Actively Recruiting Studies

This page features extramurally funded clinical trials supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Click on a disease/condition below to find studies that are actively recruiting. Updates are made to this page as new studies get funded and begin recruitment. Please check back often to find new trials supported by NIAMS.

Please check other clinical trials supported by the NIAMS that have completed recruitment or completed with published results following the links below.
View Active Studies with Completed Recruitment
View Completed Studies with Published Results

For questions, please contact the NIAMS Clinical Trials team at:

Disease / Condition


Achilles Tendinopathy

Tendinopathy Education on the Achilles, A Clinical Trial (TEACH)

The standard of care for chronic tendinopathy primarily targets a localized area of tendon pain, but this strategy is ineffective for up to 40% of patients with chronic Achilles tendinopathy. An emerging field of research indicates that changes in the central nervous system (CNS) contribute to pain in patients with orthopaedic injuries, such as tendinopathy. Yet the current standard of care for Achilles tendinopathy does not evaluate or treat CNS pain mechanisms. This study proposes a more global approach by evaluating and treating alterations in how the central nervous system processes chronic tendinopathy pain.

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Actinic Neoplasia

Photodynamic Therapy-Induced Immune Modulation: Part III

Numerous environmental and iatrogenic pro-oxidative stressors ranging from chemotherapy to ultraviolet radiation have been demonstrated to induce immunosuppression in preclinical murine (mouse) models. These stressors have also been shown to be potent inducers of the lipid mediator platelet-activating factor (PAF), which exerts immunosuppressive effects in murine mouse models. The previous work has characterized the exact pathways by which PAF-dependent immunosuppression occurs and have identified a major role of regulatory T cells (Treg). PAF released from injury acts upon the mast cell PAF receptor resulting in the formation of immunosuppressive Tregs. This process is dependent upon the cytokine IL-10 and cyclooxygenase-2 (COX-2) generated prostaglandins. Though high levels of PAF has been shown to be generated in humans in response to many of the immunosuppressive stressors that induce PAF in animal models, studies are needed to define if this PAF COX-2Treg pathway is functional in humans.

The study team has found that topical photodynamic therapy (PDT) is a very potent inducer of PAF in murine skin and induces systemic immunosuppression only in mice expressing PAF receptors. Therefore, this study is designed to test if the PAF COX-2 Treg pathway is involved in PDT-induced effects and could be pharmacologically modulated with COX-2 inhibitors to block the immunosuppression and potentially improve PDT efficacy in treating precancerous actinic keratoses lesions

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Anterior Cruciate Ligament (ACL) Injury 

Real-time Sensorimotor Feedback for Injury Prevention Assessed in Virtual Reality

Traumatic and debilitating anterior cruciate ligament (ACL) injuries occur at a 2- to 10-fold greater rate in female than male athletes, and 50-100% of females develop knee osteoarthritis within 12-20 years of initial injury. The National Public Health Agenda for Osteoarthritis recommends expanding and refining evidence- based prevention of ACL injury to reduce this burden. The study team has identified modifiable risk factors that predict ACL injury in young female athletes. The lab-based neuromuscular training targets modifiable risk factors and shows statistical efficacy in high-risk athletes, but a meaningful risk re-categorization to "low-risk" has not been achieved.  The overall objective of this proposal is to implement and test innovative augmented neuromuscular training (aNMT) methods to enhance sensorimotor learning and more effectively reduce biomechanical risk factors for ACL injury.

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A Two Arm Non-Inferiority Randomized Clinical Trial Comparing ACL Repair with BEAR Device vs. Autograft Patellar Tendon ACL Reconstruction (BEAR – MOON Trial)

Tissues which live within joints, including the anterior cruciate ligament, rotator cuff tendon, meniscus and labrum fail to heal spontaneously after injury and have high failure rates of surgical repair. The ACL represents a good model to study the problem of intra-articular healing as there are validated preclinical models and clinical outcome measures that make it possible to critically evaluate the success or failure of strategies to enhance tissue healing. The current standard of care for ACL injuries is ACL reconstruction, which is good at stabilizing the knee but requires compromising other uninjured structures around the knee to obtain a graft that is subsequently used to replace the ACL. Further the early posttraumatic OA is not mitigated despite ACL reconstruction. The preclinical studies on ACL repair called BEAR (Bridge-Enhanced ACL Repair) demonstrated a prevention of posttraumatic OA and achieved knee stability. The positive preclinical findings of BEAR compared to ACL reconstruction provided the foundation for two FDA approved preliminary clinical trials: 1) the first-in-human cohort study (“BEAR I”), and 2) a small, single-center randomized control trial (“BEAR II”). The statistical analysis of our pilot data shows a 200 patient trial will be required to demonstrate non-inferiority of BEAR (a novel paradigm changing technology) when compared to ACL reconstruction (current gold standard) for the key outcomes of anterior-posterior (AP) knee laxity and a validated patient reported outcome for knee surgery. Therefore, the study team proposes the BEAR-MOON (Bridge-Enhanced ACL Repair) multi-center randomized non-inferiority clinical trial for co-primary outcomes AP (anterior-posterior) knee laxity and International Knee Documentation Committee (IKDC) validated patient reported outcome measure.

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Anti-Phospholipid Syndrome

Certolizumab to Prevent Pregnancy Complications in High-Risk Patients With APS or SLE - (IMPACT Study: IMProve Pregnancy in APS With Certolizumab Therapy)

Antiphospholipid syndrome (APS) is an autoimmune disorder that occurs most commonly in women of reproductive age and is associated with thrombosis and adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). Traditional therapy for APS during pregnancy has been a heparin agent and low dose aspirin. However, in PROMISSE, a prospective observational study of 724 patients, 44% of pregnancies in women with APS and LAC resulted in APOs despite treatment with heparin and low dose aspirin.

Based on the observations in PROMISSE, this study hypothesizes that tumor necrosis factor-alpha blockade will significantly decrease the rate of fetal death and preterm delivery due to PE and PI in women with APS and LAC.

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Treatments Against RA and Effect on FDG-PET/CT (The TARGET Trial)

Rheumatoid arthritis (RA) is a chronic inflammatory disease, causing joint damage and disability. While remarkable progress in the treatment of RA over the past two decades has improved many outcomes, mortality rates in RA remain 1.5-3-fold above non-RA controls. Cardiovascular disease (CVD) is the leading cause of excess deaths in RA.  Most experts believe that enhanced vascular inflammation underpins accelerated atherosclerosis and CV events yet, there has been no direct proof for this hypothesis. If this is true, then RA therapies that reduce joint inflammation might also reduce CV risk. The lack of an RA-specific CV risk tool hampers evidence-based guidelines, as general population tools perform poorly in RA. These gaps in knowledge create uncertainty for patients and providers in managing RA and its comorbidities. This study proposes to use 18fluoro-deoxyglucose by positron emission tomography/computed tomography (FDG PET/CT) as a novel imaging modality to detect baseline, and disease-modifying antirheumatic drug (DMARD)-associated changes in, vascular inflammation in RA.

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Atopic Dermatitis

A Community-based Assessment of Skin Care, Allergies, and Eczema: The CASCADE Trial

Atopic dermatitis (AD) affects over 9 million children in the U.S. and often heralds the development of asthma, food allergy, skin infections and neurodevelopmental disorders. Recent advances identify skin barrier dysfunction to be the key initiator of AD and possibly allergic sensitization.

This study hypothesizes that daily emollient use from birth can prevent the development of AD in a community setting and into newborns unselected for risk. The results of a community-based clinical trial utilizing a pragmatic trial design will be immediately applicable to the population at large and will establish a new standard of care for all newborns.

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Team-Based Connected Health to Improve Access and Outcomes in Atopic Dermatitis

Skin diseases account for 30% of all physician office visits. In the United States, access to dermatologists remains a significant challenge for those in underserved or rural communities. To increase access to specialists and improve patient outcomes, this study will evaluate a team-based connected health (TCH) model that enables structured asynchronous online interactions among patients, primary care providers (PCPs), and dermatologists. The goal of TCH is to enable effective management of chronic skin diseases via high-quality and efficient online care between providers and patients. TCH purports to bring direct and expedient specialist care to patients and PCPs in a location-independent and asynchronous manner. Specifically, TCH offers several ways that patients and providers can communicate online asynchronously to manage skin diseases: (1) PCP-dermatologist, (2) patient-dermatologist, and (3) patient-PCP interactions. With PCP-dermatologist interactions, PCPs can access dermatologists online asynchronously for consultations or to request a dermatologist to assume care of patient’s skin disease. With patient-dermatologist interactions, patients can upload clinical images and history online and obtain asynchronous evaluation and recommendations from dermatologists directly. Finally, PCPs have the option of managing their patients’ skin diseases online. Importantly, TCH applies efficient workflow that maximally supports providers and fosters multi-directional, informed communication among patients, PCPs, and dermatologists.

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JAK Inhibition in Down Syndrome

People with Down syndrome (DS) display profound immune dysregulation, which could have myriad negative impacts on their health, including the development of various immune and neurological disorders. Multiple lines of evidence indicate that hyperactivation of interferon (IFN) signaling drives immune dysregulation in DS. This study aims to complete a clinical trial in adults with DS and immune skin conditions, using a pharmacological inhibitor of IFN signaling, which is expected to have multidimensional therapeutic benefits in this population.

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Bone Remodeling

Sleep Disturbance: A Novel Risk Factor for Impaired Bone Remodeling

Sleep disturbance negatively impacts many biological systems and may be detrimental to skeletal health. Bone remodeling, which is important for bone mass and strength, increases overnight, a time when millions experience disrupted sleep. Epidemiological data and animal studies suggest a link between sleep disturbance and bone but the direction and the mechanisms by which sleep affects bone are not fully understood. The overall objective of this project is to establish and quantify the skeletal effects of disrupted sleep and to investigate the mechanisms by which bone remodeling and sleep are linked. The central hypothesis is that sleep disturbance (e.g., sleep loss, circadian shifts) negatively impacts bone health by altering the balance between bone resorption and bone formation and is particularly detrimental during skeletally vulnerable periods such as during and after the menopausal transition.

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Chronic Pain

GET Living: Graded Exposure Treatment for Children and Adolescents with Chronic Musculoskeletal Pain

With up to a third of adolescents reporting recurrent or chronic musculoskeletal pain, it is a critical national health problem. The experience of chronic pain in adolescence negatively impacts overall health during this important life period and increases the risk of pain and mental health problems in adulthood. Pain-related fear is repeatedly identified as an important factor that increases the likelihood of poor outcomes among adolescents with pain, and yet pain-related fear is rarely targeted in typical pain management (TPM). Perhaps unsurprisingly, TPM yields no change in pain-related fear, and modest improvements in functional disability. To overcome limitations of TPM for pain-related fear, graded in-vivo exposure treatment (GET) was developed. While TPM focuses on pain control via pain management psychology and impairment-based physical therapy, GET is jointly delivered by a pain psychologist and physical therapist targeting functional improvement, through exposing patients to activities previously avoided due to fear of pain. GET is successful in adults with chronic musculoskeletal pain! and our pilot data of GET for adolescents with chronic pain (GET Living) is robust, with significant declines in patient fear, activity avoidance, and disability. Uniquely, GET Living also targets parent distress and behavior, and our pilot data demonstrate decreases in parent fear, avoidance, and protective behavior. GET Living also distinguishes itself with an innovative assessment approach to patient progress and clinical endpoints. In addition to standard assessment tools, GET Living utilizes electronic daily diary technology to identify exactly when improvements in outcomes are occurring/not occurring, and objective biomechanical assessment using motion analysis and physical activity monitoring via Actigraphy.

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Neuroimaging Effects of Cognitive Behavioral Therapy in Fibromyalgia

Chronic pain is an international health problem that imposes costs of over 600 billion dollars per year. This study focuses on fibromyalgia (FM), which is characterized by persistent, widespread body pain, with significant evidence of altered brain function. One of the few effective treatments for FM is cognitive-behavioral therapy (CBT), which has been shown to reduce pain intensity and pain-related disability, potentially via reductions in catastrophizing, an important psychosocial factor that plays a crucial role in shaping individual differences in pain-related outcomes.

The investigator’s previous study in FM patients confirmed that patients who are high in catastrophizing show enhanced pain-related activation in brain areas that process emotional aspects of pain (e.g., anterior insula and medial thalamus). In addition, catastrophizing was associated with altered pain-evoked functional connectivity between thalamus, anterior insula, and default mode network (DMN) structures such as medial prefrontal cortex. This study hypothesizes that CBT-produced improvements in pain will be anticipated and mediated by reductions in catastrophizing and their associated effects on pain-related brain functioning.

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Multi-site Randomized Clinical Trial of FIT Teens for Juvenile Fibromyalgia

Juvenile-onset fibromyalgia (JFM) is a chronic, debilitating pain condition that persists into adulthood for the majority of patients. The previous research has demonstrated that cognitive-behavioral therapy (CBT) is effective in reducing functional disability in adolescents with JFM. However, in order to achieve stronger and clinically meaningful improvement in functional disability and reduce pain, changing sedentary behavior and increasing engagement in moderate-vigorous physical activity is a crucial component of JFM pain management. Incorporation of physical exercise has emerged as a logical next step to enhance CBT, yet regular participation in any physical activity is difficult to initiate and maintain in JFM patients.

This study evaluates whether Fibromyalgia Integrative Training program for Teens (FIT Teens), a combined cognitive behavioral therapy and neuromuscular exercise training program are more effective in reducing disability in adolescents with Juvenile Fibromyalgia compared to CBT alone or a graded aerobic exercise (GAE) program alone.

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Granulomatosis with Polyangiitis (GPA)

Abatacept (CTLA4-Ig) for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener's) (ABROGATE)

Granulomatosis with polyangiitis (Wegener’s) (GPA) is a systemic inflammatory disease that is characterized by necrotizing, granulomatous inflammation and vasculitis of the small to medium-sized vessels. Despite the availability of medications that can induce remission, disease relapses occur in up to 75% of patients with GPA. The majority of these relapses are not severe, but can nevertheless result in incremental significant morbidity, from both GPA and the use of immunosuppressive treatment required to manage such relapses.   Abatacept (CTLA4-Ig) is comprised of the ligand-binding domain of CTLA4 plus human immunoglobulin. Through this construct abatacept carries the potential to modulate the costimulatory signal required for T cell activation. Based on laboratory data supporting a potential role for activated CD4 T cells in the pathogenesis of GPA, an open-label study was conducted to examine the role of abatacept in non-severe relapsing GPA. In 20 GPA patients treated with abatacept, 90% improved, 80% achieved remission, and 70% reached common closing. Eleven out of 15 patients were able to discontinue prednisone.

This multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of abatacept to achieve sustained glucocorticoid-free remission in patients with relapsing non-severe GPA.

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The Assessment of Prednisone In Remission Trial (TAPIR) - Patient Centric Approach

Granulomatosis with polyangiitis (Wegener’s) (GPA) is a primary systemic vasculitis, predominantly involving microscopic blood vessels with no or scanty immune deposits. GPA is strongly associated with circulating auto-antibodies to neutrophils (ANCA) and is one of a group of conditions known as ANCAassociated vasculitis (AAV). The cause of AAV is unknown. AAV has an annual incidence of 20 per million and an approximate prevalence of 200/million. It is a multi-system autoimmune disease that causes tissue damage especially to the respiratory tract and kidneys and causes early mortality, organ failure including end-stage renal disease, and chronic morbidity. Prior to the availability of effective treatment, AAV was almost universally fatal, with a 93% mortality within 2 years due to pulmonary and renal failure. Administration of cytotoxic immunosuppression (cyclophosphamide, rituximab, methotrexate) and glucocorticoids (GC) for at least one year induces remission in approximately 80% of patients. GC are a standard of care in the treatment of AAV. High doses of GC early in disease although undeniably reduce disease activity due to their anti-inflammatory and immunosuppressive properties also increase the risk of infection particularly in the elderly and in the presence of uremia. There is a major unmet need for safer therapy that leads to sustained treatment free remission in patients with relapsing disease, which will reduce drug toxicity that results from cumulative exposure to immunosuppression and glucocorticoids.

This randomized controlled trial aims to evaluate the effects of using low-dose glucocorticoids as compared to stopping glucocorticoid treatment entirely.

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Isolated Skin Vasculitis

A Randomized Multicenter Study for Isolated Skin Vasculitis

Vasculitides are uncommon diseases which can affect almost any organ. Vasculitis frequently involves the skin, as an isolated process, or as part of systemic vasculitis. Skin vasculitis represents an important source of morbidity and symptomatology as well as an opportunity for early diagnosis and treatment. Despite the important place of isolated skin vasculitis in this group of diseases, there has historically been limited emphasis placed on understanding its pathogenic mechanisms and determining its best treatment. Whereas episodes of isolated small vessel vasculitis in the skin are often self-limited, resolve over 3-4 weeks with residual hyperpigmentation, and do not recur, up to one-third of patients have persistent or recurrent disease for up to several years. The cutaneous vasculitic lesions can be itchy, painful, and cosmetically disturbing. It can ulcerate, and then be complicated by infection and scarring. In around 8-10% of patients, chronic or recurrent small vessel vasculitis can develop. In general, systemic involvement (if found) is minimal and limited to mild arthralgias, myalgias, fatigue, low-grade fever or peripheral edema. No therapy has been proven to shorten the duration of disease or decrease its severity and the frequency of the flares.  Initial long-term treatment options mainly include colchicine, dapsone, or azathioprine.

This study proposes to compare the efficacy of three of the drugs among the most commonly used ones — colchicine, dapsone, and azathioprine — for the treatment of isolated skin vasculitis, in a multi-center sequential multiple assignment randomized trial.

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Knee Arthroplasty

A Novel Physical Therapy Administered Physical Activity Intervention After TKR: A Randomized Control Trial

Total Knee Replacement (TKR) is the most successful intervention to address pain from knee osteoarthritis. However, most resume a sedentary lifestyle gain weight and subsequently remain at high risk for poor health outcomes after surgery. There is a critical need for people after TKR to adopt an active lifestyle. Outpatient Physical therapy (PT) is an ideal, low-cost setting for a physical activity intervention for people after TKR given that physical therapists are experts at prescribing and personalizing exercises to meet patients' abilities over multiple outpatient visits. Unfortunately, little study has been devoted to the efficacy of a physical therapist delivered physical activity intervention.

The objective of this study is to evaluate the preliminary efficacy over 3 months of a physical therapist-delivered physical activity intervention. The intervention starts with providing a Fitbit™ monitor at admission to PT. Next, the physical therapist provides face-to-face feedback on current activity levels and recommends step goals personalized to previous activity levels, a process that takes < 5 minutes at each visit. The intervention is integrated into standardized outpatient PT for TKR.

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Improving Physical Activity and Gait Symmetry After Total knee Arthoplasty

Total knee arthroplasty (TKA) is one of the most common surgical procedures performed in the U.S., and rates are rising rapidly. TKA results in decreased pain, increased range of motion, and improvements in some aspects of physical function for most patients. However, accumulating evidence shows that patients have persistent deficits in other critical outcomes following TKA. First, the majority of patients do not substantially increase physical activity beyond levels prior to TKA, remaining well below recommended levels. This has negative implications for both joint health and overall health. Second, gait asymmetries are common following TKA, such that patients often continue to load the non-surgical leg more heavily during walking, even when the post-surgical leg is pain free, placing the contralateral limb at risk for developing or worsening osteoarthritis. The long-term objective of this study is to improve post-TKA outcomes, particularly overall physical activity and joint loading symmetry, through implementation of a rehabilitation process that directly addresses these core domains.

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Knee Osteoarthritis

The Relation of Altered Pain Processing to Impact Loading and Response to a Gait Retraining Treatment in Knee Osteoarthritis

Knee Osteoarthritis (OA) is a major public health problem, causing substantial pain and functional limitations and effects ~12% of older adults. There are a few effective non-invasive treatments to prevent disease progression or decrease pain. The current proposal will provide evidence-based information in order to design novel and effective rehabilitation treatments for knee osteoarthritis.

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Meniscal tear and Osteoarthritis (OA)

Treatment of Meniscal Problems in Osteoarthritis

Knee osteoarthritis is a disabling problem affecting over 15 million adults in the United States. Many people who have knee arthritis also experience painful meniscal tears. There are a number of different treatments that can be used to manage meniscal tears in the presence of knee arthritis. Treatments include surgically removing the damaged part of the meniscus; strengthening exercises to improve pain and function; manual therapy including massage and mobilization; acupuncture; and others. The combination of surgery and exercise therapy was long thought to be the best treatment. However, recent studies have shown that surgery followed by physical therapy is no more effective than physical therapy by itself.

While physical therapy alone has been shown to result in similar pain relief as arthroscopic surgery, researchers have not yet done studies to determine what type of physical therapy is best for people with knee arthritis and meniscal tears. This study proposes the TeMPO (Treatment of Meniscal Problems in Osteoarthritis) Trial to compare different non-operative physical therapy regimens to gain a better understanding of how physical therapy works and what regimen will best reduce pain and improve function in persons with meniscal tear and osteoarthritis.

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Osteogenesis Imperfecta

Rare Diseases Clinical Research Network Brittle Bone Disease Consortium Longitudinal Study of Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is a rare disorder that causes bones to break easily. People with OI may have broken bones with little or no trauma, dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The purpose of this natural history study is to perform a long-term follow-up of a large group of people with osteogenesis imperfecta (OI) to improve the health and quality of life of people with OI.  The study team will collect information on medical history, number of broken bones, surgeries done, medications taken, ability to walk, pain, lung function and breathing, hearing, and bone mineral density. This study aims to perform DNA testing and collect natural history data on all individuals enrolled in this longitudinal study, see how often people with type I OI have vertebral compression fractures of the spine, follow people with all forms of OI to see how often they develop scoliosis (curvature of the spine), and look at dental health in people with OI.

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Mechanisms Underlying the Bone Modeling Effects of Combined Anabolic/Antiresorptive Administration

One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Currently, available medications reduce fracture risk but are unable to fully restore skeletal integrity. Thus, there remains an urgent need for osteoporosis treatments that rapidly and effectively restore bone strength. Unlike most chronic conditions, osteoporosis has historically been treated with only one drug at a time. Attemps to combine anabolic agents with the most commonly used antiresorptive agents (bisphosphonates) did not prove efficacious. In contrast, we recently reported that the combination of teriparatide and the receptor activator of nuclear factor-kB ligand (RANKL) inhibitor, denosumab, increases bone density and improves bone microarchitecture and estimated strength more than either drug alone and more than any vailable therapy. The study team has hypothesized that the efficacy of this combination is dependent on denosumab's capacity to fully block teriparatide's stimulation of bone resorption while allowing for teriparatide-induced stimulation of bone formation (modeling-based bone formation). In this proposal, the study team will directlyl assess the ability of teriparatide to stimulate modeling-based bone formation with bone resorption is blocked by denosumab.

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Effect of a Ghrelin Receptor Agonist on Muscle and Bone

Adults with low muscle mass also usually have low bone mass, making them vulnerable to falls, fractures, and other injuries. This study will determine the effectiveness of treatment with a ghrelin receptor agonist in improving short term indicators of muscle and bone health in adults with low bone and muscle mass. The results of this trial will inform the design of a larger definitive randomized trial designed to establish efficacy.

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Pelvic Fractures

PTH(1-34) and Pelvic Fracture Healing - a Randomized Controlled Trial

This randomized, double-blind, placebo-controlled 3-month study tests the efficacy of teriparatide (TPTD) to accelerate fracture healing in women and men ≥ 65 years of age with acute fractures of the pelvis.  The investigator hypothesizes that TPTD for 3 months as an adjunctive therapy in addition to standard of care will accelerate radiographic evidence of fracture healing and functional recovery and that differences between TPTD and placebo groups documented at 3 months of treatment will persist when evaluated up to 12 months. 

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Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable and inherited mechano-bullous disease of the skin characterized by skin fragility, blister formation, and chronic wounds. RDEB is caused by mutations in the COL7A1 gene encoding type VII collagen (C7), the major component of anchoring fibrils (AFs) that anchor the epidermis to the dermis. AFs are attenuated, diminutive, or absent in RDEB. There is no effective treatment for RDEB except palliative measures and supportive wound care.  Based on encouraging in vitro and in vivo RDEB data, the proposed study will assess the safety and efficacy of IV gentamicin in RDEB patients with nonsense mutations.

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Rheumatoid Arthritis

Skeletal Muscle Dysfunction in Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, with a prevalence of 1% worldwide. Nearly two-thirds of RA patients suffer from loss of skeletal muscle mass, which often co-occurs with central obesity, a feature of metabolic syndrome. Lower muscle mass leads to muscle weakness, a major contributor to physical impairment in patients with RA, even after multivariate adjustment for demographic and disease variables. The overarching goal is to understand at a mechanistic level the metabolic and physiologic abnormalities of skeletal muscle in patients with RA and to use that knowledge to improve therapy for skeletal muscle dysfunction in RA.  Thus, this study hypothesizes that increased lipid content in skeletal muscle contributes to insulin resistance and impaired skeletal muscle homeostasis and function in RA and that treatment with pioglitazone will improve muscle function by decreasing lipid deposition in skeletal muscle, restoring the anabolic effects of insulin and attenuating inflammation.

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Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is associated with a 2-fold increased risk of cardiovascular disease (CVD), which is not explained by traditional cardiovascular (CV) risk factors alone. This risk is likely mediated in part through systemic inflammation. Indeed, RA itself is deemed to impart a CV risk equivalent to diabetes mellitus (DM). However, unlike in DM, optimal CV management strategies in RA are lacking. Despite improved anti-inflammatory therapies for RA, the mortality gap in RA compared to the general population is still widening, in part due to suboptimal primary and secondary CV preventive care in RA. To date, there have been no published controlled intervention trials for primary CV prevention in RA, despite this clearly urgent unmet need.

One of the early stages of atherogenesis is endothelial dysfunction, and drugs that target improvement in this are promising novel strategies for CVD prevention. The fundamental feature of endothelial dysfunction is impaired nitric oxide (NO) bioavailability. Sildenafil improves endothelial function by increasing NO signaling by inhibition of phosphodiesterase-5 (PDE5). PDE5 inhibitors improve endothelial function in pulmonary hypertension and DM and were safe and well tolerated in patients with erectile dysfunction and other CV comorbidities. Furthermore, PDE inhibitors have immunomodulatory properties that may be utilized to treat autoimmune conditions like RA.

This study hypothesizes that sildenafil is a uniquely suited agent targeting endothelial dysfunction as a novel adjunctive CV prevention strategy and immunomodulatory agent in RA.  Specifically, the study team aims to determine if sildenafil use in RA improves endothelial dysfunction and atherosclerosis biomarkers.

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Cell-Based Therapy in Rheumatoid Arthritis: Proof of Concept Phase 1 Trial

Rheumatoid Arthritis (RA) affects adults in the prime of their life and their career with two peaks of onset, the first in the mid-life around the age of forty and the second in the sixties. RA affects women more frequently than men with up to 1% of the population affected. The burden to society includes but is not limited to the potential loss of individuals who are at the peak of their careers themselves who may be affected by RA or who may be responsible for caring for a family member with RA. This Phase I clinical trial in which RA patients have had an incomplete response to methotrexate receive add on therapy with a single infusion of adult bone marrow stem cells (or placebo infusion) from a healthy donor to “quiet” the immune system. If successful, cell-based therapy would represent a paradigm shift in the treatment of RA. Studies have demonstrated that early treatment of new-onset RA improves outcomes, but therapies are most often life long, expensive and have undesirable side effects. If immune tolerance can be induced and the immune system "reset" to its "pre-RA" condition, then environmental, and other lifestyle changes (e.g., quitting smoking) could be used to reduce the chance of recrudescence of RA and increase the interval to "flare."

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Treatments Against RA and Effect on FDG-PET/CT (The TARGET Trial)

Rheumatoid arthritis (RA) is a chronic inflammatory disease, causing joint damage and disability. While remarkable progress in the treatment of RA over the past two decades has improved many outcomes, mortality rates in RA remain 1.5-3-fold above non-RA controls. Cardiovascular disease (CVD) is the leading cause of excess deaths in RA.  Most experts believe that enhanced vascular inflammation underpins accelerated atherosclerosis and CV events yet, there has been no direct proof for this hypothesis. If this is true, then RA therapies that reduce joint inflammation might also reduce CV risk. The lack of an RA-specific CV risk tool hampers evidence-based guidelines, as general population tools perform poorly in RA. These gaps in knowledge create uncertainty for patients and providers in managing RA and its comorbidities. This study proposes to use 18fluoro-deoxyglucose by positron emission tomography/computed tomography (FDG PET/CT) as a novel imaging modality to detect baseline, and disease-modifying antirheumatic drug (DMARD)-associated changes in, vascular inflammation in RA.

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Molecular Transducers of Physical Activity Consortium (MoTrPAC)

Physical inactivity is a major public health challenge underlying a broad range of health problems at all ages. While physical activity (PA) has shown to produce relevant health benefits, the underlying molecular mechanisms are poorly known. The coordinated effort of clinical and animal studies supported by bioinformatics and chemical analyses will achieve the Molecular Transducers of Physical Activity Consortium (MoTrPAC) goals of assessing the molecular changes that occur in response to PA. The Consortium Coordinating Center (CCC) for the MoTrPAC will provide support for the organization, administration, planning, standardization, documentation, monitoring and reporting activities relating to the MoTrPAC. The CCC will play a pivotal role in ensuring the cohesion of the MoTrPAC by enhancing communication and integration across all study components, including the Clinical Sites, the Preclinical Animal Study Sites, the Bioinformatics Center, the Chemical Analysis Sites, and the various study committees. The CCC will develop strategies and strategic planning processes by integrating activities of the MoTrPAC investigators and facilitate interactions and communications with junior and senior investigators outside the consortium to maximize the use of the MoTrPAC resources toward achieving the overall research goals. To accomplish these goals and maximize the progress and productivity of the MoTrPAC, the CCC will promote team science, team leadership, and innovative leadership approaches across all study components. Strategic planning that follows the principles of the dynamic theory of strategy will be fostered to evaluate alternative approaches, maintain the cutting-edge scientific focus, leverage state-of-the-art coordination technologies, anticipate challenges, and maximize future opportunities to ensure the success of the consortium.

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Spinal Cord Injury

Exploration of blood flow regulation to bone in humans

Without blood flow, bone cannot maintain its integrity. Bone blood flow responds to various local and systemic factors, however, bone perfusion in humans remains relatively unstudied. This study will investigate key mechanisms that regulate bone perfusion in able-bodied and contrast responses to those with spinal cord injury (SCI). SCI is a model of chronic reduced loading with loss of sympathetic regulation.

In tibial cortical bone, the study team will: 1) determine the impact of compressive loading with and without muscle contractions; 2) determine the impact of vascular sympathetic activity and systemic perfusion pressure; 3) compare the response between able-bodied and those with SCI

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Statin-Induced Inhibition of Skeletal Muscle Adaptation to Exercise

Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity

More than 40 million Americans currently take statins for the treatment or prevention of hyperlipidemia and cardiovascular disease (CVD). Patients taking statins are also commonly advised to exercise regularly to further lower the risk for metabolic and cardiovascular disease. However, recent evidence suggests that statins can impair important exercise adaptations and that this, again, may occur as a result of statins negatively impacting mitochondria in skeletal muscle. Understanding how long-term statin therapy affects mitochondrial function in skeletal muscle is extremely important clinically, given the critical role skeletal muscle plays in maintaining metabolic and cardiovascular health. Therefore, the objectives of this study are to determine the impact of statin therapy on skeletal muscle mitochondrial function, cardiorespiratory fitness, and metabolism in humans.

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Systemic Lupus Erythematosus (SLE)

Study of Anti-Malarials in Incomplete Lupus Erythematosus

Systemic lupus erythematosus (SLE) causes major organ damage and shortens lifespan in relatively young persons. Early diagnosis and treatment are essential to improving outcomes for SLE patients. However, evidence-based approaches to early treatment interventions and the appropriate target population for these interventions are not available. We propose that individuals who have positivity for antinuclear antibodies (ANAs) and who also exhibit some of the other features that are used to classify SLE, are at high risk of progressing to the full systemic form of this disease. These individuals, who have significant levels of ANA with 1 or 2 additional items from the lupus classification criteria, are considered to have incomplete lupus erythematosus (ILE).

The primary objective is to determine whether HCQ treatment can prevent acquisition of additional clinical and immunologic features that define SLE. The secondary objectives are to determine whether HCQ treatment 1) lessens lupus disease activity as measured by standard scoring indices, 2) improves patient-reported outcomes, 3) prevents accumulation of immunologic abnormalities including autoantibodies and cytokines, and 4) has an acceptable toxicity profile.

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Lupus Intervention for Fatigue Trial

Systemic lupus erythematosus (SLE, lupus) is a systemic autoimmune disease characterized by pronounced inflammation that affects up to 1.5 million people in the US. While excess mortality has decreased in SLE patients since the 1970s, a major ongoing cause of morbidity in this population is chronic, debilitating fatigue that significantly decreases quality of life, and increases risk of work disability and associated health care costs. An urgent, unmet need in the management of patients with SLE is identification of effective strategies to reduce fatigue.

Preliminary data from lupus patients showed that regular aerobic exercise can improve quality of life and reduce fatigue. In considering other lifestyle behaviors, there is limited literature on effects of diet, energy balance, and/or nutrient density in SLE patients, but diet intervention has been favorably associated with managing fatigue in other disorders (e.g., cardiovascular disease and age-related functional decline). To study the effects of intervening on these two potential modifiable lifestyle behaviors (PA and diet) this study designed the Lupus Intervention Fatigue Trial (LIFT) to compare the effectiveness of a motivational interviewing program intervention versus a patient educational program control to reduce fatigue in persons with lupus.

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Ulnar Neuropathy

Clinical Trial for Surgery of the Ulnar Nerve (SUN) at the Elbow

Ulnar neuropathy at the elbow (UNE) is a common compressive neuropathy condition that can cause pain, tingling , and muscle loss in hand. If left untreated, it can lead to disability and job loss. Conservative treatment fails in 60% of cases, and most patients require surgery, which is often recommended to eliminate symptoms, but controversy xists over the best procedure. The two most common surgical procedures are in-situ (simple) decompression and subcutaneous anterior transposition. This study plans to conduct a multicenter randomized clinical trial to compare outcomes for two commonly used surgical procedures and develop an optimal surgical plan for individual patients.

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Low Dose Naltrexone to Improve Physical Health in Patients With Vasculitis

Symptoms clearly attributable to inflammatory disease are controllable in the great majority of patients with vasculitis. However, most patients do not feel healthy despite effective immune-suppressive treatment. Among the residual symptoms that disrupt the lives of patients with vasculitis, fatigue, poor physical function, sleep disturbance, and satisfaction with social roles are the most common and have the greatest negative impact on quality of life. Although there are multiple potential sources of these symptoms – residual autoimmune/inflammatory disease, medication side effects, co-morbidities such as obstructive sleep apnea or depression – the cause(s) often defy identification and successful management in the individual patient. Chronic pain is also high on the list of important negative influences on quality of life of patients with vasculitis.

Naltrexone is an opioid antagonist that is used in high doses for emergency treatment of opioid overdose and is FDA approved in an oral daily dose of 50 mg to prevent recidivism in alcoholics. At much lower doses of 4 – 4.5 mg daily, however, it has been shown in small, blinded, randomized trials to improve pain in fibromyalgia, gastrointestinal symptoms in Crohn’s disease, and quality of life in patients with multiple sclerosis.  The mechanism is unclear, with proposals including not only modulation of central pain-processing pathways but also mitigation of inflammatory roles of microglia. In addition to blocking opioid receptors, naltrexone blocks TLR-4, and some studies suggest that the anti-inflammatory effects of low dose naltrexone are independent of opioid receptors.

This multi-center, randomized, double-blinded, cross-over, placebo-controlled trial aims to evaluate the efficacy of low-dose naltrexone (LDN) at 4.5 mg nightly in improving self-reported physical health in patients with vasculitis.

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Venous Leg Ulcers (VLU)

Developing Strategies for Effective Debridement in Patients for Venous Leg Ulcers

Chronic non-healing venous leg ulcers (VLUs) have an intrinsic healing impairment that is associated with dysfunctional gene expression patterns. The previous study has shown that tissue from the non-healing edge of chronic VLUs exhibits characteristic histopathology including epidermal hyperproliferation, dermal fibrosis, accumulation of intracellular pro-collagen and dysregulation of genes involved in epidermal differentiation, migration and proliferation. It also has demonstrated that biopsies taken from the non-healing edges of VLUs before and after debridement have distinct morphologies and distinguishable gene expression patterns, providing the biological basis and justification of debridement. These observations are supported by the findings that primary cells grown from tissue biopsies before and after debridement also have distinct and typical genomic patterns, with cells from pre-debridement edge biopsies exhibiting a non-healing phenotype as evidenced by loss of migration and loss of ability to respond to growth factor stimuli. Moreover, using a genomic approach in a clinical trial to determine mechanism of action of cell-based therapy in patients with VLU, the study team has identified a specific set of genes responsible for therapeutic reprogramming that shifts non-healing ulcer into acute wound-like healing VLU.

The goal of this project is to use genomic profiling, candidate genes and proteins to develop guided surgical debridement to improve healing in chronic non-healing VLUs and to test the efficacy of this approach.

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Ventilator-Induced Diaphragm Dysfunction

The Effect of Intermittent Hemidiaphragm Stimulation During Surgery on Mitochondrial Function, Single Fiber Contractile Force and Catabolic Pathways in Humans

This study proposes to test the hypothesis that intermittent electrical stimulation (ES) of the human hemidiaphragm during prolonged cardiac surgeries with mechanical ventilation (MV) support prevents/attenuates ventilator-induced diaphragm dysfunction (VIDD) in the active hemidiaphragm.  Using a within-subjects experimental design, muscle samples from a stimulated hemidiaphragms will be compared with samples from the unstimulated hemidiaphragm. The study team will investigate mitochondrial dysfunction and oxidative stress during prolonged CTS/MV, and the potential of ES to attenuate or prevent VIDD, investigate the effects of ES on single fiber contractile properties and Titin integrity, and study the effect of ES on proteolytic pathways (caspase, calpain, and ubiquitin-proteasome) and ribosomal RNA markers of decreased protein synthesis implicated in VIDD.

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X-Linked Hypophosphatemia

Calcitriol Monotherapy for X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH) is characterized by increased FGF23, which impairs activation of vitamin D and promotes renal phosphate wasting leading to osteomalacia and rickets. Current treatment using 1,25- dihydroxyvitamin D(calcitriol) and phosphate is often complicated by hypercalcemia and nephrocalcinosis and does not always prevent hyperparathyroidism. Furthermore, it does not normalize growth. Thus, the study team undertook a pre-clinical study in the Hyp mouse model of XLH, to compare the effects of calcitriol alone vs treatment with FGF23 blocking antibodies on growth, serum and urine mineral ions as well as histological, histomorphometric, microarchitectural and biomechanical properties of bones. These studies revealed that calcitriol monotherapy improves growth, prevents rickets and improves the microarchitectural and biomechanical properties of bone without phosphate supplementation. The beneficial effects of calcitriol were superior to those of the FGF23 blocking antibody employed, perhaps because, as in humans, FGF23 blocking antibodies were not able to sustain increased levels of 1,25-dihydroxyvitamin D. It is notable that the beneficial effects of calcitriol occur in spite of a significant increase in circulating FGF23 and bone FGF23 mRNA expression.

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Last Updated: September 2020