Amyotrophic Lateral SclerosisPhase 1NCT02437110
HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
A Phase 1 study testing Darunavir, Ritonavir and Dolutegravir in people with Amyotrophic Lateral Sclerosis, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Amyotrophic Lateral Sclerosis
- What is being tested?
- Darunavir, Ritonavir and Dolutegravir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 122 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Apr 2019to 9 May 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
Show all 22Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.
Read more
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.
Read the 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.
- Conditions
- Amyotrophic Lateral Sclerosis
- Being tested
- Darunavir, Ritonavir, Dolutegravir, Tenofovir alafenamide (TAF)
- Keywords
- Amyotrophic Lateral Sclerosis, Antiretroviral Therapy, Virus
- Medical subject headings
- Amyotrophic Lateral Sclerosis, Virus Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DarunavirDrug
Orally-administered medication approved for HIV treatment. MOA is as a protease inhibitor. Dose is 600mg twice daily.
RitonavirDrug
Orally-administered, FDA-approved medication for HIV treatment. Used in combination with darunavir. Dose is 100mg twice daily.
DolutegravirDrug
Orally-administered, FDA-approved medication to treat HIV. It acts as an integrase inhibitor. Dose is 50mg once daily.
Tenofovir alafenamide (TAF)Drug
Orally-administered, FDA-approved medication used to treat HIV. It acts as a nucleoside reverse transcriptase inhibitor. Dose is 25mg once daily.
| Study group | Role | What they receive |
|---|---|---|
| ALS | Experimental | 20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13 Receives: Drug: Darunavir; Drug: Ritonavir; Drug: Dolutegravir; Drug: Tenofovir alafenamide (TAF) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Change in HERV-K Level
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.
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2015 (estimated)
- Study start1 Apr 2019
- Primary completion17 Nov 2022
- Study completion9 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Amyotrophic Lateral SclerosisStudies of the same condition, open and under way.
- More trials run by National Institute of Neurological Disorders and Stroke (NINDS)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 122 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Avindra Nath, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02437110
- Sponsor's protocol ID
- 150126
- Other IDs
- 15-N-0126
- Status last verified
- Dec 2022
- First submitted
- 5 May 2015
- Last updated
- 9 Jan 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 10897073Douville 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.
PubMed 21280084Moulignier 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.
PubMed 11571323
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
- ClinicalTrials.gov ID
- NCT02437110
- Acronym / sponsor ID
- 150126
- Conditions
- Amyotrophic Lateral Sclerosis
- Keywords
- Amyotrophic Lateral Sclerosis, Antiretroviral Therapy, Virus
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 122 participants (actual)
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- 1 Apr 2019 (actual)
- Primary completion
- 17 Nov 2022 (actual)
- Study completion
- 9 May 2023 (actual)
- First posted
- 7 May 2015 (estimated)
- Results
- Posted 9 Jan 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| ALS | Experimental | Drug: Darunavir, Drug: Ritonavir, Drug: Dolutegravir, Drug: Tenofovir alafenamide (TAF)20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DarunavirOrally-administered medication approved for HIV treatment. MOA is as a protease inhibitor. Dose is 600mg twice daily. | Drug | ALS |
| RitonavirOrally-administered, FDA-approved medication for HIV treatment. Used in combination with darunavir. Dose is 100mg twice daily. | Drug | ALS |
| DolutegravirOrally-administered, FDA-approved medication to treat HIV. It acts as an integrase inhibitor. Dose is 50mg once daily. | Drug | ALS |
| Tenofovir alafenamide (TAF)Orally-administered, FDA-approved medication used to treat HIV. It acts as a nucleoside reverse transcriptase inhibitor. Dose is 25mg once daily. | Drug | ALS |
Primary outcome
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 10897073Andrews 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.
- Background: PubMed 21280084Douville 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.
- Background: PubMed 11571323Moulignier 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Avindra Nath, M.D. principal investigator
National Institute of Neurological Disorders and Stroke (NINDS)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Darunavir, Ritonavir and Dolutegravir in people with Amyotrophic Lateral Sclerosis, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Change in HERV-K Level (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02437110, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2024.