than the optimal dose (which may be lower) can increase toxicity, cost, and could immunocompromise patients without additional benefit. Defining the optimum dose of cytotoxic chemotherapy is therefore critical to improve overall survival (OS) and patient quality of life.In chemotherapy for advanced NSCLC, administration of the optimal dose should improve outcomes. In the randomized phase II study of 1000 or 500 mg/mIn preclinical models of NSCLC, nab‐paclitaxel (nab‐PTX), an albumin bound and solvent free nanoparticle paclitaxel (PTX) formulation, has better transfer to tumor tissue than PTX. Compared with cremophor‐based PTX, nab‐PTX thus yielded higher mean intratumor and maximal circulating concentrations of free PTX in a xenograft model.A weekly (Days 1, 8, and 15 every 28 days) 70 mg/mWe designed a randomized phase II trial to determine the optimum dose, activity, and safety of weekly nab‐PTX (low dose 70 mg/m | PMC10166935 |
METHODS | PMC10166935 | |||
Patient eligibility | NSCLC | NSCLC | The present trial, JMTO LC14‐01, was a multi‐institutional study and was designed as a randomized, phase II trial to be performed in wide area of Japan. The protocol was approved by the independent ethics committees of participating institutions. This trial was conducted in accordance with the Ethical Guidelines for Medical and Health Research involving Human Subjects, the Declaration of Helsinki, and the Clinical Trials Act in Japan. Written informed consent was obtained from all patients. This trial was registered with the UMIN Clinical Trials Registry (UMIN000016932) and the Japan Registry of Clinical Trials (jRCTs031180214).For patients with previously treated stage IIIB‐IV or postoperative relapsed NSCLC, at least one of the previous treatment regimens had to have contained platinum‐based combination chemotherapy. In patients with | PMC10166935 |
Study treatment and assessments | Patients were randomly allocated (one to one) to receive nab‐PTX at standard 100 mg/m | PMC10166935 | ||
Outcomes | Tumors, death, Cancer | DISEASE PROGRESSION, ADVERSE EVENT, EVENT, TUMORS, CANCER | The primary end point of the study was PFS (time from randomization to the date of objective disease progression or death from any cause in the absence of progression). Secondary end points included OS (time from the date of randomization to the date of death event by any cause), ORR (the proportion with radiologically confirmed partial response and complete response), according to Response Evaluation Criteria in Solid Tumors version 1.1, frequency and extent of AEs. AEs were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. PFS and ORR were both assessed by blinded independent central review. | PMC10166935 |
Statistical analysis | NSCLC | NSCLC | Based on the earlier trials for NSCLC patients with previously treated, the sample size was calculated to ensure the median PFS in each group exceeded 2 months. The assumptions of an expected median PFS of 3 months, 5% one‐sided significance level and 80% power, and an estimated of 2 years of enrollment and 1 year of follow‐up necessitated the inclusion of at least 37 patients in each arm. We planned to enroll 80 patients for the trial, accounting for dropout.For each group, the cumulative PFS probability and median PFS were estimated using the Kaplan–Meier method. The 95% confidence interval (CI) for median PFS was estimated using the Brookmeyer and Crowley method. A test based on the maximum likelihood method for hazard assuming an exponential distribution was performed for the null hypothesis that the median PFS would be 2 months for each group. The hazard ratio (HR) was calculated using the Cox proportional hazards model. For each group, we estimated the ORR and the 95% CI. For reference, Fisher's exact test was used to make the null hypothesis that the ORRs between groups are equal. All statistical analysis was performed with SAS 9.4 software. | PMC10166935 |
RESULTS | PMC10166935 | |||
Patients | NSCLC, non‐small cell lung cancer, inappropriate stage | MAY, DISEASE, NSCLC | Between May 2015 and May 2019, 81 patients were enrolled at 13 institutions in Japan and were randomly assigned to group A (40 patients) or group B (41 patients). One patient in group A was excluded from the efficacy analysis because their disease was at an inappropriate stage (stage IB), and 2 patients in group B were excluded from this analysis because of they received an EGFR inhibitor within 2 weeks of the study treatment, had elevated ALT, and had disease at an inappropriate stage (stage IIIA) (Figure CONSORT Diagram of the study participants. Three patients were excluded from the efficacy analysis. However, these patients received study treatment and were included in the safety analysis. NSCLC, non‐small cell lung cancer.Baseline demographic and clinical characteristics of the study patients.
Abbreviations: One patient was diagnosed as stage IB and excluded from efficacy analysis. | PMC10166935 |
Therapeutic efficacy | squamous or nonsquamous, tumor | EVENTS, TUMOR, SOLID TUMORS | During the follow‐up period, events occurred in 36 (92.3%) of 39 patients in group A and 35 (89.7%) of 39 patients in group B regarding the primary endpoint. Median PFS was 3.75 months (95% CI, 1.87–5.36) in group A and 3.71 months (95% CI, 2.23–5.85) in group B (Figure Investigator‐assessed progression‐free survival and overall survival. Kaplan–Meier plots for investigator‐assessed progression‐free survival (A) and overall survival (B) in the intention‐to‐treat (ITT) population. CI, confidence interval; HR, hazard ratio.The results for OS are shown in Figure The results of PFS and OS for subgroup analysis were consistent with those for the intention‐to‐treat population (Figure Investigator‐assessed progression‐free survival by number of prior cytotoxic chemotherapies and investigator‐assessed progression‐free survival by histologic subtype of tumor. Kaplan–Meier plots for subgroup analysis of investigator‐assessed progression‐free survival (A) and overall survival (B) in the intention‐to‐treat (ITT) population. Stratification factors for overall survival were the number of prior cytotoxic chemotherapy regimens (1 or ≧2), tumor histology (squamous or nonsquamous). CI, confidence interval; HR, hazard ratio.The ORR was assessed for 39 patients who had measurable tumor lesions. The ORR was 20.5% (95% CI, 9.3–36.5) in group A and 23.1% (95% CI, 11.1–39.3%) in group B (Table Response rates for enrolled patients and for histology‐based subsets.Objective response by investigator review per Response Evaluation Criteria in solid tumors, version 1.1.Response rates by number of previous cytotoxic chemotherapies.Objective response by investigator review per Response Evaluation Criteria in solid tumors, version 1.1. | PMC10166935 |
Chemotherapy compliance status | Table Chemotherapy compliance status.The median cumulative nab‐PTX dose and dose intensity of group A was 815 mg/m | PMC10166935 | ||
Safety | death, neutropenia, leukopenia, peripheral sensory neuropathy, nab‐paclitaxel, pneumothorax, ILD, anemia, anorexia | NEUTROPENIA, LEUKOPENIA, PERIPHERAL SENSORY NEUROPATHY, ADVERSE EVENTS, PNEUMOTHORAX, LUNG INFECTION, ANEMIA, HYPERGLYCEMIA, HYPERURICEMIA, TUMOR PROGRESSION, INTERSTITIAL PNEUMONITIS, INTERSTITIAL LUNG DISEASE, ADVERSE DRUG REACTIONS, ANOREXIA | AEs occurred in 87.5% (35/40) of subjects in group A and 80.5% (33/41) in group B. Grade 3 or worse AEs occurred in 57.5% of patients (23 out of 40) in group A and 41.5% of patients (17 out of 41) in group B. Serious side effects developed in 10.0% of patients (4 out of 40) in group A and 4.9% of patients (2 out of 41) in group B (Table Treatment‐related adverse events.
Grade 5 nab‐paclitaxel induced interstitial pneumonitis.Among the AEs that occurred in 10 or more patients in group A were leukopenia in 17 patients (42.5%), neutropenia in 22 patients (55.0%), anemia in 13 patients (32.5%), and anorexia in 10 patients (25.0%). In group B, there was occurrence of leukopenia in 14 patients (34.1%), neutropenia in 11 patients (26.8%), and anemia in 10 patients (24.4%). All grades of peripheral sensory neuropathy occurred in 4 patients (10.0%) in group A and 6 patients (14.6%) in group B. These AEs were considered adverse drug reactions.Serious AEs such as discontinuation of treatment occurred in 10.0% of patients (4 out of 40) in group A and 4.9% (2 out of 41) in group B. In group A, anemia, lung infection, hyperglycemia, and pneumothorax occurred in each of the 4 patients. In group B, interstitial lung disease (ILD) occurred in 2 patients. However, it was difficult to conclude that lung infection, hyperglycemia, and pneumothorax were treatment‐related adverse events. AEs leading to death occurred in 2.5% of patients (1 out of 40) in group A and 2.4% of patients (1 out of 41) in group B. The reason for the death of the group A patient was poor general condition with hyperuricemia, and suspicion of tumor progression. On the contrary, the death in group B was due to severe drug induced ILD. | PMC10166935 |
DISCUSSION | NSCLC, toxicities, cancer | CANCER, NSCLC, SOLID TUMOR | The JMTO LC14‐01 phase II trial is the first randomized trial to evaluate optimal dose of nab‐PTX in previously treated patients with advanced NSCLC. Both 100 and 70 mg/mHigh‐dose medication is not always required to elicit clinical benefit. Indeed, greater efficacy at higher doses of chemotherapy was not observed in a solid tumor clinical trial.A study of first‐line chemotherapy for advanced NSCLC showed that 100 mg/mMost toxicities were manageable with supportive care or appropriate dose reductions, and especially well tolerated in the 70 mg/mThe cost and supply of cancer drug are issues that should be considered in the healthcare system. The trial in our current study is in line with near‐equivalence concept.Our trial had several limitations. First, pharmacokinetics or pharmacodynamics analysis was not conducted. However, pharmacokinetic data for nab‐PTX is similar for Japanese and non‐Japanese patients,In conclusion, both standard dose and low dose of nab‐PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab‐PTX 70 mg/m | PMC10166935 |
AUTHOR CONTRIBUTIONS | PMC10166935 | |||
FUNDING INFORMATION | This study was supported by Taiho Pharmaceutical Company Limited. | PMC10166935 | ||
CONFLICT OF INTEREST STATEMENT | Susumu Takeuchi reports receiving personal lecture fees from Taiho Pharmaceutical Company Limited. Kaoru Kubota received honoraria for lectures and consultation fee from Taiho. Shunichi Sugawara, Takashi Hirose, Yuji Minegishi, and Akihiko Gemma received honoraria for lectures from Taiho Pharmaceutical Company. Shinji Atagi and Masahiro Seike received grant and honoraria for lectures from Taiho Pharmaceutical Company. Satoshi Teramukai, Rintaro Noro, Kei Fujikawa, Seigo Minami, Shinichiro Iida, Hiroshi Kuraishi, Tomoiki Aiba, Masaru Matsumoto, and Masaaki Kawahara declared no conflict of interest. | PMC10166935 | ||
ETHICS STATEMENT | The protocol was approved by the independent ethics committees of participating institutions. This trial was conducted in accordance with the Ethical Guidelines for Medical and Health Research involving Human Subjects, the Declaration of Helsinki, and the Clinical Trials Act in Japan. Moreover, the written informed consent was obtained from all patients. This trial was registered with the UMIN Clinical Trials Registry (UMIN000016932) and the Japan Registry of Clinical Trials (jRCTs031180214). | PMC10166935 | ||
Supporting information |
Figure S1.
Click here for additional data file. | PMC10166935 | ||
ACKNOWLEDGMENTS | We thank patients and family members, co‐investigators, Drs. Kaoru Matsui and Shinzo Kudo for extramural review, Ms. Saori Kato and Ms. Michiko Ishii for administrative support. The study was funded by Taiho Pharmaceutical Company Limited. | PMC10166935 | ||
DATA AVAILABILITY STATEMENT | The data underlying this article will be shared on reasonable request to the corresponding author. All authors follow the FAIR principles (Findability, Accessibility, Interoperability, Reproducibility) for data access. | PMC10166935 | ||
REFERENCES | PMC10166935 | |||
Key Points | PMC10498327 | |||
Question | Were outcomes following the Health Care Hotspotting intervention different for those patients who were more vs less likely to engage with care management? | PMC10498327 | ||
Findings | SECONDARY | In this secondary analysis of randomized clinical trial data from 782 participants, greater intervention participation was associated with significantly lower readmission rates 30 and 90 days after hospital discharge and significantly lower 30- and 180-day readmission counts. | PMC10498327 | |
Meaning | readmissions | SECONDARY | These findings suggest that evaluation strategies that account for variable intervention participation can identify program effects that are missed in intent-to-treat analysis.This secondary analysis of a randomized clinical trial evaluates the association between care management and hospital readmissions among trial participants with greater engagement. | PMC10498327 |
Importance | Variability in intervention participation within care management programs can complicate standard analysis strategies. | PMC10498327 | ||
Objective | readmissions | To evaluate whether care management was associated with reduced hospital readmissions among individuals with higher participation probabilities. | PMC10498327 | |
Design, Setting, and Participants | chronic illness | CHRONIC ILLNESS | A total of 800 hospitalized patients aged 18 years and older were randomized as part of the Health Care Hotspotting randomized clinical trial, which was conducted in Camden, New Jersey, from June 2014 to September 2017. Data were collected through October 2018. In this new analysis performed between April 6, 2022, and April 23, 2023, the distillation method was applied to account for variable intervention participation. A gradient-boosting machine learning model produced predicted probabilities of engaged participation using baseline covariates only. Predicted probabilities were used to trim both intervention and control populations in an equivalent manner, and intervention effects were reevaluated within study population subsets that were increasingly concentrated with patients having higher participation probabilities. Patients had 2 or more hospitalizations in the 6-month preenrollment period and documented evidence of chronic illness and social complexity. | PMC10498327 |
Intervention | Multidisciplinary teams provided services to patients in the intervention arm for a mean 120 days after hospital discharge. Patients in the control group received usual postdischarge care. | PMC10498327 | ||
Main Outcomes and Measures | Hospital readmission rates and counts 30, 90, and 180 days postdischarge. | PMC10498327 | ||
Results | Of 800 eligible patients, 782 had complete discharge information and were included in this analysis (mean [SD] age, 56.6 [12.7] years; 395 [50.5%] female). In the intent-to-treat analysis, the unadjusted 180-day readmission rate for treatment and control groups was 60.1% vs 61.7% (adjusted odds ratio, 0.95; 95% CI, 0.71-1.28; | PMC10498327 | ||
Conclusions and Relevance | SECONDARY | This secondary analysis of a randomized clinical trial found that care management was associated with reduced readmissions among patients with higher participation probabilities, suggesting that program operation could be improved by addressing barriers to participation and refining inclusion criteria to identify patients most likely to benefit. | PMC10498327 | |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10498327 | ||
Introduction | RECRUITMENT | Randomized evaluations of complex care management programs have yielded mixed evidence of effectiveness in improving health outcomes. An approach to care for individuals with concurrent medical and social needs, complex care is distinct from other care management approaches for its interdisciplinary team-based models, prioritization of patients’ self-defined goals, and emphasis on cross-sector partnerships to improve care transitions across multiple settings.The Camden Coalition received support in 2012 from the US Centers for Medicare and Medicaid Services to refine, test, and scale their signature care management model: the Camden Core Model. In 2020, randomized clinical trial results challenged a key value proposition for complex care, finding no significant effect of the Core Model on readmissions 180 days after hospital discharge.The Health Care Hotspotting trial randomized patients after recruitment and consent, leading to complete trial enrollment within the intervention group. However, patients enrolled in the trial varied on characteristics that could have influenced participation in and responsiveness to the intervention, and while enrollment was complete within the intervention group by virtue of the trial design, the intensity and nature of care services received by enrollees varied.The original analysis of the Health Care Hotspotting trial adhered to the standard intent-to-treat (ITT) framework, in which patients are analyzed as randomized. However, variable intervention delivery meant that the average treatment effect in the main analysis was a blended estimate of effectiveness across varying doses of intervention services.In this new analysis of Health Care Hotspotting trial data, we applied the distillation method, a framework for analyzing data from randomized clinical trials that are underpowered due to low participant enrollment or variable participation levels while maintaining the trial’s original randomization. | PMC10498327 | |
Methods | PMC10498327 | |||
Study Setting | CHRONIC ILLNESSES, SECONDARY, RECRUITMENT | This was a secondary analysis of a randomized clinical trial of the Camden Core Model. From June 2014 to September 2017, 800 hospitalized patients were randomized using a tamper-proof and externally recorded randomization device to intervention vs usual care. The primary prespecified outcome was readmission within 180 days after hospital discharge. The protocol was approved by Cooper University Healthcare, the National Bureau of Economic Research, and Our Lady of Lourdes Medical Center, and written informed consent was obtained from all participants. We used the Consolidated Standards of Reporting Trials (Patients were identified through a Health Information Exchange, and study recruitment took place at 2 hospitals in Camden, New Jersey. Eligible patients were 18 years and older with 2 or more hospitalizations in the prior 6 months with evidence of multiple chronic illnesses and social complexity in their medical records. Care staff met eligible patients at hospital bedside to invite them to participate in the study and generated the random allocation sequence. Consented patients were randomized into intervention and control arms, with 399 patients enrolled in the treatment group to receive care management services and 401 randomized into the control group to receive usual postdischarge care. The final analytic sample consisted of 782 patients (393 in the treatment group and 389 in the control group) with complete discharge information. Outcome data were collected through October 2018. The participant flow diagram is shown in | PMC10498327 | |
Flow Diagram | SAID | Patients who declined to participate explicitly said no to the offer of randomization. Patients who gave a soft decline did not provide consent when approached but did not decline to participate and could be approached again during future hospitalizations if they were otherwise eligible. Patients who were unable to provide consent were either discharged or died before they could be reached or were unable to consent for reasons such as being asleep. Patients who consented but were excluded included 5 patients who consented and later asked to be removed from the trial and the last 4 patients enrolled in the trial who were excluded to keep the trial population at the target of 800 patients. For patients in the trial population to be included in the analysis sample, a record of their index admission had to have been found in the hospital discharge data. Further information is provided in Patients enrolled in the intervention arm of the trial received care management services from registered nurses, licensed practical nurses, social workers, health coaches, and community health workers for a mean 120 days after discharge from their index admission. The details of the intervention are described in the original trial report. | PMC10498327 | |
Data Sources | Data sources for the study included all-payer claims data from 5 regional hospital systems, a care coordination database, and information collected from all study participants during triage and the initial hospital visit. Claims data covered 6 months prior to and 6 months after each patient’s index discharge. These data were at the hospital-encounter level and had admission and discharge dates along with | PMC10498327 | ||
Statistical Analysis | The original analysis of trial data was completed using ITT estimates and has been published elsewhere. | PMC10498327 | ||
Stage 1: Estimating Participation | PMC10498327 | |||
Participation Definition | An ITT framework would consider all patients randomized to the intervention group as participants. We developed a participation definition for the purposes of reanalysis that acknowledged varied participation levels by categorizing intervention group enrollees as engaged participants or nonparticipants. Engaged participants were individuals in the treatment arm who met at least 2 of the 3 following criteria: received at least 3 intervention hours during the first 2 weeks of enrollment, had contact with staff at least once per week for 4 of the initial 6 weeks, were retained in the program for 60 days (half of the average treatment length) or graduated within that timeframe.The thresholds were chosen based on each measure’s distribution, together with the logical design of the intervention. The beginning period of the intervention was considered crucial as staff collected information, conducted home visits, designed care plans with patients, and built relationships, and the intervention was designed in a continuous way such that patients were expected to be engaged at least once weekly. Results of sensitivity analyses using different thresholds for the measures of engaged participation are shown in eAppendix 2 in | PMC10498327 | ||
Independent Variables and Outcome Variable | ’ | In stage 1 of the distillation analysis, a machine learning approach was used to develop predicted probabilities of engaged participation in the intervention based on prerandomization covariates. The assumption for the stage 1 model is that estimations from this model will associate with the person-level treatment effects. Failing this assumption, the method will not increase power to detect treatment effects. Patients’ demographic, social, clinical, and health utilization variables for only the baseline period were included in stage 1 modeling to estimate engaged participation. All variables were available for both intervention and control group patients. The complete list of variables is included in eAppendix 3 in | PMC10498327 | |
Modeling | We applied a gradient-boosting machine model to estimate engaged participation within the intervention group. The gradient-boosting machine model optimized the area under the receiver operating characteristic curve using 2 -way interactions of the independent variables and a learning rate of 0.001. | PMC10498327 | ||
Stage 2: Population Distillation | The stage 1 model was built with intervention patients only and then used to estimate the probability of engaged participation for all patients in the study population. The estimations from the model are a fixed function of prerandomization covariates, which were applied to both treatment and control groups equally. In the control population, these represent the probability that patients would have engaged had they been randomized to the treatment arm. The ordered probabilities were then divided into deciles, allowing us to narrow the full study population to subsets that were increasingly enriched with likely participants. We defined these distilled subsets based on the top percentage most likely to be engaged participants, ranging from 100% (the full population) to 20% (the 20% most likely to be engaged participants). | PMC10498327 | ||
Stage 3: Estimating Readmission Outcomes | readmissions | REGRESSION | In the third stage of the reanalysis, we fit regression models to decreasing fractions of the study population representing the distilled subsets to assess differences in outcomes between intervention and control group patients as the sample was sequentially concentrated by excluding patients from both trial arms with lower probabilities of engaged participation. We studied readmission rates and the average number of readmissions at 30, 90, and 180 days after patients’ index discharge dates controlling for key covariates (eAppendix 3 in | PMC10498327 |
Results | PMC10498327 | |||
Estimating Intervention Exposure or Dosage | arrest | ARREST | In total, 782 patients were included in analysis (mean [SD] age, 56.6 [12.7] years; 395 [50.5%] female and 387 [49.5%] male; 231 [29.5%] Hispanic, 427 [54.6%] non-Hispanic Black, and 124 [15.9%] non-Hispanic White). Our gradient-boosting machine model estimating intervention exposure performed well with an area under the receiver operating characteristic curve (SD) of 0.81 (0.02). Factors with the greatest associations were patient age, prior number of hospitalizations, length of index admission, housing status at enrollment, and arrest history (eAppendix 3 in | PMC10498327 |
Population Distillation: Change in Characteristics | liver disease, kidney disease | CHRONIC ILLNESSES, ARRESTED, KIDNEY DISEASE, LIVER DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE | As the population became more concentrated among those with the highest probabilities of engaged participation, a larger proportion of the most distilled sample were female (50.5% to 60.9%), were of Hispanic ethnicity (29.5% to 52.6%), did not have a high school degree (46.4% to 76.9%), reported having sufficient family support (59.8% to 69.9%), and had higher occurrences of specific chronic illnesses, including chronic obstructive pulmonary disease (44.5% to 67.9%) and kidney disease (31.6% to 57.9%). Patients with the highest probabilities of engaged participation were less likely to have been arrested (6.0% to 0.0%), to have had a substance use (32.6% to 25.6%) or alcohol-specific (13.4% to 7.1%) diagnoses at the hospital, and to have mild liver disease (11.9% to 2.6%) or moderate to severe liver disease (4.0% to 0.6%) ( | PMC10498327 |
Patient Characteristics Within Increasingly Distilled Samples | Four patients indicated another race on the baseline survey (Asian, multiracial, or other). Because of modeling requirements, categories with only 4 elements could not be included in analysis. We therefore assigned these patients the most probable race and ethnicity category (Hispanic, non-Hispanic Black, or non-Hispanic White) such that the assigned category of each patient had the largest probability of association with their engaged participation outcome label. | PMC10498327 | ||
Evaluating Intervention Effectiveness | In the odds ratio formulation for readmission rates ( | PMC10498327 | ||
Readmission Rates Between Intervention and Control Group Patients Within Increasingly Distilled Samples | Odds ratios and 95% CIs shown. In each panel, a CI is plotted at each percentage of population distillation with the center circle representing the estimated value and the outer circles representing the end points of the interval. If the interval is completely below or above the dotted reference line (y = 1), a solid circle indicates statistical significance. | PMC10498327 | ||
Readmission Outcomes With Differences Between Control and Treatment Groups Within Increasingly Distilled Samples | REGRESSION | Abbreviations: IRR, incidence rate ratio; OR, odds ratio.Sample sizes: 100% (N = 782); 60% (n = 469); 20% (n = 156).Calculations of unadjusted ORs and IRRs are based on the regression models with only the treatment group indicator included. Calculations of the adjusted ORs and IRRs are based on the full regression models with the treatment indicator and other covariates (eAppendix 3 in | PMC10498327 | |
Discussion | SECONDARY | In this secondary analysis of a randomized clinical trial, when analysis of program outcomes was concentrated on the population most likely to engage with the intervention, the estimated effectiveness of the Camden Core Model intervention increased, and the confidence intervals became statistically significant. Like other randomized evaluations with variability in patient uptake,The central motivation for the distillation method is that ITT methods for analyzing RCTs may lead to missed insights. Even when randomization occurs after patient outreach, the average treatment effect in ITT analysis is for the offer of the treatment rather than the delivery of the service itself. If a clinical trial has complete uptake and full treatment dose for all treatment arm participants, there is no difference between these concepts. However, as the rate of successful intervention delivery moves further from ideal, the ITT estimate may diverge from the intervention delivery effect. Beyond the power implications of this dilution, the ITT estimate may no longer estimate the effect that is of most policy or practical interest.Randomized clinical trials of care management interventions can be prone to incomplete enrollment or engagement because these interventions are typically prolonged and multifaceted, unlike treatments that are assigned at a point in time (ie, insurance coverage) or given immediately after randomization (ie, a vaccine). Ultimately, ITT analyses of diluted trials may overlook the effect of a treatment on the treated, potentially mistaking trial implementation challenges for an intervention failure.In our analysis, a history of criminal justice involvement and housing instability were associated with lower probabilities of engaged participation. These findings may reflect the difficulty of maintaining contact with participants whose lives are in flux, highlighting the importance of engagement strategies tailored to patient circumstances and needs.One of the Camden Coalition’s key takeaways from the Health Care Hotspotting trial’s null results was that broader investments in social services and other resources are needed to improve outcomes for individuals living with complex health and social needs. During and after the initial study, the Camden Coalition expanded its services in response to patient needs, including developing Housing First and Medical Legal Partnership programs, and deepening partnerships with addiction medicine and behavioral health providers across the region. This new analysis emphasizes the value of those activities, given that patients who were experiencing homelessness and other social needs were among the least likely to fully engage in the intervention. | PMC10498327 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.