Funding Opportunity PAR-24-115 from the NIH Guide for Grants and Contracts. This Notice of Funding Opportunity (NOFO) encourages applications for investigator-initiated mid-phase clinical trials of natural products(i.e., botanicals, dietary supplements, and probiotics), which have a strong scientific premise to justify further clinical testing. For this NOFO, natural products include promising nutritional regimens that standardize the amount of a specific naturally occurring nutritional compound (e.g., omega-3 fatty acids, anthocyanidins, or polyphenols) and have compelling preliminary evidence. All applications submitted under this NOFO must be supported by sufficient preliminary data demonstrating bioavailability (if applicable) and documentation that the natural product produces a reproducible and measurable impact on target engagement (i.e., measure of the mechanism of action). Only in cases when it is not possible/practical to measure target engagement in the patient population of interest or when there is a fundamental understanding of the products mechanism of action will this preliminary data requirement be waived. Applications submitted to this NOFO should propose a mid-phase clinical trial to do the following: determine the optimal dose or formulation of a given natural product for use in a future multi-site efficacy trial; or determine which patient phenotypes will be responders versus non-responders to the natural product to inform inclusion/exclusion criteria of a future efficacy trial. Clinical trials submitted under this NOFO are expected to be hypothesis based, milestone-driven, and directly related to the research priorities and mission of NCCIH. This NOFO will not support single-site or multi-site efficacy or effectiveness trials, nor will it support trials to test natural products for the treatment or prevention of cancer. Applicants are encouraged to contact the appropriate NCCIH Scientific/Research contact for the area of science for which they are planning to develop an application prior to submitting to this NO

Funding Opportunity PAR-24-116 from the NIH Guide for Grants and Contracts. This Notice of Funding Opportunity (NOFO) encourages applications for investigator-initiated, early phase, clinical trials of natural products (i.e., botanicals, dietary supplements, and probiotics), which have a strong scientific premise to justify further clinical testing. For this NOFO, natural products include promising nutritional regimens that standardize the amount of a specific naturally occurring nutritional compound (e.g., omega-3 fatty acids, anthocyanidins, or polyphenols) and have compelling preliminary evidence. Under this NOFO, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support decisions about further development or testing of the natural product. This NOFO will provide up to 3 years support for studies to replicate the impact of the natural product on target engagement when used by humans, and assess whether there is an association between the degree of the impact on target engagement and functional or clinical outcomes in a patient population. Applications are encouraged to design studies to determine how to optimize the impact of the natural product on target engagement by optimizing the delivery of the natural product through examination of different doses or formulations. In addition, applications can be designed to combine the natural product with another treatment approach that is known to engage the same target; or study the impact of the natural product in a target population that is more responsive. Clinical trials submitted under this NOFO are expected to be hypothesis based, milestone-driven, and directly related to the research priorities and mission of NCCIH. This R33 funding mechanism is intended to accelerate the translation of emerging basic science findings about natural products into early-stage clinical testing to determine whether continued clinical research is warranted. This NOFO will not support efficacy or effectiveness trials, nor will

Funding Opportunity PAR-24-124 from the NIH Guide for Grants and Contracts. This Notice of Funding Opportunity (NOFO) encourages applications for investigator-initiated, early phase, clinical trials of natural products (i.e., botanicals, probiotics, and products marketed as dietary supplements), which have a strong scientific premise to justify further clinical testing. For this NOFO, natural products include promising nutritional regimens that standardize the amount of a specific naturally occurring nutritional compound (e.g., omega-3 fatty acids, anthocyanidins, or polyphenols) and have compelling preliminary evidence. Under this NOFO, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support decisions about further development or testing of the natural product. This NOFO will provide up to three years (R61 phase) of support for milestone-driven testing of pharmacokinetics, bioavailability, and assessment of the natural products effect (i.e., measure of mechanism of action) when used by humans on a specified target measure. If milestones in the R61 phase are achieved, up to 3 years of additional support (R33 phase) may be awarded to replicate the impact of the natural product on target engagement(s) when used by humans and assess whether there is an association between the degree of the impact on the target engagement and clinical outcomes in a participant population. Applications are encouraged to design R33 studies to determine how to optimize the impact of the natural product on the target engagement by optimizing the delivery of the natural product through examination of different doses or formulations. In addition, applications can be designed to combine the natural product with another treatment approach that is known to impact the same target engagement measure; or study the impact of the natural product in a population that is more responsive,

Notice NOT-EB-24-002 from the NIH Guide for Grants and Contracts

Notice NOT-NS-24-058 from the NIH Guide for Grants and Contracts

Notice NOT-MH-24-340 from the NIH Guide for Grants and Contracts

Notice NOT-DE-24-013 from the NIH Guide for Grants and Contracts

Notice NOT-AG-23-080 from the NIH Guide for Grants and Contracts

Notice NOT-NS-24-054 from the NIH Guide for Grants and Contracts

Notice NOT-DA-25-029 from the NIH Guide for Grants and Contracts

Notice NOT-AR-24-006 from the NIH Guide for Grants and Contracts

Notice NOT-HD-24-002 from the NIH Guide for Grants and Contracts

Notice NOT-NR-24-006 from the NIH Guide for Grants and Contracts

Notice NOT-NS-24-025 from the NIH Guide for Grants and Contracts

Notice NOT-NS-24-052 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-DK-23-011 from the NIH Guide for Grants and Contracts. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) that were developed for the treatment of type 2 diabetes (T2D) have significant protective effects for cardiac and renal diseases for people with and without diabetes. However, SGLT2i are not currently approved for individuals with type 1 diabetes (T1D) and there is an increased risk of diabetic ketoacidosis (DKA) for this population. Despite this concern, these drugs are increasingly being prescribed off-label for people with T1D. Continuous ketone monitoring (CKM) is a rapidly evolving technology that could be utilized clinically to prevent DKA by an early warning of elevations in ketone levels.The purpose of this NOFO is to solicit applications for studies that will develop and test risk mitigation strategies that involve the clinical integration of CKM for the safe use of SGLT2i for people living with T1D so that they may benefit from the cardiac and renal protection and glucose-lowering effects of this drug class. The NOFO will support short-term, clinical trials to gain and disseminate knowledge on safety and glucose control with CKM and SGLT2i use.Possible topics include testing optimal insulin delivery in open and closed loop systems or multiple daily injections and developing clinical protocols to control or ameliorate elevated ketone levels in individuals with T1D who are receiving adjunct therapy with SGLT2i.

Notice NOT-DA-23-063 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-DA-25-053 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity is to develop artificial intelligence tools and experimental assays to identify new pharmacotherapeutics with lower toxicity and higher efficacy for substance use disorders (SUD) Areas of interest include but are not limited to: 1) Development of AI tools to identify potential target combinations, design new molecules, conduct virtual preclinical studies to predict efficacy and toxicity, and model in vitro and in vivo polypharmacology 2) Development of assays to assess the effects of compounds on multiple targets or functions

Funding Opportunity RFA-DA-25-054 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity is to develop artificial intelligence tools and experimental assays to identify new pharmacotherapeutics with lower toxicity and higher efficacy for substance use disorders (SUD) Areas of interest include but are not limited to: 1) Development of AI tools to identify potential target combinations, design new molecules, conduct virtual preclinical studies to predict efficacy and toxicity, and model in vitro and in vivo polypharmacology 2) Development of assays to assess the effects of compounds on multiple targets or functions

Notice NOT-OD-24-057 from the NIH Guide for Grants and Contracts