BLOOD PRESSURE
1992; 1: 1 13-1 19
Prospective Randomized Open Blinded End-point (PROBE) Study. A novel design for intervention trials LENNART HANSSON,' THOMAS HEDNER2 and B J d R N DA H L d F ' From the Department of Medicine, University of Goteborg. dstra Hospital', 416 85 Goteborg, and 'Department of Clinical Pharmacology, University of Goteborg. Sahlgren's Hospital, 413, 45 Goteborg. Sweden
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Hansson L, Hedner T, Dahl6f B. Prospective randomized open blindedend-point (PROBE) study. A novel designfor intervention trials. Blood Pressure 1992; 1: 113-1 19. A novel design for intervention studies is presented, the so called PROBE study (Prospective Randomized Open, Blinded Endpoint). This design is compared to the classical double-blind design. Among the advantages of the PROBE design are lower cost and greater similarity to standard clinical practice, which should make the results more easily applicable in routine medical care. Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard. Key words: intervention trial, trial design, end-point evaluation.
INTRODUCTION Ideally medical interventions should be based on knowledge and experience generated in well designed and conducted intervention trials. Such requirements are usually fulfilled by prospective, double-blind, placebo-controlled or comparative studies, provided that a sufficiently large patient population has been included 113. When assessing intervention against disease a number of aspects need to be considered. Ethical problems related to resource allocation as well as potential risks and benefits for the individual or group of patients may also become prominent [2]. Thus, when a positive therapeutic effect has been established, e.g. in a double-blind, placebo-controlled intervention trial in hypertension, it is obviously unethical to again expose a similar set of patients to prolonged administration of ineffective treatment or placebo. As an example, the recently concluded STOP-Hypertension Trial (Swedish Trial in Old Patients with Hypertension) [3,4] included patients aged 70-84 years, i.e. a group of patients in whom the value of antihypertensive therapy was not undisputed. Since the trial showed highly significant benefits from active treatment, it is obvious that, for ethical reasons, future trials cannot compare active treatment and placebo in a similar patient population. When introducing new and potentially advantageous therapeutic modalities it is considered essential to compare the new therapy with active established treatment, e.g. in a double-blind, prospective study. In most cases, such a trial will have to accumulate considerably larger numbers of patient-years than a trial in which an active therapeutic modality is compared to placebo. In practical terms this means that the possibilities of conducting large trials with active controls are limited
either by difficulties in obtaining sufficient numbers of patients or difficulties in making the studies long enough. Needless to say, a study of long duration puts special demands on the investigators to keep patients in the study. As an example, it can be mentioned that the MRC study of treatment of hypertension in older adults lost 25% of all patients to follow-up in a 5-year study [5]. Linked to all these problems is the fact that costs increase with the size and duration of the trials. The remarkable costs for performing large intervention studies can be exempified by the Multiple Risk Factor Intervention Trial (MRFIT) [6, 71 which after screening 361,662 middle-aged men in the US compared usual care and special intervention in 12,866 individuals with high risk for cardiovascular complications in a 6-year trial at a cost of $1 15 millions [7]. Other large-scale intervention trials have also been associated with considerable costs (Table I). As an alternative to the traditional placebo-controlled double-blind trials we propose a novel and simplified study design for medical intervention trials, which we call PROBE (Prospective Randomized Open Blinded End-Point). It is the purpose of this review to briefly discuss the potential advantages and disadvantages as well as the practical applications of the PROBE design.
TRADITIONAL STUDY DESIGNS Historically, a number of study designs have been used in intervention trials. The alternatives include: open retrospective trials, open prospective analyses, singleblind prospective trials, double-blind prospective placebo-controlled studies and double-blind prospective
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Table I. Costs (in US$) of some major cardiovascular intervention trials* Study
cost
References
Multiple Risk Factor Intervention Trial (MRFIT) Studies of Left Ventricular Dysfunction (SOLVD) Systolic Hypertension in the Elderly Program (SHEP) Lipid Research Clinic Project (LRC-CPPT)
115
6, 7 8 9 10
39 50
140
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* Personal communication,Dr. J. L. Probstfield, M.D., National Institutes of Health, USA.
trials comparing two or more active therapeutic modalities. Open retrospective trials Studies with this design, usually with nonrandomized or historic controls, played an important role many decades ago, e.g. in establishing the value of antihypertensive treatment, both in malignant [ l l , 121 and non malignant hypertension [ 131. While these studies were important at the time they were conducted, they do not meet today’s more stringent requirements for acceptable intervention trials. An open retrospective analysis can never be accepted as definitive proof of the existence of an effect or a phenomenon. Some recent papers on the “J-shaped curve” between blood pressure and risk of myocardial infarction can serve as examples of this [14, 151. These studies have also justifiably been criticised [ 16, 171. The value of open retrospective analyses is that they can form the basis of a hypothesis which then needs to be evaluated in a properly designed prospective trial. Open prospective trials The major difference between an open prospective and an open retrospective trial is that the former allows randomization. In all other regards it suffers from the same drawbacks as the open retrospective study, being equally open to biased interpretation of the results. Single-blind prospective trials This design has been used in several large intervention trials, e.g. the Medical Research Council Trials of Treatment of Hypertension in Older Adults [5] and in Mild Hypertension [18]. The latter trial included 17,353 hypertensive men and women in the United Kingdom who were given placebo, bendrofluazide or propranolol [18]. Part of the critique directed towards the singleblind design of the trial was that dosage adjustments frequently occurred in the actively treated patients but not in the placebo group
This illustrates that there are no advantages with a single-blind design as compared to an open design with regard to the actions of the participating physicians. On the other hand, patient compliance can be expected to benefit from a single-blind design if placebo is one of the modalities administered during the study. However, if only active therapeutic modalities are compared, little benefit can be derived from a single-blind design, since patients usually cannot be expected to have a strong bias for or against any given therapy. Double-blind, prospective, placebo-controlled trials This is the classical design of intervention trials and has traditionally been considered to provide the most reliable results. Numerous trials have been conducted in accordance with this design, e.g. the Veterans Administration Studies on the value of antihypertensive therapy in the 1960’s [19,20]. The advantages with this design are clear: physician and patient biases are avoided. The major drawback, which has been alluded to above, is that ethical considerations prohibit the use of a long-term placebo-group once a therapeutic effect has been established for a certain category of patients. Another disadvantage is that a very limited number of eligible patients are recruited into these relatively complicated trials and that poor recruitment actually may hamper research [21]. In fact, both in hypertension trials, e.g. SHEP [9] and STOP-Hypertension [22] as well as in breast cancer trials [23], only 2% or less of the screened population were recruited. Double-blind, prospective trials without placebo control This design allows the evaluation of a new therapeutic principle in comparison with an established one without causing the ethical problems associated with a longterm placebo control group. As noted above, such a trial usually requires considerably larger numbers of patient-years than a trial with a placebo control group. It is therefore reasonable to assume that regarding patient numbers, study duration and costs lead to a restrictive attitude towards this type of intervention
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PROBE study. A novel design for intervention trials
trial. This could result in the unfortunate situation that a number of new therapeutic principles never become subjected to a rigorous intervention trial. It could further lead to justified conservatism in the selection of therapies, since it could correctly be claimed that newer therapies have not been evaluated in prospective intervention trials. This can be exemplified by the position of the British Hypertension Society in their recommendation of diuretics and beta-blockers as the only therapies suitable for firstline antihypertensive treatment [24]. In other words, therapies accepted as firstline treatment for hypertension internationally, i.e. angiotensin converting enzyme inhibitors and calcium antagonists [25, 261, were not included since data from intervention trials were lacking. THE PROBE DESIGN The Prospective Randomized Open Blinded End-point (PROBE) study is a highly cost-effective alternative to the double-blind, prospective study design. This design utilizes a strict randomization procedure to allocate patients to different treatment regimens. The continuous follow-up and treatment of patients is conducted openly in a way that adheres to accepted clinical principles and medical practice. Strictly defined endpoints are blinded during the handling procedure, allowing unbiased comparison of therapies and evaluation of the study results. In addition to its lower cost, the PROBE design appears even to offer other advantages as compared to the double-blind, prospective trial. In particular, the great similarity between a PROBE study and regular clinical practice should make the results obtained in a PROBE trial much more applicable to the practical management of patients (Table 11). Randomization The purpose of randomization is that all patients in a trial should have the same chance of receiving a
Table 11. Advantages and disadvantages of the PROBE designed trial in comparison with the classical doubleblind ( D B ) prospective randomized trial
Randomization cost Investigator bias Patient compliance Reliability of end-point evaluation Similarity to clinical practice
PROBE
DB
+ + + + +
+-
-
++-
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particular treatment. This is important in order to eliminate possible biases that may lead to systematic errors [27]. In this regard a double-blind prospective randomized trial and a PROBE trial are equal.
cost Without doubt the classical double-blind, prospective, randomized trial carries considerably higher costs than the PROBE study. To a large extent this is due to the complicated packing and distribution of double-blind medication. In the PROBE design regular prescription or non-prescription drugs can be used, obviously at a much lower cost compared to double-blinded medication. This facilitates the handling of medication at all levels, in its turn also lowering costs. Finally, the number of forms and all documentation can be simplified, without compromising quality, which also helps to bring down expenditure. Investigator bias The main advantage with the double-blind trial is that investigator bias is avoided. In a properly designed, double-blind trial the investigator would not be able to identify the treatment regimens under trial. However, it is also fair to recognize that an experienced clinician who takes part in a double-blind trial is sometimes able to identify the true nature of study medication with a high degree of accuracy. As an example, in doubleblind intervention trials in which a beta-blocker has been one of the study drugs, e.g. the IPPPSH trial [28], a simple assessment of the patient’s heart rate would be an easy test by which the beta-blocker group could be separated from the non-beta-blocker group. In other trials, typical adverse effects could give similar clues to the experienced investigator. The possibility of investigator bias is, however, a drawback of the PROBE design. Therefore, measures should be taken in order to minimize such bias as much as possible. This could be done by careful instructions to investigators and by comparing therapeutic modalities of similar appeal. Patient compliance Poor compliance may affect the outcome of clinical trials in many ways [29]. If compliance is reduced to 50%, the number of subjects in a comparative trial would have to be increased about four-fold (power 95 %, significancelevel 5%) to show a difference (if there is one) [30]. Preferential compliance, e.g. with one drug in a comparative trial, could also give misleading results regarding efficacy o r safety [31].
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Compliance is notoriously difficult to assess in an acceptable manner. It appears reasonable to assume, however, that patient compliance may be negatively affected by the administration of double-blind medication, which is often distributed in anonymous looking bottles carrying code numbers. This may sometimes cause doubts and it is likely that most patients would prefer to take an ordinary, prescribed treatment regimen. Reliability of end-point evaluation This is the crucial aspect of all intervention trials aiming at the evaluation of morbidity or mortality. The selection of members in end-point committees and the adherence to strict guidelines for end-point evaluation is of utmost importance. There is no reason to believe that the reliability of end-point evaluation would differ between a PROBE study and a double-blind study, provided that the same criteria are applied. Certainly, as for other types of major intervention trial designs it is of great importance to select strictly defined and clinically undisputable end-points in the PROBE study design. Similarity to clinical practice The merits of a simple methodology have already been stressed by others [l]. Some authorities have even advocated “ultra-simple’’ studies in order to provide important answers in common medical conditions [32]. One way of increasing simplicity is to reduce the number of exclusion criteria as much as possible. Obviously fewer exclusion criteria are needed in a PROBE study in which medication is given in an open fashion, as compared to a double-blind trial. Another aspect on the similarity to clinical practice is that it should be possible to implement the results of an intervention trial in everyday clinical practice. Because of its similarity to the clinical management of patients, the PROBE study appears to have a clear advantage in this regard.
PRACTICAL ASPECTS OF THE PROBE DESIGN Evidently any intervention trial today must comply with accepted ethical standards, the Helsinki declaration and other recognized guidelines for the conduct of clinical trials. The PROBE design makes no exceptions in this regard. With regard to the inclusion of patients, the first important step is to provide the patient with adequate information about the study at hand. The patient should be informed that two (or more) therapeutic
modalities will be evaluated side by side with an aim to find out if one or the other will provide advantages in terms of strictly defined and generally accepted endpoints such as e.g. greater protection against cardiovascular morbidity and mortality in hypertension trials. The second important piece of information that should be given to the patient is that the selection of therapy will be made through a randomized procedure. Once the patient has accepted this and given his/her informed consent to participate, randomization can take place. This can be done by using closed envelopes according to a strict procedure, or ideally by contacting a special randomization center. Treatment then follows standard procedure with the drugs or therapies in question. In the case of pharmacological intervention, standard, commercially available drugs can be used. These can either be provided as a nonprescription study drug or alternatively by regular prescriptions, provided that the patient would have been a candidate for this type of treatment anyway. Certainly, the PROBE design allows for comparison of other types of medical, surgical or radiological treatment principles as well. This of course means that strict randomization to treatments and blinded end-point evaluation are applied as outlined above. Study records, including records of possible endpoints, must be of the highest quality. In this respect the PROBE study does not differ from a regular doubleblind, randomized prospective trial, with the exception that forms relating to medication can be kept much simpler in a PROBE study. The practical handling of an endpoint as well as the blinding procedure is outlined in Fig. 1. Final evaluation of the blinded end-points is made by an entirely independent end-point committee. Strict guidelines for the work of this committee are essential and consensus should be reached among the members of the committee before an end-point can be accepted as such. As in a classical, double-blind trial, a safety committee and a steering committee are required also in the PROBE study. In order to ensure the highest possible standards, statistical analyses and data handling should be performed by independent bodies and not directly by any of the parties involved in the management of the study. Finally, audit site visits at participating centers should be performed in order to ensure Good Clinical Trial Practice. In none of these respects does the PROBE study differ from the double-blind, prospective, randomized trial. PROBE STUDIES IN PROGRESS Several studies using the PROBE design are currently in
PROBE study. A novel design f o r intervention trials
Evaluation of end-points in a PROBE-study
Investigator Report
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I
Local coordinator
!
Coordinating centre Registrationand blinding
I---
1
End-point committee
IL
~
Evaluation
1
II
; /SteeringoTmKl Fig. I . The practical handling of an end-point in a PROBE
Study. The blinding of the information and the blinded evaluation by the end-point committee are crucial. The dashed arrow indicates that the safety committee may advise the steering committee, e.g. as regards the premature stopping of the trial provided that certain predetermined stopping rules have been applied. progress or in the final stage. In one of these, the BBB trial (Behandla Blodtryck Battre p r e a t Blood Pressure Better]) the aims were to evaluate whether blood pressure can be further reduced in “well treated” hypertensive patients, whether this would increase the number or severity of side-effects and finally whether a further lowering of blood pressure would have positive effects on cardiovascular morbidity and mortality [33]. Treated hypertensive patients with diastolic blood pressures in the range 90- 100 mmHg were randomized to either intensified treatment aiming at a diastolic blood pressure < 80 mmHg, or to unchanged treatment
1 17
in a PROBE designed trial. Regarding the first two aims it is obvious that a difference in treated diastolic blood pressure of 7 mmHg can be obtained and that this difference can be maintained for several years while at the same time being associated with a significant reduction in adverse effects [34]. Another ongoing trial using the PROBE design is the CAPPP trial (Captopril Prevention Project) [35]. This trial, which started in April 1990, aims at evaluating whether antihypertensive treatment based on the angiotensin converting enzyme inhibitor captopril may reduce cardiovascular mortality during a 5-year period in 10,900 hypertensive patients compared to a nonangiotensin converting enzyme inhibition based treatment [35]. At present (June 1992) approximately 8,000 patients have been enrolled in this trial. A similar approach is used in the NORDIL Study (Nordic Diltiazem) the aim of which is compare diltiazem-based treatment with diuretics and betablockers regarding hard end-points in some 12,000 patients in Finland, Norway and Sweden. The HOT Study (Hypertension Optimal Treatment) is a multinational trial in 18,000 patients that will investigate if therapeutic aims of G90, G85 or G80 mmHg in diastolic blood pressure will affect cardiovascular morbidity and mortality. In addition, the value of a low dose of aspirin (75 mg/day) will be compared to placebo. Finally, the STOP Hypertension I1 Study (Swedish Trial in Old Patients with Hypertension) will also use the PROBE design [36]. In this trial, which is based on the positive findings in STOP Hypertension I [4] demonstrating the benefits of diuretics and betablockers in elderly hypertensives, those therapies will be evaluated against newer agents, i.e. angiotensin converting enzyme inhibitors and calcium antagonists. At least two different agents will be used from each class of compounds in order to minimize investigator bias. CONCLUSIONS The basis of sound medical judgements should be derived from data obtained in reliable intervention trials. This is in the interest of all concerned parties, i.e. patients, physicians, academia, insurance companies, industry and society. However, the prohibitive costs and the complexity of conducting large-scale, doubleblind, intervention trials may lead to a situation where the number of necessary or even vital studies that can be conducted will become limited. This could lead to a slow-down of progress in important medical areas relying on data generated in such intervention trials. We therefore propose a new type of trial design, the PROBE design (Prospective Randomized Open
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Blinded End-point), which is a cost-effective alternative to the classical double-blind, prospective, randomized trial. In addition to its lower cost, the PROBE design appears advantageous by being more similar to clinical practice and perhaps by offering improved patient compliance. REFERENCES
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1. MacMahon S, Sharpe N. Future directions for ran-
domized trials of cardiovascular disease prevention in hypertensive patients. J Cardiovasc Pharmacol 1990; 16 (SUPPI7): S96-S9. 2. Hedner T, Hansson L. A utilitarian or deontological approach toward primary prevention of cardiovascular disease. Acta Med Scand 1988; 224: 293-302. 3. Dahlof B, Hansson L, Lindholm L, Rgstam L, ScherstCn B, Wester PO. STOP-Hypertension-Swedish Trial in Old Patients with Hypertension. J Hypertens 1986; 4: 511-3. 4. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. STOP-Hypertension (Swedish Trial in Old Patients with Hypertension). Lancet 1991; 338: 1281-5. 5 . MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1992; 304: 405-12. 6. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial. Risk factor changes and mortality results. JAMA 1982; 248: 146577. 7. Kolata G. Heart study produces a surprise result. Science 1982; 218: 31-2. 8. The SOLVD Investigators. Studies of Left Ventricular Dysfunction (S0LVD)-Rationale, design and methods: two trials that evaluate the effect of enalapril in patients with reduced ejection fraction. Am J Cardiol 1990; 66: 3 15-22. 9. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. J Am Med ASSOC1991; 365: 3255-64. 10. Lipid Research Clinic Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. J Am Med Assoc 1984; 251: 351-64. 11. Dustan HP, Schneckloth RE, Corcoran AC, Page IH. The effectiveness of long-term treatment of malignant hypertension. Circulation 1958; 18: 644-51. 12. Harington M, Kincaid-Smith P, McMichael J. Results of treatment in malignant hypertension. A 7-year experience in 94 cases. Br Med J 1959; 2: 969-80. 13. Bjork S, Sannerstedt R, Falkheden T, Hood B. The effect of active drug treatment in severe hypertensive disease. An analysis of survival rates in 381 cases of combined treatment with various hypotensive agents. Acta Med Scand 1960; 166: 175-87. 14. Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet 1987; i: 581-4. 15. Alderman MH, Ooi WL, Madhavan S, Cohen H. Treatment-induced blood pressure reduction and the risk of myocardial infarction. JAMA 1989; 262: 920-4.
16. Hansson L. Editorial: How far should blood pressure be lowered? What is the role of the J-curve? Am J Hypertens 1990; 3: 726-9. 17. Zanchetti A, Amery A, Berglund G, et al. Clinical Round Table: How much should blood pressure be lowered? The problem of the J-shaped curve. J Hypertens 1989; 7 (SUPPI 6): S338-S48. 18. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 97-104. 19. Veterans Administration Cooperative Study Group on Antihypertensive Agents, Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressure averaging 115 through 129 mmHg. JAMA 1967; 202: 1028-34. 20. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. 11. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 1143-52. 21. MacIntyre IMC. Editorial. Tribulations for clinical trials. Poor recruitment is hampering research. Br Med J 1991; 302: 1099-1100. 22. Dahlof B, Hansson L, Lindholm L, ScherstCn B, Wester PO. STOP-Hypertension-preliminary communication from the pilot study of the Swedish Trial in Old Patients with Hypertension. J Hypertens 1987; 5 (Suppl5): S607s10. 23. De Vita VT. Breast cancer therapy: exercising all our options. N Engl J Med 1989; 320: 527-9. 24. British Hypertension Society Working Party. Treating mild hypertension. Agreement from the large trials. Br Med J 1989; 298: 694-8. 25. The 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-8. 26. WHO/ISH Fifth Mild Hypertension Conference. The 1989 guidelines for the management of mild hypertension. Memorandum from a WHO/ISH meeting. J Hypertens 1989; 7: 689-93. 27. Altman DG. Editorial. Randomisation: essential for reducing bias. Br Med J 1991; 302: 1481-2. 28. The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: The International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens 1985; 3: 379-92. 29. Anonymous. Editorial. Patient compliance in therapeutic trials. Lancet 1991; 337: 823-4. 30. Goldsmith CH. The effect of differing compliance distribution on the planning and statistical analysis of therapeutic trials. In: Sacket DL, Haynes RB, eds. Compliance with therapeutic regimens. London: Johns Hopkins University Press, 1976; 137-51. 3 1. Feinstein AR. Clinical biostatistics XXX. Biostatistical problems in “compliance bias”. Clin Pharmacol Ther 1974; 16: 846-57. 32. Yusuf S, Collins R, Pet0 R. Why do we need some large sample randomized trials? Stat Med 1984; 3: 409-20. 33. The BBB Study Group. The BBB Study: A prospective randomized study of intensified antihypertensive treatment. J Hypertens 1988; 6: 693-7. 34. Hansson L, Dahlof B, Abelin J for the BBB Study Group.
PROBE study. A novel design for intervention trials
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Reduction in blood pressure and adverse effects in the BBB Study. (Abstract) Presented at the 5th European Meeting of Hypertension (ESH), Milan, June 7-10, 1991. 35. The CAPPP Group. The Captopril Prevention Project: A prospective intervention trial of angiotensin converting enzyme inhibition in the treatment of hypertension. J Hypertens 1990; 8: 985-90. 36. Hansson L, Dahlof B, De Faire U et al. for the STOPHypertension I1 Study Group. The Second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension 11): Evaluating established versus new therapeutic regi-
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mens in the treatment of hypertension. Blood Pressure 1992 (in press). Submitted March 25, 1992; accepted May 29, 1992 Address for correspondence: Lennart Hansson, M.D. Deptartment of Medicine Ostra Hospital CK2 S-416 85 Goteborg Sweden
1992; 1: 1 13-1 19
Prospective Randomized Open Blinded End-point (PROBE) Study. A novel design for intervention trials LENNART HANSSON,' THOMAS HEDNER2 and B J d R N DA H L d F ' From the Department of Medicine, University of Goteborg. dstra Hospital', 416 85 Goteborg, and 'Department of Clinical Pharmacology, University of Goteborg. Sahlgren's Hospital, 413, 45 Goteborg. Sweden
Blood Press Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/19/14 For personal use only.
Hansson L, Hedner T, Dahl6f B. Prospective randomized open blindedend-point (PROBE) study. A novel designfor intervention trials. Blood Pressure 1992; 1: 113-1 19. A novel design for intervention studies is presented, the so called PROBE study (Prospective Randomized Open, Blinded Endpoint). This design is compared to the classical double-blind design. Among the advantages of the PROBE design are lower cost and greater similarity to standard clinical practice, which should make the results more easily applicable in routine medical care. Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard. Key words: intervention trial, trial design, end-point evaluation.
INTRODUCTION Ideally medical interventions should be based on knowledge and experience generated in well designed and conducted intervention trials. Such requirements are usually fulfilled by prospective, double-blind, placebo-controlled or comparative studies, provided that a sufficiently large patient population has been included 113. When assessing intervention against disease a number of aspects need to be considered. Ethical problems related to resource allocation as well as potential risks and benefits for the individual or group of patients may also become prominent [2]. Thus, when a positive therapeutic effect has been established, e.g. in a double-blind, placebo-controlled intervention trial in hypertension, it is obviously unethical to again expose a similar set of patients to prolonged administration of ineffective treatment or placebo. As an example, the recently concluded STOP-Hypertension Trial (Swedish Trial in Old Patients with Hypertension) [3,4] included patients aged 70-84 years, i.e. a group of patients in whom the value of antihypertensive therapy was not undisputed. Since the trial showed highly significant benefits from active treatment, it is obvious that, for ethical reasons, future trials cannot compare active treatment and placebo in a similar patient population. When introducing new and potentially advantageous therapeutic modalities it is considered essential to compare the new therapy with active established treatment, e.g. in a double-blind, prospective study. In most cases, such a trial will have to accumulate considerably larger numbers of patient-years than a trial in which an active therapeutic modality is compared to placebo. In practical terms this means that the possibilities of conducting large trials with active controls are limited
either by difficulties in obtaining sufficient numbers of patients or difficulties in making the studies long enough. Needless to say, a study of long duration puts special demands on the investigators to keep patients in the study. As an example, it can be mentioned that the MRC study of treatment of hypertension in older adults lost 25% of all patients to follow-up in a 5-year study [5]. Linked to all these problems is the fact that costs increase with the size and duration of the trials. The remarkable costs for performing large intervention studies can be exempified by the Multiple Risk Factor Intervention Trial (MRFIT) [6, 71 which after screening 361,662 middle-aged men in the US compared usual care and special intervention in 12,866 individuals with high risk for cardiovascular complications in a 6-year trial at a cost of $1 15 millions [7]. Other large-scale intervention trials have also been associated with considerable costs (Table I). As an alternative to the traditional placebo-controlled double-blind trials we propose a novel and simplified study design for medical intervention trials, which we call PROBE (Prospective Randomized Open Blinded End-Point). It is the purpose of this review to briefly discuss the potential advantages and disadvantages as well as the practical applications of the PROBE design.
TRADITIONAL STUDY DESIGNS Historically, a number of study designs have been used in intervention trials. The alternatives include: open retrospective trials, open prospective analyses, singleblind prospective trials, double-blind prospective placebo-controlled studies and double-blind prospective
1 14
L. Hansson et 01.
Table I. Costs (in US$) of some major cardiovascular intervention trials* Study
cost
References
Multiple Risk Factor Intervention Trial (MRFIT) Studies of Left Ventricular Dysfunction (SOLVD) Systolic Hypertension in the Elderly Program (SHEP) Lipid Research Clinic Project (LRC-CPPT)
115
6, 7 8 9 10
39 50
140
Blood Press Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/19/14 For personal use only.
* Personal communication,Dr. J. L. Probstfield, M.D., National Institutes of Health, USA.
trials comparing two or more active therapeutic modalities. Open retrospective trials Studies with this design, usually with nonrandomized or historic controls, played an important role many decades ago, e.g. in establishing the value of antihypertensive treatment, both in malignant [ l l , 121 and non malignant hypertension [ 131. While these studies were important at the time they were conducted, they do not meet today’s more stringent requirements for acceptable intervention trials. An open retrospective analysis can never be accepted as definitive proof of the existence of an effect or a phenomenon. Some recent papers on the “J-shaped curve” between blood pressure and risk of myocardial infarction can serve as examples of this [14, 151. These studies have also justifiably been criticised [ 16, 171. The value of open retrospective analyses is that they can form the basis of a hypothesis which then needs to be evaluated in a properly designed prospective trial. Open prospective trials The major difference between an open prospective and an open retrospective trial is that the former allows randomization. In all other regards it suffers from the same drawbacks as the open retrospective study, being equally open to biased interpretation of the results. Single-blind prospective trials This design has been used in several large intervention trials, e.g. the Medical Research Council Trials of Treatment of Hypertension in Older Adults [5] and in Mild Hypertension [18]. The latter trial included 17,353 hypertensive men and women in the United Kingdom who were given placebo, bendrofluazide or propranolol [18]. Part of the critique directed towards the singleblind design of the trial was that dosage adjustments frequently occurred in the actively treated patients but not in the placebo group
This illustrates that there are no advantages with a single-blind design as compared to an open design with regard to the actions of the participating physicians. On the other hand, patient compliance can be expected to benefit from a single-blind design if placebo is one of the modalities administered during the study. However, if only active therapeutic modalities are compared, little benefit can be derived from a single-blind design, since patients usually cannot be expected to have a strong bias for or against any given therapy. Double-blind, prospective, placebo-controlled trials This is the classical design of intervention trials and has traditionally been considered to provide the most reliable results. Numerous trials have been conducted in accordance with this design, e.g. the Veterans Administration Studies on the value of antihypertensive therapy in the 1960’s [19,20]. The advantages with this design are clear: physician and patient biases are avoided. The major drawback, which has been alluded to above, is that ethical considerations prohibit the use of a long-term placebo-group once a therapeutic effect has been established for a certain category of patients. Another disadvantage is that a very limited number of eligible patients are recruited into these relatively complicated trials and that poor recruitment actually may hamper research [21]. In fact, both in hypertension trials, e.g. SHEP [9] and STOP-Hypertension [22] as well as in breast cancer trials [23], only 2% or less of the screened population were recruited. Double-blind, prospective trials without placebo control This design allows the evaluation of a new therapeutic principle in comparison with an established one without causing the ethical problems associated with a longterm placebo control group. As noted above, such a trial usually requires considerably larger numbers of patient-years than a trial with a placebo control group. It is therefore reasonable to assume that regarding patient numbers, study duration and costs lead to a restrictive attitude towards this type of intervention
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PROBE study. A novel design for intervention trials
trial. This could result in the unfortunate situation that a number of new therapeutic principles never become subjected to a rigorous intervention trial. It could further lead to justified conservatism in the selection of therapies, since it could correctly be claimed that newer therapies have not been evaluated in prospective intervention trials. This can be exemplified by the position of the British Hypertension Society in their recommendation of diuretics and beta-blockers as the only therapies suitable for firstline antihypertensive treatment [24]. In other words, therapies accepted as firstline treatment for hypertension internationally, i.e. angiotensin converting enzyme inhibitors and calcium antagonists [25, 261, were not included since data from intervention trials were lacking. THE PROBE DESIGN The Prospective Randomized Open Blinded End-point (PROBE) study is a highly cost-effective alternative to the double-blind, prospective study design. This design utilizes a strict randomization procedure to allocate patients to different treatment regimens. The continuous follow-up and treatment of patients is conducted openly in a way that adheres to accepted clinical principles and medical practice. Strictly defined endpoints are blinded during the handling procedure, allowing unbiased comparison of therapies and evaluation of the study results. In addition to its lower cost, the PROBE design appears even to offer other advantages as compared to the double-blind, prospective trial. In particular, the great similarity between a PROBE study and regular clinical practice should make the results obtained in a PROBE trial much more applicable to the practical management of patients (Table 11). Randomization The purpose of randomization is that all patients in a trial should have the same chance of receiving a
Table 11. Advantages and disadvantages of the PROBE designed trial in comparison with the classical doubleblind ( D B ) prospective randomized trial
Randomization cost Investigator bias Patient compliance Reliability of end-point evaluation Similarity to clinical practice
PROBE
DB
+ + + + +
+-
-
++-
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particular treatment. This is important in order to eliminate possible biases that may lead to systematic errors [27]. In this regard a double-blind prospective randomized trial and a PROBE trial are equal.
cost Without doubt the classical double-blind, prospective, randomized trial carries considerably higher costs than the PROBE study. To a large extent this is due to the complicated packing and distribution of double-blind medication. In the PROBE design regular prescription or non-prescription drugs can be used, obviously at a much lower cost compared to double-blinded medication. This facilitates the handling of medication at all levels, in its turn also lowering costs. Finally, the number of forms and all documentation can be simplified, without compromising quality, which also helps to bring down expenditure. Investigator bias The main advantage with the double-blind trial is that investigator bias is avoided. In a properly designed, double-blind trial the investigator would not be able to identify the treatment regimens under trial. However, it is also fair to recognize that an experienced clinician who takes part in a double-blind trial is sometimes able to identify the true nature of study medication with a high degree of accuracy. As an example, in doubleblind intervention trials in which a beta-blocker has been one of the study drugs, e.g. the IPPPSH trial [28], a simple assessment of the patient’s heart rate would be an easy test by which the beta-blocker group could be separated from the non-beta-blocker group. In other trials, typical adverse effects could give similar clues to the experienced investigator. The possibility of investigator bias is, however, a drawback of the PROBE design. Therefore, measures should be taken in order to minimize such bias as much as possible. This could be done by careful instructions to investigators and by comparing therapeutic modalities of similar appeal. Patient compliance Poor compliance may affect the outcome of clinical trials in many ways [29]. If compliance is reduced to 50%, the number of subjects in a comparative trial would have to be increased about four-fold (power 95 %, significancelevel 5%) to show a difference (if there is one) [30]. Preferential compliance, e.g. with one drug in a comparative trial, could also give misleading results regarding efficacy o r safety [31].
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Compliance is notoriously difficult to assess in an acceptable manner. It appears reasonable to assume, however, that patient compliance may be negatively affected by the administration of double-blind medication, which is often distributed in anonymous looking bottles carrying code numbers. This may sometimes cause doubts and it is likely that most patients would prefer to take an ordinary, prescribed treatment regimen. Reliability of end-point evaluation This is the crucial aspect of all intervention trials aiming at the evaluation of morbidity or mortality. The selection of members in end-point committees and the adherence to strict guidelines for end-point evaluation is of utmost importance. There is no reason to believe that the reliability of end-point evaluation would differ between a PROBE study and a double-blind study, provided that the same criteria are applied. Certainly, as for other types of major intervention trial designs it is of great importance to select strictly defined and clinically undisputable end-points in the PROBE study design. Similarity to clinical practice The merits of a simple methodology have already been stressed by others [l]. Some authorities have even advocated “ultra-simple’’ studies in order to provide important answers in common medical conditions [32]. One way of increasing simplicity is to reduce the number of exclusion criteria as much as possible. Obviously fewer exclusion criteria are needed in a PROBE study in which medication is given in an open fashion, as compared to a double-blind trial. Another aspect on the similarity to clinical practice is that it should be possible to implement the results of an intervention trial in everyday clinical practice. Because of its similarity to the clinical management of patients, the PROBE study appears to have a clear advantage in this regard.
PRACTICAL ASPECTS OF THE PROBE DESIGN Evidently any intervention trial today must comply with accepted ethical standards, the Helsinki declaration and other recognized guidelines for the conduct of clinical trials. The PROBE design makes no exceptions in this regard. With regard to the inclusion of patients, the first important step is to provide the patient with adequate information about the study at hand. The patient should be informed that two (or more) therapeutic
modalities will be evaluated side by side with an aim to find out if one or the other will provide advantages in terms of strictly defined and generally accepted endpoints such as e.g. greater protection against cardiovascular morbidity and mortality in hypertension trials. The second important piece of information that should be given to the patient is that the selection of therapy will be made through a randomized procedure. Once the patient has accepted this and given his/her informed consent to participate, randomization can take place. This can be done by using closed envelopes according to a strict procedure, or ideally by contacting a special randomization center. Treatment then follows standard procedure with the drugs or therapies in question. In the case of pharmacological intervention, standard, commercially available drugs can be used. These can either be provided as a nonprescription study drug or alternatively by regular prescriptions, provided that the patient would have been a candidate for this type of treatment anyway. Certainly, the PROBE design allows for comparison of other types of medical, surgical or radiological treatment principles as well. This of course means that strict randomization to treatments and blinded end-point evaluation are applied as outlined above. Study records, including records of possible endpoints, must be of the highest quality. In this respect the PROBE study does not differ from a regular doubleblind, randomized prospective trial, with the exception that forms relating to medication can be kept much simpler in a PROBE study. The practical handling of an endpoint as well as the blinding procedure is outlined in Fig. 1. Final evaluation of the blinded end-points is made by an entirely independent end-point committee. Strict guidelines for the work of this committee are essential and consensus should be reached among the members of the committee before an end-point can be accepted as such. As in a classical, double-blind trial, a safety committee and a steering committee are required also in the PROBE study. In order to ensure the highest possible standards, statistical analyses and data handling should be performed by independent bodies and not directly by any of the parties involved in the management of the study. Finally, audit site visits at participating centers should be performed in order to ensure Good Clinical Trial Practice. In none of these respects does the PROBE study differ from the double-blind, prospective, randomized trial. PROBE STUDIES IN PROGRESS Several studies using the PROBE design are currently in
PROBE study. A novel design f o r intervention trials
Evaluation of end-points in a PROBE-study
Investigator Report
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I
Local coordinator
!
Coordinating centre Registrationand blinding
I---
1
End-point committee
IL
~
Evaluation
1
II
; /SteeringoTmKl Fig. I . The practical handling of an end-point in a PROBE
Study. The blinding of the information and the blinded evaluation by the end-point committee are crucial. The dashed arrow indicates that the safety committee may advise the steering committee, e.g. as regards the premature stopping of the trial provided that certain predetermined stopping rules have been applied. progress or in the final stage. In one of these, the BBB trial (Behandla Blodtryck Battre p r e a t Blood Pressure Better]) the aims were to evaluate whether blood pressure can be further reduced in “well treated” hypertensive patients, whether this would increase the number or severity of side-effects and finally whether a further lowering of blood pressure would have positive effects on cardiovascular morbidity and mortality [33]. Treated hypertensive patients with diastolic blood pressures in the range 90- 100 mmHg were randomized to either intensified treatment aiming at a diastolic blood pressure < 80 mmHg, or to unchanged treatment
1 17
in a PROBE designed trial. Regarding the first two aims it is obvious that a difference in treated diastolic blood pressure of 7 mmHg can be obtained and that this difference can be maintained for several years while at the same time being associated with a significant reduction in adverse effects [34]. Another ongoing trial using the PROBE design is the CAPPP trial (Captopril Prevention Project) [35]. This trial, which started in April 1990, aims at evaluating whether antihypertensive treatment based on the angiotensin converting enzyme inhibitor captopril may reduce cardiovascular mortality during a 5-year period in 10,900 hypertensive patients compared to a nonangiotensin converting enzyme inhibition based treatment [35]. At present (June 1992) approximately 8,000 patients have been enrolled in this trial. A similar approach is used in the NORDIL Study (Nordic Diltiazem) the aim of which is compare diltiazem-based treatment with diuretics and betablockers regarding hard end-points in some 12,000 patients in Finland, Norway and Sweden. The HOT Study (Hypertension Optimal Treatment) is a multinational trial in 18,000 patients that will investigate if therapeutic aims of G90, G85 or G80 mmHg in diastolic blood pressure will affect cardiovascular morbidity and mortality. In addition, the value of a low dose of aspirin (75 mg/day) will be compared to placebo. Finally, the STOP Hypertension I1 Study (Swedish Trial in Old Patients with Hypertension) will also use the PROBE design [36]. In this trial, which is based on the positive findings in STOP Hypertension I [4] demonstrating the benefits of diuretics and betablockers in elderly hypertensives, those therapies will be evaluated against newer agents, i.e. angiotensin converting enzyme inhibitors and calcium antagonists. At least two different agents will be used from each class of compounds in order to minimize investigator bias. CONCLUSIONS The basis of sound medical judgements should be derived from data obtained in reliable intervention trials. This is in the interest of all concerned parties, i.e. patients, physicians, academia, insurance companies, industry and society. However, the prohibitive costs and the complexity of conducting large-scale, doubleblind, intervention trials may lead to a situation where the number of necessary or even vital studies that can be conducted will become limited. This could lead to a slow-down of progress in important medical areas relying on data generated in such intervention trials. We therefore propose a new type of trial design, the PROBE design (Prospective Randomized Open
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Blinded End-point), which is a cost-effective alternative to the classical double-blind, prospective, randomized trial. In addition to its lower cost, the PROBE design appears advantageous by being more similar to clinical practice and perhaps by offering improved patient compliance. REFERENCES
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16. Hansson L. Editorial: How far should blood pressure be lowered? What is the role of the J-curve? Am J Hypertens 1990; 3: 726-9. 17. Zanchetti A, Amery A, Berglund G, et al. Clinical Round Table: How much should blood pressure be lowered? The problem of the J-shaped curve. J Hypertens 1989; 7 (SUPPI 6): S338-S48. 18. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 97-104. 19. Veterans Administration Cooperative Study Group on Antihypertensive Agents, Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressure averaging 115 through 129 mmHg. JAMA 1967; 202: 1028-34. 20. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. 11. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 1143-52. 21. MacIntyre IMC. Editorial. Tribulations for clinical trials. Poor recruitment is hampering research. Br Med J 1991; 302: 1099-1100. 22. Dahlof B, Hansson L, Lindholm L, ScherstCn B, Wester PO. STOP-Hypertension-preliminary communication from the pilot study of the Swedish Trial in Old Patients with Hypertension. J Hypertens 1987; 5 (Suppl5): S607s10. 23. De Vita VT. Breast cancer therapy: exercising all our options. N Engl J Med 1989; 320: 527-9. 24. British Hypertension Society Working Party. Treating mild hypertension. Agreement from the large trials. Br Med J 1989; 298: 694-8. 25. The 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-8. 26. WHO/ISH Fifth Mild Hypertension Conference. The 1989 guidelines for the management of mild hypertension. Memorandum from a WHO/ISH meeting. J Hypertens 1989; 7: 689-93. 27. Altman DG. Editorial. Randomisation: essential for reducing bias. Br Med J 1991; 302: 1481-2. 28. The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: The International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens 1985; 3: 379-92. 29. Anonymous. Editorial. Patient compliance in therapeutic trials. Lancet 1991; 337: 823-4. 30. Goldsmith CH. The effect of differing compliance distribution on the planning and statistical analysis of therapeutic trials. In: Sacket DL, Haynes RB, eds. Compliance with therapeutic regimens. London: Johns Hopkins University Press, 1976; 137-51. 3 1. Feinstein AR. Clinical biostatistics XXX. Biostatistical problems in “compliance bias”. Clin Pharmacol Ther 1974; 16: 846-57. 32. Yusuf S, Collins R, Pet0 R. Why do we need some large sample randomized trials? Stat Med 1984; 3: 409-20. 33. The BBB Study Group. The BBB Study: A prospective randomized study of intensified antihypertensive treatment. J Hypertens 1988; 6: 693-7. 34. Hansson L, Dahlof B, Abelin J for the BBB Study Group.
PROBE study. A novel design for intervention trials
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Reduction in blood pressure and adverse effects in the BBB Study. (Abstract) Presented at the 5th European Meeting of Hypertension (ESH), Milan, June 7-10, 1991. 35. The CAPPP Group. The Captopril Prevention Project: A prospective intervention trial of angiotensin converting enzyme inhibition in the treatment of hypertension. J Hypertens 1990; 8: 985-90. 36. Hansson L, Dahlof B, De Faire U et al. for the STOPHypertension I1 Study Group. The Second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension 11): Evaluating established versus new therapeutic regi-
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mens in the treatment of hypertension. Blood Pressure 1992 (in press). Submitted March 25, 1992; accepted May 29, 1992 Address for correspondence: Lennart Hansson, M.D. Deptartment of Medicine Ostra Hospital CK2 S-416 85 Goteborg Sweden
