- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02437110
HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
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 up to 12 study visits over a period of 72 weeks. After starting study drugs, they will have study visits at Weeks 1 and 4 and then every 4 weeks until Week 28. 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 may have a repeat lumbar puncture.
After the Week 48 visit, their participation is finished.
Study Overview
Status
Conditions
Intervention / Treatment
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 blood levels of HERV-K 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 a ratio of HERV-K:RPP30 greater than or equal to 13. 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 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 25 HIV-negative, HTLV-negative ALS patients with high ratio of HERV-K:RPP30. The study duration for each participant will be up to 72 weeks. Participants will be followed regularly for safety, clinical, and neurophysiological outcomes.
Outcome Measures:
The primary outcome measure will be the percent decline in HERV-K concentration. 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. 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 and maximal inspiratory pressure as measured by handheld spirometer, electrical impedance myography (EIM), the change in neurofilament levels in blood and/or CSF, and the change in urine p75ECD levels.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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 criteria as determined by a neurologist with neuromuscular subspecialty training.
A ratio of HERV-K:RPP greater than or equal to 13 measured by quantitative PCR at the screening visit.
Duration of disease less than 2 years, or if greater than 2 years, disease progression at a rate that in the judgement of the investigator would allow for completion of the study.
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 24 months for participants enrolling at the NIH Clinical Center.
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.
Participation in any other investigational drug trial or using investigational drug (within 4 weeks prior to the Day 0 visit and thereafter).
History of severe sulfonamide allergy (i.e. anaphylaxis).
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
Serum creatinine, serum phosphorous, total bilirubin, triglycerides, amylase, or lipase greater than 2.0 times the upper limit of normal
Estimated glomerular filtration rate <60mg/dl.
Platelet concentration of <100,000/ (micro)l.
PT and PTT >1.2 times the upper limit of normal for participants enrolling at the NIH Clinical Center.
Hemoglobin <10mg/dL.
Positive Hepatitis B Surface Antigen and Hepatitis C Virus Antigen
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: ALS
20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13
|
Orally-administered medication approved for HIV treatment.
MOA is as a protease inhibitor.
Dose is 600mg twice daily.
Orally-administered, FDA-approved medication for HIV treatment.
Used in combination with darunavir.
Dose is 100mg twice daily.
Orally-administered, FDA-approved medication to treat HIV.
It acts as an integrase inhibitor.
Dose is 50mg once daily.
Orally-administered, FDA-approved medication used to treat HIV.
It acts as a nucleoside reverse transcriptase inhibitor.
Dose is 25mg once daily.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percent Change in HERV-K Level
Time Frame: 24 weeks
|
Blood samples were obtained during the screening visit and week 24 (post-treatment with antiretroviral drugs).
The percent change in HERV-K level was measured using quantitative PCR: 100% x (screening visit - week 24 visit measurement) / screening visit.
|
24 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The secondary objective of this study is to assess the safety of an antiretroviral regimen of darunavir + ritonavir, dolutegravir, and TAF in patients with ALS.
Time Frame: Each study visit through week 36
|
Safety labs and assessments
|
Each study visit through week 36
|
Collaborators and Investigators
Investigators
- Principal Investigator: Avindra Nath, M.D., National Institute of Neurological Disorders and Stroke (NINDS)
Publications and helpful links
General Publications
- Andrews WD, Tuke PW, Al-Chalabi A, Gaudin P, Ijaz S, Parton MJ, Garson JA. Detection of reverse transcriptase activity in the serum of patients with motor neurone disease. J Med Virol. 2000 Aug;61(4):527-32. doi: 10.1002/1096-9071(200008)61:43.0.co;2-a.
- Douville R, Liu J, Rothstein J, Nath A. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol. 2011 Jan;69(1):141-51. doi: 10.1002/ana.22149.
- Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology. 2001 Sep 25;57(6):995-1001. doi: 10.1212/wnl.57.6.995.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Metabolic Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Spinal Cord Diseases
- TDP-43 Proteinopathies
- Proteostasis Deficiencies
- Sclerosis
- Motor Neuron Disease
- Amyotrophic Lateral Sclerosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Protease Inhibitors
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- HIV Integrase Inhibitors
- Integrase Inhibitors
- HIV Protease Inhibitors
- Viral Protease Inhibitors
- Tenofovir
- Ritonavir
- Darunavir
- Dolutegravir
Other Study ID Numbers
- 150126
- 15-N-0126
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Amyotrophic Lateral Sclerosis
-
Washington University School of MedicineMassachusetts General HospitalSuspendedAmyotrophic Lateral Sclerosis, Familial | Amyotrophic Lateral Sclerosis, SporadicUnited States
-
University of Sao Paulo General HospitalPontifícia Universidade Católica do ParanáUnknownAMYOTROPHIC LATERAL SCLEROSISBrazil
-
Neuromed IRCCSRecruitingAmyotrophic Lateral Sclerosis (ALS)Italy
-
Humanitas Mirasole SpAKU Leuven; UMC Utrecht; University of Sheffield; Istituto Superiore di Sanità; University... and other collaboratorsActive, not recruitingAmyotrophic Lateral Sclerosis (ALS)United Kingdom, Germany, France, Netherlands, Belgium, Ireland, Italy
-
The Methodist Hospital Research InstituteMassachusetts General Hospital; The Center for Clinical and Translational Sciences... and other collaboratorsActive, not recruiting
-
CytokineticsCompletedAmyotrophic Lateral Sclerosis (ALS)United States, Netherlands, Canada, Belgium, United Kingdom, France, Germany, Ireland, Italy, Portugal, Spain
-
Columbia UniversityALS AssociationTerminatedAmyotrophic Lateral Sclerosis (ALS)United States
-
El Instituto Nacional de Neurologia y Neurocirugia...CompletedAmyotrophic Lateral Sclerosis | Amyotrophic Lateral Sclerosis, SporadicMexico
-
University Hospital, GenevaCompletedAmyotrophic Lateral Sclerosis 11Switzerland
-
Fondazione Don Carlo Gnocchi OnlusFondazione Salvatore MaugeriCompleted
Clinical Trials on Darunavir
-
Shanghai Public Health Clinical CenterUnknownCoronavirus | Pneumonia, PneumocystisChina
-
Janssen-Cilag International NVCompletedHIV Infections | Human Immunodeficiency Virus | Acquired Immunodeficiency Syndrome Virus | AIDS VirusUnited Kingdom, Belgium, Germany, Spain, Portugal, Israel, Denmark, Russian Federation, Austria, Hungary, Switzerland
-
Hamad Medical CorporationCompletedPneumonia | COVID | CoronavirusQatar
-
Janssen Research & Development, LLCCompleted
-
Germans Trias i Pujol HospitalFundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la...Completed
-
Juan A. ArnaizUnknownAcquired Immune Deficiency Syndrome VirusSpain
-
Janssen Pharmaceutical K.K.Completed
-
Fundación FLS de Lucha Contra el Sida, las Enfermedades...ViiV HealthcareCompleted
-
Fundación FLS de Lucha Contra el Sida, las Enfermedades...Completed