Long-term Clinical Trial Follow-up Research Articles

Characteristics and treatment patterns of long-surviving patients with multiple myeloma: over 13 years of follow-up in the Connect® MM Registry

BackgroundOver the last 15 years, improvements in patient management and treatments have been associated with longer survival in patients with multiple myeloma (MM). The Connect MM Registry is a long-running, US, multicenter, prospective observational cohort study of patients with newly diagnosed MM (NDMM). We assessed the demographics, clinical characteristics, and treatment patterns of long-term survivors (LTS) enrolled in this registry. MethodsAdults with NDMM (N=3,011) were enrolled from 250 community, academic, and government sites across the US from 2009-2016. Baseline characteristics, treatment patterns, quality of life (QoL), and overall survival (OS) were examined among LTS, defined as patients with follow-up of ≥8 years after enrollment. ResultsAs of February 7, 2023, 518 patients were LTS and 2,493 were non-LTS. LTS were generally younger and had better performance status at enrollment compared with non-LTS. Most (65%) LTS received stem cell transplants and few (2%) experienced disease progression within 6 months of starting first line of therapy. At data cutoff, 63% of LTS were still on treatment at their most recent visit. QoL scores and QoL questionnaire completion rates were consistently higher among LTS than non-LTS. The estimated 8-year OS rate of all patients enrolled in the registry was 40%, comparable to an observed 8-year survival of 39% from the Surveillance, Epidemiology, and End Results (SEER) database. ConclusionThis analysis provides insights on long-surviving patients with MM using real-world data and therefore presents generalizability beyond data obtained in long-term follow-up of clinical trials, underscoring the need for longitudinal follow-up through registries. DisclosuresHoward R. Terebelo, James Omel, Lynne I. Wagner, James W. Hardin Brian G. Durie, Mohit Narang, Kathleen Toomey, and Rafat Abonour report serving on a scientific steering committee for Bristol Myers Squibb. Robert M. Rifkin reports serving on a scientific steering committee for Bristol Myers Squibb; employment, stock, and other ownership interests with McKesson; participation on data safety monitoring board for CARsgen; and advisory role with Amgen, Bristol Myers Squibb; Coherus BioSciences, Genmab, Fresenius Kabi, and Janssen. Sikander Ailawadhi reports serving on a scientific steering committee for Bristol Myers Squibb; consulting fees from BeiGene, Bristol Myers Squibb, Cellectar, GSK, Janssen, Pfizer, Regeneron, Sanofi, and Takeda; and research funding from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Cellectar, GSK, Janssen, Pharmacyclics, and Sanofi. Cristina J. Gasparetto reports serving on a scientific steering committee for Bristol Myers Squibb; support for travel from Bristol Myers Squibb, Karyopharm, and Sanofi; advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and for Bristol Myers Squibb, Karyopharm, and Sanofi. Prashant Joshi, E. Dawn Flick, Edward Yu, and Ying-Ming Jou report employment and stock and other ownership interests with Bristol Myers Squibb. Hans C. Lee reports serving on a scientific steering committee for Bristol Myers Squibb; consulting fees from Allogene, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Monte Rosa Therapeutics, Pfizer, Regeneron, Sanofi, and Takeda; and grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Regeneron, and Takeda. Sundar Jagannath reports serving on a scientific steering committee for Bristol Myers Squibb; consulting fees from Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech, Regeneron Sanofi, and Takeda; support for travel from ASCO, ASH, and IMS; participation on data safety monitoring boards for Bristol Myers Squibb, Janssen, and Sanofi; and leadership or fiduciary role for ASH, IMS, and SOHO. MicroAbstractPatient characteristics, treatment patterns, quality of life, and survival were analyzed among long-surviving patients of multiple myeloma from the Connect® MM Registry. Long survivors were generally younger and healthier at diagnosis when compared with non-long survivors. The results provided insights beyond the long-term follow-up of clinical trials, indicating the importance of real-world longitudinal follow-up.

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded.

Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease-modifying treatments have reported their efficacy and safety, long-term natural history data are lacking for comparison. The aim of this prospective study was to report 4-year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number. The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number. In SMA type II (n = 226), the 4-year mean change was -2.20 points. The largest mean changes were observed in sitters aged 5-14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4-year mean change was -2.75 points. The largest mean changes were in those aged 7-15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4-year changes. Our findings provide natural history reference data for comparison with long-term follow-up of clinical trials or real-world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

Abstract P3-07-24: Role of tumor cell-derived lactic acid in the PD-1/PD-L1 blockade resistant tumor

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis (PD-1/PD-L1 blockade therapy) has shown remarkable clinical impact in multiple cancer types. Despite the recent success of PD-1/PD-L1 blockade therapy, acquired resistance, emerging as late relapses or recurrences, has been reported in the long-term follow-up of clinical trials. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. In particular, glycolytic metabolites, such as glucose and lactate, regulate T cell proliferation and function. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts the therapeutic efficacy of, and resistance to, PD-1/PD-L1 blockade therapy. Here, we found that increased lactic acid functionally contributes to an immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade therapy resistant tumors through decreasing PD-L1 and PD-L1 antibody interaction. Furthermore, combinating PD-L1 targeting with our PD-L1-antibody-drug conjugate (ADC) and reducing lactic acid by an MCT-1 inhibitor, AZD3965, within the tumor microenvironment effectively eradicated the resistant tumor cells. Together, our results suggest a new combination treatment strategy to improve the therapeutic efficacy of immune checkpoint blockade therapies Citation Format: Wonkyung Oh, Seung-Oe Lim. Role of tumor cell-derived lactic acid in the PD-1/PD-L1 blockade resistant tumor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-24.

Abstract P063: Tumor cell-derived lactic acid inhibit anti-tumor immunity in the immune checkpoint blockade resistant tumor

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of PD-1/PD-L1 blockade therapy, acquired resistance, emerging as late relapses or recurrences, has been reported in the long-term follow-up of clinical trials. However, the resistance mechanisms of PD-1/PD-L1 blockade therapy are still unclear. Here we found that tumor cell-derived lactate rendered the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade resistant tumors. Interestingly, increased lactate in the PD-1/PD-L1 blockade resistant tumors enhanced PD-1/PD-L1 interaction. Furthermore, combining a PD-L1-antibody-drug conjugate (ADC) with AZD3965, a MCT inhibitor eradicated the resistant tumor cells synergistically in 4T1 syngeneic murine models. Together, our results suggest a new combination treatment strategy to improve the therapeutic efficacy of immune checkpoint blockade therapies. Citation Format: Wonkyung Oh, Alyssa Min Jung Kim, Ruoxuan Sun, Seung-Oe Lim. Tumor cell-derived lactic acid inhibit anti-tumor immunity in the immune checkpoint blockade resistant tumor [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P063.

Event-Free and Overall Survival in over 6,000 Patients Treated with Frontline Immunochemotherapy for Follicular Lymphoma between 2002-2018: First Report from the International FLIPI24 Consortium

Event-Free and Overall Survival in over 6,000 Patients Treated with Frontline Immunochemotherapy for Follicular Lymphoma between 2002-2018: First Report from the International FLIPI24 Consortium

Cardiovascular Toxicity of Novel HER2-Targeted Therapies in the Treatment of Breast Cancer.

Purpose of ReviewHER2-targeted therapies have led to improved clinical outcomes in early and advanced breast cancer (BC). We review the long-term cardiotoxicity of HER2-targeted therapy in early and advanced BC, our current knowledge of cardiotoxicity of novel HER2-targeted therapies, and propose a cardiac monitoring (CM) strategy for this population.Recent FindingsLong-term data from studies with HER2-targeted therapy in the adjuvant setting have failed to demonstrate an increase in cardiotoxicity over time, and rates of cardiotoxicity seen with novel HER2 agents remain low. Despite over a decade of experience with HER2-targeted therapy, CM in clinical practice is inconsistent in patients with early BC and almost non-existent in advanced BC.SummaryLong-term follow-up of clinical trials with HER2-targeted agents in early and advanced BC has failed to demonstrate increased rates of cardiotoxicity over time, attesting to the long-term safety of this class of drugs for the majority of patients, although the long-term cardiac safety of newer HER2 agents in the non-clinical trial setting is largely unknown. We propose CM incorporating clinical history, cardiac imaging, and biomarkers.

Cost-Effectiveness and Cost-Utility Analysis of ABVD Versus Beacopp in the Treatment of Advanced-Stage Hodgkin Lymphoma

Background:Treatment options for advanced-stage Hodgkin lymphoma include ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or combinations of BEACOPPbaseline and BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, hereinafter referred to as BEACOPP). There remains clinical equipoise over the best initial treatment strategy, as both strategies have similar 10-year overall survival in long-term clinical trial follow-up. There is a trade-off that occurs with inferior progression-free survival in the ABVD strategy, but higher rates of hematologic toxicity, infertility, and second malignancy in the BEACOPP strategy. The overall lifetime cost of each strategy is also unknown.Methods:We developed a Markov decision-analytic model to compare ABVD versus BEACOPP for a hypothetical cohort of transplant-eligible patients with newly-diagnosed advanced-stage Hodgkin lymphoma. The model simulates their clinical course over a 20-year time horizon. Baseline probability estimates and utilities were derived from a systematic review of published studies. Direct medical costs were obtained from publicly available administrative databases or from the literature and applied to the health states. All costs and benefits were discounted by 1.5%. A Canadian public health payer's perspective was considered and costs are presented in 2018 Canadian dollars (Table 1). Sensitivity analyses were performed for key variables.Results:Based on a 20-year model, life expectancy was 12.6 years with ABVD and 13.6 years with BEACOPP, yielding an expected survival benefit with BEACOPP of 1.0 years. The quality-adjusted life expectancy (QALY) was 10.4 years with ABVD and 11.4 years with BEACOPP, leading to an expected quality-adjusted survival benefit with BEACOPP of 1.0 QALYs. The direct costs were $98,081 for ABVD and $81,296 for BEACOPP, making BEACOPP the cost-saving strategy with a net benefit of $16,785. In the base-case analysis, BEACOPP was associated with both cost-savings and improved quality-adjusted outcomes over ABVD, making it the dominant treatment strategy. Sensitivity analyses demonstrated that the model was robust to key variables including probability of death from secondary malignancy, probability of relapse post-primary and salvage therapy, and probability of infertility secondary to BEACOPP. In sensitivity analysis of treatment-related mortality secondary to BEACOPP, the threshold value was found to be 6.5% mortality over the 6-month treatment period, a value much greater than that reported in the literature. The threshold utility of infertility was found to be 0.72 for ABVD to have a greater QALY than BEACOPP, a value lower than the utility derived from a systemic review of the literature (0.87). We assumed all infertile patients underwent a cycle of fertility preservation or IVF, which is a conservative approach, and likely overestimates BEACOPP costs. In sensitivity analysis of costs, the BEACOPP strategy was non-dominant if the cost of three months of brentuximab was decreased to $19,360 (compared to its current price of $59,110 per three months), or if the cost of fertility preservation was greater than $37,615 per patient, which is higher than the average amount for this treatment in Canada. In these scenarios, BEACOPP was still more effective, but more expensive; however, the maximum ICER was still less than $10,000 per QALY for both costs, considerably lower than conventional willingness to pay (WTP) thresholds of $50,000. Probabilistic sensitivity analyses (10,000 simulations) were performed. For the WTP threshold of $50,000, BEACOPP was the dominant strategy 72% of the time, and overall the most cost-effective strategy 87.5% of the time (Figure 2).Conclusions:The preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is a BEACOPP regimen. This strategy maximizes life expectancy, quality-adjusted life years, and is the most cost-effective strategy, accounting for increased rates of hematologic toxicity, secondary malignancy, and infertility in patients receiving the BEACOPP strategy. The model was robust to sensitivity analyses of key variables tested through plausible ranges obtained from the published literature. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pilot study of the ability to probabilistically link clinical trial patients to administrative data and determine long-term outcomes.

Clinical trials are important but extremely costly. Utilization of routinely collected administrative data may simplify and enhance clinical trial data collection. The aim of this study was to test the feasibility of use of administrative databases in Ontario, Canada, for long-term clinical trial follow-up, specifically (a) to determine whether limited patient identifiers held by the Canadian Cancer Trials Group can be used to probabilistically link with individuals in the Institute for Clinical Evaluative Sciences databases and if so, (b) the level of concordance between the two data sets. This retrospective study was conducted through collaboration of established health service (Institute for Clinical Evaluative Sciences) and clinical trial (Canadian Cancer Trials Group) research groups in the province of Ontario, Canada, where healthcare is predominantly funded by the government. Adults with pre-treated metastatic colorectal cancer previously enrolled in the Canadian Cancer Trials Group CO.17 and CO.20 randomized phase III trials were included, limited to those in Ontario. The main outcomes were rate of successful probabilistic linkage and concordance of survival data, stated a priori. Probabilistic linkage was successful in 266/293 (90.8%) participants. In those patients for whom linkage was successful, the Canadian Cancer Trials Group (trial) and the Institute for Clinical Evaluative Sciences (administrative) data sets were concordant with regard to the occurrence of death during the period of clinical trial follow-up in 206/209 (98.6%). Death was recorded in the Institute for Clinical Evaluative Sciences, but not the Canadian Cancer Trials Group, for 57 cases, where the event occurred after the clinical trial cut-off dates. The recorded date of death matched closely between both databases. During the period of clinical trial conduct, administrative databases contained details of hospitalizations and emergency room visits not captured in the clinical trial electronic database. Prospective use of administrative data could enhance clinical trial data collection, both for long-term follow-up and resource utilization for economic analyses and do so less expensively than current primary data collection. Recording a unique identifier (e.g. health insurance number) in trial databases would allow deterministic linkage for all participants.

Repeat BCG Vaccination Creates Lasting Reductions of HbA1c in Subjects with Long-Term Type 1 Diabetes—Long-Term Clinical Trial Follow-up

We report on a randomized, placebo-controlled prospective examination of adult subjects with long-term type 1 diabetes who received 2 bacillus Calmette-Guerin (BCG) vaccine doses 4 weeks apart and were studied for up to 5 years. All enrolled subjects had disease >10 years duration without complications. Starting after year 3 of follow-up, only BCG vaccinated subjects had lowered HbA1c for 1 year (Year 05 data: BCG-treated HbA1c 6.18+/-.34 [n=9], placebo 7.07+/-.41 [n=3], reference subjects with type 1 diabetes 7.22+/-.17 [n=34, p=0.02]). Continuing follow-up of 6 subjects who have been followed for a total of 8 years, 4 years after the first documented lowering of HbA1c (Phase 1 trial participants), confirms the ability of repeat BCG vaccination to maintain lowered HbA1c levels without hypoglycemia in long-term disease (BCG-treated HbA1c 6.65+/-.26 vs. placebo 7.22+/-.38, p=0.0002) for a total of 5 continuous years. For all BCG-treated subjects, the stable reductions in HbA1c were not associated with hypoglycemia. BCG-treated subjects had no change in their enrollment use of insulin pumps and none utilized a CGM device. The apparent stable and long-lasting impact of BCG on blood sugars in humans with type 1 diabetes appears to be the result of a novel mechanism, as documented with metabolomics, mRNAseq, and epigenetic methods; namely, a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization on cellular levels. BCG via epigenetics also resets T-regulatory genes for genetic reprogramming of tolerance. Trials are being designed to confirm the value of BCG for blood sugar control in humans. The identification of a novel mechanism for blood sugar lowering with BCG opens the door for future trials in both type 1 and 2 diabetes with a safe, novel and affordable approach. Disclosure W. Kuhtreiber: None. L. Tran: None. S.E. Janes: None. A.A. DeFusco: None. H. Zheng: None. D.L. Faustman: None.

Is adjuvant oxaliplatin (Ox) overutilized in colon cancer (CC): 408 cases from the practices of 102 oncologists.

e14564 Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox (O'Connell ASCO 2012). In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: U.S.-based oncologists were recruited to complete a survey and contribute treatment data for their last three patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the two groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with Stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed widely in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]

Is adjuvant oxaliplatin (Ox) overutilized in colon cancer (CC)? 408 cases from the practices of 102 oncologists.

479 Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox. (O’Connell ASCO 2012) In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: US-based oncologists were recruited to complete a survey and contribute treatment data for their last 3 patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the 2 groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed extensively in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]

Safety and Stability of Retrovirally Transduced Chimeric Antigen Receptor T Cells

Evaluation of: Scholler J, Brady TL, Binder-Scholl G et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl Med. 4(132), 132-153 (2012). Adoptive cellular therapy with genetically engineered T cells is predicated on generating effective and persisting T-cell-mediated immunity. Gammaretroviral vector-mediated gene transfer in T cells is the technological basis for promising therapy in both HIV and cancer. Because of concerns over delayed adverse events caused by persisting retroviral vector-engineered cells, the US FDA mandates long-term follow-up of clinical trials. Scholler et al. report FDA-mandated safety data and demonstrate that retrovirally transduced T cells persist in the blood of patients for more than a decade after treatment. These persisting T cells proliferated ex vivo in the presence of antigens and showed no evidence of either insertional oncogenesis or clonal expansion in 11 subjects followed for up to 11 years, supporting the long-term safety and persistence of retrovirally transduced T cells.

Phase 3 Efficacy and Tolerability Study of OnabotulinumtoxinA for Urinary Incontinence From Neurogenic Detrusor Overactivity

We assessed the efficacy, safety and effects on quality of life of onabotulinumtoxinA in patients with neurogenic detrusor overactivity. In this 52-week, international, multicenter, double-blind, randomized, placebo controlled trial 416 patients with neurogenic detrusor overactivity and urinary incontinence (14 or more episodes per week) resulting from multiple sclerosis (227) and spinal cord injury (189) were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo. The primary end point was the change from baseline in the mean number of urinary incontinence episodes per week at week 6. Maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life total score were secondary end points. Adverse events were monitored. OnabotulinumtoxinA at a dose of 200 U in 135 patients and 300 U in 132 decreased mean urinary incontinence at week 6 by 21 and 23 episodes per week, respectively, vs 9 episodes per week in 149 on placebo (each dose p<0.001). Also, maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life score were significantly improved over values in the placebo group (each dose p<0.001). Median time to patient re-treatment request was greater for onabotulinumtoxinA 200 and 300 U than for placebo (256 and 254 days, respectively, vs 92). The most common adverse events were urinary tract infection and urinary retention. Of patients who did not catheterize at baseline 10% on placebo, 35% on 200 U and 42% on 300 U initiated catheterization due to urinary retention. OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms vs placebo. Clean intermittent catheterization initiation due to urinary retention appeared to increase in a dose dependent fashion. No clinically relevant benefit in efficacy or duration was identified for the 300 U dose over the 200 U dose.

Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy

Long-term follow-up of clinical trials with lipid-lowering medications has suggested a continuation of event reduction after study completion. To evaluate the persistence of the benefit of lipid-lowering therapy in decreasing mortality after the end of clinical trials, when all patients were advised to take the same open-label lipid-lowering therapy. Through searches of MEDLINE, the Cochrane Library, the Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov until June 2010 we identified randomized clinical trials of lipid-lowering agents with a second report describing results after the end of the trial. Among the 459 trials reviewed, only 8 including 44,255 patients and 8144 deaths qualified for the meta-analysis. All-cause and cardiovascular mortality were lower in the active intervention group during the first phase (0.84, 95% confidence interval [CI] 0.76-0.93; P = .0006 and 0.72, 95% CI 0.63-0.82, P < .0001, respectively) when 71 ± 23% of the patients randomized to receive active therapy actually received it compared with 13 ± 5% of patients who received active therapy although they were randomized to placebo (P = .0001). The lower mortality among those initially randomized to active therapy persisted during the second phase (odds ratio 0.90, 95% CI 0.84-0.97, P = .0035, and 0.82 95% CI 0.73-0.93, P = .0014), when patients in both randomized groups received active therapy in the same proportions (5 ± 2% for both groups). Numerous sensitivity analyses support the conclusions of the paper. The decrease in mortality with lipid-lowering therapy in clinical trials persists after discontinuation of randomized therapy when patients in the treatment and placebo groups receive active therapy.

Long-term follow-up of clinical trials of multiple sclerosis therapies

Results from registry studies can provide valuable information about the prevalence and clinical course of different forms of multiple sclerosis (MS). Such studies can also help identify medical practice patterns in a real-world setting and important risk factors that may affect long-term outcomes in patients with MS. To date, however, these observational studies have provided less information than well-planned, randomized, controlled trials on the long-term treatment effects of disease-modifying therapies (DMTs). Short-term clinical trial results have indicated that currently available DMTs are effective in reducing disease activity, manifested by relapse or MRI change, and may slow disease progression. Because MS is a chronic disease that evolves over a period of 30 to 40 years, determining the long-term effects of treatment is of critical importance to both patients and providers. This article discusses long-term studies of DMTs in patients with MS. Exploratory data provided thus far support the hypothesis that early optimal treatment aimed at reducing disease activity can improve longer-term outcomes by delaying disease progression.

Persistence of Mortality Reduction After the End of Randomized Therapy in Clinical Trials of Blood Pressure–Lowering Medications

Long-term follow-up of clinical trials of blood pressure-lowering medications has suggested a continuation of event reduction after study completion. We evaluated the persistence of mortality benefit of these agents after the end of clinical trials, when all of the patients were advised to take the same open-label therapy. We performed a meta-analysis of randomized clinical trials using blood pressure-lowering medications, used in patients with hypertension, myocardial infarction, or left ventricular systolic dysfunction, (n=18; 132 854 patients; 11 988 deaths) when a second report describing results after the end of the trial was available. During the randomized (first) phase, 80% (interquartile range: 75% to 83%) of the patients randomized to receive active therapy actually received it compared with 16% (interquartile range: 7% to 22%) of those randomized to control. In this phase, mortality was lower in the intervention group (odds ratio: 0.84 [95% CI: 0.79 to 0.90]; P<0.0001). Mortality was also lower during the open-label follow-up (second) phase (odds ratio: 0.85 [95% CI: 0.79 to 0.91]; P<0.0001), when all of the patients were advised to take the same therapy, and rates of receiving active therapy were similar in the 2 groups (59% [interquartile range: 46% to 77%], among those originally randomized to active, and 43% [interquartile range: 20% to 68%], in the control). Several sensitivity analyses indicated stability of the effects. In studies of antihypertensive medications, a decrease in overall mortality persists after the end of trial phase, when most patients in both the intervention and control groups receive active therapy. These analyses imply that earlier intervention would result in better clinical outcomes.

Cancer registries: a novel alternative to long-term clinical trial follow-up based on results of a comparative study

Data collection and review were identified as major contributors to the cost of randomized clinical trials (RCTs). We proposed and assessed a novel alternative for long-term clinical trial follow-up based on the data captured through an accredited Cancer Registry (CR) that is part of the National Cancer Database (NCDB). Patients from Mayo Clinic, Rochester, enrolled in the North Central Cancer Treatment Group N934653 (COST) trial (98 patients) and the American College of Surgeons Oncology Group Z0030 trial (55 patients) were included in the study. Demographic, treatment, and long-term outcome data were compared between the hospital-based CR and the RCTs' databases. Concordances were used to estimate the agreement between two databases. Kaplan-Meier curves were plotted to examine the consistency of time-to-event long-term outcomes of the CR and RCT databases. High concordances (>95%) were observed for most demographic and treatment variables between the CR data and RCT data. The vital status concordances were 100% and 94.5% between the CR and COST and Z0030 databases, respectively. Three discrepant death dates were observed, one in the COST trial and two in the Z0030 trial. The concordances of disease-free status between the CR and RCT databases were 99.0% and 87.3%, and 15 discrepant disease recurrence cases were identified: 4 for COST and 11 for Z0030. The analysis has been focused on patients from a single site, Mayo Clinic, Rochester, enrolled in two large RCT evaluating surgical treatments. The findings herein need to be confirmed in a broader setting, such as multi-center, multi-registry including nonsurgical trials. CR data were nearly identical to data from two randomized phase III trials in different disease types and conducted by two different cooperative groups. The NCDB Cancer Registries represent a feasible alternative for obtaining long-term follow-up data for large clinical trials.