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

Phase 1

Completed

Conditions: Amyotrophic Lateral Sclerosis

Interventions: Drug: Darunavir
Drug: Ritonavir
Drug: Dolutegravir
Drug: Tenofovir alafenamide (TAF)

Registration Number: NCT02437110

Lead Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

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 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 122

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ALS	Darunavir	20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13
ALS	Ritonavir	20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13
ALS	Tenofovir alafenamide (TAF)	20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13
ALS	Dolutegravir	20 participants with ALS and a level of HERV-K:RPP30 greater than or equal to 13

Primary Outcome Measures

Name	Time	Method
Percent Change in HERV-K Level	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.

Secondary Outcome Measures