Funded Projects

NOFO Title: HEAL Initiative: Back Pain Consortium (BACPAC) Research Program: Phase 2 Clinical Trials (UG3/UH3 Clinical Trial Required)
NOFO Number: RFA-AR-19-029
Summary:

The chronic low back pain (cLBP) subgroup with comorbid depression or anxiety disorders, known as high negative affect (NA), needs better non-opioid, comprehensive pain treatment options. Data shows that the combination of antidepressants (AD) and fear avoidance physical therapy is more efficacious at improving pain, function, depression, and anxiety in cLBP patients with high NA than each treatment alone or a control condition. Research also finds that an enhanced fear avoidance rehabilitation protocol (EFAR; fear avoidance-based physical therapy, pain education, and motivational messaging) further improves outcomes. To address the unmet needs of cLBP patients with high NA, this study will test in a randomized trial whether the combination of AD and EFAR is more effective than each treatment alone at relieving pain, improving function, combating depression, and preventing opioid misuse. This multimodal combination approach of pharmacotherapy and behavioral therapy is novel to the field and has the potential to shift current treatment paradigms.

NOFO Title: HEALing Communities Study: Developing and Testing an Integrated Approach to Address the Opioid Crisis (Data Coordinating Center) (UM1- Clinical Trials Not Allowed)
NOFO Number: RFA-DA-19-017
Summary:

Although there are effective prevention and treatment programs and services to address opioid misuse, opioid use disorder (OUD), and overdose, gaps remain between those needing and those receiving prevention and treatment, in part because of a need to better understand how to make these programs and services most effective at a local level. The National Institutes of Health (NIH) and the Substance Abuse and Mental Health Services Administration (SAMHSA) launched the HEALing Communities Study to generate evidence about how tools for preventing and treating opioid misuse and OUD are most effective at the local level. This multisite implementation research study will test the impact of an integrated set of evidence-based practices across health care, behavioral health, justice, and other community-based settings. The goal of the study is to reduce opioid-related overdose deaths by 40 percent over three years. As the Data Coordinating Center, RTI will provide coordination and facilitate communications to unite the HEALing Communities Study research centers into a cohesive research cooperative.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

Although effective, current pharmacotherapies for opioid use disorder (OUD) present serious limitations. For example, methadone, a mu opioid receptor (MOP) full agonist, has significant abuse liability and causes withdrawal after chronic use, while buprenorphine (Bup), an MOP partial agonist and kappa opioid receptor (KOP) antagonist, produces limited respiratory depression and is less effective than methadone in reducing drug use, craving, and relapse. To address the limitation of currently available MATs, this project uses a phased plan that will fast-track the IND development of a next-generation medication for OUD based on small-molecule compounds targeting the nociception opioid receptor (NOP)—with no misuse or dependence liability—that have shown promising efficacy in reducing oxycodone intake in rhesus monkeys trained to self-administer, with efficacies similar to that of buprenorphine. The project’s ultimate goal is to file an IND application for an NOP agonist as a promising new approach to treat illicit and prescription OUD that may offer an alternative to buprenorphine.

NOFO Title: HEAL Initiative: HEALthy Brain and Child Development Study (HEALthy BCD) (Collaborative R34 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-19-029
Summary:

The Planning for the HEALthy Early Development Study will contribute to the design and recommended protocol for a future large-scale, multi-site research study to prospectively examine human brain, cognitive, behavioral, social, and emotional development of children beginning prenatally through ages 9–10 and to determine the impact of maternal pre- and postnatal substance use on short- and long-term development of children. The planning study will link investigators across 6 research sites who have complementary experience and expertise in the areas that are essential to designing the study. Planning activities will be accomplished using a coordinated set of 10 working groups. By the end of the planning phase, the 6 consortium sites will have produced and tested a recommended protocol for the future multi-site study and will have established feasibility of carrying out the study protocol at each of the 6 linked sites.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

There is increasing evidence that satellite glial cells (SGCs) surrounding neurons in the dorsal root ganglia modulate sensory processing and are important for chronic pain. Tissue inhibitor of metalloproteinase 3 (TIMP3) signaling occurs in SGCs and has unique plethoric functions in inhibiting matrix metalloproteinases, the tumor necrosis factor-?-converting enzyme, and the vascular endothelial growth factor receptor 2, all of which have been implicated in inflammation and pain. This study will test the hypothesis that expression of TIMP3 in SGCs is critical for the neuroimmune homeostasis in sensory ganglia, as well as for the development of pain, and therefore could be a novel therapeutic target for acute and chronic pain. Given the expression of TIMP3 in human SGCs and the strong validation of multiple small molecules targeting TIMP3 signaling, including FDA-approved drugs, in various animal models of pain and in cultured human SGCs, the successful completion of this research project has a high likelihood of rapid translation into therapeutic testing in inflammatory pain conditions that are a risk for opioid abuse.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

Innovative interventions being conducted in emergency departments (EDs) for the treatment of opioid use disorders (OUD) have engaged more OUD individuals in treatment and saved lives. However, individuals who present to the ED following an opioid overdose, particularly those who have received naloxone reversal, are often resistant to accepting treatment. An innovative state-funded project called FAVOR Overdose Recovery Coaching Evaluation (FORCE) was initiated to try to address this problem wherein trained peer recovery coaches are called to the ED as soon as an opioid overdose victim is admitted. The proposed project will assess the feasibility and replicability of this model, assess whether the FORCE approach leads to more opioid overdose survivors entering formal substance use disorder treatment at one month compared to treatment as usual, and assess whether the FORCE approach leads to better retention in SUD treatment for OUD overdose survivors over time.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

Very little research has been conducted on better understanding of phenotypic characterization of individuals with OUD (beyond DSM-5 diagnoses) and how these features predict illness severity, treatment retention or outcomes. The primary objective of the deep phenotyping study is to provide a comprehensive phenotypic characterization (e.g., domains of negative affect, reward salience, cognitive control, mental health) of a heterogeneous sample of individuals (n = 1,000) who currently meet one or more DSM-5 diagnostic criteria for OUD and are in treatment for OUD. In a subset of this sample (n = 100), the investigators conduct digital phenotyping to examine the utility of ecological momentary assessment (EMA), digital sensing and social media to predict retention, medication adherence and opioid use outcomes in patients receiving buprenorphine for OUD. It is anticipated that this foundational study will inform the feasibility and utility of such assessments that can be successfully embedded into imminent and future CTN and other OUD clinical trials.

NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041
Summary:

There is currently no recognized way of accurately predicting who will recover from post-traumatic headache (PTH) during the acute phase following concussion and who will go on to develop persistent post-traumatic headache (PPTH), a condition that is difficult to treat effectively. Clinical experience suggests that early treatment is most effective, before headache patterns become persistent, but treating all patients with PTH would expose some patients to unnecessary treatment. Clinicians lack the information needed to make informed treatment decisions. Therefore, the study goals are to develop a prognostic biomarker signature for PPTH using clinical data and structural and functional brain neuroimaging and to assess the predictive accuracy of an ensemble biomarker signature for the early identification of patients at high risk for PPTH. This study can be translated into clinical practice and integrated into PTH clinical trials for early identification of those individuals who are at high risk for PPTH.

NOFO Title: PHS 2016-02 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42])
NOFO Number: PA-16-303
Summary:

The ability to de-risk lead compounds during pre-clinical development with advanced “organoid-on-a-chip” technologies shows promise. Development of microphysiological models of the peripheral nervous system is lagging. The technology described herein allows for 3D growth of high-density axonal fiber tracts, resembling peripheral nerve anatomy. The use of structural and functional analyses should mean drug-induced neural toxicity will manifest in these measurements in ways that mimic clinical neuropathology. The goals of this proposal are to establish our human model using relevant physiological measurements in tissues fabricated from human iPS cells and to validate the model system with a library of compounds, comparing against conventional cell culture models. Validating the peripheral nerve model system with drugs known to induce toxicity via a range of mechanisms will demonstrate the ability of the system to predict various classifications of neuropathy, yielding a high-content assay far more informative than traditional in vitro systems.

NOFO Title: HEAL Initiative: HEALthy Brain and Child Development Study (HEALthy BCD) (Collaborative R34 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-19-029
Summary:

Despite increased efforts to understand the neurodevelopmental sequelae of in utero opioid and other substance exposure on long-term behavioral, cognitive, and societal outcomes, important questions remain, specifically, 1) How is brain growth disrupted by fetal substance and related pre- and post-natal exposures? and 2) How are these disrupted growth patterns causally related to later cognitive and behavioral outcomes? This project seeks to formulate an approach to addressing these key questions and decipher the individual and cumulative effect of these intertwined pre- and post-natal exposures on child neurodevelopment. First, researchers will address the legal, ethical, and mother-child care and support concerns implicit in this study. Next, they will integrate across our areas of neuroimaging expertise to develop, implement, and harmonize a multi-modal MRI and EEG protocol to assess maturing brain structure, function, and connectivity. Finally, researchers will develop and test advanced statistical approaches to model and analyze this multidimensional and longitudinal data.

NOFO Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-19-018
Summary:

Head and neck cancer is particularly susceptible to nociceptive and neuropathic pains because it is dense with sensitive anatomic structures and richly innervated. Transcranial magnetic resonance imaging–guided focused ultrasound (FUS) is a new stereotactic modality capable of delivering high-intensity energy through the intact human skull with submillimeter precision. This clinical trial will target the spinothalamic and spinoreticular pain circuits by unilateral FUS mesencephalotomy, an effective procedure for cancer pain but limited by the accuracy of its era. The primary aim is to assess the safety and preliminary effectiveness in six head and neck cancer patients with opioid-resistant pain. Researchers will investigate the potential mechanism of pain relief as the mesencephalotomy target involves the confluence of the ascending and descending pain systems. Aims 2 and 3 will investigate these systems with electrophysiology specific for the spinothalamic tract and carfentenil positron emission tomography imaging that measures the brain’s endogenous opioids.

NOFO Title: HEAL Initiative: Behavioral Research to Improve MAT: Behavioral and Social Interventions to Improve Adherence to Medication Assisted Treatment for Opioid Use Disorders (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-AT-19-006
Summary:

Young people are disproportionately affected by the opioid crisis due to lack of access to medications for opioid use disorder (OUD) and poor adherence to these treatments. The Youth Opioid Recovery Support (YORS) model is an innovative wraparound approach that attempts to address barriers to treatment engagement in the young adult population, especially difficulties with medication adherence. The YORS model components include home delivery of extended-release naltrexone for OUD, engagement of families in collaborative treatment planning and monitoring focusing on medication adherence, assertive outreach from the treatment team by text messaging and social media to promote engagement and adherence, and contingency management to provide incentives for medication adherence. If the refining and testing demonstrates the efficacy of the YORS intervention, future work could include an economic analysis, a larger multisite study, longer intervention duration, study of extended-release buprenorphine, and study of step-down to less intensive interventions.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

A large number of probationers/parolees with opioid use disorder have limited access to effective treatment. This study is the first random clinical trial in the United States that will assess the effectiveness of buprenorphine treatment using MedicaSafe, a system composed of secure pre-packaged buprenorphine/naloxone cartridges, designed to be dispensed by a SmartKey device that enables clinicians to track patient adherence. The study will initiate treatment at a community corrections office compared to referral to a community program. The public health impact of the proposed study would be widespread, as this model of care could be implemented throughout many areas of the United States with high rates of opioid use disorder in their probation/parolee populations that lack access to methadone treatment.