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

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ClinicalTrials.gov Identifier: NCT02437110
Recruitment Status : Enrolling by invitation
First Posted : May 7, 2015
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

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:

  • Participants will be screened with medical history, physical exam, and blood and breathing tests.
  • Visit 2: participants will have medical history, questionnaires, and blood drawn. Their strength will be tested by pushing on a machine. They will blow into a tube that measures the air they can hold in their lungs.
  • After Visit 2, participants will start taking the 4 study drugs twice a day.
  • Participants will have study visits at Weeks 1, 2, and 4, then every 4 weeks until Week 36. They will be asked how they are feeling and have an exam and blood drawn. At 2 visits, they will have tests of strength, breathing, and their ALS symptoms. Some visits may be done at their ALS doctor s office.
  • At Week 24, they will stop taking the study drugs.
  • After the Week 36 visit, their participation is finished.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: Darunavir Drug: Ritonavir Drug: Raltegravir Drug: Zidovudine Phase 1

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 blood levels of the HERV-K transcript > 1000 copies/ml. 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 up to 24 weeks in 20 HIV-negative, HTLV-negative ALS patients with high blood levels of HERV-K . The study duration for each participant will be approximately 44 weeks with an 8-week screening window, 24-week treatment phase, and 12-week follow-up phase. If participants have an undetectable (<1000 copies/ml) level of HERV-K viral load at two consecutive study visits before the end of the 24-week treatment phase, the study drugs will be discontinued as the primary outcome will have been satisfied at that point. Participants will stay on the antiretroviral regimen for at least 8 weeks regardless of if they have undetectable HERV-K viral load levels prior to that. Participants will be followed regularly for safety, clinical, and neurophysiological outcomes.

Outcome Measures:

The primary outcome will be the proportion of participants with ALS who have undetectable (<1000 copies/ml) blood levels of HERV-K viral load as measured by quantitative PCR within 24 weeks of starting an antiretroviral regimen of darunavir + ritonavir, dolutegravir, and tenofovir alafenamide fumerate (TAF). The secondary objectives will be: (a) the proportion of participants with ALS who have undetectable (<1000 copies/ml) blood levels of HERV-K viral load within 24 weeks of starting the antiretroviral regimen; and (b) the safety of antiretrovirals in volunteers with ALS as measured by the frequency and type of adverse events (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 as measured by handheld spirometer, neurophysiological measures, and the change in neurofilament levels in blood and/or CSF.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
Study Start Date : April 23, 2015
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : December 31, 2018



Intervention Details:
  • Drug: Darunavir
    Orally-administered medication approved for HIV treatment. MOA is as a protease inhibitor. Dose is 600mg twice daily.
  • Drug: Ritonavir
    Orally-administered, FDA-approved medication for HIV treatment. Used in combination with darunavir. Dose is 100 mg twice daily.
  • Drug: Raltegravir
    Orally-administered, FDA-approved medication to treat HIV. It acts as an integrase inhibitor. Dose is 400mg twice daily.
  • Drug: Zidovudine
    Orally-administered, FDA-approved medication used to treat HIV. It acts as a nucleoside reverse transcriptase inhibitor. Dose is 300mg twice daily.


Primary Outcome Measures :
  1. The proportion of participants with an undetectable HERV-K gag RNA level by quantitative PCR within 24 weeks of starting an antiretroviral regimen of darunavir, ritonavir, raltegravir, and zidovudine [ Time Frame: 24 weeks ]

Secondary Outcome Measures :
  1. Safety and feasibility of up to 24 weeks of darunavir, ritonavir, raltegravir, and zidovudine for patients with ALS [ Time Frame: 24 weeks ]
  2. The proportion of participants with an undetectable HERV-K env or pol RNA level by quantitative PCR within 24 weeks of starting an antiretroviral regimen of darunavir, ritonavir, raltegravir, and zidovudine [ Time Frame: 24 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • Detectable HERV-K viral load in blood at a minimum of 1000 copies/ml as measured by quantitative PCR at the screening visit.
  • Vital capacity at least 60% of predicted value for gender, height and age at the screening visit
  • 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 at a specialized ALS clinic and will maintain this clinical care throughout the study.
  • Subject has had neuroimaging within the last 18 months.

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.
  • History of having undergone gastrostomy at the time of screening.
  • Participation in any other investigational drug trial or using investigational drug (within 12 weeks prior to Screening and thereafter).
  • Known sulfonamide allergy.
  • 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 for the NIH Clinical Center.
    • Serum creatinine, serum phosphorous, urine glucose, urine protein, total bilirubin, triglycerides, amylase, or lipase greater than 2.0 times the upper limit of normal for the NIH Clinical Center.
    • Estimated glomerular filtration rate <60mg/dl.
    • Creatine kinase greater than 3.0 times the upper limit of normal for the NIH Clinical Center.
    • Platelet concentration of <100,000/ (micro)l.
    • PT and PTT >1.2 times the upper limit of normal for the NIH Clinical Center.
    • Hemoglobin <10mg/dL.
    • Positive Hepatitis B Surface Antigen and Hepatitis C Virus Antibody

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02437110


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Avindra Nath, M.D. National Institute of Neurological Disorders and Stroke (NINDS)

Additional Information:
Publications:
Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT02437110     History of Changes
Other Study ID Numbers: 150126
15-N-0126
First Posted: May 7, 2015    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 6, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
Amyotrophic Lateral Sclerosis
Virus
Antiretroviral Therapy

Additional relevant MeSH terms:
Sclerosis
Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Ritonavir
Darunavir
Raltegravir Potassium
Zidovudine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
HIV Integrase Inhibitors
Integrase Inhibitors
Antimetabolites
Reverse Transcriptase Inhibitors