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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 : Recruiting
First Posted : May 7, 2015
Last Update Posted : May 16, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Tracking Information
First Submitted Date  ICMJE May 5, 2015
First Posted Date  ICMJE May 7, 2015
Last Update Posted Date May 16, 2019
Study Start Date  ICMJE April 23, 2015
Estimated Primary Completion Date February 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
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-positive ALS. [ Time Frame: one year ]
HERV-K Level
Original Primary Outcome Measures  ICMJE
 (submitted: May 5, 2015)
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 ]
Change History Complete list of historical versions of study NCT02437110 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
To assess the safety of an antiretroviral regimen of darunavir + ritonavir, dolutegravir, and TAF in patients with ALS. [ Time Frame: 24 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 5, 2015)
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
Official Title  ICMJE HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
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 study visits at Weeks 1and then every 4 weeks until Week 24. 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 36 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 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 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 up to 60 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 as measured by handheld spirometer, electrical impedance myography (EIM), the change in neurofilament levels in blood and/or CSF, and the chanage in uring p75ECD levels.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Amyotrophic Lateral Sclerosis
Intervention  ICMJE
  • 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: dolutegravir
    Orally-administered, FDA-approved medication to treat HIV. It acts as an integrase inhibitor. Dose is 50 mg once daily.
  • Drug: Tenofovir alafenamide (TAF)
    Orally-administered, FDA-approved medication used to treat HIV. It acts as a nucleoside reverse transcriptase inhibitor. Dose is 25 mg once daily.
Study Arms  ICMJE Experimental: ALS
20 participants with ALS and a level of HERV-K >1000 copies/ml
Interventions:
  • Drug: Darunavir
  • Drug: Ritonavir
  • Drug: dolutegravir
  • Drug: Tenofovir alafenamide (TAF)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 5, 2019)
200
Original Estimated Enrollment  ICMJE
 (submitted: May 5, 2015)
20
Estimated Study Completion Date  ICMJE February 1, 2022
Estimated Primary Completion Date February 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.
  • Time from symptom onset less than 2 years.
  • 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Amanda M Wiebold (301) 594-5194 amanda.wiebold@nih.gov
Contact: Avindra Nath, M.D. (301) 496-1561 natha@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02437110
Other Study ID Numbers  ICMJE 150126
15-N-0126
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
Study Sponsor  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Avindra Nath, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date April 16, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP