Background: About 5 million adults in the United States have age-related brain disorders. These include Alzheimer disease (AD), mild cognitive impairment (MCI), and other dementias. The number of people with these disorders will likely increase as the population ages and life span increases. Inflammation is thought to play a role in AD and MCI. Researchers want to know if an enzyme called PDE4B increases inflammation in people with AD or MCI. Objective: To test whether medical imaging using a new radiotracer ([18F]PF-06445974) can measure PDE4B in the brains of people with AD or MCI. Eligibility: People aged 50 years and older with AD or MCI. Healthy volunteers are also needed. Design: Participants will have up to 5 clinic visits with 3 imaging scans of the brain. They will have be screened. They will have a physical exam with blood tests. This will include tests of their heart and nerve function, including memory. Participants will have 2 positron emission tomography (PET) scans. One will use a standard radiotracer. The other will use the study radiotracer. They will receive each tracer through a tube attached to a needle inserted into a vein. During the scan with the study tracer, participants will have a second tube inserted into a vein in the wrist; this tube will be used to draw blood during the scan. Participants will lie on a bed that slides into a doughnut-shaped machine. These visits will take about 6 hours each. Participants will have 1 magnetic resonance imaging (MRI) scan. They will lie on a bed that slides into a cylinder. This visit will take up to 2 hours....

Type: Interventional

Start Date: Jul 2026

open study

Background: Phosphodiesterase-4B (PDE4B) is a protein in the brain that may play a role in several mental health disorders. Researchers want to know if drinking alcohol increases the binding of a radioactive tracer to PDE4B in the brain because of increased activity and/or amount of the protein. This knowledge may help create new ways to treat people with alcohol use disorder (AUD). Objective: To learn if alcohol increases PDE4B activity in the brain. Eligibility: Healthy people aged 21 to 70 years who drink socially but do not have AUD. They must be enrolled in protocol 14-AA-0181"NIAAA Natural History Protocol". Design: Participants will have up to 4 clinic visits with up to 3 imaging scans of the brain; these will include 1 or 2 positron emission tomography (PET) scans and 1 magnetic resonance imaging (MRI) scan. The first PET scan will be a baseline. Participants will receive a radioactive tracer through a tube inserted into a vein. A second tube will be inserted so that blood can be drawn during the scan. Participants will lie on a bed that slides into a doughnut-shaped machine. This visit will take about 6 hours. For the next PET scan, participants will receive alcohol (ethanol) through a tube in a vein until they have a blood alcohol concentration that is equal to the legal driving limit. This is the same as 4 or 5 drinks for most people. After the scan, participants must remain at the clinic for a few hours until their blood alcohol drops. This visit will take 14 to 16 hours. The MRI scan of the brain will take up to 2 hours in a separate clinic visit.

Type: Interventional

Start Date: Dec 2025

open study

Background: SARS-CoV-2 is the virus that causes COVID-19. Some people who recover from COVID-19 have long-term symptoms that affect the brain. These include headaches; loss of taste and smell; sleep problems; thinking problems; depression; and anxiety. Researchers want to know if a tracer (a substance that is injected into a person s body before an imaging scan) can help identify inflammation in people with these brain disorders. Objective: To see if a radioactive tracer ([11C]PS13) can highlight brain inflammation in those who had COVID-19 but still have symptoms that affect the brain. Eligibility: Adults aged 18 to 70 years with post COVID-19 brain disorders who are enrolled in protocol 000089 or 000711. Healthy volunteers are also needed. Design: Participants will have up to 5 clinic visits. Participants will be screened. They will have blood tests and a test of their heart function. They will have imaging scans: Magnetic resonance imaging (MRI): They will lie on a table that slides into a metal tube. Pictures will be taken of the brain. Positron emission tomography (PET): A needle attached to a thin tube will be inserted into a vein in the arm. The tracer will be injected through the tube. Another needle attached to a thin tube will be inserted into the wrist or inside of the elbow of the other arm to draw blood. They will lie still on a bed while a machine captures images of their brain. The scan will last about 2 hours. Study involvement is 11 to 14 weeks....

Type: Interventional

Start Date: Jun 2025

open study

Study Description: Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant s ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant s impact in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. Objectives: The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, suvorexant s impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:<TAB> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

Type: Interventional

Start Date: Feb 2023

open study

This study will investigate how genetic and environmental factors contribute to the development of melanoma, a type of skin cancer, and related conditions. Individuals >=4 weeks with a personal or family history of melanoma or atypical spitzoid/Spitz tumor may be eligible for this study. Participants will: - Fill out one or two questionnaires about their personal and family medical history. - Provide written consent for researchers to review their medical records and pathology materials related to their care and those of deceased relatives with melanomas, tumors, cancer, or other related illnesses for whom they are the next-of-kin or legally authorized representative. - Donate a blood or cheek cell sample to be used for genetic studies. (The blood sample is collected through a needle in an arm vein. The cheek cell sample is obtained either by gently brushing the inside of the mouth with a soft brush or by swishing a tablespoon of mouthwash and then spitting it into a container.) - Undergo a skin biopsy (removal of a small piece of skin tissue) for genetic study. For this procedure, the area of skin to be removed is numbed with a local anesthetic and a 1/4-inch piece of skin is excised with a cookie cutter-like instrument. The wound is then covered with a band-aid. Participants may be asked to travel to the NIH Clinical Center for evaluation, including a medical history, physical examination, and some of the following procedures: - Full body skin examination to evaluate the type and number of moles and document any evidence of sun damage to the skin. The examination involves all the skin from the scalp to the bottoms of the feet. After the examination, a medical photographer will photograph the skin, with close-ups of skin lesions marked by the examiner. If there are parts of the skin the participant does not want examined or photographed, he or she can tell the examiner. - Blood draw of about 120 milliliters (4 ounces) or less - Skin biopsy - Cheek cell sample - X-rays, ultrasound and magnetic resonance imaging (MRI) studies to detect tumors or changes in tumors or other types of changes in specific tissues. MRI is a diagnostic test that uses strong magnetic fields and radiowaves to examine body tissues. The subject lies on a table that is moved into a large tunnel-like machine (the scanner) for about 45 minutes to 1 hour. When the tests are finished, a doctor will discuss the results with the participant and the need, if any, for clinical follow-up....

Type: Observational

Start Date: Jul 2002

open study

This is an interventional study that will test whether a breathing exercise called Inspiratory Muscle Strength Training (IMST) can safely and effectively lower blood pressure during late pregnancy. The goal is to see if a home-based breathing training can help prevent or reduce high blood pressure disorders in pregnancy. The main objectives are to make sure the training is safe and tolerable for pregnant women and to examine blood pressure and blood vessel health. Participants in their third trimester will be randomly assigned to either do moderate resistance IMST or a minimal resistance sham IMST, for 5 to 8 minutes a day over six weeks.

Type: Interventional

Start Date: Jun 2026

open study

Study Description: This is a natural history protocol designed to characterize the clinical spectrum of trisomy 8 mosaicism and trisomy 8-associated autoinflammatory disease (TRIAD) and related autoinflammatory disorders and further evaluate approaches to screening, diagnosis, and management. We will enroll affected patients and their unaffected relatives and collect a variety of clinical data and biological specimens for research analyses to better understand disease mechanisms. Biological samples from affected participants may include biopsies from the oral mucosa, skin, and bone marrow; swabs of the mouth, skin, and vagina; urine, stool, and saliva collections; and hair and fingernail clippings. Other clinical data may include imaging studies (such as magnetic resonance imaging [MRI], x-rays, and echocardiogram), questionnaires, and results from medical consults and clinically indicated procedures. Biological samples from unaffected relatives of participants may include blood, mouth swabs, stool, urine, and saliva. Participants may be seen in person or remotely via telehealth and provide send-in samples. After the initial baseline assessment, optional follow-up visits will occur approximately every 1 to 2 years, depending on the scientific needs of the study team and the participant s clinical status and interest. Objectives: Primary Objectives: 1. Characterize the clinical spectrum and natural history of trisomy 8 mosaicism and related disorders. 2. Characterize the immunologic profile in blood, tissue, and bone marrow of participants with trisomy 8 mosaicism and related disorders. Secondary Objectives: 1. Determine appropriate screening and diagnostic workup of individuals with trisomy 8 mosaicism and related disorders. 2. Identify the long-term risk of and association with neoplasm among individuals with trisomy 8 mosaicism. 3. Characterize the distribution of trisomy 8 cells in different tissues and cell types and describe how this contributes to disease manifestations and variability. 4. Evaluate or characterize immune responses to targeted therapeutics to better understand the pathophysiology of trisomy 8 mosaicism and related disorders. Exploratory Objectives: 1. Identify the specific genes and immunologic pathways that lead to disease manifestations seen in patients with trisomy 8. 2. Identify new genetic diseases that lead to mucosal ulcers and understand the immunologic mechanisms that contribute to mucosal ulcerations. Endpoints: Primary Endpoints: 1. Clinical characterization of participants with trisomy 8 mosaicism and related disorders based on history, physical examination, radiologic imaging, and laboratory testing. 2. Characterization of immunologic profile of participants with trisomy 8 mosaicism and related disorders over time in comparison to healthy controls using cellular and molecular techniques including, but not limited to immune cell phenotyping, transcriptomics, proteomics, and ex vivo functional studies. Secondary Endpoints: 1. Characterization of laboratory, radiologic, biopsy, and physical exam findings. 2. Identification of individuals with trisomy 8 who develop malignancy and assessment of risk factors including but not limited to history, findings on bone marrow biopsies and complete blood counts (CBCs), next-generation sequencing (NGS) for risk variants, and flow cytometry. 3. Determination of the percentage of trisomy 8 cells in various tissue types including bone marrow, blood, fibroblasts cultured from skin, and biopsy samples, and the association with clinical phenotype. 4. Assessment of immune response to therapeutics based on inflammatory markers, clinical history, and physical exam findings. Exploratory Endpoint: 1. Identification of genes that may lead to mucosal ulcerative disease when mutated or over/underexpressed.

Type: Observational

Start Date: Jul 2026

open study

The main purpose of this study is to assess the concentrations of nipocalimab (pharmacokinetics [PK]) in the breast milk after administration of a single dose of nipocalimab into the vein, in healthy lactating women.

Type: Interventional

Start Date: Jun 2026

open study

The purpose of this study is to see how feasible it is to enroll participants with schizophrenia and for them to complete the study/assessments. It will also assess how safe and tolerable aticaprant is when compared with placebo in participants with schizophrenia.

Type: Interventional

Start Date: Mar 2026

open study

The aims of this clinical trial will test whether or not the onset of nearsightedness is delayed in a group of children randomized to nightly drops in 0.05% atropine in both eyes, in comparison to children who receiving nightly placebo drops in both eyes. The primary outcome is the two-year cumulative incidence of nearsightedness. The second aim of this project will determine whether atropine is associated with slower eye growth in children receiving nightly drops of atropine versus placebo.

Type: Interventional

Start Date: May 2026

open study

The purpose of this study is to evaluate how well brenipatide (LY3537031) is tolerated what side effects may occur, and the safety and efficacy in participants with Irritable Bowel Syndrome-Constipation (IBS-C). The study drug will be administered subcutaneously (SC) (under the skin) when compared with placebo. The study will last approximately 35 weeks.

Type: Interventional

Start Date: Apr 2026

open study

The purpose of this study is to evaluate the efficacy and safety of standard chemotherapy with or without INCB161734 in participants with metastatic pancreatic ductal adenocarcinoma (PDAC).

Type: Interventional

Start Date: Apr 2026

open study

Researchers are looking for new ways to treat high-risk, localized non-small cell lung cancer (NSCLC) that has been removed with surgery. People with high-risk, localized NSCLC are often treated with surgery. Researchers want to learn if participants can receive 1 or 2 trial treatments to help prevent NSCLC from coming back after surgery. One trial medicine is intismeran (also called V940/mRNA-4157) and the other is subcutaneous pembrolizumab (also called SC pembrolizumab and MK-3475A). Intismeran is designed to help a person's immune system attack their specific cancer. SC pembrolizumab is an immunotherapy treatment which helps the immune system fight cancer. The main purpose of this study is to evaluate whether adjuvant intismeran autogene (V940) in combination with SC pembrolizumab and berahyaluronidase alfa (MK-3475A) or intismeran monotherapy improves disease-free survival (DFS) compared with placebo in participants with completely resected high-risk Stage I NSCLC.

Type: Interventional

Start Date: May 2026

open study

Using both tobacco and cannabis during pregnancy is more common in minoritized groups and can make quitting smoking in pregnancy and remaining smoke free postpartum difficult. Investigators will test an intervention to address prenatal depressive symptoms to encourage people to quit tobacco and cannabis during pregnancy and stay quit postpartum.

Type: Interventional

Start Date: Jun 2026

open study

Researchers are looking for new ways to treat Psoriatic Arthritis (PsA). This study will help find out if a study medicine called tulisokibart (MK-7240) can treat symptoms of active PsA. This study assesses the efficacy, safety, and tolerability of tulisokibart in adult participants with active PsA. In this study, researchers will look at different doses of tulisokibart. Researchers want to learn if at least one of the study doses of tulisokibart works better than a placebo to lessen PsA symptoms. A placebo looks like the study medicine but has no study medicine in it. Using a placebo helps researchers better understand the effects of the study medicine.

Type: Interventional

Start Date: Apr 2026

open study

The main purpose of this study is to see how the safety and efficacy of a farnesoid X receptor (FXR) agonist (LY4395089), given together with mirikizumab compares with mirikizumab (alone) in adults with moderately to severely active Crohn's disease (CD). This study is part of the IIBD master protocol and will last approximately 62 weeks.

Type: Interventional

Start Date: May 2026

open study

Study IIBD is a master protocol that will support a collection of individual sub studies that share key design components. Participants will be assigned to the appropriate study prior to randomization to a treatment group. The studies aim to evaluate the efficacy and safety of new treatments in adults with moderately to severely active ulcerative colitis or Crohn's disease and will last at least 62 weeks.

Type: Interventional

Start Date: May 2026

open study

Postoperative complications after surgical procedures, including following total knee arthroplasty (TKA), have a negative impact on the health and well-being of surgical patients. Older adults (≥65 years) are particularly vulnerable to postoperative complications and their associated morbidities due to the biological aging process. Older adults comprise nearly half of surgical patients worldwide, and this number is expected to increase in the next 10-20 years as the aging population continues to grow. TKA is the most common procedure undergone by older adults, and the rate of TKA procedures is also expected to rise. Despite perioperative guidelines and protocols to prevent postoperative complications, the prevalence of postoperative complications following TKA is approximately 12%. Given these statistics, millions of older adults undergoing TKA may be at risk for postoperative complications and their associated morbidities in the coming decades. Therefore, additional interventions are needed to combat postoperative complications in this population. The body's natural response to surgery, also known as the surgical stress response (SSR), contributes to postoperative complications through complex mechanisms involving the autonomic nervous system (ANS). Increased sympathetic nervous system (SNS) activity, or the body's fight-or-flight response, causes dysregulation in feedback systems that regulate the stress response, potentially leading to poorer outcomes. Interventions, such as breathwork, that induce the parasympathetic nervous system (PNS), or the body's rest-and-digest response, have been shown to balance the ANS, regulate stress biology, and improve outcomes. This study will examine the feasibility of adding a breathwork intervention (Box Breathing), compared to an attention control, to standard perioperative care for older adults undergoing TKA. This study will also examine the proof of concept that Box Breathing, compared to an attention control, may help regulate the SSR by assessing an objective measure of stress-related biology, diurnal cortisol rhythm, and gathering self-report information on pain, anxiety, depression, and quality of recovery following TKA.

Type: Interventional

Start Date: Jul 2026

open study

This is a phase 3 randomized, double -masked study comparing the efficacy of EYP-1901 against Aflibercept.

Type: Interventional

Start Date: Feb 2026

open study

The main purpose of the study is to evaluate the efficacy of selnoflast compared with placebo in participants with atherosclerosis, at high-risk for major adverse cardiovascular event (MACE), who are currently on standard-of-care (SOC) therapy.

Type: Interventional

Start Date: Jun 2026

open study

This is a multicenter, multinational, randomized, active-controlled, operationally seamless Phase 2/3 study of BMN 333 in treatment-naïve pediatric participants with achondroplasia (ACH). The study consists of a Phase 2 part and a Phase 3 part.

Type: Interventional

Start Date: Apr 2026

open study

Background: Glioblastoma is a common brain cancer in adults. Treatment includes surgery, radiation, and chemotherapy. But this cancer can return after treatment and is often fatal. Researchers want to know if a study drug (LMP744) can kill glioblastoma tumor cells. Objective: To test LMP744 in people with glioblastoma. Eligibility: People aged 18 years or older with glioblastoma that returned after treatment. Design: Participants will be screened. They will have a surgery to remove a small sample of tumor tissue (biopsy) from the brain. This will be done under protocol 03-N-0164. They will stay in the clinic for 1 night. They will also have imaging scans and tests of their heart function. Participants will have a central line installed: A flexible tube will be inserted into a vein in the chest. It will be attached to a port under the skin. This port will be used to draw blood and give medicines without having to insert new needles into a vein. LMP744 will be given through the central line for 5 days in a row. Participants will remain in the clinic for this time. Participants will then have a second surgery to remove as much of their tumor as possible. They will remain in the clinic until they recover from the surgery. Then they will recover at home after surgery. Participants will return to the clinic to receive the study drug for 5 days in a row through the central line, once a month for up to 12 months. Blood tests, heart function tests, and periodic imaging scans will be repeated during these visits. Participants will continue to have telehealth visits every 3 months after they stop taking the drug.

Type: Interventional

Start Date: Jul 2026

open study

Distal shoe space maintainers are the standard of care for guiding the eruption of permanent first molars following the premature loss of the primary second molars. Although this therapy represents established clinical practice, prospective evidence regarding soft tissue complications and predictors of treatment outcomes remains limited. This observational study will prospectively collect clinical outcome data during routine treatment visits. The aims of the study are to characterize patterns of complications, evaluate outcomes related to patient adherence, and identify predictors of treatment success. Ultimately, this study seeks to support the development of standardized strategies for clinical monitoring and complication management.

Type: Observational

Start Date: Aug 2026

open study

This randomized, double-blind, placebo-controlled trial evaluates whether oral zinc plus phytase supplementation modifies clinical response to intradetrusor botulinum toxin injection in patients with overactive bladder. Participants will receive either zinc plus phytase supplementation or matching placebo for five days prior to intradetrusor botulinum toxin injection. Participants will be followed for six months after treatment to assess need for repeat botulinum toxin injection, urinary symptoms, and patient-reported outcomes related to overactive bladder.

Type: Interventional

Start Date: Feb 2026

open study

The purpose of this trial is to learn about the safety and effectiveness of the antibody GEN1079 in participants with certain types of cancer. The trial has multiple parts. The first part of the trial tests different doses of GEN1079 to find out if it is safe and determine what are the best doses to use. The second and third parts continue to test the safety of and whether GEN1079 works in additional participants with specific cancer types and at doses chosen based on results from the previous parts of the trial. For each participant, the trial will last approximately 33 to 67 weeks but this may vary for each person. This includes up to 21 days for screening prior to receiving trial treatment, approximately 6 to 12 weeks of treatment (the duration of treatment may vary for each participant), and approximately 24 to 52 weeks of follow up after trial treatment ends (the duration of follow up may vary for each participant). During the screening, tumor tissue either collected prior to this trial or freshly collected during screening will be provided by all participants. Participation in the trial will require visits to the site, with more frequent visits at the start of treatment and then less frequent visits afterwards. At site visits, there will be various tests (such as blood draws) and procedures (such as recording of heart activity, computed tomography [CT] scans) to monitor whether the treatment is safe and effective. All participants will receive active drug; no one will be given placebo.

Type: Interventional

Start Date: Apr 2026

open study