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

Full Study Summary:

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.

• More Information

  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 ] [ Designated as safety issue: No ]
  
  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 ] [ Designated as safety issue: Yes ]
  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 ] [ Designated as safety issue: No ]
  
  For more information, please visit https://clinicalt...CT02437110&rank=1

• Eligibility Criteria

  Gender:

  Female, Male

  Minimum Age:

  18

  Maximum Age:

  N/A

  Min Vital Capacity (% predicted normal):

  60

  Time since Symptom Onset:

  Time since Diagnosis:

  Can participants use Riluzole?

  Yes

  
  

  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.

• Site Contact Information

  National Institutes of Health Clinical Center
  9000 Rockville Pike
  Bethesda, Maryland 20892
  United States