Concorde Trial Research Articles

Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE.

CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial. Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm. The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology. The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations.

OC-0108 Impact of the Radiation Therapy Quality Assurance in the phase II/III CONCORDE trial.

OC-0108 Impact of the Radiation Therapy Quality Assurance in the phase II/III CONCORDE trial.

Informative censoring of surrogate end-point data in phase 3 oncology trials

BackgroundKaplan–Meier (K-M) analysis, the cornerstone of cancer clinical trial interpretation, assumes that censored patients are no more or less likely to experience an event than those followed. We sought to investigate the patterns of censoring in surrogate end-points of oncology randomised controlled trials (RCTs) and examine the relationship between censoring in practice-changing treatments that failed to demonstrate survival gain. MethodsIn this cross-sectional study of phase III RCTs published in the New England Journal of Medicine, Lancet, and JAMA, between 2010 and 2020, K-M curves of surrogate end-points with statistical significance were extracted. The reverse K-M method (i.e., events and censoring are flipped) was used to examine differential censoring using the analogous reverse hazard ratio and restricted mean survival time. Sensitivity analysis was performed by partially restoring the balance in censoring between study arms. ResultsOf the 73 eligible studies with significant surrogates, 33 (45%) reported significant overall survival benefit (concordant trials), and 40 (55%) did not (discordant trials). The proportion of studies with significant differential censoring in surrogates was 43% (17/40) and 51% (17/33) in discordant and concordant trials, respectively. Trials with a significant censoring imbalance in the experimental arm occurred only in discordant trials (15% vs 0%, odds ratio [OR] = 12.62, P = 0.033), compared to excessive censoring in the control arm which occurred more in concordant trials (28% vs 52%; OR = 0.36, P = 0.036). Although censoring imbalance occurred in both groups, after sensitivity analysis, 50% of the discordant trials lost their statistical significance, compared to 15% of concordant trials (OR = 5.6, P = 0.0018). ConclusionCensoring imbalance between study arms of RCTs suggests a potential systemic bias and raises uncertainty regarding the validity of the results. Informative censoring may explain the inconsistency between therapies that seem to improve disease outcomes without concomitant survival benefit and should trigger further investigation.

Abstract IA09: Realizing the promise of prevention (at the personal and population levels)

Abstract IA09: Realizing the promise of prevention (at the personal and population levels)

Neuronal representation of task performance in the medial frontal cortex undergoes dynamic alterations dependent upon the demand for volitional control of action

Neural network contributing to forelimb task performance in the frontal cortex is dynamically reorganized by the necessity for volitional control of action. Neurons in the posterior medial prefrontal cortex (pmPFC) exhibit clear activity modulation when monkeys volitionally select the correct response tactic from multiple choices, but such activity disappears if selection of a tactic is unnecessary. Prompted by these results, we studied how the requirement to select an appropriate tactic affects the neural representation of action in downstream cortical areas. Two monkeys performed a spatial arm-reaching task with either left or right targets. The task required the monkeys to reach either toward (concordant trials) or away from (discordant trials) an illuminated target. Under the dual-tactic condition, concordant and discordant trials were randomly intermixed, requiring the selection of a response tactic. Under the single-tactic condition, only concordant trials were presented, allowing the monkeys to use the same tactic. Neurons in the pmPFC exhibited clear activity related to task performance under the former condition, but such activity disappeared under the latter condition. In contrast, neurons related to task performance were present under both conditions in supplementary motor area (SMA) and presupplementary motor area (pre-SMA). However, the efficacy of action representation by SMA but not pre-SMA neurons dramatically improved under the single-tactic condition. These results suggest that selection of the appropriate response tactic reorganizes neural circuits in specific motor areas in the medial frontal cortex, in addition to the pmPFC.

CD4 decline in seroconverter and seroprevalent individuals in the precombination of antiretroviral therapy era

Studies based on seroconverters have increased our understanding of HIV disease. It is not clear, however, whether their disease progression differs from that of the general HIV population, given their reasons for presenting for testing. Using linear mixed models we compared CD4 decline rates for a seroconverter (CASCADE) and seroprevalent group (Concorde trial) with time origin being dates of seroconversion and randomization, respectively. Follow-up was censored at the earlier of last alive date and 1 January 1996. Analyses were adjusted for risk group, age and sex. To explore the role of symptomatic seroconversion we further categorized seroconverters into two groups: with and without an HIV test interval below 30 days as proxy. The 7226 seroconverter and 1746 seroprevalent eligible individuals were mainly men (78 and 85%, respectively) infected through sex between men (52 and 63%) with mean [95% confidence interval (CI)] baseline CD4 cell count of 610 (602, 619) and 492 (479, 505) cells/μl, respectively. There was no evidence that rate of CD4 decline differs between the two groups even after adjusting for potential confounders (P = 0.67). Estimated loss in the year after reaching an arbitrary threshold of 400 cells/μl was 67 (95% CI 65, 69) and 67 (64, 69) cells/μl in the seroconverter and seroprevalent group, respectively. Whereas seroconverters with test interval below 30 days (n = 310) experienced faster decline, there was no difference in rates between other seroconverters and seroprevalent individuals (P = 0.87). These data suggest that estimates of HIV progression derived from seroconverters are likely to hold more generally for the HIV-infected population.

Parametric randomization-based methods for correcting for treatment changes in the assessment of the causal effect of treatment.

We develop parametric maximum likelihood methods to adjust for treatment changes during follow-up in order to assess the causal effect of treatment in clinical trials with time-to-event outcomes. The accelerated failure time model of Robins and Tsiatis relates each observed event time to the underlying event time that would have been observed if the control treatment had been given throughout the trial. We introduce a bivariate parametric frailty model for time to treatment change and time to trial endpoint. Estimating equations which respect the randomization are constructed and compared to maximum likelihood methods in a simulation study. The Concorde trial of immediate versus deferred zidovudine in HIV infection is used as a motivating example and illustration of the methods.

Randomization-based methods for correcting for treatment changes: examples from the Concorde trial.

We develop analysis methods for clinical trials with time-to-event outcomes which correct for treatment changes during follow-up, yet are based on comparisons of randomized groups and not of selected groups. A causal model relating observed event times to event times that would have been observed under other treatment scenarios is fitted using the semi-parametric approach of Robins and Tsiatis (avoiding assumptions about the relationship between treatment changes and prognosis). The methods are applied to the Concorde trial of immediate versus deferred zidovudine, to investigate how the results would have differed if no participant randomized to deferred zidovudine had started treatment before reaching ARC or AIDS. We consider issues relating to model choice, non-constant treatment effects and censoring.

Markers of HIV infection in the Concorde trial. Concorde Co-ordinating Committee.

The Concorde trial compared immediate (Imm) with deferred (Def) AZT monotherapy in asymptomatic HIV-positive participants. Haematological and immunological markers and weight were measured throughout, and correlated with clinical endpoints. Markers associated with disease progression (CD4 lymphocyte count and percentage, platelets, p24 antigen and beta 2 microglobulin favoured Imm: those associated with toxicity (haemoglobin, neutrophils and white cell count) favoured Def. CD8 and total lymphocyte count did not differ significantly between groups. In multivariate analysis, the combination of baseline CD4, p24 antigen and beta 2m was the best baseline predictor of disease. Including change in CD4 and beta 2m at 12 weeks, or changes over follow-up in these markers significantly improved the fit. Markers were also incorporated into the definition of 'clinical' endpoints. Hazard ratio estimates from end-points that included CD4 < 50 and CD4 < 25 were closest to those for AIDS or death alone, but added very few extra events. Use of other landmark CD4 counts (100 or greater) or relative decreases in counts (25% or more) increased the number of events, but overestimated the effect of immediate AZT. Although AZT had a beneficial effect on the surrogate markers of efficacy evaluated, these changes did not predict clinical outcome, nor could the markers be usefully incorporated into an endpoint definition.

Increased Zidovudine Prescribing Associated With Lamivudine Availability

To the Editor. —We previously described a significant decrease in zidovudine use in British Columbia following the announcement of the Concorde Trial during the first quarter of 1993. 1 We conducted the present analysis to assess recent rates of prescribing zidovudine in the province. The distribution of antiretroviral drugs in British Columbia is free of charge through the provincial Centre for Excellence in HIV/ AIDS [human immunodeficiency virus/acquired immunodeficiency syndrome] Treatment Program. 1 For physicians to prescribe zidovudine, they must complete a patient enrollment form that serves as the drug prescription. This application is accompanied by a CD4 cell count determination. Individuals infected with HIV are eligible to receive zidovudine from this program if they have at least one CD4 cell count less than 0.50×10 9 /L (500/μL). There is no other legal source of zidovudine in the province. Lamivudine (3TC, Epivir) first became available through an open-label expanded-access program

Clinical Pharmacology

One of the principal themes of clinical pharmacology is the scientific study of drug effects in humans. The issue of what drug effects to measure, surrogate end points, has been emphasized by two recent clinical trials: the Cardiac Arrhythmia Suppression Trial¹reported in 1993 and the CONCORDE trial²reported in 1994. The Cardiac Arrhythmia Suppression Trial was designed to test the hypothesis that giving antiarrhythmic drugs that suppress premature ventricular beats would prolong survival in patients who recovered from myocardial infarctions. The patients were randomized to receive placebo or one of three antiarrhythmic drugs. The patients receiving active drugs had a higher 1-year mortality than those receiving placebo, and the trial was stopped.¹The investigators concluded that suppressing asymptomatic ventricular premature beats with these antiarrhythmic drugs was not beneficial and appeared to be harmful. This was clearly contrary to the conventional wisdom that assumed that any intervention

AZT EFFECT ON THE BONE MARROW — A NEW PERSPECTIVE ON THE CONCORDE TRIAL

The Concorde trial shows an increase in CD4 + lymphocytes, but not a higher survival, in AZT treated asymptomatic patients. Our murine bone-marrow experiments show that in chronic AZT treatments a large increase in the lymphoids/erythroids compartment is due to host cytotoxicity. We put forward a mathematical formula for predicting cytotoxicity of given drug protocols, which can be used for modulating the schedule so as to increase its efficacy while maintaining its toxicity low. Our study suggests that in chronic treatments a large, single, daily dose will be less toxic than the same dose divided into several daily dosings.

Generalists' Prudence May Lead to Better Outcomes

Markson et al 1 have provided evidence of slower adoption of therapeutic modalities by primary care providers compared with specialists, using zidovudine in patients with the acquired immunodeficiency syndrome as an example. They imply that such patterns of adoption represent inferior care by primary care providers. Another interpretation of their observations should be offered, however. Specialists frequently use the latest diagnostic and therapeutic modalities, in some cases prior to demonstration of superior efficacy. The result could be seen as reckless embracement of newer is better, and the result has often been hazardous to patients. Certainly after the results of the Concorde Trial, 2 prudent physicians should take pause at the suggestion that broadly supplying zidovudine to patients with the acquired immunodeficiency syndrome represents superior health care. Other examples of overenthusiastic adoption of new technology might include prostatic serum antigen screening for prostatic carcinoma and the widespread use of cholesterol-lowering

Perspectives in Drug Therapy of HIV Infection

Current key issues in the drug therapy of HIV infection include the timing of treatment initiation, the use of multiple-drug therapy and the duration of treatment. Although most clinicians agree that symptomatic HIV disease should be treated, there is no consensus as to whether patients should be treated before symptoms develop; the results of the Concorde trial failed to demonstrate any long term improvement in disease progression or survival when antiretroviral therapy was initiated in asymptomatic individuals rather than deferring it until the development of AIDS or ARC. However, combination therapy may prove to be the most effective long term option. In the future, monitoring viral load or viral resistance may be a useful aid in determining whether antiretroviral therapy should be stopped or changed, particularly if any clinical benefits are transient or if adverse effects persist. New antiretroviral therapies must be evaluated in terms of both risks (associated adverse effects) and benefits (increase in survival, delay in disease progression or improvement in quality of life). There is an urgent need to identify the best surrogate markers to permit more rapid evaluation of therapeutic strategies.

Future treatment strategies in HIV infection.

EFFECTIVENESS OF EARLY TREATMENT WITH ZIDOVUDINE: In terms of progression to AIDS-related complex, AIDS or death, clinical trials have not yet shown any long-term benefit for early compared with deferred treatment with zidovudine. The Concorde trial showed a short-term benefit, as did two of the AIDS Clinical Trials Group studies, but the number of deaths in these short-term trials was too small to draw definitive conclusions. USE OF CD4 CELL COUNTS AS A MARKER OF AIDS: Most trials of zidovudine treatment have shown a slower decline in CD4 cell counts. However, it is still not clear whether these markers can predict long-term survival although they appear to have some value in predicting short-term benefits. SECOND-LINE THERAPY: In patients who are intolerant of or have failed to respond adequately to zidovudine, treatment with didanosine or zalcitabine has shown some short-term benefit, mainly in asymptomatic patients or those with AIDs-related complex. No substantial long-term benefit was observed. Zalcitabine appeared to show a slight increase in survival compared with didanosine. Treatment strategies still being developed include multidrug combinations, the combination of a nucleoside with a non-nucleoside reverse transcriptase inhibitor, or the use of a combination of drugs that affect different stages of the HIV life cycle, such as proteinase inhibitors. More sensitive assays, such as RNA polymerase chain reaction, may allow treatment to be tailored more closely to the needs of the individual patient.

Rates of Prescribing Zidovudine Post Concorde Trial

To the Editor. —We conducted the present analysis to assess the impact of the publication 1 of the preliminary analysis of the Concorde Trial 2 and its associated publicity 3,4 on zidovudine utilization in the province of British Columbia. The distribution of antiretroviral drugs in British Columbia is free of charge through the provincial Centre for Excellence in HIV/AIDS [human immunodeficiency virus/acquired immunodeficiency syndrome]. In order for physicians to prescribe zidovudine, they complete a patient enrollment form that serves as the drug prescription. This application is usually accompanied by a CD4 cell count determination. Individuals infected with HIV are eligible to receive zidovudine from this program if they have at least one CD4 cell count less than 0.50 ×10 9 /L (500/μL). There is no other legal source of zidovudine in the province. A total of 564 new zidovudine requests were received during the first 9 months of 1993. As

Effectiveness of zidovudine in treatment of advanced HIV infection

Since the introduction of zidovudine, an inhibitor of retroviral reverse transcriptase, there has been continuing controversy regarding the usefulness of this agent. Questions have been raised about the optimal time to initiate therapy and about the duration of benefit achieved with this form of antiretroviral treatment. Preliminary findings of the Concorde trial,¹a multicenter double-blind, randomized study, failed to demonstrate a significant benefit in survival or rate of disease progression in patients with immediate use of zidovudine therapy compared with deferred treatment. The guidelines promulgated by the expert panel convened after the results of the Concorde trial were presented attempted to address these issues using data from controlled clinical trials.²The panel suggested that antiretroviral therapy was optional in asymptomatic persons with CD4 lymphocyte counts of 0.20 to 0.50X10⁹/L (200 to 500/μL) but that zidovudine should be given to human immunodeficiency virus (HIV)-infected individuals who were

Combination therapy for infection due to human immunodeficiency virus type 1.

The preliminary results of the Concorde trial demonstrated the transient clinical benefit of monotherapy with zidovudine (AZT) in asymptomatic persons infected with human immunodeficiency virus type 1 (HIV-1). This result, which has been widely disseminated and discussed, was predictable given the previous demonstration of the development of resistance to AZT in isolates from individuals receiving prolonged treatment with the drug and given the finding that didanosine (ddI) is more efficacious than continued therapy with AZT in individuals who have received > or = 6 months of AZT monotherapy. On the basis of these findings, interest in combinations of antiretroviral agents has continued to grow. Many in vitro studies of nucleoside and nonnucleoside inhibitors of reverse transcriptase combined with interferon-alpha or inhibitors of protease have been published. In addition, numerous clinical trials of various combinations have been completed or are under way. Dr. Martin Hirsch and his colleagues at the Massachusetts General Hospital have been among the leaders of this effort. He and Dr. Angela Caliendo review, in this AIDS Commentary, the current state of our knowledge regarding the potential utility of combination therapy for infection with HIV-1.

The Concorde findings considered

The eagerly-awaited results of the Concorde trial were revealed last week in theLancet [9 April].1Preliminary findings that were published just over a year ago in a letter to theLancet [April 3, 1993]* caused considerable controversy at the time. However, the original conclusions from the Concorde study remain unchanged, despite any minor differences in figures that may have emerged. According to the investigators, the results of the Concorde trial are sufficient to discourage the early use of zidovudine in symptom-free HIV-infected adults. Furthermore, in their view, doubt has now been cast on the‘uncritical use of CD4 counts as “surrogate endpoints” in trials’.Inevitably, controversy will continue to reign, especially in view of a number of criticisms that have been levelled at the study.

Use of Antiretroviral Drugs in HIV Disease Declines Following Preliminary Results From Concorde Trial

THE USE of antiretroviral therapy to treat asymptomatic human immunodeficiency virus (HIV) infection appears to be sharply down. Records kept by the Ontario HIV Project Centre in Canada, which distributes all antiretroviral drugs in the province, show an overall decrease by 45.4% in the number of patients starting therapy with zidovudine (Retrovir, commonly called AZT, Burroughs Wellcome, Research Triangle Park, NC) since the July 1993 Ninth International Conference on AIDS, held in Berlin, Germany. Rates are now the lowest since the first-line antiretroviral was first licensed in 1987, says Anita Rachlis, MD, medical director of the HIV Project Centre. She reported the finding at the First National Conference on Human Retroviruses and Related Infections, held in Washington, DC. Among asymptomatic patients, the records show that there has been a 52% decrease, apparently because of the presentation at the Berlin meeting of data with the longest follow-up time to date on