RFA-HD-98-005: BODY WEIGHT SUPPORTED AMBULATION TRAINING AFTER SPINAL CORD INJURY

Department of Health
and Human Services (HHS)

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BODY WEIGHT SUPPORTED AMBULATION TRAINING AFTER SPINAL CORD INJURY Release Date: March 5, 1998 RFA: HD-98-005 P.T. National Institute of Child Health and Human Development Letter of Intent Receipt Date: May 11, 1998 Application Receipt Date: June 11, 1998 PURPOSE The National Center for Medical Rehabilitation Research (NCMRR) of the National Institute of Child Health and Human Development (NICHD) seeks to initiate a clinical trial of body-weight-supported ambulation training following spinal cord injury. The purpose of this Rehabilitation Clinical Trial is to examine the use of variable lower extremity loading during ambulation to enhance neurophysiologic control and facilitate the individual’s ability to walk. Medications and electrical or magnetic stimulation techniques may be used as adjuncts for weight- supported ambulation training. The primary outcome measures must include functional walking in a natural environment without assistive devices other than simple canes or a walker. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Rehabilitation of Walking after Spinal Cord Injury, is related to the priority area of chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions and organizations are not eligible as applicants, but may participate in collaboration. Applications may include collaborative arrangements between scientists from a single institution or multiple institutions. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) mechanism. The cooperative agreement is an assistance mechanism in which it is anticipated that the NIH will have substantial involvement with the recipient during the performance of the planned activity. The nature of the NIH"s involvement is described under the "Terms and Conditions" of the award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated award date is September 28, 1998. This RFA is a one-time solicitation. FUNDS AVAILABLE Depending upon the scope of work, up to $800,000 (direct costs) per year is available to support this RFA. It is expected that one award will be made. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the award may be less than $800,000. Although this program is provided for in the financial plans of the NICHD, an award pursuant to this RFA is contingent on the scientific and technical merit of the applications and on the availability of funds for this purpose. RESEARCH OBJECTIVES Background Advances in the effectiveness of acute care following spinal cord injury (SCI) have resulted in an increasing proportion of persons with incomplete losses of sensory or motor functioning. Both basic studies in animal models of SCI and clinical studies in humans with SCI have shown that reducing the loading on the lower extremities (i.e., increasing body weight support) during ambulation training can enhance locomotor patterns. Preliminary clinical studies have also shown functional improvements in walking and stair-climbing that persist after treatment. These changes occur in persons with incomplete losses of sensory or motor functioning, but apparently not in persons with functionally complete SCI. A controlled clinical trial is needed to evaluate the potential of this treatment to improve ambulation in persons with SCI. This RFA is directly responsive to recommendations of the National Advisory Board on Medical Rehabilitation Research that NCMRR implement a strategy of encouraging Phase III clinical trials relevant to medical rehabilitation. Purpose of Proposed Research The primary goal of the proposed study should be to initiate a clinical efficacy trial of body-weight support during ambulation training in persons with incomplete SCI. Research activities should be conducted by clinical investigators skilled in the rehabilitation of people with SCI and knowledgeable about spinal cord neurophysiology, ambulation training, gait analysis, and the assessment of disability. The ultimate goal should be to determine the efficacy of weight- supported ambulation training, and determine its effects on the functional limitations and disabilities of persons with incomplete SCI. Secondary goals may include evaluating the adjunctive effects of various medications or electrical stimulation regimens. Study samples may also include, but should not be limited to, persons with clinically or neurophysiologically complete SCI. Research Plan Objectives of the RFA will be met through the initiation of a randomized, controlled trial to test the efficacy of body-weight-supported ambulation training of persons with incomplete SCI. It is expected that the trial will include an appropriate placebo control condition. Additional treatment comparisons or treatment enhancements (e.g., electrical stimulation) may be added if solidly supported by the research literature and/or preliminary data. The trial must be designed, however, to allow differentiation of the effects of weight-supported training alone from the effects of the additional treatments. Applicants must demonstrate the ability to manage a complex trial, recruit and randomize the required number of study participants, implement the various study procedures, and maintain high rates of follow-up during the course of the trial. The study should consist of five phases: 1) an initial phase during which the protocol is finalized (e.g., study procedure, data collection manuals, data management, training, establishment of the Data Monitoring and Safety Committee, etc.) after consultation with the NCMRR Program Officer, 2) a pilot phase in which the feasibility of study procedures is assessed, 3) a recruitment period, 4) a period of intervention and follow-up, and 5) data analysis and dissemination. Applicants should pay special attention to the choice of an appropriate placebo condition, the issue of masking, and subject inclusion and exclusion criteria. The screening/evaluation protocol for the proposed trial should include a grading system for the levels of impairment, functional limitations, and disability of the subjects which is well grounded in the research literature. Response to treatment may be dependent on the remaining functional capabilities of the spinal cord, so those capabilities must be characterized. It is recommended that the study population include subjects with various degrees of ambulation losses. Subjects who have previously received rehabilitation and/or ambulation training may be included in the study. However, individuals who have received interventions that chronically alter the nervous system (e.g., implantation of pumps for antispastic medication or implantation of stimulation electrodes) should be excluded unless the design of the study can control for possible confounds. Choices of outcome measures (primary and secondary) should be well-defined and clearly justified. Primary outcome measures must include a functional measure of ambulation in a natural environment. Secondary outcome measures must include, but are not limited to: 1) measures of lower extremity impairment such as muscle strength and/or endurance, 2) a measure of global functional status, 3) health status/quality-of-life indicators, and 4) a measure of social/vocational status. It is recommended that applicants also consult with members of the spinal cord injured population to identify related outcomes significant to them for which additional measures need to be included. All costs required for these studies must be included in the application and must be fully justified. These costs include quality control, data management and data analysis, study monitoring, and travel. SPECIAL REQUIREMENTS The awardee will be required to submit annual progress reports to NCMRR which may be included in, or submitted as an addendum to, the annual awardee noncompeting continuation progress report. These reports should include recruitment data, indices of quality control, reports of significant side effects or morbidity and changes in the protocol. The Data Monitoring and Safety Committee may require additional information. The awardee also will be requested to present a final oral report to the National Advisory Board for Medical Rehabilitation Research. TERMS AND CONDITIONS OF THE AWARD The following Terms and Conditions of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, DHHS grant administration regulations at 45 CFR Part 74 and other DHHS and NIH grant administration policies. Business management aspects of these awards will be administered by the Grants Management Branch, NICHD, in accordance with DHHS and NIH grants administration requirements. The administrative and funding instrument used shall be a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCMRR scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the purpose of the NCMRR is to support and/or stimulate the recipient"s activity by involvement in, and otherwise working jointly with, the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. The awardee will be expected to cooperate with the NCMRR Program Officer and other participating staff at the NICHD, in the design and conduct of the protocol, analysis of data, and reporting of results from the project, and will be expected to disseminate the research findings in a timely manner through peer- reviewed publications. A. Awardee Rights and Responsibilities. 1. Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results. 2. Scientific coordination, development and monitoring of the protocol. All proposed protocol modifications will be submitted by the Principal Investigator to the NCMRR Program Officer for review and approval, subject to negotiation with the awardee. 3. Implementation of the data collection method and strategy. 4. Establishment of mechanisms for quality control and monitoring. The awardee is responsible for ensuring accurate and timely assessment of the progress of their study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis, (2) as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense, and (3) sufficiently staffed. 5. Establishment of procedures to comply with the requirements of 45 CFR Part 46 for the protection of human subjects. The Principal Investigator is responsible for obtaining approval from the Institutional Review Board (IRB) prior to enrolling patients, and, once enrollment has commenced, from the IRB, and the NCMRR Program Officer prior to changing the protocol. 6. The awardee(s) will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current DHHS, PHS and NIH policies. B. NIH Staff Responsibilities. The NCMRR Program Officer , who will have substantial scientific/programmatic involvement, will: 1. attend meetings of the Data Monitoring and Safety Committee as a non-voting member. The NCMRR retains the option of conducting periodic, external reviews of progress. 2. serve as a resource with respect to other NCMRR activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort. 3. participate in the planning and coordination of research activities in the following ways: o Assist in reviewing and evaluating each stage of the project before subsequent stages are started. o Assist in the efficient conduct of the trial. o Collaborate in analysis and reporting of results to the community of investigators and health care recipients. o Review the data management and quality assurance systems using consultants as appropriate. Relevant information will be derived from biannual and annual progress reports and site visit findings. 4. monitor protocol progress, and may request that the study be closed to accrual for reasons including: o an accrual rate insufficient to complete the study in a timely fashion, o accrual goals being met early, o poor protocol performance, o patient safety and regulatory concerns, o study results that are already conclusive, and o emergence of new information that diminishes the scientific importance of the study question. The NCMRR reserves the right to curtail or terminate the study and award in the event of: o failure to implement the collaborative protocol in a timely fashion, o substantial shortfall in patient recruitment, follow up, data reporting, quality control, or other major breech of the protocol, o substantive changes in the agreed upon protocol with which the NCMRR does not concur, o reaching a major study end point substantially before schedule with persuasive statistical significance, or o human subject ethical issues that dictate premature termination. The NCMRR will have access to and may periodically review all data generated under an award. NIH policies governing possible co-authorship of publications with NIH staff will apply in all cases. In general, to warrant co-authorship, NIH staff must have contributed to the following areas: a) design of the concepts or experiments being tested, b) performance of significant portions of the activity, c) interpretation of findings, and d) preparation and authorship of pertinent manuscripts. C. Collaborative Responsibilities. An independent Data Monitoring and Safety Committee (DMSC) will be a required component of the study. The DMSC is the main oversight body of the clinical trial and has primary responsibility to review progress, monitor patient accrual, data management, and patient safety, and cooperate on the publication of results. The DMSC will document progress in written reports to the Principal Investigator, and the Director of NCMRR and Director of NICHD through the NCMRR Program Officer, and will provide periodic supplementary reports to designated NIH staff upon request. An operating budget for the DMSC shall be specified and justified in the application. Applicants should not name DMSC members until an award is made and after consultation with the NCMRR Program Officer, however, within the application, they should specify the process by which DMSC members will be identified and the qualifications of the types of individuals to be sought. The DMSC is organized by the Principal Investigator in consultation with the NCMRR Program Officer and will be appointed by the awardee’s institution. The DMSC will be composed of external, nonparticipating peer investigators, including those of data coordinating/statistical centers, if any, and the NCMRR Program Officer. An initial meeting of the DMSC will be convened by the Principal Investigator soon after an award is made. The final structure and membership of the DMSC will be established at the first meeting. The Principal Investigator will not be a member or routine attendee of the DMSC after its first meeting. The NCMRR Program Officer will have nonvoting membership on the DMSC and, as appropriate, its subcommittees. Such a Committee usually will meet at least yearly. A Chairperson, other than the NIH representative, will be selected by a vote of the members. The Chairperson is responsible for coordinating the DMSC activities, for preparing meeting agendas, and for scheduling and chairing meetings. D. Arbitration. When agreement between the awardee and the NCMRR staff cannot be reached on scientific/programmatic issues that may arise after the award, an arbitration panel will be formed. The panel will consist of one person selected by the Principal Investigator of the study, one person selected by the NCMRR staff and a third selected by these two individuals. The decision of the arbitration panel, by majority vote, will be binding. The NICHD review procedure in no way affects the right of a recipient of a cooperative agreement to appeal an adverse determination under the terms of PHS regulations at 42 CFR Part 50, Subpart D, and DHHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103- 43). Applicants should read the NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. The Guidelines are available on the Internet at http://grants.nih.gov/grants/guide/notice-files/not94-100.html . LETTER OF INTENT Prospective applicants are asked to submit by May 11, 1998, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Stephen M. Tuel at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for this RFA. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: asknih@od.nih.gov. The PHS 398 may also be downloaded over the Internet from http://grants.nih.gov/grants/funding/funding.htm. The RFA label available in the application package PHS 398 (rev. 5/95) must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title (BODY WEIGHT SUPPORTED AMBULATION TRAINING AFTER SPINAL CORD INJURY) and number (HD-98- 005) must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application and three signed, exact photocopies, and the completed checklist in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC-7710 BETHESDA MD 20892-7710 BETHESDA MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03 MSC-7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications prepared in response to this RFA must be received by June 11, 1998. If an application is received after that date, it will be returned to the applicant. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. Preparation of the Application The general instructions provided in PHS-398 for the preparation of applications must be used. Because the "Terms and Conditions of Award" will be included in all awards issued as a result of this RFA, it is critical that each applicant provides specific plans for responding to the terms and conditions of award and requirements stated in the RFA. Plans must take into account NIH staff involvement, as well as how all the responsibilities of the awardee will be fulfilled. The following items apply to all applications: 1. Clinical trial designs should include an adequate number of participants and should be of sufficient duration to assure statistical power to address the study questions of efficacy, long-term safety and duration of effect, as well as to address possible gender and minority subgroup differences. To this end, biostatistics and clinical trial design expertise should be included from the first efforts in study planning and design. 2. A rationale for selection of the target patient cohort and an estimate of the number of participants required to complete the clinical study should be provided. Criteria and calculations used to estimate sample size should be included. The patient cohort should be described and its selection justified. The cohort should be defined, as appropriate, by age, sex, race, education, geographic location, occupation, etc. An accrual rate should be estimated. If multiple institutions are involved, the proposal should include verification of the co-investigators" willingness to participate, and pertinent additional information regarding the cooperating institutions" staff qualifications, resources, research plans, including patient availability and data flow, as well as corresponding budget requirements. 3. In addition, if multiple institutions will be involved, a description should be presented of how implementation of the trial will be standardized across participating centers. Items that should be addressed include, but are not limited to: o training to standardize the diagnosis, enrollment (inclusion/exclusion criteria) and treatment of subjects, o programs to standardize data management and confidentiality, and o procedures to ensure patient safety. If preliminary data are not available, the proposal should include a pilot phase to validate these items. 4. Any known or potential complications should be described, along with the techniques and procedures to monitor any adverse events. 5. A willingness to work cooperatively with the NCMRR and NICHD staff in the implementation and conduct of the study should be indicated. 6. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NICHD. Incomplete, non-responsive, or ineligible applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD Division of Scientific Review, in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to this RFA. Applications judged to be competitive will be discussed in depth and assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration. A summary statement will be prepared, and the Principal Investigator and the official signing for the applicant organization will be notified. Review Criteria o Overall feasibility and the likelihood of achieving the clinical trial goals and the potential for a successful trial. o Adequacy of the experimental design to evaluate the clinical efficacy of body- weight-supported ambulation training. o Adequacy of the statistical features of the study including sample size projections and power estimates, randomization procedures, methods of analysis, and the use of sequential analyses of data. o Availability of suitable subjects for the clinical trial and the likelihood of them participating throughout the study. o Operational aspects of the project including plans for patient recruitment, retention, and follow-up, masking procedures, standardization of data collection, and quality control of data. o Qualifications and research experience of the Principal Investigator, and for multi-center trials, of a core of Center Investigators. o Evidence for appropriate leadership and proposed organization and committee structures of the clinical trial. o Pilot phase experience including evidence of patient accession and retention, and the feasibility of the intervention and study measures. If preliminary data are not available, the proposal should include a pilot phase to validate these items. o Grounding of the project in the relevant literature, including biological mechanisms and supporting clinical data for any adjunct interventions and measures. o Adequacy of the Data Monitoring and Safety Committee. o Adequacy of plans to address NIH policy on inclusion of women and minorities, including addressing possible gender and minority subgroup differences in the response to the intervention. o Reasonableness/appropriateness of the requested budget and project duration in relation to the proposed research. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated award date is September 28, 1998. Applications recommended by the NICHD Advisory Council will be considered for award based upon (a) scientific and technical merit of the application as determined by peer review, (b) program priorities, and (c) availability of funds. Schedule Letter of Intent Receipt Date: May 11, 1998 Application Receipt Date: June 11, 1998 Review by NICHD Advisory Council: September 15, 1998 Anticipated Award Date: September 28, 1998 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Additional information on the National Center for Medical Rehabilitation Research is available on the Web at http://silk.nih.gov/silk/NCMRR/. Direct inquires regarding programmatic issues to: Stephen M. Tuel, MSE, MD National Center for Medical Rehabilitation Research National Institute of Child Health and Human Development Building 61E, Room 2A03 MSC-7510 Bethesda, MD 20892-7510 Telephone: (301) 402-2242 FAX: (301) 402-0832 Email: tuels@box-t.nih.gov Direct inquiries regarding fiscal matters to: Mary Ellen Colvin Grants Management Branch National Institute of Child Health and Human Development Building 61E, Room 8A17 - MSC-7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 Email: mc113b@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.929 Medical Rehabilitation Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and to promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or, in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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