- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04385719
Drug-drug Interactions Between Remdesivir and Commonly Used Antiretroviral Therapy (RemTLAR)
An Open-label, Randomized, Single Intravenous Dosing Study to Investigate the Effect of Fixed-dose Combinations of Tenofovir/Lamivudine or Atazanavir/Ritonavir on the Pharmacokinetics of Remdesivir in Ugandan Healthy Volunteers
Study Overview
Detailed Description
The study is designed as an open-label, randomized, fixed sequence, single intravenous dosing study to assess the effects of antiretrovirals on remdesivir pharmacokinetics.
The selection of healthy volunteers, as opposed to patients with HIV, avoids the greatest possible extent confounding factors, such as enzyme or transporter activity alteration in inflammatory states, concomitant medications potentially impacting drug disposition and other factors which are commonly present in a population of patients and cannot be easily eliminated.
Objectives:
Primary objective
- To assess the safety and tolerability of single intravenous doses of remdesivir in adult healthy volunteers
- To evaluate the intracellular pharmacokinetics of single dose intravenous remdesivir with or without co-administration of oral fixed-dose combination tenofovir/lamivudine with patients serving as their own controls
Secondary objectives
- To evaluate the difference in plasma and intracellular pharmacokinetics of intravenous remdesivir among healthy volunteers receiving tenofovir/lamivudine versus healthy volunteers receiving tenofovir/lamivudine plus atazanavir/ritonavir tablets.
- To generate a population pharmacokinetic model to describe inter-individual variability in intracellular pharmacokinetics of remdesivir
Exploratory objectives
1. To describe polymorphic variants of relevant kinases that activate TFV and explore possible consequences on remdesivir PK.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Kampala, Uganda
- Infectious Diseases Institute
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
- Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- Healthy men and women aged 18 to 55 years of age, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
At screening, and all other visits, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position and again (when required) in the standing position. Sitting vital signs should be within the following ranges:
I. axillary body temperature between 35.5-37.0 °C II. systolic blood pressure, 90-139 mmHg III. diastolic blood pressure, 50-89 mmHg IV. Pulse rate, 50-90 bpm. If pulse rate is between 40 and 50 bpm, the Investigator may decide to enroll the subject if he/she has history of athletic practice or other regular high cardio-vascular activity and ECG assessment is within normal range.
Subjects should be excluded if their standing vital signs (relative to sitting) show findings which, in the opinion of the Investigator, are associated with clinical manifestation of postural hypotension (i.e. absence of any other cause). The Investigator should carefully consider enrolling subjects with either a > 20 mmHg decrease in systolic or a >10 mm Hg decrease in diastolic blood pressure, accompanied by a > 20 bpm increase in heart-rate (from sitting to standing).
- Subjects must weigh at least 40 kg to participate in the study and must have a body mass index (BMI) within the range 18-30 Kg/m2. BMI= Body weight (kg) / [Height (m)]2
- HIV antibody negative at screening.
- Women of childbearing potential must be willing to use a highly effective contraception method (eg. IUD or hormonal contraceptive implant, complete abstinence (if genuinely followed)) or consistent use of a barrier method such as male or female condoms plus oral progestin contraceptives for the duration of the study. Non-surgically sterilized men must agree to abstain from sexual intercourse for the duration of the study or use condoms for contraception for the duration of the study.
- Hemoglobin concentration equal or greater than 10 g/dL
Exclusion Criteria:
- Significant disease affecting cardiac, respiratory, gastrointestinal or neurological symptoms which in the clinician's medical judgment could be worsened by participating in this study or the presence of medical or surgical conditions which could prevent the subject from complying with study procedures.
- Serum alanine transaminase (ALT) levels above 2x upper limit of normal (ULN) or total bilirubin > 1.3x ULN
- Serum creatinine levels above 1.5x upper limit of normal
- Evidence of QT prolongation on electrocardiogram (ECG) QTc (Rate adjusted QT interval) > 450ms (men) or 460ms (women)
- Pregnant women or female subjects who are unwilling to use a suitable contraceptive method for the duration of the study (IUD or contraceptive implant)
- Likely to be poorly adherent based on clinician's medical judgement
- Known to be current injection drug user
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Study A Sequence 1
Single dose remdesivir 150mg IV on Day 1 Wash out period Day 2-7 TDF/3TC 300/300mg tablets OD from Day 8-14 single dose remdesivir 150mg IV on Day 14 |
Remdesivir (GS-5734) is a nucleoside analogue with in vitro activity against filoviruses EBOV, SUDV, BDBV and MARV, in addition to arenaviruses and coronaviruses
Other Names:
|
Experimental: Study A Sequence 2
TDF/3TC 300/300mg tablets OD from Day 1-7 single dose remdesivir 150mg IV on Day 7 Wash out period Day 8-14 Single dose remdesivir 150mg IV on Day 15 |
Remdesivir (GS-5734) is a nucleoside analogue with in vitro activity against filoviruses EBOV, SUDV, BDBV and MARV, in addition to arenaviruses and coronaviruses
Other Names:
|
Experimental: Study B
TDF/3TC/ATV/r 300/300/300/100mg tablets OD from Day 1-7 single dose remdesivir 150mg IV infusion on Day 7
|
Remdesivir (GS-5734) is a nucleoside analogue with in vitro activity against filoviruses EBOV, SUDV, BDBV and MARV, in addition to arenaviruses and coronaviruses
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of adverse events categorised by body system
Time Frame: 30 days
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The number of adverse events will be tabulated by body system.
All safety parameters will be listed by cohort, subject and visit/time and summarized by treatment and visit/time.
No formal statistical hypotheses of the safety or tolerability are to be tested.
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30 days
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Percentage of participants with adverse events categorised by body system
Time Frame: 30 days
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The incidence of adverse events will be tabulated by body system.
All safety parameters will be listed by cohort, subject and visit/time and summarized by treatment and visit/time.
No formal statistical hypotheses of the safety or tolerability are to be tested.
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30 days
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Peak Concentration (CMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
Time Frame: last measurable time-point (24 hours)
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maximum plasma and intracellular concentration [Cmax] of remdesivir with or without co-administration of antiretroviral drugs.
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last measurable time-point (24 hours)
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Time to maximum concentration (TMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
Time Frame: last measurable time-point (24 hours)
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Time to maximum concentration of remdesivir in plasma and PBMCs with or without co-administration of antiretroviral therapy
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last measurable time-point (24 hours)
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Terminal elimination half-life of remdesivir in plasma and PBMCs
Time Frame: 24 hours
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terminal elimination half life of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
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24 hours
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Area under concentration-time curve (AUC) of remdesivir
Time Frame: last measurable time-point (24 hours)
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Area under concentration-time curve of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
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last measurable time-point (24 hours)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Geometric mean ratio and 90% confidence intervals of remdesivir CMax with and without antiretroviral therapy.
Time Frame: 24 hours
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CMax of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
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24 hours
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Geometric mean ratio and 90% confidence intervals of remdesivir TMax with and without antiretroviral therapy.
Time Frame: 24 hours
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TMax of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
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24 hours
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Geometric mean ratio and 90% confidence intervals of remdesivir terminal elimination half-life with and without antiretroviral therapy.
Time Frame: 24 hours
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t 1/2 of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
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24 hours
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Geometric mean ratio and 90% confidence intervals of remdesivir area under concentration-time curve, with and without antiretroviral therapy.
Time Frame: 24 hours
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AUC (0-t) of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
t is the last measurable time-point
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24 hours
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Mohammed J Lamorde, PhD, Infectious Diseases Institute, Uganda
Publications and 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 (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- RNA Virus Infections
- Virus Diseases
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Sexually Transmitted Diseases, Viral
- Sexually Transmitted Diseases
- Lentivirus Infections
- Retroviridae Infections
- Immunologic Deficiency Syndromes
- Immune System Diseases
- Slow Virus Diseases
- HIV Infections
- Acquired Immunodeficiency Syndrome
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Antimetabolites
- Remdesivir
Other Study ID Numbers
- PK-24
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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