EbolaPhase 2RemTLARNCT04385719
Drug-drug Interactions Between Remdesivir and Commonly Used Antiretroviral Therapy
A Phase 2 study testing Remdesivir in people with Ebola and HIV/AIDS, run by Makerere University at 1 site in Uganda.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- What is being tested?
- Remdesivir
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUganda
- Study dates
- 5 May 2021to 16 Jul 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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:
- 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).
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- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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
- To describe polymorphic variants of relevant kinases that activate TFV and explore possible consequences on remdesivir PK.
- Being tested
- Remdesivir
- Keywords
- Ebola, HIV, Pharmacokinetics, Remdesivir, Drug Interactions
- Medical subject headings
- Hemorrhagic Fever, Ebola, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RemdesivirDrug
Also called GS-5734
Remdesivir (GS-5734) is a nucleoside analogue with in vitro activity against filoviruses EBOV, SUDV, BDBV and MARV, in addition to arenaviruses and coronaviruses
| Study group | Role | What they receive |
|---|---|---|
| Study A Sequence 1 | Experimental | 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 Receives: Drug: Remdesivir |
| Study A Sequence 2 | Experimental | 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 Receives: Drug: Remdesivir |
| Study B | Experimental | TDF/3TC/ATV/r 300/300/300/100mg tablets OD from Day 1-7 single dose remdesivir 150mg IV infusion on Day 7 Receives: Drug: Remdesivir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of adverse events categorised by body system
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.
Measured: 30 days
Percentage of participants with adverse events categorised by body system
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.
Measured: 30 days
Peak Concentration (CMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
maximum plasma and intracellular concentration [Cmax] of remdesivir with or without co-administration of antiretroviral drugs.
Measured: last measurable time-point (24 hours)
Time to maximum concentration (TMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
Time to maximum concentration of remdesivir in plasma and PBMCs with or without co-administration of antiretroviral therapy
Measured: last measurable time-point (24 hours)
Terminal elimination half-life of remdesivir in plasma and PBMCs
terminal elimination half life of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
Measured: 24 hours
Area under concentration-time curve (AUC) of remdesivir
Area under concentration-time curve of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
Measured: last measurable time-point (24 hours)
Secondary outcomes (4)
Geometric mean ratio and 90% confidence intervals of remdesivir CMax with and without antiretroviral therapy.
CMax of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
Measured: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir TMax with and without antiretroviral therapy.
TMax of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
Measured: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir terminal elimination half-life with and without antiretroviral therapy.
t 1/2 of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy.
Measured: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir area under concentration-time curve, with and without antiretroviral therapy.
AUC (0-t) of remdesivir in plasma and PBMCS will be compared with and without antiretroviral therapy. t is the last measurable time-point
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2020
- Study start5 May 2021
- Primary completion2 Jul 2021
- Study completion16 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for EbolaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Makerere University
- Sponsor type
- University, hospital or other
- Collaborators
- University of Liverpool, European and Developing Countries Clinical Trials Partnership (EDCTP), University of Turin, Italy
- Responsible party
- Sponsor
- Investigators
- Mohammed J Lamorde, PhD, Principal investigator, Infectious Diseases Institute, Uganda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04385719
- Sponsor's protocol ID
- PK-24
- Acronym
- RemTLAR
- Status last verified
- Aug 2021
- First submitted
- 29 Mar 2020
- Last updated
- 25 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 34814933
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04385719
- Acronym / sponsor ID
- RemTLAR / PK-24
- Keywords
- Ebola, HIV, Pharmacokinetics, Remdesivir, Drug Interactions
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Makerere UniversityUniversity, hospital or other
- Collaborators
- University of Liverpool, European and Developing Countries Clinical Trials Partnership (EDCTP), University of Turin, Italy
- Study start
- 5 May 2021 (actual)
- Primary completion
- 2 Jul 2021 (actual)
- Study completion
- 16 Jul 2021 (actual)
- First posted
- 13 May 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- 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
- To describe polymorphic variants of relevant kinases that activate TFV and explore possible consequences on remdesivir PK.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Study A Sequence 1 | Experimental | Drug: RemdesivirSingle 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 |
| Study A Sequence 2 | Experimental | Drug: RemdesivirTDF/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 |
| Study B | Experimental | Drug: RemdesivirTDF/3TC/ATV/r 300/300/300/100mg tablets OD from Day 1-7 single dose remdesivir 150mg IV infusion on Day 7 |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- 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:
- 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).
Key exclusion criteria (7 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RemdesivirAlso: GS-5734Remdesivir (GS-5734) is a nucleoside analogue with in vitro activity against filoviruses EBOV, SUDV, BDBV and MARV, in addition to arenaviruses and coronaviruses | Drug | Study A Sequence 1, Study A Sequence 2, Study B |
Primary outcome
Number of adverse events categorised by body system
Time frame: 30 days
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.
Percentage of participants with adverse events categorised by body system
Time frame: 30 days
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.
Peak Concentration (CMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
Time frame: last measurable time-point (24 hours)
maximum plasma and intracellular concentration [Cmax] of remdesivir with or without co-administration of antiretroviral drugs.
Time to maximum concentration (TMax) of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma
Time frame: last measurable time-point (24 hours)
Time to maximum concentration of remdesivir in plasma and PBMCs with or without co-administration of antiretroviral therapy
Terminal elimination half-life of remdesivir in plasma and PBMCs
Time frame: 24 hours
terminal elimination half life of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
Area under concentration-time curve (AUC) of remdesivir
Time frame: last measurable time-point (24 hours)
Area under concentration-time curve of remdesivir in peripheral blood mononuclear cells (PBMCs) and Plasma with or without co-administration of antiretroviral therapy.
4 secondary outcomes
Geometric mean ratio and 90% confidence intervals of remdesivir CMax with and without antiretroviral therapy.
Time frame: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir TMax with and without antiretroviral therapy.
Time frame: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir terminal elimination half-life with and without antiretroviral therapy.
Time frame: 24 hours
Geometric mean ratio and 90% confidence intervals of remdesivir area under concentration-time curve, with and without antiretroviral therapy.
Time frame: 24 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2021.
- Derived from this study: PubMed 34814933Walimbwa 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mohammed J Lamorde, PhD principal investigator
Infectious Diseases Institute, Uganda
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Remdesivir in people with Ebola and HIV/AIDS, run by Makerere University at 1 site in Uganda.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of adverse events categorised by body system (time frame: 30 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04385719, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2021.