Key Dates

Related Announcements

NOT-OD-20-077
PA-20-135 Emergency Competitive Revision to Existing NIH Awards (Emergency Supplement - Clinical Trial Optional)
NOT-HL-20-789 - Notice of Expiration of NOT-HL-20-757

NOT-HL-20-800 - Notice of Expiration of NOT-HL-20-782

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

NHLBI is issuing this Notice of Special Interest (NOSI) due to the urgent need for early phase clinical trials to evaluate new or existing interventions that may prevent or treat Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NHLBI seeks to leverage existing clinical trials expertise and, using NHLBI programs that are actively conducting Phase I-III clinical trials, to rapidly initiate and conduct Phase I-Phase I/II (bridging) clinical trials in patients at risk for SARS-CoV-2 infection and/or patients with COVID-19. It is strongly recommended that the parent activity code be one of the following: P01, R01, R33, R41, R42, R43, R44, U01, U24, U54, UH3, or UM1.

Topics of specific interest to the NHLBI include the safety and efficacy of interventions for primary prevention and/or treatment of COVID-19, associated clinical phenotypes, and surrogate outcomes, relevant to heart, lung, and blood (HLB) diseases.

Programs currently conducting research without an active Phase I-III clinical trial may wish to consider applications to NOT-HL-20-757.

Background

Coronaviruses are a diverse family of viruses that cause a range of disease in humans and animals, and there are currently no approved coronavirus vaccines or therapeutics. In January 2020, a novel coronavirus, SARS-CoV-2, was identified as the causative agent of an outbreak of viral pneumonia centered around Wuhan, China. Current information regarding confirmed cases is changing daily and can be found on the Centers for Disease Control and Prevention website (https://www.cdc.gov/coronavirus/index.html).

Patients diagnosed with this illness have reported symptoms such as fever, cough, shortness of breath, fatigue, myalgias, headache, sore throat, abdominal pain, and diarrhea. Patients admitted to the hospital generally have pneumonia and abnormal chest imaging, and complications include acute respiratory failure, acute respiratory distress syndrome (ARDS), and acute myocardial injury. The severity of illness and course of the infection is heterogenous and appears to be more severe in the elderly and in individuals with underlying comorbidities, including cardiovascular and chronic respiratory diseases. Emerging evidence indicates that cytokine storm is associated with severity and early cardiac injury. Additionally, ARDS, thrombocytopenia and disseminated intravascular coagulopathy (DIC) are associated with severity and mortality.

Specific Area of Research Interest

This NOSI is applicable to active NHLBI, Phase I-III single or multisite clinical trials that seek to conduct Phase I-Phase I/II (bridging) for COVID-19. For the purposes of this NOSI, the definition of a bridging study is a study performed to provide clinical data that allows extrapolation of existing data from a population for whom an intervention product has been approved, in order to bring the intervention product to a new population (e.g., into a new disease indication, adults into peds, etc.). In addition to the primary aim of assessing the safety of the intervention product, secondary aims may include: 1) further testing of the intervention's feasibility and acceptability; 2) determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout biological signature in response to product; 3) determining the pharmacokinetics of the dose and formulation of the product to be used in future trials to justify the frequency of dosing; and 4) developing functional biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness studies in heterogeneous populations or subpopulations. The specific activities proposed will depend on the product under study and available preliminary data on the product. Supported research is expected to inform future efforts to diagnose, prevent, mitigate, or treat this viral infection and associated manifestations.

Research examples that would be responsive to this NOSI includes but are not limited to:

• Evaluation of FDA approved and novel JAK kinase inhibitors for safety and definition of biologic signature for early assessment of responsiveness correlated to clinical outcome
• Evaluation of existing and novel agents to determine most efficacious route of administration, and dosing to abrogate mucus production and composition to limit disease course and progression
• Determination of safety and dosing of combination therapies (e.g. antiviral agent plus immunomodulator) to limit infectivity and disease progression
• Evaluation (e.g. safety, route of administration, dosing) of existing and novel agents to augment host response via time-limited activation of innate and adaptive host defense mechanisms.
• Evaluation of the potential role of nitric oxide in SARS-CoV-2 associated cardiopulmonary disease with biologic signature(s) and/or surrogate outcomes correlated with clinical outcomes
• Evaluation of the safety, feasibility and dosing of IL-1 receptor blockade for cardiac and pulmonary complications of COVID-19. Identification of biologic signatures, surrogate outcomes, clinical outcomes, that predict early efficacy.
• Safety and feasibility of non-traditional or alternative anticoagulation strategies in COVID-19 patients due to prothrombotic and the inflammatory state in some patients. Identification of biologic signatures and surrogate outcomes correlated with clinical outcomes.
• Evaluation of safety, route of administration, and dosing of existing and novel agents to prevent/reduce viral entry and/or augment host defense mechanisms and/or prevent/limit HLB single- or multi-organ system injury
• Novel cell therapies to reduce/control inflammation or augment host defense mechanisms and/or prevent/limit HLB single- or multi-organ system injury
• Studies to determine safety and dosing of drugs to increase platelet production to combat thrombocytopenia
• Evaluation of safety, feasibility, and dosing of new and existing agents for cardiovascular disease for use in COVID-19 patients to abrogate disease expression and/or progression, and related cardiovascular injury

Research proposals from programs conducting clinical research outside of an active Phase I-III clinical trial that do not have the appropriate investigator team expertise in safety, efficacy and/or management trials are not responsive to this NOSI and will be withdrawn without review.

Required Capabilities

Applicants responding to this NOSI must have appropriate capabilities, infrastructure, and attributes. These key components are expected to ensure qualified personnel and site capabilities for the safe conduct of Phase I-Phase I/II (bridging) for COVID-19.

Initiation of Enrollment
Investigators applying for this NOSI must be prepared to initiate enrollment within the first quarter of the award.

Experience in the Conduct of Clinical Trials
It is essential that investigators applying for these awards have expertise and well-documented past performance in the conduct of Phase I-III clinical trials.

Coordination of Clinical Trials and Associated Activities
The awardees will be responsible for all administrative duties, filing adverse event reports, maintenance of all regulatory documents, communications, protocol, consent and forms development, quality control, milestone tracking, and analysis and reporting of outcomes.

Personnel
While necessary personnel may be added to implement the study, the original team must have relevant expertise already in place, along with an appropriate infrastructure to enable the leveraging of existing HLB trials.

Application and Submission Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additions:

• Applications for this initiative must be submitted to PA-20-135 - Emergency Competitive Revision to Existing NIH Awards (Emergency Supplement - Clinical Trial Optional) or its subsequent reissued equivalent.
• Applications will be accepted on a rolling basis from May 1, 2020 through October 5, 2020 by 5:00 PM local time of the applicant organization. This NOSI expires on August 1, 2020. An application submitted in response to this NOSI that is received on August 1, 2020 or later will be withdrawn.
• For funding consideration, applicants must include NOT-HL-20-782 in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications that do not include NOT-HL-20-782 in box 4B will not be considered for this initiative.
• Requests may be for up to two years of support.
• To be eligible for an Emergency Competitive Revision, the parent award must be an active NHLBI Phase I-III clinical trial award when the supplement application is submitted (e.g., within the originally reviewed and approved project period), regardless of the time remaining on the current project.. A project period of up to 2 years may be requested, with a justification of the time period and an emphasis on efficient study implementation and conduct.
• Competitive revision applications to PA-20-135 must use an application form package with the Competition ID containing "NOT-HL-20-782". NIH will accept applications using form packages with the Competition IDs of NOT-HL-20-782-FORMS-E" or NOT-HL-20-782-FORMS-F" until June 25, 2020. Applications submitted on or after June 25, 2020 must use NOT-HL-20-782-FORMS-F. See NOT-OD-20-026 for details.
• Applicants are strongly encouraged to notify the program contact at the Institute supporting the parent award that a request has been submitted in response to this FOA in order to facilitate efficient processing of the request.
• The Research Strategy section of the application is limited to 6 pages, and should include the following information:
  • Discussion of the scientific rationale and data, including with the therapeutic candidate, that supports its use in COVID19 disease and for the patient population in which testing will occur and the intended treatment population.
  • Specific Aims, study design, and endpoints.
  • Risk/Benefit Profile: Risk/benefit profile and draft of the Investigator’s Brochure (IB), if available.
• Letters of Support are required from relevant third parties, regulatory entities, as available. If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized organization representative (AOR)

Section IV. PHS Human Subjects and Clinical Trials Information

Section 2 Study Population Characteristics

Section 2.7 Study Timeline

A table or graph of the overall study timeline must be included and may not exceed 4 pages. This is expected to be a visual representation (such as a Gantt Chart) of estimated trial duration and key milestones. Milestones must be relevant, measurable, results-focused and time-bound (e.g., IND/IDE approval, drug/device supply, recruitment milestones, etc.). A narrative is not expected in this section. The period of time for the study duration is expected to be displayed in months and must include, but is not limited to, the following:

• Finalization of the clinical trial protocol and informed consent forms
• Procurement of agent/device for intervention, packaging, shipping, as appropriate
• Forms and MOP development
• Registration of the clinical trial(s) in ClinicalTrials.gov
• Completion of all required regulatory approvals (e.g., IND/IDE approval from the FDA)
• Initiation of enrollment
• Contracts/third party agreements, including intervention product supply
• Training of study staff
• Anticipated date of enrollment of the first participant

Section 3 - Protection and Monitoring Plan

3.3 Data and Safety Monitoring Plan

Describe the process that will be utilized to identify anticipated and unanticipated problems and describe procedures for adverse event reporting, intervention discontinuation, and stopping guidelines, with an appropriate ongoing monitoring process. Parent trial Data and Safety Monitoring Boards (DSMBs) may be proposed to monitor the proposed trial, however, NHLBI reserves the right to require additional expertise be added, or an independent monitoring process.

Section 5 - Other Clinical-Trial Related Attachments

5.1 Other Clinical Trial-related Attachments

Applicants must provide a detailed table listing the characteristics of trials that demonstrate experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Early Phase Clinical Trial Experience.pdf" and may not exceed 3 pages.

The table columns should include:

Column A: clinical study title (include ClinicalTrials.gov number)
Column B: applicant's role in the study
Column C: a brief description of the study design
Column D: planned enrollment
Column E: actual enrollment
Column F: number of sites
Column G: whether the studies were completed on schedule or not
Column H: publication reference(s)

Inquiries

Please direct all inquiries to:

Patricia Noel, PhD
National Heart, Lung, and Blood Institute
Division of Lung Diseases
Telephone: 301-435-0202
Email: noelp@nih.gov

Nahed El Kassar, MD, PhD
National Heart, Lung, and Blood Institute
Division of Blood Diseases and Resources
Telephone: 301-827-8268
Email: nahed.elkassar@nih.gov

Emily Tinsley PhD, MS
National Heart, Lung, and Blood Institute
Division of Cardiovascular Sciences
Telephone: 301-435-0519
Email: emily.tinsley@nih.gov