Background:SARS-CoV-2 is the virus that causes COVID-19. Some people who recover from an acuteCOVID-19 infection may continue to have symptoms that persist for months or years. Thesecan 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-19infection.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 ongoingneurologic symptoms.Design:Participants will have 7 clinic visits in 7 months.Participants will be screened. They will have a physical exam with blood tests. Swabswill be used to collect cells from inside the mouth and nose. They may opt to have animaging scan.Participants will also have other tests before they are given the study drug. Theseinclude eye and skin exams; tests of their memory and thinking; and tests of involuntarybody functions, such as heart rate, blood pressure, sweating, and digestion. Their gripstrength and walking pace will be measured. They will wear a heart rate monitor for 24hours. 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 insertedinto 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 1dose of the drug.Participants will have 4 follow-up visits over 6 months. Tests may be repeated duringthese visits.
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.
Secondary objectives:
- To determine if one dose of intravenous Pembrolizumab can normalize markers of
immune exhaustion in neuro-PASC.
- To determine if one dose of intravenous Pembrolizumab can lead to clinically
relevant improvement in subjective and objective measures of ability.
Exploratory objectives:
- To determine if one dose of intravenous Pembrolizumab can change measures of
SARS-CoV-2 antigen.
- To determine if one dose of intravenous Pembrolizumab can change measures of
cytokines.
- To determine if one dose of intravenous Pembrolizumab can lead to improvement in
subjective measures of symptoms.
Endpoints:
Primary endpoint:
- Number of adverse events and serious adverse events.
Secondary endpoints:
- Number of participants with normalization of PD-1 expression on CD8 T cells.
- Number of participants achieving a minimal clinically important difference in
measures of function:
- Work Disability Functional Assessment Battery (WDFAB)
- PROMIS Global Health
- Short Form 36 (SF-36)
- PROMIS Cognitive Function
- Montreal Cognitive Assessment (MoCA)
- Incremental shuttle walk test
Exploratory endpoints:
- Detection of viral antigen
- Change in cytokine profile
- Statistically significant positive change from baseline:
- PROMIS Depression score
- PROMIS Anxiety
- PROMIS Fatigue
- PROMIS Sleep Disturbance
- WHO post COVID-19 functional scale
- Patient Post-COVID-19 Functional Status (PCFS) scale (0-4).
- Provider Post-COVID-19 Functional Status (PCFS) scale (0-4).
- FUNCAP55
- Multidimensional Fatigue Inventory (MFI)
- Pittsburgh Sleep Quality Index (PSQI)
- Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)
- Post Exertional Malaise Visual Analogue Scale
- Patient Global Impression of Change
- Physician Global Impression of Change
- Brief tablet-based neurocognitive testing
- Near Infrared Spectroscopy of muscle
- Actigraphy
- Hand grip strength
- Holter monitoring for 24 hrs
- Orthostatic Intolerance Questionnaire/Orthostatic Intolerance Daily Activities
Scale (OIQ/OIDAS)
- Dysautonomia measures in response to the QSART, Valsalva maneuver or head-up
tilt table testing.
- Ophthalmology Examination
Drug: Keytruda
Single dose of Pembrolizumab 200 mg IV
- 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.
- Provides documentation of at least one positive COVID-19 Test. Approved test can
include the following:
- PCR, NAA, or other EUA Approved test to confirm active COVID infection.
- A positive anti-nucleocapsid antibody test.
- A positive home Antigen test is acceptable when documentation of a photograph
of the test with a phone-based date and time stamp is provided.
- A positive anti-Spike antibody test is accepted in unvaccinated individuals or
those who had antibody testing prior to vaccination.
- Previously diagnosed with mild-moderate COVID-19 (WHO Clinical Progression Scale
between 2-5. 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. 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.
- 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-19.
- 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.
EXCLUSION CRITERIA:
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.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Investigator: NIH Clinical Center Office of Patient Recruitment (OPR)
Contact: 800-411-1222
ccopr@nih.gov
Ladifatou N Fouanta, R.N.
(301) 529-6340
ladifatou.fouanta@nih.gov
Avindra Nath, M.D.
(301) 496-1561
natha@mail.nih.gov
Avindra Nath, M.D., Principal Investigator
National Institute of Neurological Disorders and Stroke (NINDS)