Doravirine Concentrations and Antiviral Activity in Cerebrospinal Fluid in HIV-1 Infected Individuals

• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia (Other)
• Overall Status: Completed
• CT.gov ID: NCT04079452
• Collaborator: Institut d'Investigació Biomèdica de Bellvitge (Other), Hospital Universitari de Bellvitge (Other)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Months): 6.4
• Patients Per Site Per Month: 2.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV-1-infection	Drug: Doravirine; Drug: Descovy	Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Doravirine Concentrations and Antiviral Activity in Cerebrospinal Fluid in HIV-1 Infected Individuals
• Actual Study Start Date: Feb 18, 2020
• Actual Primary Completion Date: Aug 31, 2020
• Actual Study Completion Date: Aug 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doravirine + Descovy® TAF/FTC Doravirine (MK-1439) 100 mg administered orally once daily in combination with Tenofovir alafenamide (TAF) and emtricitabine (FTC) coformulated as single tablet (Descovy® TAF/FTC 25/200 mg) and administered orally once daily during 4 weeks	Drug: Doravirine; Doravirine 100 mg tablet; Other Names: MK-1439 ; Drug: Descovy; Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet; Other Names: TAF/FTC

Outcome Measures

Primary Outcome Measures

1. Total Doravirine Concentrations in Cerebrospinal Fluid [4 Weeks]

   Total Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF

2. Total Doravirine Concentrations in Blood Plasma [4 Weeks]

   Total Doravirine concentrations in blood plasma

3. Total Doravirine Concentration CSF/Plasma Ratio [4 Weeks]

   total Doravirine CSF/plasma ratio

4. HIV-1 RNA in Cerebrospinal Fluid [4 Weeks]

   Number of patients with HIV-1 RNA cerebrospinal fluid <40 copies/ml

5. HIV-1 RNA in Blood Plasma [4 Weeks]

   Number of patients with HIV-1 RNA in blood plasma <40 copies/ml

6. Unbound Doravirine Concentrations in CSF [4 Weeks]

   Unbound Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF

7. Doravirine Concentrations in Blood Plasma [4 Weeks]

   Unbound Doravirine concentrations in blood plasma

8. Unbound Doravirine Concentration CSF/Plasma Ratio [4 Weeks]

   Unbound Doravirine CSF/plasma ratio

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Universitari de Bellvitge	L'Hospitalet De Llobregat	Barcelona	Spain	08907

Sponsors and Collaborators

• Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Institut d'Investigació Biomèdica de Bellvitge
• Hospital Universitari de Bellvitge

Investigators

• Principal Investigator: Daniel Podzamczer, PhD Chief, Hospital Universitari de Bellvitge

Study Documents (Full-Text)

• Study Protocol - Jun 26, 2019
• Statistical Analysis Plan - Jun 26, 2019
• Informed Consent Form - Apr 10, 2019

More Information

Publications

None provided.

• Responsible Party: Daniel Podzamczer, PhD: chief of the HIV and STD Unit (Infectious Disease Service), Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• ClinicalTrials.gov Identifier: NCT04079452
• Other Study ID Numbers: DORACeNeS; 2018-003915-24
• First Posted: Sep 6, 2019
• Last Update Posted: Apr 28, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daniel Podzamczer, PhD: chief of the HIV and STD Unit (Infectious Disease Service), Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia: Doravirine
• Additional relevant MeSH terms: Emtricitabine tenofovir alafenamide

Study Results

Participant Flow

Arm/Group Title	Doravirie+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Doravirine + Descovy® TAF/FTC
Arm/Group Description	Doravirine (MK-1439) 100 mg administered orally once daily in combination with Tenofovir alafenamide (TAF) and emtricitabine (FTC) coformulated as single tablet (Descovy® TAF/FTC 25/200 mg) and administered orally once daily during 4 weeks Doravirine: Doravirine 100 mg tablet Descovy: Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet
Overall Participants	15
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	47
Sex: Female, Male (Count of Participants)
Female	2 13.3%
Male	13 86.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	15 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Spain	15 100%

Outcome Measures

1. Primary Outcome

Title	Total Doravirine Concentrations in Cerebrospinal Fluid
Description	Total Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

Descriptive analysis was performed for all participants (15), defining median and IQR of Doravirine concentrations in CSF

Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Median (Inter-Quartile Range) [ng/ml]	58.6

2. Primary Outcome

Title	Total Doravirine Concentrations in Blood Plasma
Description	Total Doravirine concentrations in blood plasma
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doravirie+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Median (Inter-Quartile Range) [ng/ml]	417.6

3. Primary Outcome

Title	Total Doravirine Concentration CSF/Plasma Ratio
Description	total Doravirine CSF/plasma ratio
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Median (Inter-Quartile Range) [ratio]	0.13

4. Primary Outcome

Title	HIV-1 RNA in Cerebrospinal Fluid
Description	Number of patients with HIV-1 RNA cerebrospinal fluid <40 copies/ml
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Count of Participants [Participants]	13 86.7%

5. Primary Outcome

Title	HIV-1 RNA in Blood Plasma
Description	Number of patients with HIV-1 RNA in blood plasma <40 copies/ml
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Count of Participants [Participants]	14 93.3%

6. Primary Outcome

Title	Unbound Doravirine Concentrations in CSF
Description	Unbound Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

Descriptive analysis was performed for all participants (15), defining median and IQR of Doravirine concentrations in CSF

Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Median (Inter-Quartile Range) [ng/ml]	44.6

7. Primary Outcome

Title	Doravirine Concentrations in Blood Plasma
Description	Unbound Doravirine concentrations in blood plasma
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doravirie+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Median (Inter-Quartile Range) [CSF Unbound DORAVIRINE conc. ng/ml]	53.5

8. Primary Outcome

Title	Unbound Doravirine Concentration CSF/Plasma Ratio
Description	Unbound Doravirine CSF/plasma ratio
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
Measure Participants	15
Median (Inter-Quartile Range) [ratio]	0.99

Adverse Events

Time Frame	6 weeks
Arm/Group Title	Doravirine+TAF/FTC Arm (Single Arm)
Arm/Group Description	Doravirine (100 mg)+ Tenofovir Alafenamide (TAF) and emtricitabine (FTC) co-formulated (TAF/FTC 25/200 mg)
All Cause Mortality
	Doravirine+TAF/FTC Arm (Single Arm)
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	Doravirine+TAF/FTC Arm (Single Arm)
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Doravirine+TAF/FTC Arm (Single Arm)
	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)
Gastrointestinal disorders
Diarrhea	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Thoracic pain	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.