Phase I Open-Label Safety Trial of Pembrolizumab for Neurological Post-Acute Sequelae of SARS-CoV-2 (PD1-PASC I)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- The primary outcome of this study is to determine the safety of a single dose of intravenous Pembrolizumab in participants with neurological post-acute sequalae of SARS-CoV-2 infection.
研究概览
简要总结
Background:
SARS-CoV-2 is the virus that causes COVID-19. Some people who recover from an acute COVID-19 infection may continue to have symptoms that persist for months or years. These can include neurological symptoms, such as headaches, loss of taste or smell, dizziness, or trouble walking. Pembrolizumab is a drug approved to treat certain cancers. Researchers think this drug might reduce long-term neurologic symptoms after a COVID-19 infection.
Objective:
To test pembrolizumab in people with ongoing neurologic symptoms of COVID-19.
Eligibility:
People aged 18 years or older who had COVID-19 at least 6 months ago and have ongoing neurologic symptoms.
Design:
Participants will have 7 clinic visits in 7 months.
Participants will be screened. They will have a physical exam with blood tests. Swabs will be used to collect cells from inside the mouth and nose. They may opt to have an imaging scan.
Participants will also have other tests before they are given the study drug. These include eye and skin exams; tests of their memory and thinking; and tests of involuntary body functions, such as heart rate, blood pressure, sweating, and digestion. Their grip strength and walking pace will be measured. They will wear a heart rate monitor for 24 hours. They will wear devices on a wrist and thigh to measure activity for 10 days.
Participants will have a lumbar puncture (spinal tap): A thin needle will be inserted into their lower back to draw out a sample of the fluid around their spinal cord.
Pembrolizumab is given through a needle inserted into a vein. Participants will receive 1 dose of the drug.
Participants will have 4 follow-up visits over 6 months. Tests may be repeated during these visits.
详细描述
Study Description:
Despite clinical recovery from an acute SARS-CoV-2 infection, some individuals continue to experience ongoing symptoms for months to years afterwards, with many of these symptoms being neurologic. These neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC) may be related to persisting viral antigen that leads to immune exhaustion. This study will primarily evaluate the safety of one dose of intravenous Pembrolizumab therapy in neuro-PASC participants with evidence of immune exhaustion. Pembrolizumab therapy may have positive clinical and laboratory effects on participants with persistent neurological symptoms, which will be measured as secondary outcomes.
Objectives:
Primary Objective:
-To determine the safety of a single dose of intravenous Pembrolizumab in participants with neurological postacute sequalae of SARS-CoV-2 infection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 110 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •To be eligible to participate in this study, an individual must meet all the following criteria:
- •Stated willingness to comply with all study procedures and availability for the duration of the study.
- •Male or female, aged at least 18 or older.
- •-Documentation of the SARS-CoV-2 infection that led to development of PASC confirmed either by a positive testing by a commercial laboratory or a positive home test followed by confirmatory nucleocapsid antibody testing.
- •Previously diagnosed with mild-moderate COVID-19 (WHO Clinical Progression Scale between 2-
- •Participants who had severe acute COVID-19 requiring hospitalization or ICU care are excluded.
- •If participants had multiple SARS-CoV-2 infections, they would need to be at least 6 months after the last infection.
- •All participants would need to have a negative SARS-CoV-2 nasal swab at the time of enrollment.
- •Exhibiting persistent neurologic symptoms evidenced by a self-reported illness narrative of the development of persistent PASC symptoms after recovering from a SARS-CoV-2 infection. These include symptoms such as fatigue, cognitive difficulties, sleep disturbances, orthostatic intolerance, and any ongoing issues with gait instability, vision, speech, swallowing, sensation, or strength. Symptoms must persist for at least 6 months after the diagnosis of acute COVID-
- •All participants will have PD-1 expression on CD8 T cells that is one SD above the mean value of normal controls as established in the SINS Lab and published previously.
- •Moderate to severe PASC symptom severity, as determined using PCFS (minimal score of 3).
- •Ability of participant to understand and sign a written informed consent document.
- •Prior completion of a clinical brain MRI after the diagnosis of COVID-19, or willingness to complete a brain MRI.
- •Agrees not to have vaccinations over the course of the study.
- •Participants of childbearing potential must agree to use a combination of contraception (defined as two forms of effective birth control) or have had surgical sterilization, from the time of enrollment until 4 months after the dose of study drug.
- •Participants capable of sperm donation must agree to not donate sperm from the time of enrollment until 4 months after the dose of study drug.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •For participants who have not completed a brain MRI since onset of symptoms: inability to complete brain MRI with gadolinium including contraindicated metal in the body, prior allergic reaction to gadolinium, eGFR <45 mmol/L, or claustrophobia that is unable to be adequately treated with a low dose oral benzodiazepine.
- •Contraindication to a research lumbar puncture, including use of anticoagulant medication, platelets < 50,000/uL, PT or PTT >1.5 x ULN for the NIH Clinical Center, if risk of lumbar puncture is increased for other reasons such as space occupying lesion, skin infection at site of the puncture or otherwise inability to complete the procedure.
- •A condition that would significantly confound interpretation of the clinical and research tests as determined by the study investigators. This could include traumatic brain injury, substance use disorder, active malignancy, systemic immunologic disorders, current or previous long-term immune suppressive therapy.
- •Any premorbid medical condition that would potentially cause fatigue and exercise intolerance. This includes many chronic medical diseases, such as congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, severe arthritis, uncontrolled asthma, renal failure, fibromyalgia, and ME/CFS.
- •Symptom severity that makes it impossible for the participant to travel to NIH.
- •Received a SARS-CoV-2 vaccine dose within less than 4 weeks of enrollment or is planning for any additional vaccines during the study.
- •Prior treatment for PASC with immunomodulatory therapies such as check point inhibitors which in the opinion of the investigators could impact the outcome of this study.
- •Current medications include oral steroids or other immunosuppressive medications which in the opinion of the investigators could impact the outcome of this study.
- •Active participation in a clinical protocol which includes any intervention that may affect the results of the current study.
- •Abnormal anti-thyroid panel (anti-TPO and anti-TG) test at screening visit.
- •ANA titer of 1:80 or greater, positive anti-CCP.
- •Abnormal screening blood tests exceeding any of the limits defined below or as deemed exclusionary by the investigators on review at baseline:
- •Aspartate aminotransferase and alanine aminotransferase values >2x upper limit of normal precluding the use of acetaminophen
- •Fasting triglyceride > 300 mg/dL.
- •Total bilirubin >2x upper limit of normal (unless participant has Gilbert syndrome)
- •Creatinine Clearance or eGFR <60 ml/minute (adjusted for race)
- •Hemoglobin < 10 g/dL
- •Absolute neutrophil count < 1000/microliter
- •Platelet count <130,000/mm3 (if platelet clumping is present on hematology slide review, platelet count <100,000/mm3 is considered exclusionary to study)
- •Hemoglobin A1c >= 6%
- •Thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) within normal limits. If TSH is not within normal limits then the participant may be eligible if thyroxine (T4) is within normal limits. Participants are not excluded if they are on a stable dose of replacement thyroid medication; dose may be adjusted as needed.
- •Previously documented anaphylaxis or severe systemic reaction to check point inhibitors, acetaminophen, or diphenhydramine.
- •A severe psychiatric condition, which based on the assessment of the study investigators, will impact the ability to complete the study.
- •Pregnancy or planning to get pregnant.
- •Currently lactating/breastfeeding.
- •Current or previous malignancy. A history of malignancy that has fully resolved with surgical resection only (e.g. no chemotherapy, radiation therapy, or immunotherapy) will be allowed.
- •Current or past substance use disorder within last five years. Marijuana use within the past five years will not be an exclusion.
- •Infection with HIV, tuberculosis, hepatitis B or C.
研究组 & 干预措施
Open Label
Single dose of Pembrolizumab 200 mg IV
干预措施: Keytruda (Drug)
结局指标
主要结局
The primary outcome of this study is to determine the safety of a single dose of intravenous Pembrolizumab in participants with neurological post-acute sequalae of SARS-CoV-2 infection.
时间窗: From screening to Day 180.
次要结局
- To determine if one dose of intravenous Pembrolizumab can lead to clinically relevant improvement in subjective and objective measures of ability.(Comparison between baseline, day 30, day 60 , and day 180 visits.)
- To determine if one dose of intravenous Pembrolizumab can normalize markers of immune exhaustion in neuro-PASC.(Comparison between baseline, day 30, day 60 , and day 180 visits.)