The JUMBO proposal for a Multiple Risk Factor Intervention Trial. 1969

‘JUMBO’ MRFIT Protocol 1969 Submission to NIH

These Specific Aims were submitted to NIH in May 1969 with an investigator-initiated proposal for JUMBO, an optimal multiple risk factor intervention trial (MRFIT) from 4 centers and a Houston coordinating center. It was state-of-the-art, developed by Remington, Stamler, Taylor and colleagues, based on their experience and recommendations of the 1968 Makarska Conference on Mass Field Trials in CHD prevention. It was rejected by NIH on “policy grounds,” due to the in-house plans for its own MRFIT at the National Heart Institute. The sad story of JUMBO and of the NHI MRFIT is published in the Am. J. of Epidemiology in 2019.

Specific Aims:

1. Assessment of CHD prevention by multifactorial intervention: The objective of this national cooperative trial is to assess ability to achieve primary prevention of coronary heart disease (CHD) in free-living, high-risk, middle-aged American men. The basic hypothesis is that premature mortality from CHD can be significantly reduced by altering customary habits of diet, cigarette usage, and sedentary living, i.e. by controlling major known coronary risk factors. Changes in mode of life of the experimental group are to include altered nutrition to lower elevated serum lipid levels and reduce obesity; elimination of cigarette smoking; and correction of sedentary living habit through regular exercise for enhancement of cardiopulmonary fitness. In addition, for participants with elevated blood pressure responding inadequately to the foregoing measures, pharmacologic therapy is to be utilized in the experimental group with the aim of reducing blood pressure to within the clinically accepted normal range. 
   The key end point to be used for scientific evaluation of the prophylactic regimen is effect on mortality rate from coronary heart disease over a seven year period. The trial is designed to detect with high probability (.95) a reduction of 40 per cent in both CHD incidence and mortality rates in the experimental group, compared with the control group Further, it is designed to detect with high probability (.90) a reduction of 25 per cent in total mortality rate. In addition, assessment is to be made of effect of the experimental regimen on such other major disease end points as incidence and mortality from all cardiovascular diseases (particularlyCHD plus stroke plus peripheral vascular disease).
2. Assessment of preventive effect of various forms of intervention: A second objective is to assess whether primary prevention of CHD results from modification of diet and exercise habits alone, independent of cessation of cigarette smoking and control of hypertension, and whether the latter two forms of intervention summate with the former in preventive effect. To accomplish this goal, eligible high-risk volunteers for the trial are to be stratified into four subgroups prior to randomization: (1) hypercholesterolemia only; (2) hypercholesterolemia + hypertension; (3) hypercholesterolemia + cigarette smoking; (4) hypercholesterolemia + hypertension + cigarette smoking. Men are then to be assigned to experimental and control regimens from each of these subgroups. For experimental subgroup 1. intervention is to entail only modification of diet and exercise habits. For the other experimental subgroups, in addition to change in diet and exercise habits, control of hypertension and/or cigarette smoking (as required) is to be undertaken. CHD incidence is to be the key end point for this subgroup analysis. The Study as designed has a high probability (.95) of detecting a 50 per cent reduction in CHD incidence in any experimental subgroup, compared with its randomly assigned control subgroup.
3. Evaluation of interrelationships between risk factor changes and CHD prevention: The Study has the additional purpose of evaluating interrelationships between changes in serum lipids, weight, cigarette smoking, blood pressure, and exercise habit, and patterns of CHD incidence. Changes prescribed for the experimental group and subgroups will induce significant changes in coronary risk factors in men continuing as active participants. It is anticipated that these will represent a majority, i.e., it is estimated that dropout over the seven years of the Study will not exceed 45 per cent.
   Status with respect to key risk factors is to be systematically monitored throughout the Study for both experimental and control groups. The objectives with regard to these intermediate end points in the hypercholesterolemic, high-risk men continuing as active participants in the experimental group and subgroups are: to lower mean serum cholesterol concentration by at least 15 per cent; to reduce serum triglyceride levels of hypertriglyceridemic men by at least 15 per cent; to convert at least 50 per cent of cigarette smokers into non-cigarette smokers; to reduce high blood pressure to near normal or within normal ranges; to effect and sustain a mean reduction in body weight of obese men of at least 7 per cent; and to improve cardiovascular fitness of at least a majority of participants, as demonstrated objectively by a significant reduction in pulse rate in standardized graded exercise tests. Since extensive evidence from prospective studies demonstrates that coronary risk factors and CHD mortality rates are closely correlated, it is reasonable to hypothesize that changes in these risk factors will be related to incidence and mortality from CHD.
4. Evaluation of possible harmful effects of the experimental regimens: A fourth major aim is to make repeated measurements throughout the Study to determine whether the experimental regimens are producing any harmful or toxic effects.
5. Enhancement of knowledge on CHD natural history and epidemiology: Assessment of the efficacy of the experimental regimens in this controlled Study requires the simultaneous long-term observation of a large sample of high-risk men randomly allocated to the control group and therefore receiving no recommendations from the research project. This control group is also to provide further information concerning the natural history and epidemiology of coronary heart disease in coronary-prone,middle-aged, free-living American men, in addition to the primary purpose of the control group, i.e., to provide simultaneous valid assessment of the change induced by the experimental regimen.
6. Enhancement of knowledge on methodology of cooperative field trials on prevention of cardiovascular disease: An investigation of this scope can be done only as a national cooperative undertaking among several research groups adhering to a common protocol. In this Study, each of the Research Centers — located in a large metropolitan area — is to mount a major effort for this purpose from a broad base in its community. Another aim of this investigation, therefore, is to acquire further experience and knowledge concerning the principles, techniques, procedures, organization, and total methodology of such long-term major collaborative mass field trials on primary prevention of chronic, non infectious, premature cardiovascular disease.
7. Creation of a firmer scientific basis for the effort to control the CHD epidemic: The final key objective is to provide a firmer scientific basis for recommendations to the medical community and the general public about the value and desirability of change of mode of life and treatment of coronary risk factors for the prophylaxis of premature CHD .