Cecilia, Kentucky

Testing Olaparib for One or Two Years, With or Without Bevacizumab, to Treat Ovarian Cancer

PRIMARY OBJECTIVE: I. To determine investigator assessed progression-free survival using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (non-inferiority) for one versus (vs.) two years of maintenance olaparib. SECONDARY OBJECTIVES: I. To evaluate overall survival (OS360) in the modified intent to treat (ITT) population, with time at risk for progression/death starting 360 days after randomization. II. To evaluate progression-free survival (PFS), PFS2 and overall survival (OS) in the ITT population. III. To evaluate PFS, PFS2, and OS in the as-treated population. IV. To evaluate toxicity, including rates of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and other secondary malignancies, in the safety population. EXPLORATORY OBJECTIVE: I. To evaluate the moderating effect of physician-choice bevacizumab (as stratified) on randomized treatment effect estimates. TRANSLATIONAL OBJECTIVES: I. To assess BRCA reversion mutations in circulating tumor deoxyribonucleic acid (ctDNA) as a predictor of poor response in the BRCA mutated (BRCAm) population. II. To correlate a combined assay assessing quantitative BRCA1 and RAD51C promoter methylation and pathogenic variants in core homologous recombination repair (HRR) genes with clinical homologous recombination deficiency (HRD) testing and outcomes in the BRCA wildtype (BRCAwt) population. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (REFERENCE): Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study. ARM II (EXPERIMENTAL): Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

INJECTABLE COLD ENERGY THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN ASSOCIATED WITH OSTEOARTHRITIS OF THE KNEE

Effect of Sex on Orthostatic Intolerance and Cardiovascular Response During Lunar Descent and Ascent

Phase I, Visit one Alpha (1A); OIG (Orthostatic Intolerance Garment) Measurement: Participants will lie supine while torso and anthropometric measurements are acquired. The investigators will utilize the same procedures developed and adopted by the Orion Program to obtain foot, leg, and torso circumference measurements at pre-determined intervals. This detailed measurement procedure has shown to be effective at providing precise compression levels at pre-determined anatomical locations. The target levels of compression will be verified by the manufacturer, using a Hosiery and Allied Trades Research Association (HATRA) test instrument that is identified in the British Standard for testing compression in elastic stockings. Tilt Familiarization: Participants will be instructed to lie supine without moving throughout the Familiarization tilt test. After instrumentation with brachial blood pressure, continuous blood pressure monitoring, and electrocardiogram (ECG) for heart rate, baseline measures will be obtained for at least 2 minutes while the test is explained. Participants will be tilted to 80˚ head-up and instructed to remain still and quiet. After allowing the participant to become familiar with the tilt procedure and the feeling of being upright, the bed will be lowered back to horizontal (flat) and a timer started for a 20-minute supine rest period. Plasma and Blood Volume Measurement: An intravenous (IV) catheter will be inserted into a vein in the participant's arm or hand using standard techniques. All blood samples will be obtained using the IV catheter in the participant's arm, unless it becomes clogged, and another IV catheter cannot be placed in another arm or hand vein. In this situation, blood could be drawn from the participant's arm or hand vein using a butterfly needle. Participants will be supine for 20 minutes before this test begins. A clip will be placed on the participant's nose so that they are breathing only through their mouth. Participants will breathe through a mouthpiece connected to a rebreathing circuit containing 100% oxygen, which is scrubbed by soda lime to remove carbon dioxide. After ~5 minutes, a ~10 mL blood sample will be collected using the IV catheter. Thereafter, a small amount of carbon monoxide will be added into the breathing circuit, and the participant will breathe this mixture of carbon monoxide and oxygen for ~10 min. Then, a second ~10 mL blood sample will be obtained. Analysis of the blood samples (i.e., hematocrit, hemoglobin, and carboxyhemoglobin) will be used to calculate red blood cell mass, plasma volume, and total blood volume. Normovolemic Tilt Test at one unit of gravity (1G): This test will be similar to the Tilt Familiarization session, but baseline data will be collected for ~5 minutes while supine. After tilting up, participants will remain quiet, relaxed, and not move for up to 20 minutes or until presyncope. Brachial blood pressure will be measured, and ultrasound images obtained to quantify stroke volume approximately every minute. Blood pressure and ECG will be continuously monitored before, during, and after the tilt. A tilt test will be terminated if any of the following test termination criteria are met: sudden drop in heart rate (>15 bpm), systolic blood pressure (>25 mmHg) or diastolic blood pressure (>15 mmHg); significant cardiac arrhythmias such as an ectopic rhythm >4 beats; absolute systolic blood pressure <70 mmHg; symptoms such as nausea, clammy skin, profuse sweating, pallor, light-headedness, dizziness, or tingling; or participant request. In the event a tilt test is terminated prior to 20 minutes, the participant will be brought to a head-down tilt position until recovered. Visit one Bravo (1B); Plasma Volume + Furosemide Infusion: Plasma volume will be measured as described in Phase 1A. After the plasma volume test is complete, a 20 mg of Furosemide will be administered intravenously. This dose has been demonstrated to produce plasma volume losses similar to spaceflight and bedrest. An oral potassium supplement of 20 mEq (Milliequivalent) will be given as a prophylactic prior to the furosemide infusion. Induction of Hypovolemia: Following Furosemide infusion, participants will remain in the CVL (Cardiovascular and Vision Laboratory) and be observed while remaining seated (except for bathroom trips) for 2 hours. During this time urine volume and periodic blood pressure will be obtained. Participants will self-collect urine using urine collection bottles and provide to the test operator to document the time of urine collection and volume produced. Participants will be given a standardized volume of water at intervals throughout the study day. Participants will be provided snacks as needed throughout the duration of their stay in the laboratory. Hypovolemic Tilt Tests (1-G, 0.75-G, 0.50-G): Following the 2-hour period for diuresis to develop, participants will undergo 3 tilt tests (80°, 50°, and 30° head-up tilt) for up to 20 minutes each to simulate 1-G, 0.75-G, and 0.50-G exposures. The tilt tests will occur in a random order and participants will remain supine for 20 minutes to fully recover between tests. The timing, monitoring, and test termination criteria will be identical to that described in Normovolemic Tilt Test (1G) above. Immediately prior to each tilt test, a blood sample (5 mL) will be drawn using the IV catheter and analyzed for hematocrit and hemoglobin concentration, which will then be used to calculate the change in plasma volume since the baseline test. Alternatively, if the IV becomes clogged and another IV cannot be placed, these blood samples could be drawn from an arm or hand vein using a butterfly needle (5 mL) or by pricking the finger (80 μL). Phase II, Visit two Alpha (2A); OIG Fit Check: Participants will don their custom OIG garments to ensure there were no errors in garment development. Visit two Bravo (2B): Plasma Volume + Furosemide Infusion Participants will complete the same testing protocol as occurred in Phase 1B. Induction of Hypovolemia: Participants will complete the same testing protocol as occurred in Phase 1B. Hypovolemic Tilt Tests (1-G, 0.75-G, 0.50-G) + OIG: Following the 2-hour period for diuresis to develop, participants will don their custom-made OIG and assume the supine posture for ~20 minutes prior to starting the first tilt test. The order of the 3 tilt tests (80°, 50°, and 30° head-up tilt) will be the same order as occurred in Phase 1B, Hypovolemic Tilt Tests (1-g, 0.75-G, 0.50-G). Visits 2A and 2B can be combined.

Fluid Loading Countermeasures

Upon arrival for each visit, participants will be told which study session they will be participating in that day. Food and water consumption as well as fluid loading will be timed throughout the day during other testing described below. Participants will be asked to empty their bladder, and body weight will be measured using a standard calibrated medical scale. Then, an intravenous (IV) catheter (a small plastic tube) will be inserted into a vein in the participant's arm. This IV catheter will remain in their arm for the duration of the study day. This is the same method that is used in a doctor's office or hospital. All blood samples will be obtained using the IV catheter in the arm. Next, a test called Carbon Monoxide Re-Breathing (CORB) will be done to measure plasma volume, which is the liquid part of blood. A clip will be placed on the participant's nose so that they are breathing only through their mouth. Participants will breathe through a mouthpiece connected to a rebreathing circuit containing 100% oxygen, which is scrubbed by soda lime to remove carbon dioxide. After ~5 minutes, the first blood sample (~10 Milliliters [mL]) will be collected from an arm vein using the IV catheter. Thereafter, a small amount of carbon monoxide will be added into the breathing circuit, and the participant will breathe this mixture of carbon monoxide and oxygen for ~10 min. Then, a second ~10 mL blood sample will be obtained. Analysis of the blood samples (i.e., hematocrit, hemoglobin, and carboxyhemoglobin) will be used to calculate red blood cell mass, plasma volume, and total blood volume. The total amount of carbon monoxide will be determined based on the participant's body weight (1 mL/kg body mass for men; 0.8 mL/kg body mass for women), and this dose should result in no symptoms. Mild symptoms of carbon monoxide toxicity may occur at carboxyhemoglobin levels >10% but given the dose of carbon monoxide administered in this study, reaching this level is unlikely. Participants will be seated for the duration of the study, except for short bathroom breaks allowed periodically during the study session. The volume of urine and the time of collection will be measured and recorded throughout the day. Participants will be provided food during the morning as well as water to drink during the first 5 hours of each visit. Meals will be like those typically consumed by astronauts on the International Space Station. During 3 of the visits, participants will be given additional fluids to drink on a set schedule (Fluid Loading). Participants will not be allowed to consume any fluids or food during the last 3.5 hours of the visit. Participants will be asked about the presence of gastrointestinal symptoms periodically throughout each study session. Additionally, we ask that participants report to the PI/study lead if any off-nominal gastrointestinal symptoms occur in the day of the study visit after testing is completed. During the last 3.5 hours of each visit, 5 additional blood samples will be obtained (one each hour), used to calculate the change in plasma volume at each time point. Participant blood pressure and heart rate will be measured periodically throughout the day. (IRB protocol section 4.0)

Effect of Naltrexone Hydrochloride ER and Bupropion Hydrochloride ER Combination (Contrave®/Mysimba®) on Major Adverse Cardiovascular Events (MACE)

This multi-center, prospective, randomized, pragmatic, double-blinded study has been designed to capture cardiovascular (CV) outcomes during the real-world use of NB after initial randomization. The aim of the study is to assess whether patients receiving treatment with NB are at an elevated risk of experiencing MACE compared with patients receiving placebo. Both patient groups will also be counselled to lose weight via a reduced-calorie diet and increased physical activity.

Combination of Intranasal Scopolamine and Sensory Augmentation to Mitigate G-transition Induced Motion Sickness and Enhance Sensorimotor Performance

The primary specific aim is to evaluate the use of intranasal scopolamine gel (DPI-386) in operational field settings. Both astronauts and non-astronaut participants in the field testing will be recruited to test the feasibility and efficacy of the intranasal scopolamine gel (0.4 mg dosage). This testing will include only the active drug (no placebo); however, control astronaut subjects will also be recruited who choose other motion sickness countermeasures. The goal is to recruit astronauts from free-flier missions like SpaceX Polaris Dawn (8 active, 8 control), from Private Astronaut Missions to the International Space Station (ISS) like Axiom (8 active, 8 control), and from standard missions to the International Space Station (8 active, 8 control). Astronaut participants who choose to take intranasal scopolamine gel will be required to complete a 15 min training session to learn how to apply the medication, and then a 15 min debrief on any symptoms, side effects and comments on the efficacy and feasibility of self-administering the medication. Astronaut participants will also have the option to self-administer the drug during preflight activities that involve exposure to a motion environment (e.g., centrifuge training). For each time subjects choose to self-administer the drug, subjects will be asked to complete a short 15 min survey to describe the operational environment (e.g., centrifuge levels), any symptoms subjects experienced, side effects and comment s on the efficacy and feasibility of self-administering the medication. All astronauts, both active and control, will be tasked to complete a short inflight and postflight survey (15-30 min each) to summarize symptoms by day, record what medications were taken, rate their effectiveness, and summarize their recommendations on what others can do (or avoid) to improve recovery. This test may also involve non-astronaut test personnel during operational activities that involve provocative motion, e.g., capsule recovery simulations, centrifuge training, and parabolic flights. Participants for this part of the study will be recruited from personnel who are already involved and medically cleared for these operational activities and are interested in trying the drug to prevent or treat symptoms in addition to their primary task(s). In order to participate in these field test activities, subjects will be required to complete a 15 min training session to learn how to apply the medication, and then a 15 min debrief on any side effects and comments on the efficacy and feasibility of self-administering the medication. To prevent motion sickness, participants will administer the medication at least 30-45 min before the motion starts (e.g., centrifuge, launch, re-entry). To use the medication to treat motion sickness, participants will administer the medication while symptoms are still mild. Following the operational exercise, a short survey will be used to obtain the timing of the administration relative to the motion stressor, the operational environmental conditions (e.g., sea state or centrifugation levels), description of motion sickness symptoms and side effects, and subjective comments about the feasibility and efficacy of intranasal scopolamine gel.

Combination of Intranasal Scopolamine and Sensory Augmentation to Mitigate G-transition Induced Motion Sickness and Enhance Sensorimotor Performance

The primary specific aim is to evaluate the use of intranasal scopolamine gel (DPI-386) and sensory augmentation (SA) as an integrated countermeasure to mitigate motion sickness and enhance sensorimotor performance. The proposed intranasal scopolamine gel formulation (Defender Pharmaceuticals, Inc.) offers a safe non-invasive method to self-administer with a rapid onset of action. The proposed sensory augmentation will utilize vibrotactile feedback of pitch and roll tilt using a portable belt (Engineering Acoustics, Inc.). The investigators will utilize exposure to simulated capsule wave motion on a 6DOF platform to provide an operationally relevant platform to induce motion sickness and impair performance on functional tasks. The investigators hypothesize that the combination of intranasal scopolamine gel and sensory augmentation of Earth vertical will be more effective to mitigate motion sickness and improve task performance than when administered separately. Using a randomized double-blind cross-over design, the investigators will compare motion sickness symptom severity and time to endpoint (symptom level defined as severe malaise) in 30 subjects during exposure to simulated wave motion on a 6DOF platform inside of a crew capsule mockup. The investigators will compare four conditions: (1) intranasal scopolamine gel (0.4 mg) with sensory augmentation, (2) intranasal scopolamine gel (0.4 mg) without sensory augmentation, (3) placebo control with sensory augmentation, and (4) placebo control without sensory augmentation. The wave motion stressor will begin 30 min post drug administration and will not exceed 45 min in duration. Performance on a series of functional tasks (dual-task tracking and eye-hand target acquisition) will be performed pre, during, immediately post, and following 15 min of recovery of each test. The bioavailability of scopolamine for each session will be estimated from plasma concentrations obtained at drug administration and then every 15 min up to 2-hr post-dosage. Subjective side effects and performance on the Psychomotor Vigilance Test (PVT) will also be obtained at 15 min intervals. A small pilot study including 10 subjects tested once each will be performed to verify the experimental protocol including that the simulated capsule wave motion will provoke motion sickness symptoms. These pilot sessions will not include the medication nor the blood sampling.

Comparing Cisplatin Every Three Weeks to Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer

PRIMARY OBJECTIVES: I. To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). (Phase II) II. To determine whether radiation with cisplatin weekly is non-inferior to radiation with cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. (Phase III) III. To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced SCCHN. (Phase III) SECONDARY OBJECTIVES: I. To assess and compare progression-free survival (PFS) between arms. II. To assess and compare locoregional failure and distant metastasis between arms. III. To assess acute and late toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0). IV. To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) (primary PRO), between arms. V. To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms. VI. To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory objective). VII. To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms. VIII. To assess long-term PFS, OS, and toxicity between arms. IX. To assess 3-year restricted-mean survival time for OS and PFS between arms (if long-term update is warranted). EXPLORATORY OBJECTIVE: I. To collect blood and tissue specimens for future translational science studies. For instance, to examine how germline and somatic genetic variants, such as TP53, CDKN2A, PIK3CA, PTEN, NFE2L2, and KEAP1, may influence cisplatin-related efficacy and toxicity, and to assess the effect of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use and genomic activation of PIK3CA (mutation or amplification) or loss of PTEN, the negative regulator of PI3K, on disease-free survival or overall survival. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I (NON-OROPHARYNGEAL CANCER [OPC]/p16-NEGATIVE OPC group and p16-NEGATIVE OPC/CANCER OF UNKNOWN PRIMARY [CUP] group): Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive cisplatin intravenously (IV) once every 3 weeks (Q3W) (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity. ARM II (NON-OROPHARYNGEAL CANCER [OPC]/p16-NEGATIVE OPC group and p16-NEGATIVE OPC/CANCER OF UNKNOWN PRIMARY [CUP] group): Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive cisplatin IV once a week (QW) for 7 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, or magnetic resonance imaging (MRI) or position emission tomography (PET) scan throughout the study.

Study to Evaluate the Efficacy, Immunogenicity, and Safety of RSVpreF in Adults.

Study Of Oral Elagolix Tablets In Combination With Combined Oral Contraceptive Capsules/Tablets To Assess Dysmenorrhea Response In Adult Female Participants With Endometriosis And Associated Moderate To Severe Pain