- 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.
- To learn how drugs usually taken for HIV infection affect people with Amyotrophic Lateral
- Adults at least 18 years old with ALS and high levels of HERV-K but no HIV.
- Participants will be screened with medical history, physical exam, and blood and
- 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.
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.
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.
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.
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.
- INCLUSION CRITERIA:
Subjects must meet all of the following inclusion criteria to be eligible to participate in
- 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
- 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
- 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.
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
- Diabetes mellitus
- 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
- Absolute neutrophil count of < 1000/ (micro)l.
- Platelet concentration of <100,000/ (micro)l.
- Hemoglobin <10mg/dL.