Vol. 18, No. 3, February 3, 1989 NOTICES "OTHER SUPPORT" IN PHS GRANT APPLICATIONS ...................(84/109)....... 1 National Institutes of Health Index: NATIONAL INSTITUTES OF HEALTH "OTHER SUPPORT" IN NIH R&D CONTRACT PROPOSALS ...............(112/130)...... 1 National Institutes of Health Index: NATIONAL INSTITUTES OF HEALTH BIOMEDICAL WORKSHOP ON SUPERCOMPUTING TECHNIQUES ............(133/169)....... 1 Division of Research Resources Index: RESEARCH RESOURCES DATED ANNOUNCEMENTS (RFPs AND RFAs) EVALUATION OF CONTROL MEASURES AGAINST HUMAN INFECTIOUS DISEASES OTHER THAN AIDS (RFP) ..............................(175/212)....... 2 National Institute of Allergy and Infectious Diseases Index: ALLERGY AND INFECTIOUS DISEASES PREPARATION OF RADIOLABELED SPHINGOLIPIDS (RFP) .............(215/265)....... 2 National Institute of Neurological Disorders and Stroke Index: NEUROLOGICAL DISORDERS AND STROKE DEVELOPMENT OF LIVE, ATTENUATED, COLD-ADAPTED (CA) INFLUENZA VACCINES (RFP) ..............................................(268/301)....... 3 National Institute of Allergy and Infectious Diseases Index: ALLERGY AND INFECTIOUS DISEASES SHALLOW WATER MARINE ORGANISM COLLECTION (RFP) ..............(304/357)....... 3 National Cancer Institute Index: CANCER HMG CoA REDUCTASE INHIBITORS IN THE ELDERLY: PILOT STUDY (RFA) (360/398).... 4 National Heart, Lung, and Blood Institute (644/1733) Index: HEART, LUNG, AND BLOOD ONGOING PROGRAM ANNOUNCEMENTS RESEARCH GRANTS ON FRONTAL LOBE EPILEPSIES ..................(404/555)...... 5 National Institute of Neurological Disorders and Stroke Index: NEUROLOGICAL DISORDERS AND STROKE ERRATUM DEVELOPMENT OF SOMATIC CELL GENE THERAPY APPROACHES FOR SPECIFIC INBORN METABOLIC DISEASES (RFA) .............................(564/575)....... 7 National Institute of Diabetes and Digestive and Kidney Diseases Index: DIABETES, DIGESTIVE AND KIDNEY DISEASES NOTICES "OTHER SUPPORT" IN PHS GRANT APPLICATIONS P.T. 34; K.W. 1014002, 1014006 National Institutes of Health The PHS 398 (Rev. 9/86) and PHS 2590 (Rev. 9/86) grant application forms include a section on OTHER SUPPORT, where applicants are expected to list all, including both Federal and non-Federal, active support and pending and planned requests for support of research and research-related activities by all key personnel listed for each application. This information is important to PHS review-award processes to help evaluate the compatibility of application requests with investigators' capabilities and responsibilities, and eliminate unwarranted duplication of support for investigators' efforts. Application instructions emphasize the requirement for complete, accurate, and reliable information. In signing the face page of the application the principal investigator/program director and the applicant institution official certify that the application information is accurate and complete. Applicants are reminded of the necessity to provide the full and reliable information requested. As noted in the instructions, "Incomplete, inaccurate, or ambiguous information about OTHER SUPPORT could lead to delays in review of the application." Further, applicants should be cognizant that serious consequences could result if failure to provide complete and accurate information be construed as an attempt to mislead PHS agency advisory groups and staff in their review and award responsibilities. "OTHER SUPPORT" IN NIH R&D CONTRACT PROPOSALS P.T. 34; K.W. 1014002, 1014006 National Institutes of Health Documentation required in Section J of the NIH uniform Request for Proposal format includes Standard Form 1411, Contract Pricing Proposal Cover Sheet, which instructs offerors to identify any contracts or subcontracts they have been awarded "for the same or similar items" within the past three years. Additionally, offerors are required to provide a Summary of Related Activities, identifying all active federal contracts, cooperative agreements, grants, and commercial agreements, and submitted proposals, including actual and proposed levels of effort for all key individuals in the proposal to NIH. As for PHS grant applications, mentioned just above, offerors should be aware that serious consequences could result if their failure to provide complete and accurate information be construed as an attempt to mislead agency advisory groups and staff in their review and award responsibilities. BIOMEDICAL WORKSHOP ON SUPERCOMPUTING TECHNIQUES P.T. 42; K.W. 1004000 Division of Research Resources The Pittsburgh Supercomputing Center (PSC) is conducting a 4 and 1/2 day workshop on supercomputing techniques for biomedical researchers May 1-5, 1989. This workshop is funded by a grant from the Division of Research Resources' Biomedical Research Technology (BRT) Program of the National Institutes of Health (NIH). The workshop is aimed at experienced FORTRAN programmers, but prior supercomputing experience is not necessary. The topics include an introduction to VMS (half-day, optional), the Cray-VAX interface, the UNICOS operating system, optimization techniques, an overview of available biomedical software and a description of access paths to the PSC. Travel, meals, and hotel accommodations are covered for U.S. academic participants under the grant. A limited number of openings for industry-based biomedical researchers may be available for a fee of $1,000. Enrollment is limited to 20 participants. THE DEADLINE FOR SUBMISSION OF APPLICATIONS IS MARCH 15, 1989. Vol. 18, No. 3, February 3, 1989 - Page 1 For application forms and further information, call or write to: Cherolyn A. Brooks User Services Pittsburgh Supercomputing Center 4400 Fifth Avenue Pittsburgh, Pennsylvania 15213 Telephone: (412) 268-5206, or 1-800-222-9310 (Pennsylvania); 1-800-221-1641 (outside Pennsylvania) DATED ANNOUNCEMENTS (RFPs AND RFAs) EVALUATION OF CONTROL MEASURES AGAINST HUMAN INFECTIOUS DISEASES OTHER THAN AIDS RFP AVAILABLE: RFP-NIH-NIAID-MIDP-90-3 P.T. 34; K.W. 0715125, 0740000, 0740075, 0755018 National Institute of Allergy and Infectious Diseases The National Institutes of Health (NIH) has a requirement for "Evaluation of Control Measures Against Human Infectious Diseases Other Than AIDS." The Microbiology and Infectious Diseases Program of the National Institute of Allergy and Infectious Diseases has a requirement to evaluate new and improved vaccine and therapy candidates in an efficient and expeditious manner. The successful offeror should have demonstrated capabilities to establish and maintain the facilities and staff necessary to conduct prophylactic and therapeutic studies on candidate vaccines, other biologicals and drugs in volunteers and the capability to manage and analyze data generated by the studies. This NIAID-sponsored project will take approximately five years to complete. Three cost-reimbursement contracts are anticipated. RFP-NIH-NIAID-MIDP-90-3 will be issued on or about January 31, 1989, with a closing date for receipt of proposals tentatively set for March 31, 1989. To receive a copy of the RFP, please supply this office with two (2) self-addressed mailing labels. All responsible sources may submit a proposal which will be considered by NIAID. Request for the RFP should be directed to: Mr. William C. Roberts National Institute of Allergy and Infectious Diseases Westwood Building, Room 707 5333 Westbard Avenue Bethesda, Maryland 20892 Telephone: (301) 496-2508 This advertisement does not commit the Government to award a contract. PREPARATION OF RADIOLABELED SPHINGOLIPIDS RFP AVAILABLE: RFP NIH-NINDS-89-07 P.T. 34; K.W. 1003006, 0780017 National Institute of Neurological Disorders and Stroke The National Institute of Neurological Disorders and Stroke (NINDS) has a requirement for the preparation and delivery of radiolabeled glycolipids and other sphingosine glycoconjugates. The Contractor shall synthesize and deliver to the NINDS 1 gram per year of: 1) 14C-glucocerebroside specifically labeled in the D-glucose portion of the molecule with a minimum specific activity of 1000 d.p.m. per nanomole as described in the Journal of Biological Chemistry, Vol. 240, pg. 39, l965; 2) 14C-sphingomyelin with a minimum specific activity of 1000 d.p.m. per nanomole as described in the Journal of Biological Chemistry, Vol. 24l, pg. l081, l966; and 3) 14C-ceramidetrihexoside labeled exclusively in the terminal molecule of galactose with a specific activity of 1000 d.p.m. per nanomole as described in Chemistry and Physics of Lipids, Vol. 22, pg. l97, l978, or appropriate modifications of these procedures that provide the respective pure radiocarbon-labeled sphingolipid(s). The preparations shall consist of a Vol. 18, No. 3, February 3, 1989 - Page 2 single (homogeneous) sphingolipids as confirmed by elemental analysis, thin-layer and/or high-pressure liquid chromatography. It is anticipated that one contract award will be made under this RFP for a three-year period. The RFP will be available on or about January 30, l989, with a closing date for receipt of proposals for March 3l, l989. This requirement represents the recompetition of a current contract with the Weizmann Institute of Science and the incumbent is expected to reapply. To receive a copy of the RFP, you must supply this office with two self-addressed mailing labels. All responsible sources may submit a proposal which will be considered by the Government. The RFP will be available upon written request to: Contracting Officer Contracts Management Branch National Institute of Neurological Disorders and Stroke, NIH Federal Building, Room 90l 7550 Wisconsin Avenue Bethesda, Maryland 20892 Attn: RFP-NIH-NINDS-89-07 DEVELOPMENT OF LIVE, ATTENUATED, COLD-ADAPTED (CA) INFLUENZA VACCINES RFP AVAILABLE: RFP-NIH-NIAID-MIDP-90-4 P.T. 34; K.W. 0740075, 0780005 National Institute of Allergy and Infectious Diseases The Influenza Program of the National Institute of Allergy and Infectious Diseases has a requirement for the continued development of live, attenuated, cold-adapted (ca) influenza vaccines. The offeror should demonstrate capabilities and facilities for providing seed stocks of live, attenuated, cold-adapted (ca) influenza virus vaccine reassortants for use in clinical trials. In addition to providing seed vaccines, the capability to further develop and expedite the methodology required to obtain reassortant vaccines is needed. This NIAID-sponsored project will take approximately three years to complete. One cost-reimbursement contract is anticipated. RFP-NIH-NIAID-MIDP-90-4 will be issued on or about February 3, 1989, with a closing date for receipt of proposals tentatively set for April 5, 1989. To receive a copy of the RFP, please supply this office with two (2) self-addressed mailing labels. All responsible sources may submit a proposal which will be considered by NIAID. Request for the RFP should be directed to: Ms. Joyce U. Sagami National Institute of Allergy and Infectious Diseases Westwood Building, Room 707 5333 Westbard Avenue Bethesda, Maryland 20892 Telephone: (301) 496-2509 This advertisement does not commit the Government to award a contract. SHALLOW WATER MARINE ORGANISM COLLECTION RFP AVAILABLE: NCI-CM-97597-30 P.T. 34; K.W. 0780005 National Cancer Institute The Developmental Therapeutics Program (DTP), Division of Cancer Treatment (DCT), National Cancer Institute (NCI), wishes to establish contracts for the collection of marine organisms for evaluation as sources of potential antineoplastic agents. This solicitation is for a continuation of the original contract awarded in 1986 and terminated in 1987. The ultimate goal of this effort is to discover agents of novel structural types which can be developed for the selective treatment of cancer in man. Vol. 18, No. 3, February 3, 1989 - Page 3 Contractors should be able to provide qualified personnel, materials and equipment for the collection, storage and shipping of 1000 marine samples per year to NCI-designated extraction and isolation facilities. Collections will comprise approximately 1-1.5 kg of each organism collected at depths down to 100 feet. Properly relaxed and preserved voucher specimens of each organism will be submitted for unambiguous identification and deposit in a designated repository. The contractor will be expected to provide detailed documentation, including identification of each organism collected, habitat, and location of the collection site in a computer format provided by NCI. The collection team should include a qualified marine taxonomist and certified SCUBA divers experienced in marine organism collection. The Principal Investigator should be experienced in the organization of collection programs, and have at least five (5) years of experience in marine organism collection. The program focuses on the collection of invertebrate species from as wide a variety of classes and genera as possible. To this end, the geographic location of proposed collection areas will be important and while the Indo-Pacific region has been the focus of previous collections, other areas will be favorably considered if suitably justified. All necessary negotiations with foreign governments and local agencies concerning the collection and shipment of organism will be carried out by the contractor. The government anticipates two (2), incrementally funded awards to be made to cover a period of two (2) years for each award. All responsible sources may submit a proposal which will be considered by the National Cancer Institute. This is not a Request for Proposal (RFP). RFP NCI-CM-97597-30 will be available to interested offerors on or about February 8, 1989, with a closing date of March 27, 1989. A copy of the RFP may be obtained by written or telephone request to: Ms. Elsa B. Carlton Contract Specialist Treatment Contracts Section, Research Contracts Branch National Cancer Institute 6120 Executive Blvd., Room 603 Bethesda, Maryland 20892 Telephone: (301) 496-8620 HMG CoA REDUCTASE INHIBITORS IN THE ELDERLY: PILOT STUDY RFA AVAILABLE: 89-HL-06-H P.T. 34; K.W. 0755015, 0715040, 0765025, 0760035, 0710100 National Heart, Lung, and Blood Institute Application Receipt Date: May 8, 1989 The Lipid Metabolism-Atherogenesis Branch of the Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute (NHLBI), announces the availability of a Request for Applications (RFA) on the above subject. Copies of the RFA are currently available from staff of the NHLBI. This program, which is also of interest to the National Institute on Aging, will support the design and performance of a pilot study for a collaborative randomized clinical trial to determine whether lowering elevated serum cholesterol levels after age 60, by use of one of a new class of potent cholesterol-lowering drugs, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, will reduce mortality due to the sequelae of atherosclerotic cardiovascular disease and thereby prolong life. This pilot study should consider possible protocols for such a trial, evaluate possible mechanisms for minimizing the cost of conducting such a trial successfully, and assess the feasibility of recruiting eligible participants into such a trial and sustaining their participation. The administrative and funding mechanism to be used to undertake this program will be cooperative agreements, an assistance mechanism. Requests for copies of this RFA should be addressed to: Dr. David J. Gordon Project Officer Lipid Metabolism-Atherogenesis Branch National Heart, Lung, and Blood Institute Federal Building, Room 404 7550 Wisconsin Avenue Bethesda, Maryland 20892 Telephone: (301) 496-1681 Vol. 18, No. 3, February 3, 1989 - Page 4 ONGOING PROGRAM ANNOUNCEMENTS RESEARCH GRANTS ON FRONTAL LOBE EPILEPSIES P.T. 34; K.W. 0715060, 0785035, 0785210, 0710100 National Institute of Neurological Disorders and Stroke Application Receipt Dates: February 1, June 1, and October 1 I. INTRODUCTION The Epilepsy Branch, Division of Convulsive, Developmental, and Neuromuscular Disorders, National Institute of Neurological Disorders and Stroke (NINDS), encourages the submission of research grant applications related to frontal lobe epilepsies. II. BACKGROUND Over 500,000 patients in the United States suffer from frontal lobe epilepsy, and 30 percent of these patients continue to have incapacitating frontal lobe seizures despite appropriate drug therapy. Therapeutic surgery is less likely to achieve remission or significant control of intractable seizures originating from the frontal lobe than from the temporal lobe. In November 1987, an international workshop on frontal lobe seizures and epilepsies was held in France. Proceedings will be published in 1989. The conference highlighted the need for characterization and classification of frontal lobe seizures based on neurobehavioral, electroclinical, anatomical, physiochemical and pathologic studies. The new information and concepts so generated will lead to a more dynamic understanding of frontal lobe brain function and will suggest new approaches for diagnosis and therapy of frontal lobe epilepsies. Collaborative basic and clinical research is needed to define the subtypes of frontal lobe epilepsies, their etiologies, their natural histories, and their pathophysiologies. To understand frontal lobe epilepsy, the organization of the entire brain and its functional systems (cognition, language, memory, personality, movement) must be studied. The chemically defined anatomical substrates, neurotransmitters, cellular events, and neuronal circuitry underlying frontal lobe seizures and epilepsies still remain unknown. Behavioral scientists have attempted to define the contribution of frontal lobe neuronal ensembles to human behavior. Although ablation of specific functional subdivisions in animal models provide consistent behavioral and physiological effects, such findings cannot always be extrapolated to the human brain. Epileptologists also have difficulty localizing certain ictal clinical manifestations to specific frontal lobe areas and predicting the risk of neurologic deficit following therapeutic surgery. Collaborative research could help achieve these goals. Studies of frontal lobe seizures have been stimulated by clinical research utilizing intensive monitoring (CCTV/EEG) including intracranial recording techniques, multimodal brain imaging, and regional cerebral metabolism and blood flow measurements. Attempts are being made to characterize subgroups of frontal lobe seizures. One such subgroup consists of seizures emanating from the paralimbic and heteromodal components of the frontal lobe which may be misdiagnosed as hysterical seizures or as temporal lobe complex partial seizures. Mapping of human cortical functions during surgery with local anesthesia has provided a unique opportunity for the performance of stimulation studies on the human brain. These can be integrated with microstimulation studies in animal models. This could lead to identification of phenomena (for example, electromyography in specific muscle groups or specific autonomic signs) that could be monitored during intensive monitoring (CCTV/EEG) of seizure patients in order to localize the focus of seizure origin and to define the neuronal pathways of seizure propagation. Currently available technology would allow in vivo definition of the most common neuropathological and biochemical correlates of the subvarieties of frontal lobe epilepsy. Positron emission tomography (PET) studies of patients with epilepsy have usually employed only measurements of blood flow or oxygen and glucose utilization. PET techniques have now been developed to measure such variables as protein synthesis, blood brain barrier integrity, tissue pH, water content, receptor binding for certain ligands, and brain metabolism of antiepileptic drugs. This ability of PET to assess regional biochemical Vol. 18, No. 3, February 3, 1989 - Page 5 functions in situ could provide a method of neurochemically subdividing the frontal lobe epilepsies. Magnetic resonance imaging (MRI) resolution currently allows identification of certain frontal regions (for example, the supplementary motor area, the supra-callosal region, and the inferior frontal gyrus). Nuclear magnetic resonance (NMR) spectroscopy could be used to study biochemical processes in human epilepsies with studies of carbon and phosphorus containing compounds (for example, ATP), as well as such ions as potassium. III. RESEARCH GOALS Investigators are encouraged to submit projects involving animal or human studies to address these issues. Examples of research goals include but are not limited to the following: 1) rational classification of frontal lobe seizures and epilepsies based on neurobehavioral, electroclinical, biochemical, anatomical substrates, and pathologic findings; 2) criteria for diagnosis by clinical and EEG features; 3) elucidation of functional organization and metabolism of the frontal lobes and the effect of lesions in specific areas of the frontal lobes; 4) identification of neuronal pathways for the spread of frontal lobe seizures; 5) improved pharmacological and surgical interventions for the control of frontal lobe epilepsies. IV. MECHANISM OF SUPPORT Support for this program will be through the regular research grant, FIRST award, or program project or center grant. Those applying for a program project or center grant should obtain a copy of the NINDS instructions that supplement those in the PHS 398 grant application from the NINDS contact identified at the end of this announcement. V. APPLICATION AND REVIEW PROCEDURES Applications should be prepared on Form PHS 398 (revised 9/86) according to instructions contained in the application kit. Application kits are available from most institutional business offices or may be obtained from the Division of Research Grants at the address given below. Check "yes" in item two on the face sheet of the application and type "Grants Related to Frontal Lobe Epilepsies" in the space provided. Applications will be judged on scientific merit and program relevance in accordance with NIH policy and procedures involving peer review. An initial review will be made by an appropriate study section of the Division of Research Grants for regular research grants and FIRST awards, and by a standing committee for program projects and centers. A second level of review will be made by an appropriate National Advisory Council. Deadlines for the receipt of the applications are: February l, June 1, and October 1. The original and six copies of the application should be mailed to the following address: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, Maryland 20892** For further information, applicants may contact: James J. Cereghino, M.D. National Institutes of Health NINDS, DCDND, EB Federal Building, Room 114 7550 Wisconsin Avenue Bethesda, Maryland 20892 Telephone: (301) 496-1917 This program is described in the Catalog of Federal Domestic Assistance No. 13.853, Clinical Basis Research and No. 13.854, Biological Basis Research, NINDS. Awards will be made under the authority of the Public Health Service Act, Title IV, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 4 CFR Part 74. This program is not subject to intergovernmental review requirements of Executive Order 12372 or Health Systems Agency Review. Vol. 18, No. 3, February 3, 1989 - Page 6 ERRATUM DEVELOPMENT OF SOMATIC CELL GENE THERAPY APPROACHES FOR SPECIFIC INBORN METABOLIC DISEASES RFA AVAILABLE: 89-DK-04 P.T. 34; K.W. 0715135, 1002058, 0780015, 0755020 National Institute of Diabetes and Digestive and Kidney Diseases This notice is to correct the Application Receipt Date that was published in the NIH Guide for Grants and Contracts on January 20, 1989, Vol. 18, No. 2. The correct Application Receipt Date is July 17, 1989. Vol. 18, No. 3, February 3, 1989 - Page 7 FULL TEXT OF RFAs FOR ONLINE ACCESS REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS: RFA NIH 89-HL-06-H HMG CoA REDUCTASE INHIBITORS IN THE ELDERLY: PILOT STUDY NATIONAL HEART, LUNG, AND BLOOD INSTITUTE P.T. 34; K.W. 0755015, 0715040, 0765025, 0760035, 0710100 Application receipt date: May 8, 1989 PURPOSE The Division of Heart and Vascular Diseases invites cooperative agreement applications for investigators to participate, with the assistance of the National Heart, Lung and Blood Institute (NHLBI), in the design and performance of a pilot study for a multicenter randomized clinical trial to determine whether lowering elevated serum cholesterol levels after age 60, by use of one of a new class of potent cholesterol- lowering drugs, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, will reduce mortality due to the sequelae of atherosclerotic cardiovascular disease. The assistance mechanism used to support the study is the cooperative agreement, which is similar to the traditional NIH research grant. It differs from a research grant in the extent and nature of NHLBI staff involvement. Applications received in response to the RFA will participate in a single competition. A center selected as a Clinical Center also may serve as the Coordinating Center for the overall study; however, separate applications would be required. DISCIPLINES AND EXPERTISE The expertise appropriate for this research program includes a knowledge of lipid metabolism and pharmacology, understanding of both the epidemiologic and clinical aspects of cardiovascular disease, appreciation of the special clinical problems arising in treating elderly patients, and experience in the design and conduct of collaborative clinical trials. Experience and skill in laboratory methods for lipid and lipoprotein measurement are appropriate for Clinical Centers. Skills in data base management and biostatistics are appropriate for the Coordinating Center. BACKGROUND Scientific Background The importance of cholesterol in the development of atherosclerotic coronary heart disease (CHD) has been established by observational epidemiologic studies and by metabolic, pathologic, and genetic studies in humans and selected animal models. However, the evidence that this disease can be arrested or reversed in humans by lowering plasma cholesterol levels is derived almost entirely from studies of middle-aged (35-59 year old) men with marked hypercholesterolemia and/or clinically manifest CHD. The guidelines issued in October 1987 by the National Cholesterol Education Program's (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults did not discriminate further by age or sex, except to allow room for physician judgment in applying their recommendations to women and to the elderly, given the absence of direct evidence of efficacy in such patients. The uncertainty of the extrapolation of clinical trials conducted in middle-aged men to older men and women is a matter of considerable consequence to the public health. While myocardial infarctions in middle- age are responsible for tragic losses of life and productivity, nearly 80% of all CHD deaths in the U.S. occur after age 65. In addition, CHD was recently estimated to account for one million hospitalizations, six million outpatient visits and $8.1 billion in direct health care costs annually in this age group. All these numbers can be expected to increase over the next four decades, as the aging of the "baby boom" generation and gains in longevity shift the age distribution of the U.S. population upward. The high prevalence (nearly 50%) of hypercholesterolemia in this age group provides an avenue by which preventive measures might reduce this toll. Although epidemiologic data from Framingham and other studies suggest that the relative contribution of plasma cholesterol levels to CHD risk diminishes with increasing age, the absolute numbers of deaths and myocardial infarctions attributable to high plasma cholesterol levels in these studies appear to increase. However, while subgroup analyses focusing on older participants in the Los Angeles Veterans Domiciliary Study, Coronary Drug Project (CDP), and Lipid Research Clinics (LRC) Coronary Primary Prevention Trial (CPPT) suggest that cholesterol-lowering treatment may be worthwhile after as well as before age 60, adequate experimental confirmation is lacking. Circulating levels of cholesterol, specifically cholesterol associated with the LDL fraction, have been established as a major etiologic factor in CHD. However, the clinical trials that have demonstrated that lowering LDL-cholesterol levels reduces subsequent incidence of CHD events have been confined by and large to middle-aged men, with hypercholesterolemia (e.g., the CPPT) or established CHD (e.g., the CDP). The ratio between the percent reduction in CHD incidence and the percent reduction in cholesterol levels associated with treatment in these trials, approximately 2:1, is almost exactly that predicted by numerous observational epidemiologic studies of this relationship. This relationship has been quantified most precisely in the follow-up of more than 350,000 men screened for participation in the NHLBI's Multiple Risk Factor Intervention Trial (MRFIT); CHD mortality rates increased by 0.8% for each 1 mg/dl increment in serum cholesterol level. This relationship held throughout the cholesterol distribution and was independent of other risk factors; even cholesterol levels between 182 and 202 mg/dl (the second quartile) were associated with appreciably higher risk than were levels below 182 mg/dl. While the follow-up of men screened for MRFIT supports extrapolation of the clinical trial results to lower cholesterol levels, and the Framingham and LRC Mortality Follow-Up studies support their extrapolation to women, epidemiologic studies suggest that the prognostic power of cholesterol levels diminishes with advancing age. Subdivision of the participants in several cohort studies into those above or below age 50 at entry shows that the increment in CHD risk per increment in total or LDL cholesterol level is nearly always substantially lower in the older group. While most studies have too few participants over 60 years of age at entry to permit meaningful analysis, recently published data from Framingham, based on 4 years of follow-up of cholesterol measurements performed in 1977-9 (when all participants were at least 57 years old and their average age was nearly 70 years), estimated an 0.5% increment in the CHD incidence rate per 1 mg/dl increment in plasma cholesterol level. Thus, the projected benefit of a given reduction in cholesterol levels is about 60% as great in this cohort as in the younger MRFIT cohort. Note that when the potential number of CHD events that could be prevented annually is considered, this diminution in prognostic strength is more than offset by the steep increase in event rates with advancing age. It may be argued on theoretical grounds that the diminution with advancing age of the prognostic strength of a chronic disease risk factor like cholesterol, which acts cumulatively over extended time periods, need not imply a parallel diminution of the risk reduction that can be attained by treating that risk factor. As the cohort with the highest cholesterol levels within a population ages, the most susceptible members die of CHD, leaving behind those who are relatively resistant to the atherosclerotic sequelae of hypercholesterolemia, who are joined by others with hypercholesterolemia of more recent onset. At the same time, since even "normal" cholesterol levels in the U.S. population are high enough to produce significant coronary atherosclerosis in those who live long enough, those who reach old age tend to be relatively homogeneous, in that most have been exposed to potentially damaging cholesterol levels. Thus, the etiologic role of atherosclerotic progression may be masked in observational studies of the elderly. However, this role may be unmasked when a drug that can potentially reduce LDL cholesterol to levels at which plaques may cease to progress is administered in a randomized trial. Given the increasing sensitivity of coronary blood flow to further plaque progression as the lumen narrows, it might even be argued that the effects of such intervention may be enhanced in patients with significant coronary atherosclerosis. The following empirical results are also pertinent: (1) In the CPPT placebo group, cholesterol levels at intake were only about 60% as predictive of subsequent CHD incidence rates in 50-59 year-old as in 35-49 year-old men. Yet the risk reduction obtained by treating with cholestyramine was similar in older and younger participants. Note that the older men were treated well into their sixties. (2) The prognostic strength of cholesterol is diminished in post- infarction patients (probably because of the predominance of myocardial status in determining prognosis). In the CDP placebo group, mortality rates (70% due to CHD) increased by an estimated 0.4% for each 1 mg/dl increment in cholesterol levels. Yet the reductions in CHD incidence rates associated with nicotinic acid and clofibrate treatment in this study were approximately in the same proportion to cholesterol reduction as in the CPPT. (3) A trial of a high-polyunsaturated diet in 846 veterans (mean age 65.5 years) living in the Los Angeles Domicile in the 1960s reported a (non-significant) 23% reduction in CHD incidence (its primary end point) and a (significant) 37% reduction in all "hard" cardiovascular end points. Although there were too few primary end points to give statistical significance, the apparent treatment benefit per cholesterol reduction was quite similar to that observed in the younger (mean age 47.7 years) CPPT cohort. Also, when the Veterans cohort was subdivided by age, the apparent treatment benefit was almost as large above as below age 65. As in the CPPT, all-cause mortality was essentially unaffected by treatment. The limited efficacy and tolerability of available drugs and the difficulty of maintaining lifelong compliance to therapeutic diets have been significant practical impediments to successful lowering of cholesterol levels. In older patients, the administration of cholesterol- lowering drugs is often further complicated by interactions with drugs taken for other more pressing conditions, and efforts to lower cholesterol levels are not pursued aggressively. However, the advent of a new class of cholesterol-lowering drugs, the HMG CoA reductase inhibitors, promises to remove these limitations and could dramatically change the way clinicians treat hypercholesterolemia. The FDA approved one of these drugs, lovastatin, for general release in September, 1987. HMG CoA reductase catalyzes the synthesis of mevalonic acid, an early and rate-limiting step in intracellular cholesterol synthesis. Inhibition of this enzyme induces a compensatory increase in hepatic production of low- density lipoprotein (LDL) receptors which permit hepatocytes to meet their cholesterol requirements by catabolizing circulating LDL. The 40% mean fall in circulating LDL cholesterol level reported for lovastatin (40 mg, bid) substantially exceeds that obtained with other classes of cholesterol-lowering drugs in a similar setting, a fact which reflects its efficacy in individual patients and the rarity of non-responders and non- compliers to therapy. Lovastatin also lowers levels of triglyceride and apolipoprotein B, while slightly raising levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein AI. The HMG CoA reductase inhibitors are also very well tolerated by most patients and have caused few clinically significant adverse reactions to date. Because these drugs are competitive inhibitors of HMG CoA reductase and because the natural substrate is readily diverted to other metabolic pathways, the toxic accumulation of poorly degradable sterol precursors seen with some other inhibitors of cholesterol synthesis does not occur. Before its release, lovastatin was used in more than 1,300 hypercholesterolemic patients (including more than 100 between ages 60 and 72), some for as long as four years. Although significant elevations in serum transaminase levels were seen in 1-2% of patients who have received the drug, these levels have not been associated with liver damage and returned to normal when the drug was discontinued. Cataracts have been observed in dogs receiving very high doses of lovastatin but not in patients receiving therapeutic doses of the drug; however, the possibility of a low-grade adverse effect on the lens has not been ruled out. Since its release in 1987, several instances of myositis have been reported in patients receiving lovastatin, especially in combination with drugs such as cyclosporin and gemfibrozil. A few cardiac transplant patients receiving lovastatin and cyclosporin have gone on to develop rhabdomyolysis and renal failure. Thus, HMG CoA reductase inhibitors must be used cautiously (if at all) in conjunction with other potentially myotoxic drugs. No clinically significant interactions have been observed when lovastatin is co-administered with beta-blockers, digoxin, anticoagulants, diuretics, calcium channel blockers, or nonsteroidal anti- inflammatory drugs. Two other HMG CoA reductase inhibitors at an advanced stage of development, pravastatin and simvastatin, are probably very similar to lovastatin. Overall, because of their efficacy, ease of administration, low toxicity, and compatibility with other drugs, the HMG CoA reductase inhibitors appear to be well-suited for use in older patients in whom cholesterol- lowering interventions have not previously been seriously pursued. These same properties should make them excellent agents for addressing other important issues not yet settled by clinical trials, including the demonstration of a favorable effect of cholesterol-lowering on all-cause mortality rates, the benefit of treating more moderate cholesterol elevations (50th to 90th percentiles) and the benefits and safety of using regimens that can potentially lower plasma cholesterol to levels where regression of atherosclerotic plaques may occur. REFERENCES 1. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham Study. JAMA 257:2176-2180, 1987. 2. Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneficial effects of colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 257:3233-3240, 1987. 3. Brensike, JF, Levy, RI, Kelsey, SF, et al.: Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: Results of the NHLBI Type II Coronary Intervention Study. Circulation 69:313-324, 1984. 4. Canner PL, Berge KG, Wenger NK, et al for the Coronary Drug Project Research Group. Fifteen year mortality in Coronary Drug Project patients: Long term benefit with niacin. J Am Coll Cardiol 8:1245-1255, 1986. 5. Castelli WP, Garrison RJ, Wilson PWF, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. JAMA 256:2835-2838, 1986. 6. Committee of Principal Investigators, WHO Clofibrate Trial. A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 40:1069-1118, 1978. 7. NIH Consensus Conference. Lowering blood cholesterol to prevent heart disease. JAMA 253:2080-2086, 1985. 8. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 231:360-381, 1975. 9. Cupples AL, D'Agostino RD. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Heart Study, 30-year follow-up: Section 34. In Kannel WB, Wolf PA, Garrison RJ (eds): The Framingham Study: An Epidemiologic Investigation of Cardiovascular Disease. Bethesda, MD. U.S. Department of Health and Human Services, 1987, DHHS publication no. (NIH) 87-2703. 10. Dayton S, Pearce ML, Hashimoto S, et al. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 40 (suppl 2):1-63, 1969. 11. Expert Panel. Report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 148:36-39, 1988. 12. Feinlieb M, Gillum RF. Coronary heart disease in the elderly: The magnitude of the problem in the United States. In Wenger NK, Furberg CD, Pitt E (eds): Coronary Heart Disease in the Elderly. New York, Elsevier, 1986, pp. 29-59. 13. Frick MH, Elo O, Heinonen O, et al. Helsinki Heart Study: Primary- prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J. Med 317:1237-1245, 1987. 14. Goldstein JL, Kita T, Brown MS. Defective lipoprotein receptors and atherosclerosis: Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med 309:288-296, 1983. 15. Gordon DJ, Rifkind BM. 3-hydroxy-3-methyglutaryl coenzyme A (HMG CoA) reductase inhibitors: a new class of cholesterol-lowering agents. Ann Intern Med; 107:759-761, 1987. 16. Grundy SM. Cholesterol and coronary heart disease: A new era. JAMA 256:2849-2858, 1987. 17. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 319:24-33, 1988. 18. Havel RJ, Hunninghake DB, Illingworth DR, et al. Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolemia. A multicenter study. Ann Intern Med 107:609-615, 1987. 19. Hoeg JM, Brewer HB. 3-hydroxy-3-methyglutaryl coenzyme A (HMG CoA) reductase inhibitors in the treatment of hypercholesterolemia. JAMA 258:3532-3536, 1987. 20. Levy RI, Brensike JF, Epstein SE, et al. The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: Results of the NHLBI Type II Coronary Intervention Study. Circulation 69:325-337, 1984. 21. The Lipid Research Clinics Investigators. The Coronary Primary Prevention Trial: Design and implementation. J Chron Dis 32:609-631, 1979. 22. Lipid Research Clinics Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA 251:351-364, 1984. 23. Lipid Research Clinics Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 251:365-374, 1984. 24. The Lovastatin Study Group II. Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia. JAMA 256:2829-2834, 1987. 25. Manninen V, Elo O, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 260:641-651, 1988. 26. Martin JJ, Hulley SB, Brown WS, et al. Serum cholesterol, blood pressure and mortality: Implications from a cohort of 361,622 men. Lancet 2:933-936, 1986. 27. The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J Chron Dis 31:201-306, 1978. See Table 20. 28. Rose G, Shipley M. Plasma cholesterol concentration and death from coronary heart disease: 10 year results of the Whitehall study. Brit Med J 293:306-307, 1986. 29. Stamler J, Wentworth D, Neaton JD, for the MRFIT Research Group. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the multiple risk factor intervention trial (MRFIT). JAMA 256:2823-2828, 1987. Administrative Background This project originated from the recommendations of working groups convened in 1985 and 1986 to advise the Arteriosclerosis, Hypertension, and Lipid Metabolism Advisory Committee (AHLMAC) on research opportunities in areas where consensus was still lacking after the 1984 NIH Consensus Conference on Treatment of High Blood Cholesterol. A randomized clinical trial of cholesterol-lowering in older men and women, using an HMG CoA reductase inhibitor, was strongly endorsed by AHLMAC at their January 1987 meeting. The NHLB Advisory Council recommended approval of this initiative in May 1987. Funding of the present pilot study was recommended by the NHLB Advisory Council in September, 1988. This program complements two recently implemented NHLBI programs in the Division of Epidemiology and Clinical Applications: (1) the Epidemiology and Biometry Program's Study of risk factors and precipitants for coronary heart disease and stroke in the elderly and (2) the Clinical Applications and Prevention Program's trial of lovastatin and low-dose warfarin in coronary bypass graft recipients. It also complements several ongoing NHLBI-sponsored angiographic studies, two of which involve lovastatin, of the impact of cholesterol-lowering on progression (or regression) of existing coronary atherosclerosis. The aforementioned trials address mainly middle-aged patients with established CHD, and none is designed so as to yield adequate data on long term safety of HMG CoA reductase inhibitors. GOAL OF THE ACTIVITY The primary purpose of this RFA is to stimulate a collaborative pilot study of the feasibility of a randomized clinical trial of cholesterol- lowering in older men and women, using an HMG CoA reductase inhibitor. OVERVIEW The objective of this RFA is to design and test the feasibility of a randomized clinical trial to determine whether aggressive cholesterol- lowering treatment with an HMG CoA reductase inhibitor after age 60 will reduce cardiovascular morbidity and mortality and thereby prolong life. Such a study (if positive) would extend the scientific base of evidence for treating hypercholesterolemia to the age group with the highest incidence of CHD and prevalence of hypercholesterolemia, but in whom convincing data linking high cholesterol levels with CHD risk and cholesterol-lowering with risk reduction are now lacking. If negative, such a trial would save millions of dollars in unnecessary cholesterol- lowering therapy and enable us to target our resources toward lowering cholesterol levels earlier in life. The present two-year Pilot Study should address three key issues that will determine whether such a full-scale trial is feasible: (1) Can a protocol consistent with current standards of clinical practice be designed to address the major research questions and monitor the safety of study participants? (2) How can the costs of doing such a trial be minimized? Many earlier trials of cholesterol-lowering have been very expensive. Innovative proposals to reduce costs without sacrificing quality are strongly encouraged. For example, can certain aspects of patient care (e.g., dietary instruction, adherence counseling) be conducted on a group rather than individual basis? Can aspects of the conduct of the trial be integrated into the participant's routine health care, so as to eliminate redundancy? What organizational structures would maximize the efficiency of conduct of such a trial? (3) Can adequate numbers of men and women be recruited to participate in such a trial? It is estimated that each center would have to be able to recruit at least 15 study participants per month, to keep the total number of centers and the duration of recruitment within manageable limits. Applicants who can project larger recruitment rates (while maintaining data quality) should so indicate. In addition, the Pilot Study may provide preliminary data on compliance and efficacy of HMG CoA reductase inhibitors in this age group, although this is not its primary objective. Several features of this study are specified so that applicants have common understanding of factors necessary for the collaborative effort, e.g., its magnitude, phases, and the handling of certain central functions. Many characteristics of the subjects to be studied are specified. However, the specific design of the pilot study for a collaborative trial of HMG CoA reductase inhibitors in older men and women is in the hands of the investigators. The collaborative protocol will be developed by the Project Steering Committee, composed of the awardees and the NHLBI Project Scientist. The protocol will be subject to peer review by an uninvolved expert group. The study will move into its second (or operational) phase only with the concurrence of both the awardees and the Institute. SCOPE OF ACTIVITY The pilot study is envisioned as taking place in five field centers and as involving approximately 700 subjects. (A full-scale trial may require up to 16 field centers and 5,600 subjects to assure adequate statistical power --- see Appendix.) Applicants should plan the study in two phases I) collaborative protocol development, II) sample recruitment and data collection and analysis. This is described further under the section "Study Phases". Central functions of the collaborative activity: a Coordinating Center, may be but probably will not be performed by one of the field centers. This will require separate applications and is described in detail under the section "Central Functions". Each applicant should propose the study design he or she believes most appropriate for this project. Each application should include a description of the characteristics of the reference population and of the sample to be selected. Applicants should discuss any factors which they believe should exclude a participant from the study. It is anticipated that the study would involve both men and women; statistical power considerations for a full-scale trial may dictate that the age range be set higher for women than men. It is also anticipated that the entry criteria for LDL cholesterol will specify "moderate" elevations, i.e., in the range where the use of an HMG CoA reductase inhibitor would be permissible but not mandatory according to the Natonal Cholesterol Education Program's adult treatment guidelines and current standards of medical practice, and thus that a randomized trial would be ethically consistent with these standards. It is further anticipated that all participants would be provided with appropriate dietary counseling before they are considered for drug therapy, in accordance with current standards of practice. Finally, it is anticipated that other exclusions would be kept to a minimum to assure the broadest possible applicability of the results to older patients, many of whom have other risk factors and illnesses. An example of a possible design for a full-scale trial along these lines is provided for illustrative purposes as an Appendix. Whatever strategy is proposed for subject selection, applicants should provide a detailed justification for the projected selection plan, an estimate of the number of subjects in the source population and in the final examination sample, as well as an estimate of the necessary time and effort. Applicants unable to recruit at least 15 participants per month into the study are unlikely to receive awards. Applicants should indicate what data they propose for collection in the collaborative endeavor, both for the current pilot study and for an eventual full-scale trial, and provide justification for each component of their proposed examinations. Outcome measures should be chosen so as to address the efficacy and any adverse effects of HMG CoA reductase inhibitors in the study population in the most cost-effective way. All centers must be willing to implement the selection and examination strategies developed collaboratively by the Steering Committee during protocol development and to supply their data and necessary specimens to the Coordinating Center for combination and analysis. STUDY COMPONENTS 1. Clinical Centers A Clinical Center is an institution that is actively involved in the recruitment, evaluation and treatment of study participants. It should consist of an interdisciplinary team of clinical investigators, and appropriate personnel, such as a research nurse coordinator and clerical staff. Applications for Clinical Centers should provide evidence that they will be capable of randomizing at least 15 participants into the study per month. Clinical Centers should describe their experience in recruiting older patients from well-defined populations. Clinical Centers would be required to submit protocol data expeditiously. The principal investigator and co-investigators in each Clinical Center should be skilled in collaborative clinical investigation, lipid metabolism, gerontology, and epidemiology. There should be evidence of strong institutional support for the Clinical Center, and a stated willingness to follow the common protocol agreed upon in Phase I (see below). An organizational structure for the Clinical Center should be set forth in the application, delineating lines of authority and responsibility for dealing with problems in all general areas. Applicants should document their ability to perform the standardized plasma lipid and lipoprotein determinations required for monitoring drug response with high precision and accuracy. The applicant should include a succinct discussion of previous relevant investigational efforts. The applicant should also discuss in detail the important design considerations for a clinical trial of cholesterol-lowering in older men and women and suggest solutions to perceived problems. Applicants are encouraged to suggest protocols for a full-scale trial, as well as for the pilot study. 2. Central Functions The Coordinating Center will have primary responsibility for collecting, editing, storing and analyzing data generated by the Clinical Centers. It should also be prepared to assume a key role in protocol development, designing a data collection system, and assuring quality control. The Coordinating Center would be expected to provide appropriate biostatistical, data management and coordination expertise, and to make a major contribution to the development of the study protocol and manual of operations. The Coordinating Center would also be expected to provide appropriate detailed data reports to the Steering Committee and to the Data and Safety Monitoring Committee at regular intervals and would be responsible for the logistics and planning of meetings of these committees and their subcommittees. The Project Scientist will serve as a liaison between the Coordinating Center and these committees. Applications should provide a detailed description of prior experience as a Coordinating Center in multi-center studies. The application should also discuss in detail the important design considerations for a clinical trial of cholesterol-lowering in older men and women and suggest solutions to key problems. Applicants are encouraged to suggest protocols for a full-scale trial, as well as for the pilot study. 3. Steering Committee A Steering Committee including each of the principal investigators of the Clinical Centers and the Coordinating Center and the NHLBI program scientist will be responsible for making the major scientific decisions governing the conduct of the Pilot Study. Each member of the Steering Committee will have one vote. A chairman will be appointed at the first meeting. It is anticipated that the Steering Committee will meet on a monthly basis during protocol development (Phase I) and on a semi-annual basis thereafter. Subcommittees of the Steering Committee, including Executive and Publications committees, may be established as necessary with NHLBI representation. 4. Data and Safety Monitoring Committee A Data and Safety Monitoring Committee composed of experts in relevant medical, statistical, and bioethical fields will be established to review periodically the progress of the study, oversee participant safety and evaluate results. The chairman of the Steering Committee, the principal investigator of the Coordinating Center and the NHLBI program scientist may participate as ex-officio, non-voting members of this Committee. External members will be appointed by the NHLBI. STUDY PHASES The Pilot Study is envisioned as involving up to five Clinical Centers and one Coordinating Center and lasting for two years. The Pilot Study would have two phases: I Protocol development 12 months II Sample recruitment and data collection and analysis 12 months Phase I will be considered as the 01 period of the grant, and will be twelve months long. After the protocol is completed, it will be reviewed by an expert group appointed by the NHLBI. Progression to Phase II is dependent on the favorable recommendation of the protocol by the expert group and the concurrence of the NHLBI. At the end of the twelve-month period of Phase I, the Coordinating Center should be ready to implement data collection and quality control systems. The protocol for the Pilot Study will be implemented in Phase II. It is anticipated that Clinical Centers will recruit and randomize participants, initiate treatment, collect the outcome data specified in the protocol, and provide these data to the Coordinating Center. The Coordinating Center would collect, process and analyze the data and provide reports to the committees responsible for monitoring the progress of the Pilot Study (see below). If the Pilot Study's objectives are met, additional Clinical Centers may be solicited in a separate RFA to provide a sufficient recruitment base to meet the sample size requirement (probably more than 5,000 participants) of a full-scale trial. It is anticipated that as many as eleven additional Clinical Centers may be required. STUDY RESPONSIBILITIES, GOVERNANCE, AND FUNDING The primary governing body of the study will be the Steering Committee, composed of the principal investigators of the study centers and NHLBI Program Scientist. Subcommittees will be formed on such topics as study design and execution, quality control, and publications, and will also have NHLBI representation. Unless otherwise explicitly provided, the non-NHLBI investigators will have the lead role in the Steering Committee and its subcommittees. The first meeting of the Steering Committee will be convened by the NHLBI Program Scientist. All major scientific decisions will be determined by vote of the Steering Committee. The Committee will have primary responsibility for the development of the study protocol, facilitating the conduct of the study, and reporting of the study results. It is expected that data will be submitted centrally and that the protocol will define rules regarding access to data and publications. A Data and Safety Monitoring Committee to be appointed by the Institute, will review progress at least semi-annually and report to the Institute. TERMS AND CONDITIONS OF AWARD It is anticipated that up to six awards will be made under this RFA for a total of approximately 2.5 million dollars (including direct and indirect costs for field centers and all central functions) over a two-year period. Funding is expected to begin in February 1990. Applications from foreign institutions will be considered only if the applicant provides detailed evidence of unique opportunities not available in a U.S. population. The administrative and funding mechanism to be used to undertake this program will be cooperative agreements, an assistance mechanism. Under the cooperative agreement, the NIH assists, supports and/or stimulates and is involved substantially with recipients in conducting a study by facilitating performance of the effort in a "partner" role. Consistent with this concept, the tasks and activities in carrying out the studies will be shared among the awardees and the Institute project scientist. The tasks or activities in which awardees will have substantial responsibilities include protocol development, patient recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, collaboration with other awardees, and collaboration with the NHLBI project scientist. The NHLBI project scientist will have substantial responsibilities in protocol development, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, collaboration with awardees, coordination and performance monitoring. It is anticipated that awardees will have lead responsibilities in protocol development, final data analysis and interpretation, and in the preparation of most publications. The NHLBI project scientist will have lead role responsibilities in quality control and interim data and safety monitoring and in the preparation of some publications. The NHLBI project scientist will have membership on the Steering Committee and its subcommittees and on the Data and Safety Monitoring Committee. The Institute reserves the right to terminate or curtail the study (or an individual award) in the event of (a) substantial shortfall in patient recruitment, follow-up, data reporting, quality control or other major breech of the protocol, or (b) substantive changes in the agreed-upon protocol with which the Institute does not agree, or (c) reaching a major study end point substantially before schedule with persuasive statistical significance, or (d) human subject ethical issues that may dictate a premature termination. Any disagreement that may arise in scientific matters between award recipients and NHLBI may be brought to arbitration. An arbitration panel will be composed of three members --- one selected by the Steering Committee (with NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardees' right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, subpart D and HHS regulations at 45 CFR part 16. These special Terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS and NIH grant administration policy statements. REVIEW PROCEDURES AND CRITERIA General Considerations All applicants will be judged on the basis of the scientific merit of their proposed study and their documented ability to conduct the essential components as outlined in the Activities Sought and Overview sections of this Request for Applications. Review Method Upon receipt, applications will be reviewed for their responsiveness to the objectives of this RFA. If an application is judged unresponsive, the applicant will be contacted and given the opportunity to withdraw the application, or have it considered for the regular NIH grant program. All applications responsive to this RFA will be reviewed initially for scientific and technical merit by a special review group, convened purpose by the Division of Extramural Affairs, NHLBI, to review these applications. Subsequently, they will be reviewed by the National Heart, Lung, and Blood Advisory Council, most likely at its February, 1990 meeting. Following primary scientific merit review, some applicants may receive further inquiry from Institute program staff. This may focus upon scientific or technical questions arising from the peer review or upon primarily operational and administrative questions. The inquiry may involve no more than a telephone call or letters, or it may take the form of a site visit or a reverse site visit. If an application submitted in response to the RFA is substantially similar to a research grant or cooperative agreement application already submitted to the NIH for review, the applicant will be asked to withdraw the pending application before the new one is accepted. Simultaneous submission of substantially similar applications will not be allowed. Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the study. Applications will be judged primarily on the scientific quality of the application, the availability of an appropriate study sample, the experience of the investigators and their capability to perform the work proposed, and a demonstrated willingness to collaborate with other Clinical Centers, the Coordinating Center, and NHLBI staff. Criteria for review of applications will be as follows: For Clinical Centers: 1. Documentation of the specific competence and previous experience of professional, technical, and administrative staff pertinent to the operation of a Clinical Center in the proposed Pilot Study. Evaluation will include the following: familiarity and experience in recruiting participants in a randomized trial; providing counseling on lipid-lowering diets and drugs; handling laboratory specimens; maintaining a double-blind design; working in collaboration with other investigators under a common protocol; and meticulous and expeditious handling of study data. Specific experience in the recruitment and treatment of older people and the ability to address the special problems (intercurrent illnesses, use of other medications, etc.) that may affect the performance of a randomized trial in this age group will be emphasized. 2. Documentation of access to an age-eligible target population from which trial participants can be recruited in sufficient numbers to meet or exceed the goals specified above. 3. Understanding and awareness of the scientific, ethical, and practical issues underlying the proposed trial and appropriateness of plans to deal with them. 4. Appropriateness of the budget for the work proposed. Innovative proposals to minimize administrative costs and maximize efficiency of recruitment and management are strongly encouraged. Given the large numbers of participants that may be required for a full-scale trial, a low cost per participant may be a critical determinant of whether such a trial is feasible. 5. Adequacy of the proposed facility and space. 6. Evidence of the degree of institutional commitment and support for the proposed program, including the relative position of the proposed project staff within the applicant's organizational structure. For Coordinating Center: 1. Documentation of the specific competence and previous experience of professional, technical, and administrative staff pertinent to the operation of a coordinating center for a collaborative clinical trial, as well as available on-site medical consultation, and the time these professionals will devote to the project. Prior experience in similar studies in the collection of data from multiple clinical and laboratory sites, as well as experience in monitoring the quality and timeliness of such data, must be demonstrated. 2. The approach to and likelihood of soliciting cooperation from the participating clinical centers and exercising appropriate leadership in matters of study design and direction and of data acquisition, management, and analysis. 3. Suitability of the proposed data management and data analysis plans. 4. Appropriateness of the budget for the work proposed. Innovative proposals to minimize administrative costs and maximize efficiency of data handling are strongly encouraged. 5. The adequacy of the proposed facility, technical hardware, and space. 6. The organizational and administrative structure of the proposed program. 7. Evidence of the degree of commitment and support of the organization/institution for the proposed program, including the relative position of the proposed project staff within the applicant's organizational structure. Each applicant for clinical center and for coordinating center should submit an adequately justified budget for the entire anticipated project period of two years. Estimates of staffing needs, including the principal investigator, other investigators, and support staff should be submitted. The budgets for each phase should be clearly delineated. The following information is provided to assist applicants in the preparation of budgets. Detailed budgets will vary according to policies of the applicant and specific needs identified in the response to this announcement. The 01 period (Phase I) of the grant should be for a 12-month period, beginning in February 1990. The 02 period of the grant will be for 12 months, corresponding to Phase II (recruitment, randomization and the beginning of treatment and clinical assessment for men and women who have been randomized). Phase I activities will require phasing-in of staff, with full staffing before the end of the period. Budgets should allow for approximately 2-3 key persons (including the principal investigator) per center to attend Steering Committee Meetings. The detailed budget for this phase should be estimated on the basis of monthly two-day meetings in Bethesda, Maryland during Phase I and one such meeting during Phase II. For Coordinating Center applications, the estimate should also include the time and effort of key personnel needed to participate in the planning and development of forms, a manual of operations and a data entry system. Coordinating Center staff necessary for conducting training should be available for a training meeting to be held in Bethesda about one month before the end of Phase I, for approximately three days. Detailed budget estimates for Phase II should be based on the applicant's proposed plan. METHOD OF APPLYING Letter of Intent Prospective applicants are asked to submit a letter of intent to apply to this RFA as a clinical center or a coordinating center. This letter should include the names of any participating institutions and all investigators, together with a descriptive title. Such a letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for application. Letters of intent are requested solely for planning purposes. The NHLBI Staff will not provide responses to such letters. Letters of intent to apply to this RFA, should be received no later than March 6, 1989 and should be addressed to: Dr. Fred P. Heydrick Review Branch Division of Extramural Affairs National Heart, Lung and Blood Institute National Institutes of Health Westwood Building, Room 548B Bethesda, Maryland 20892 (301)-496-7363 Format for Applications Submit applications on form PHS 398 (revised 9/86), the application form for the traditional NIH research project grant. Copies of this form are available in the applicant institution's office of sponsored research, or may be obtained from the following: Office of Grants Inquiries Division of Research Grants Westwood Building, Room 449 National Institutes of Health Bethesda, Maryland 20892 Use the conventional format for research project grant applications and ensure that the points identified in the section above on "Review Procedures and Criteria" are fulfilled. To identify the application as a response to the RFA, CHECK "YES" on item 2 of page 1 of the application and enter the title "HMG CoA Reductase Inhibitors in the Elderly: Pilot Study" and enter the RFA number NIH-89-HL-06-H in the space provided. Groups of investigators wishing to apply both as a clinical center and a coordinating center must submit separate applications. THE RFA LABEL FOUND IN THE FORM PHS-398 APPLICATION KIT MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED APPLICATION FORM PHS-398. FAILURE TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR REVIEW. Application procedure Send or deliver the completed, signed application and four (4) complete photocopies of it to the following, making sure that the original application with the RFA label attached is on top: Division of Research Grants Westwood Building, Room 240 National Institutes of Health Bethesda, Maryland 20892** SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. FRED P. HEYDRICK AT THE ADDRESS LISTED UNDER "LETTER OF INTENT." IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA. Applications must be received by May 8, 1989. An application not received by this date will be considered ineligible. Timetable Letter of intent March 6, 1989 Application receipt date May 8, 1989 Review by the National Heart, Lung, and Blood Advisory Council February 8-9, 1990 Anticipated award date February, 1990 Inquiries: Inquiries regarding this announcement may be directed to the following: Dr. David J. Gordon Program Scientist Lipid Metabolism-Atherogenesis Branch National Heart, Lung, and Blood Institute Federal Building, Room 404 7550 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-1681 APPENDIX: OUTLINE OF A FULL SCALE CLINICAL TRIAL OF CHOLESTEROL-LOWERING IN OLDER MEN AND WOMEN The following outline pertains to a protocol that was developed in the NHLBI to estimate the size and cost of a randomized trial to address the research issues involved in cholesterol-lowering by an HMG CoA reductase inhibitor in older men and women. It is offered as an example of a study design to which a pilot study might be directed. Applicants are in no way bound to address their proposed pilot study to the specific eligibility criteria, treatment regimens, visit schedules, etc., used in this appendix. However, applicants should provide detailed justification of their own choices in these areas (whether or not they are congruent with those presented here) and should document their impact on sample size and study power. I. Eligibility Criteria A. Age/Sex Three equal blocks: 60-67 year old men 68-75 year old men 68-75 year old women B. LDL Cholesterol 160-200 mg/dl (after diet) C. Other No serious illness or functional impairment NOTE: Prior CHD and other CHD risk factors (e.g., hypertension) are not automatic exclusions. II. End Points A. Cardiovascular Mortality (includes stroke, congestive failure, etc., as well as CHD) B. All-Cause Mortality C. CHD Incidence (fatal plus nonfatal) III. Treatment Arms A. Diet plus HMG CoA reductase inhibitor Target LDL cholesterol = 90-120 mg/dl B. Diet plus placebo Target LDL cholesterol = 160-200 mg/dl IV. Duration 5 years after recruitment ends (Mean follow-up = 6 years) NOTE: Three years of post-treatment follow-up for all-cause mortality. V. Sample Size (Both treatment arms) - 5550 --- (1850 in each block (see IA)) VI. Study Power ` = .05 ` = .01 End Point 1-Tailed 2-Tailed 1-Tailed 2-Tailed Cardiovascular Mortality 96% 92% 85% 79% All-Cause Mortality 6-Year 79% 69% 55% 46% 9-Year 95% 90% 82% 75% CHD Incidence (Fatal plus Nonfatal) 91% 85% 75% 67% These power estimates were calculated under the following assumptions: (1) Mortality and morbidity rates in the control group will be similar to those in comparably aged participants in the Framingham Heart Study. In six years mean follow-up, it is estimated that 21.1% of this cohort will die (6.3% due to CHD, 4.1% due to other CVD) and 9.7% of those free of CHD at entry will suffer a fatal or nonfatal CHD event. (2) When possible attrition in adherence and efficacy over the course of the study are taken into account, it is projected that the mean LDL cholesterol level will be 60 mg/dl (33%) lower in the group receiving the active drug than in the control group. (3) Each 1 mg/dl reduction in LDL cholesterol level will be accompanied by a 0.6% decrease in CVD mortality and CHD incidence rates and no change in non-CVD mortality. (4) The aforementioned reduction in CHD risk develops gradually and is not fully realized until two years after treatment is initiated. VII. Study Structure A. 16 Clinical Centers, with 360 participants per center, staffed primarily with nurse practitioners/physician's assistants under M.D. supervision. B. Duration of Recruitment 2 years (possibly 3 years for Pilot Centers) C. Clinic Visits (1) Four pre-randomization, at one month intervals. (2) Initially at one- to two-month intervals, then every three or four months. D. Data Collection (1) Cholesterol (total, HDL, LDL (est.)) and triglyceride, SGOT and/or SGPT, CPK at all visits. (2) Resting electrocardiogram at entry. (3) Ophthalmologic exam at entry, at first annual exam, and at one annual exam thereafter. VIII. Other Important Research Issues In addition to its formal hypothesis concerning reduction in primary end points (see II.) by cholesterol-lowering, this protocol could provide useful data on several issues of broad relevance to all age groups. A. Are HMG CoA reductase inhibitors safe for long-term use? The detection of subtle adverse effects (e.g., a small increase in incidence of lenticular opacities) associated with chronic use of these drugs and evaluation of the benefits of treatment relative to the risk of such effects is attainable only by a careful placebo controlled randomized trial. B. Does cholesterol-lowering reduce cardiovascular risk in women as in men? No previous trial of cholesterol-lowering has included enough women to address this question; nearly all have included men only. C. Is the CHD risk-reduction ensuing from a given cholesterol reduction obtained with an HMG CoA reductase inhibitor similar to that obtained with cholestyramine? D. Are fatal and non-fatal atherosclerotic events equally affected? To date, only secondary prevention trials have had sufficient power to address mortality. E. Does the relation between cholesterol-lowering and CHD and other cardiovascular risk apply to lower starting levels of LDL cholesterol than used in the CPPT? The proposed trial addresses a much broader portion of the cholesterol distribution **THE MAILING ADDRESS GIVEN FOR SENDING APPLICATIONS TO THE DIVISION OF RESEARCH GRANTS OR CONTACTING PROGRAM STAFF IN THE WESTWOOD BUILDING IS THE CENTRAL MAILING ADDRESS FOR THE NATIONAL INSTITUTES OF HEALTH. 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