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

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier:
NCT02437110
First received: May 5, 2015
Last updated: June 30, 2017
Last verified: February 1, 2017
  Purpose

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 Intervention Phase
Amyotrophic Lateral Sclerosis Drug: Darunavir Drug: Ritonavir Drug: Raltegravir Drug: Zidovudine Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):

Primary Outcome Measures:
  • 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:
  • Safety and feasibility of up to 24 weeks of darunavir, ritonavir, raltegravir, and zidovudine for patients with ALS [ Time Frame: 24 weeks ]
  • 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 ]

Estimated Enrollment: 20
Study Start Date: April 23, 2015
Estimated Study Completion Date: December 31, 2018
Estimated Primary Completion Date: December 31, 2017 (Final data collection date for primary outcome measure)
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.
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 levels of plasma expression of the gag, env, and pol RNA transcripts 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 outcomes of ALS symptoms, quality of life, motor strength, and pulmonary function.

Study Population

We will study a subset of ALS patients who have plasma levels of the HERV-K gag transcript > 1000 copies/ml. About 30% of ALS patients may have detectable levels of HERV-K; about 10% 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 10% 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 10 HIV-negative, HTLV-negative ALS patients with high plasma levels of HERV-K gag. 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 (<100 copies/ml) level of HERV-K gag RNA 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 gag RNA levels prior to that. Participants will be followed regularly for safety and clinical outcomes.

Outcome Measures

The primary outcome will be the proportion of participants with ALS who have undetectable (<100 copies/ml) plasma levels of HERV-K gag RNA expression as measured by quantitative PCR within 24 weeks of starting an antiretroviral regimen of darunavir + ritonavir, raltegravir, and zidovudine. The secondary objectives will be: (a) the proportion of participants with ALS who have undetectable (<100 copies/ml) plasma levels of either HERV-K pol or env RNA transcripts 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), vital capacity as measured by handheld spirometer, and quantitative muscle testing by dynamometry.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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 criteria31 as determined by a neurologist with neuromuscular subspecialty training.
  • Detectable plasma HERV-K gag RNA transcript 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, must be on a stable dose for at least 30 days prior to the screening visit, or stopped taking riluzole 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.

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.
  • Women 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. Women 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, dronederone, lovastatin, simvastatin, rifampin, rifapentine, cisapride, pimozide, midazolam, triazolam, dihydroergotamine, ergonovine, ergotamine, methylergonovine, St. John s wort, alfuzosin, salmeterol, or sildenafil for pulmonary arterial hypertension.
  • 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.
    • Total bilirubin, lactate-L, triglycerides, amylase, or lipase greater than 2.0 times the upper limit of normal for the NIH Clinical Center.
    • Creatine kinase greater than 3.0 times the upper limit of normal for the NIH Clinical Center.
    • Absolute neutrophil count of < 1000/ (micro)l.
    • Platelet concentration of <100,000/ (micro)l.
    • Hemoglobin <10mg/dL.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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)
  More Information

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
Study First Received: May 5, 2015
Last Updated: June 30, 2017

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
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
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

ClinicalTrials.gov processed this record on July 27, 2017