Clinical trial NCT04079452: Doravirine Concentrations and Antiviral Activity in Cerebrospinal Fluid in HIV-1 Infected Individuals
Official title: Doravirine Concentrations and Antiviral Activity in Cerebrospinal Fluid in HIV-1 Infected Individuals
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1-infection
Keywords: Doravirine
Lead sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Sponsor class: OTHER
Collaborators: name: Institut d'Investigació Biomèdica de Bellvitge
name: Hospital Universitari de Bellvitge
First posted: 2019-09-06
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated a good efficacy and safety profile in clinical trials. It functions by inhibiting viral replication of both wild-type virus and most common NNRTI variants. It is dosed orally once daily and always given in combination with other HIV-1 active agents as part of highly active antiretroviral therapy. Initial pharmacokinetic studies demonstrated not extensive binding to plasma proteins, which may be crucial determinant for penetration to different reservoirs such as the central nervous system (CNS). This study will address two important issues: The pharmacokinetic profile of Doravirine in cerebrospinal fluid (CSF) as well as the maintenance of HIV suppression in CSF. The assessment of concentrations as well as the antiviral activity of new antiretroviral drugs in compartments such as CNS is relevant to avoid HIV-related neurocognitive disorders as well as for future cure strategies. In addition, the role of unbound ARV drug concentrations has been scarcely evaluated.

Detailed description: 15 asymptomatic, virologically suppressed, HIV infected patients will be offered to switch their antiretroviral treatment to Doravirine+Emtricitabine/TAF. After 4 weeks of treatment all subjects will undergo lumbar puncture and bloods in order to assess CSF and plasma (total and unbound) Doravirine concentrations. HIV RNA also will be assessed. All subjects will complete a follow up visit 4 weeks after

Eligibility criteria: Inclusion Criteria:

1. Asymptomatic, HIV-1 infected individuals ≥ 18 years of age
2. Be on a stable ART continously or ≥3 consecutive months preceding the screening visit. Patients already receiving TAF/FTC+DoravirineC for at least three consecutive months will be eligible.
3. Plasma HIV-1 RNA at screening \<40 copies/mL for at least 3 months at the Screening visit.
4. Signed and dated written informed consent prior to inclusion.
5. Subjects must agree to utilize a highly effective method of contraception during heterosexual intercourse from the screening visit throughout the duration of the study.

Exclusion Criteria:

1. Severe hepatic impairment (Child-Pugh Class C)
2. Ongoing malignancy
3. Active opportunistic infection
4. Primary resistance to any of the ARV included in the study or history of virologic failure with risk of resistance selection to any of the study drugs.
5. Any verified Grade 4 laboratory abnormality
6. ALT or AST ≥ 3xULN and/or bilirubin ≥ 1.5xULN
7. Adequate renal function: Estimated glomerular filtration rate ≥ 50 mL/min
8. Females who are pregnant (as confirmed by positive serum pregnancy test) or breastfeeding.
9. Current treatment with antiaggregant or anticoagulant therapy.
10. History of any neurologic disease/condition/treatment may alter the blood brain barrier permeability.

Primary outcomes:
measure: Total Doravirine Concentrations in Cerebrospinal Fluid
timeFrame: 4 Weeks
measure: Total Doravirine Concentrations in Blood Plasma
timeFrame: 4 Weeks
measure: Total Doravirine Concentration CSF/Plasma Ratio
timeFrame: 4 Weeks
measure: HIV-1 RNA in Cerebrospinal Fluid
timeFrame: 4 Weeks
measure: HIV-1 RNA in Blood Plasma
timeFrame: 4 Weeks
measure: Unbound Doravirine Concentrations in CSF
timeFrame: 4 Weeks
measure: Doravirine Concentrations in Blood Plasma
timeFrame: 4 Weeks
measure: Unbound Doravirine Concentration CSF/Plasma Ratio
timeFrame: 4 Weeks
Secondary outcomes:
Other outcomes:
Locations:
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
Study officials:
affiliation: Hospital Universitari de Bellvitge
name: Daniel Podzamczer, PhD Chief
role: PRINCIPAL_INVESTIGATOR
References: