a Medical Statistics Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
b Cardiovascular Institute, Göteburg University, Sweden
c Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway
d Department of Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
e Statistics Collaborative, Washington DC, USA
Received February 17, 2004; revised July 27, 2004; accepted September 9, 2004 * Corresponding author. Fax: +44 20 7637 2853 (E-mail: stuart.pocock{at}lshtm.ac.uk).
Abstract
AIMS: This article describes a challenging data monitoring experience that occurred in a major international randomized placebo-controlled trial in patients with heart failure, in which the accumulating interim data showed an excess of deaths on the active treatment.
METHODS AND RESULTS: The MOXonidine CONgestive Heart Failure trial was a randomized comparison of moxonidine, a central sympathetic inhibitor, with placebo. It was planned to recruit 4500 patients with heart failure. The primary endpoint was all-cause mortality, and average follow-up was anticipated to be around 2.5 years until 724 deaths occurred. The trial Data Monitoring Board (DMB) was to conduct safety monitoring reviews of interim data at least every six months, and make their recommendations to the Executive Committee. Within a few months of the study starting, the Data Monitoring Board (DMB) observed an emerging trend of an excess of deaths on moxonidine compared with placebo. This article describes the sequence of events that unfolded: several DMB meetings to evaluate the accumulating evidence, a DMB recommendation to stop the trial, consequent dialogue with the Executive Committee and sponsor leading to a final decision to stop the trial. Ten months after the first patient was randomized, the study was stopped based on 46 versus 25 deaths in 990 moxonidine and 943 placebo patients, respectively, P=0.01. The final published evidence had 54 versus 32 deaths, P=0.012.
CONCLUSIONS: This study illustrates the problems faced by a DMB, and subsequently the trial Executive Committee and sponsor, in deciding how to act in the face of an emerging (and agonizing) negative trend for mortality in a major international trial.
Introduction
It is appropriate standard practice for a major randomized clinical trial to have an independent Data Monitoring Board (DMB) whose purpose is "to protect the safety of trial participants, the credibility of the study and the validity of study results".1 The ethical importance of such a DMB"s role is particularly relevant when the interim data suggest possible negative (harmful) effects of a new treatment, especially if this concerns an excess of death. It has been noted that "the handling of such emerging negative trends is among the most complicated and ethically challenging scenarios in monitoring clinical trials through repeated interim analyses".2
The aim of this article is to document one such data monitoring experience in a major international placebo-controlled randomized trial the MOXonidine CONgestive Heart Failure (MOXCON) Trial.3 We describe first how the DMB"s evaluation of the emerging excess mortality on the active drug, moxonidine, led to a recommendation to stop the trial. We then document the consequent dialogue amongst the DMB, Executive Committee and sponsor that led to a final decision to stop. The consequent published results are presented and commented on.
Study design
The MOXCON Trial3 was undertaken to evaluate the long-term efficacy of sustained-release moxonide, a central sympathetic nervous system inhibitor on fatal and non-fatal outcomes in patients with chronic heart failure being treated with other relevant background therapy.
Moxonidine reduces plasma noradrenaline (NA) levels, known to be elevated in heart failure, and a prognostic factor for mortality. A shorter acting version is a well-tolerated and effective anti-hypertensive agent. Previous short-term trials of related drugs had revealed reductions in plasma NA, favourable haemodynamic effects and symptomatic improvement.
MOXCON was designed as a randomized double-blind placebo controlled trial in patients with NYHA class II to IV heart failure, with ejection fraction ⩽35%. Moxonidine SR or matching placebo was given in a forced titration in four stages, from an initial low dose to a dose of 1.5mg BID, unless symptomatic hypotension, worsening renal function or other severe side effects were noted.
The primary endpoint was all-cause mortality, and the main secondary endpoints were: (1) hospitalisation due to worsening heart failure, (2) the combination of such hospitalisation or death, and (3) cardiovascular mortality.
The study was powered to detect a 20% reduction in mortality relative to an anticipated 2.5 year all-cause mortality rate in the placebo arm of 22.75%, using a log rank test, two-sided 5% type I error and 80% power. This required around 4500 patients to be recruited and then followed until 724 deaths occurred. Patient recruitment was at 425 centres in 17 countries. The study was sponsored by Eli Lilly and Company and Solvay Pharmaceuticals. Executive and Steering Committees (chair Jay Cohn) oversaw study conduct, a Clinical Endpoint Committee (chair Marc Pfeffer) adjudicated events, and a Data Monitoring Board (DMB) monitored the interim results, as explained below. The DMB had five members: three clinicians, Lars Wilhelmsen (Chair), Kenneth Dickstein, Gary Francis and two statisticians, Stuart Pocock and Janet Wittes. All interim reports were prepared by Larry Meinert.
The DMB were also to monitor patient safety in an ongoing Phase II trial (MOXSE) which was comparing five different dose levels of moxonidine with placebo in heart failure patients.4 The prime purpose of MOXSE was to determine the relation of plasma NA levels with dose, a key issue in deciding the dose of moxonidine for the MOXCON trial.
The DMB had a planning meeting with sponsor representatives present on 28th March 1998, at which point the MOXSE trial was already underway. Some concerns were expressed about the complexity of starting MOXCON before MOXSE was completed, especially as regards the difficulty of selecting the moxonidine dose for MOXCON so soon.
Statistical stopping guidelines
The primary efficacy results for all-cause mortality were to be monitored four times over the course of the study, when 25%, 50%, 75% and 100% of the expected 724 deaths had occurred. The nominal two-sided P-values for early stopping for efficacy (ie fewer deaths on moxonide compared with placebo) were 0.0001 at the 25% analysis and 0.001 at the 50% and 75% analyses.
The DMB was also to conduct safety monitoring reviews at least every 6 months throughout the course of the study. A safety stopping criterion for all cause mortality was one-sided P<0.05 with at least a 20% observed increase in all cause mortality for moxonidine versus placebo.
Data monitoring in MOXCON
Randomization began in May 1998 and since there was quite rapidly accelerating recruitment, the DMB"s first face-to-face meeting to inspect interim data was on 20th October 1998. The DMB also inspected near-final results of the MOXSE trial. There were no discernable safety concerns and the DMB recommended that the MOXCON study continue as planned.
The DMB next met by teleconference on 2 February 1999, by which time 1469 patients had been randomized. The main concern was that there were 25 deaths in the moxonidine group and 14 in the placebo group, P=0.08. The DMB consensus was that the total number of deaths was too small upon which to make a definitive assessment. While a face-to-face DMB meeting had been provisionally planned for 9 March 1999, the DMB concluded it would be inadvisable to wait until then, and that a teleconference be held in the interim.
Accordingly, the DMB"s next meeting (by teleconference) was on 16th February 1999. By then 1639 patients had been recruited (839 moxonidine, 800 placebo). The unfavourable trend in mortality had increased further, with 37 deaths reported in the moxonidine group compared with 20 deaths in the placebo group, log rank P=0.02.
The DMB were faced with the disconcerting observation of almost twice as many deaths on moxonidine compared with placebo; this difference was in excess of the pre-defined statistical stopping boundary.
Additional data pertinent to the DMB"s decision making was:
The DMB decided, on the basis of this totality of available evidence, to recommend to the Executive Committee that the trial be stopped. The principal argument was that since all-cause mortality was the primary endpoint of the study, the observed negative trend in mortality suggested that a true reduction in mortality due to moxonidine was highly unlikely to be present and detectable with more data. On the other hand, continuing MOXCON"s recruitment and follow-up of patients might confer a real risk of further excess deaths attributable to moxonidine, an ethically highly undesirable prospect.
Decision-making following the DMB recommendation
On transmitting this recommendation to the Executive, which included the essential data on which it was based, the chairman of the DMB proposed a joint meeting of the DMB, Executive Committee and sponsor representatives as soon as possible. Any additional data that accrued in the interim would be available at that meeting. Fortunately, many involved were attending the upcoming American College of Cardiology annual conference, so this meeting took place on 9th March 1999, less than 3 weeks after the DMB recommendation, a short period of trial continuation that both the DMB and Executive Committee thought appropriate.
At the time of the meeting, 46 deaths had been reported in the moxonidine group and 25 deaths in the placebo group. That is, a further 15 deaths had occurred (9 moxonidine, 5 placebo) making the difference slightly more significant than earlier, P=0.01.
The members of the Executive Committee debated extensively regarding whether: (1) the DMB"s recommendation be accepted at this point or (2) additional follow-up and recruitment be sought, i.e., the study continue as planned for the time being with a view to reviewing the situation again a few weeks later.
While noting that the DMB is an advisory body only, the Executive Committee and Sponsor were fully aware of the difficulties that might arise were they not to accept a sustained recommendation to stop by the DMB. For instance, such a recommendation is new information which should be made available to the Institutional Review Boards of participating centres. This emphasises the power and ultimate responsibility of the independent DMB in this situation.
This type of occasion often highlights the inevitable divergence of roles, and hence views, from the two committees. Both committees have ethical and scientific responsibilities, but the two emphases differ. The DMB"s remit is primarily ethical: based on all the available evidence, taking account of all patient interests (i.e., those already randomized, those due to be randomized, those in the broader community of similar patients requiring treatment in future) it is necessary to decide whether it is ethical for the study to continue as planned. The Executive Committee"s remit also concerns scientific and organizational issues: having established the study operations they wished the study"s design and conduct to be of the highest possible standards so that it gives the most reliable evidence regarding the efficacy and safety of the randomized active treatment, thus enhancing scientific knowledge and the care of future patients.
Such full achievement of scientific understanding may be inhibited by the early termination of a study for ethical reasons, since fewer patients followed for less time inevitably means that estimates of treatment effect have poorer precision. Thus, there is a scientific basis for the Executive to want the study to continue longer:
An additional factor is that many individuals have devoted considerable collaborative effort in MOXCON with the plausible hope of contributing to a therapeutic advance of major importance. Hence there was considerable collective disappointment in the prospect of such early trial termination for safety reasons, which understandably provokes some reluctance by Executive Committee members to accept the DMB"s recommendation. It is also important to recognize that the ultimate decision-making responsibility rests with the sponsor"s Senior Management.
After a lengthy discussion, the DMB and Executive Committee reached the following consensus:
In fact, the sponsor"s Senior Management decided on 11th March to stop the MOXCON trial. Patient recruitment stopped that day. All investigators were immediately informed of the reason and need to terminate the trial, and were advised that patients already in the study should visit them as soon as possible so that their randomized treatment could be stopped. Within a few days the sponsor issued a press release explaining how and why the study had stopped early.
The published results
Follow-up for analysis had ceased immediately on 12th March, so that the final results included all deaths that occurred on or before that date. Compared with data available on the 9th March meeting there were 15 additional deaths (8 moxonidine, 7 placebo). The final results were based on 1934 randomized patients (990 moxonidine, 943 placebo). There were 54 deaths on moxonidine compared with 34 on placebo, log rank P=0.012. The survival plot (Fig. 1) revealed a steadily diverging treatment difference in the risk of dying.
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These results were presented at the next available international cardiological meetings, the European Society of Cardiology and the American Heart Association in August and November 1999, respectively. Achieving publication was less straightforward, since acceptance in one of the major general medical journals could not be obtained. Hence to avoid further delay, MOXCON has now appeared in a specialist journal3 more than three years after attempts to publish were begun. This reflects a common trend whereby important results of major trials not showing a therapeutic advance have difficulty in gaining publication in the leading journals.
So for some years the only publicly accessibly MOXCON results were brief accounts in the magazine SCRIP6 and a European Society of Cardiology meeting report.7
Concluding remarks
The MOXCON trial is an informative example of the difficulties in deciding whether and when to stop a major trial when emerging data suggest a major hazard of a new treatment. This problem has been referred to as "the agonizing negative trend" in data monitoring, in an article presenting several previous examples.2
There is a clear tension between two conflicting undesirable outcomes to be avoided:
The statistical stopping guideline for harm in MOXCON was rather non-stringent: one-sided P<0.05 with no correction for multiple testing. In hindsight, one might prefer a more stringent rule to reduce the risk of stopping too soon. Note that in practice the evidence for a mortality excess at the point of deciding to stop MOXCON had reached two-sided P=0.01.
However, the MOXCON experience illustrates that the collaborative process leading to the decision to stop a trial for harm requires substantially more insight into data, their interpretation and the consequences of one"s actions than just a helpful statistical guideline.
Acknowledgments
We are grateful to members of the MOXCON trial Executive Committee and representatives of the sponsors, Eli Lilly and Company and Solvay Pharmaceuticals for their helpful comments in the development of this article.
References