Clinical trial NCT04385719: Drug-drug Interactions Between Remdesivir and Commonly Used Antiretroviral Therapy
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ebola
HIV/AIDS
Keywords: Ebola
HIV
Pharmacokinetics
Remdesivir
Drug Interactions
Lead sponsor: Makerere University
Sponsor class: OTHER
Collaborators: name: University of Liverpool
name: European and Developing Countries Clinical Trials Partnership (EDCTP)
name: University of Turin, Italy
First posted: 2020-05-13
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Ebola and HIV are found predominately in the same regions of the world and countries in sub-Saharan Africa are most affected by both diseases. For Ebola, no approved therapies exist. However, new investigational drugs are being evaluated to understand if they are effective against the Ebola virus. Remdesivir is an anti-Ebola investigational drug for the treatment of Ebola. Little is known about how the blood levels of remdesivir relate to how effective it is in patients with HIV taking antiretroviral therapy. This study will explore how commonly utilized ART (tenofovir/lamivudine and atazanavir/ritonavir) affect the drug levels of remdesivir.

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

1. To assess the safety and tolerability of single intravenous doses of remdesivir in adult healthy volunteers
2. 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

1. 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.
2. 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.

Eligibility criteria: Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. 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.
4. 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).
5. 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
6. HIV antibody negative at screening.
7. 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.
8. Hemoglobin concentration equal or greater than 10 g/dL

Exclusion Criteria:

1. 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.
2. Serum alanine transaminase (ALT) levels above 2x upper limit of normal (ULN) or total bilirubin \> 1.3x ULN
3. Serum creatinine levels above 1.5x upper limit of normal
4. Evidence of QT prolongation on electrocardiogram (ECG) QTc (Rate adjusted QT interval) \> 450ms (men) or 460ms (women)
5. Pregnant women or female subjects who are unwilling to use a suitable contraceptive method for the duration of the study (IUD or contraceptive implant)
6. Likely to be poorly adherent based on clinician's medical judgement
7. Known to be current injection drug user

Primary outcomes:
measure: Number of adverse events categorised by body system
timeFrame: 30 days
measure: Percentage of participants with adverse events categorised by body system
timeFrame: 30 days
measure: Peak Concentration (CMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
timeFrame: last measurable time-point (24 hours)
measure: Time to maximum concentration (TMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
timeFrame: last measurable time-point (24 hours)
measure: Terminal elimination half-life of remdesivir in plasma and PBMCs
timeFrame: 24 hours
measure: Area under concentration-time curve (AUC) of remdesivir
timeFrame: last measurable time-point (24 hours)
Secondary outcomes:
measure: Geometric mean ratio and 90% confidence intervals of remdesivir CMax with and without antiretroviral therapy.
timeFrame: 24 hours
measure: Geometric mean ratio and 90% confidence intervals of remdesivir TMax with and without antiretroviral therapy.
timeFrame: 24 hours
measure: Geometric mean ratio and 90% confidence intervals of remdesivir terminal elimination half-life with and without antiretroviral therapy.
timeFrame: 24 hours
measure: Geometric mean ratio and 90% confidence intervals of remdesivir area under concentration-time curve, with and without antiretroviral therapy.
timeFrame: 24 hours
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
Study officials:
affiliation: Infectious Diseases Institute, Uganda
name: Mohammed J Lamorde, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Walimbwa SI, Kaboggoza JP, Waitt C, Byakika-Kibwika P, D'Avolio A, Lamorde M. 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 (RemTLAR). Trials. 2021 Nov 23;22(1):831. doi: 10.1186/s13063-021-05752-1.