HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
=================
Brief Summary
-----------------
Background: - Some people with Amyotrophic Lateral Sclerosis (ALS) have a high level of the virus HERV-K in their blood. Researchers do not think this virus causes ALS. But they don t know why some people with ALS have a high level of it. They want to know if HERV-K can be suppressed by drugs that are used to treat HIV infection. Objectives: - To learn how drugs usually taken for HIV infection affect people with Amyotrophic Lateral Sclerosis (ALS). Eligibility: - Adults at least 18 years old with ALS and high levels of HERV-K but no HIV. Design: Interested participants can contact the study team and, if eligible, the study team will arrange for a screening blood draw to determine the HERV-K level. Participants with a high HERV-K level will be screened with medical history, physical exam, questionnaires, nerve conduction test, lumbar puncture, and blood and breathing tests. After screening, participants will start taking the 4 study drugs. Participants will have up to 12 study visits over a period of 72 weeks. After starting study drugs, they will have study visits at Weeks 1 and 4 and then every 4 weeks until Week 28. They will be asked how they are feeling and have an exam and blood drawn. At 3 visits, they will have tests of nerve conduction, breathing, and their ALS symptoms. At Week 24, they will stop taking the study drugs and have a repeat lumbar puncture. After the Week 48 visit, their participation is finished.

Detailed Description
-----------------
Objective: In this Phase I, proof-of-concept study, we aim to determine whether an antiretroviral regimen approved to treat human immunodeficiency virus (HIV) infection would also suppress levels of Human Endogenous Retrovirus-K (HERV-K) found to be activated in a subset of patients with amyotrophic lateral sclerosis (ALS). We propose to measure the of blood levels of HERV-K by quantitative PCR before, during, and after treatment with an antiretroviral regimen. We will evaluate the safety of the antiretroviral regimen for participants with ALS and also explore clinical and neurophysiological outcomes of ALS symptoms, quality of life, and pulmonary function. Study Population: We will study a subset of ALS patients who have a ratio of HERV-K:RPP30 greater than or equal to 13. About 30% of ALS patients may have detectable levels of HERV-K; about 20% of patients with ALS have a level >1000 copies/ml. To show whether the HERV-K could be suppressed, we will recruit from the approximately 20% of patients with the high levels so that the antiretroviral effect can be determined. Design: This is an open-label study of a combination antiretroviral therapy for 24 weeks in 25 HIV-negative, HTLV-negative ALS patients with high ratio of HERV-K:RPP30. The study duration for each participant will be up to 72 weeks. Participants will be followed regularly for safety, clinical, and neurophysiological outcomes. Outcome Measures: The primary outcome measure will be the percent decline HERV-K concentration measured by quantitataive PCR. Percent decline for a patient is measured by: 100 x (screening visit - week 24 visit measurement) / screening visit. The safety of antiretrovirals in volunteers with ALS as measured by the frequency and type of AEs, the ability to remain on assigned treatment (tolerability), physical examinations, laboratory test results, vital signs, and weight/body mass index (BMI). Efficacy will be explored by measuring the change in mean scores of: the ALS Functional Rating Scale-Revised (ALSFRS-R), the ALS Specific Quality of Life Inventory-Revised (ALSSQOL-R), the ALS Cognitive Behavioral Screen (ALS-CBS), vital capacity and maximal inspiratory pressure as measured by handheld spirometer, electrical impedance myography (EIM), the change in neurofilament levels in blood and/or CSF, and the change in uring p75ECD levels.

Official Title
-----------------
HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: Darunavir
* Drug: Ritonavir
* Drug: Dolutegravir
* Drug: Tenofovir alafenamide (TAF)


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Subjects must meet all of the following inclusion criteria to be eligible to participate in this study: Age 18 years or older at the time of the screening visit. Able to provide informed consent and comply with study procedures. ALS diagnosed as probable, laboratory-supported probable or definite according to the World Federation of Neurology El Escorial revised criteria32 as determined by a neurologist with neuromuscular subspecialty training. A ratio of HERV-K:RPP greater than or equal to 13 measured by quantitative PCR at the screening visit. Duration of disease less than 2 years, or if greater than 2 years, disease progression at a rate that in the judgement of the investigator would allow for completion of the study. If taking riluzole or edaravone, must be on a stable dose for at least 30 days prior to the screening visit, or stopped taking riluzole or edaravone at least 30 days prior to the screening visit. Subject has a competent caregiver who can and will be responsible for administering study drug. If there is no caregiver, another qualified individual must be available to do this. Subject has established care with a neurologist and will maintain this clinical care throughout the study. Subject has had neuroimaging within the last 24 months for participants enrolling at the NIH Clinical Center. EXCLUSION CRITERIA: A participant will be excluded if he or she has any of the following: Dependence on daytime mechanical ventilation (invasive or non-invasive, including Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPap) at the time of the screening visit. Participation in any other investigational drug trial or using investigational drug (within 4 weeks prior to the Day 0 visit and thereafter). History of severe sulfonamide allergy (i.e. anaphylaxis). History of positive test or positive result at screening for HIV or HTLV-1. Participants must not be able to become pregnant (e.g., post-menopausal for at least one year, surgically sterile, or using adequate methods of contraception) or breastfeed for the duration of the study. Adequate methods of contraception include: implanted contraception, intrauterine device in place for at least 3 months, or barrier method in conjunction with spermicide. Participants of childbearing potential must have a negative pregnancy test at screening and be non-lactating. Presence of any of the following clinical conditions at the time of screening: Drug abuse or alcoholism Unstable medical disease (such as unstable angina or chronic obstructive pulmonary disease), or active infectious disease (such as Hepatitis C or tuberculosis), or current malignancy Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit Dementia Diabetes mellitus Hemophilia Use of contraindicated medications: amiodarone, dronedarone, lovastatin, simvastatin, rifampin, rifapentine, rifabutin, cisapride, pimozide, midazolam, triazolam, dihydroergotamine, ergonovine, ergotamine, methylergonovine, St. John s wort, alfuzosin, salmeterol, sildenafil for pulmonary arterial hypertension, oxcarbazepine, phenobarbital, phenytoin or dofetilide. Safety Laboratory Criteria at the screening visit: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3.0 times the upper limit of normal Serum creatinine, serum phosphorous, total bilirubin, triglycerides, amylase, or lipase greater than 2.0 times the upper limit of normal Estimated glomerular filtration rate <60mg/dl. Platelet concentration of <100,000/ (micro)l. PT and PTT >1.2 times the upper limit of normal for participants enrolling at the NIH Clinical Center. Hemoglobin <10mg/dL. Positive Hepatitis B Surface Antigen and Hepatitis C Virus Antigen

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALS<br>20 participants with ALS and a level of HERV-K >1000 copies/ml | Drug: Darunavir<br>* Orally-administered medication approved for HIV treatment. MOA is as a protease inhibitor. Dose is 600mg twice daily.<br>Drug: Ritonavir<br>* Orally-administered, FDA-approved medication for HIV treatment. Used in combination with darunavir. Dose is 100mg twice daily.<br>Drug: Dolutegravir<br>* Orally-administered, FDA-approved medication to treat HIV. It acts as an integrase inhibitor. Dose is 50mg once daily.<br>Drug: Tenofovir alafenamide (TAF)<br>* Orally-administered, FDA-approved medication used to treat HIV. It acts as a nucleoside reverse transcriptase inhibitor. Dose is 25mg once daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to assess whether an antiretroviral regimen of darunavir + ritonavir, dolutegravir, and TAF for 24 weeks will suppress blood levels of HERV-K RNA below the limit of detection (1000 copies/ml) in patients with HERV-K-posi... | HERV-K Level | One Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The secondary objective of this study is to assess the safety of an antiretroviral regimen of darunavir + ritonavir, dolutegravir, and TAF in patients with ALS. | Safety labs and assessments | Each study visit through week 36 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Virus, Amyotrophic Lateral Sclerosis, Antiretroviral Therapy