Endpoints to primary objectives
- Adverse events, physical exam findings, vital signs (blood pressure, body temperature, respiratory rate), ECG findings (QTc, PR, QRS intervals), safety laboratory assessments, and SAEs
- Single pharmacokinetic parameters in peripheral blood mononuclear cells (PBMCs): maximum intracellular concentration [Cmax], time to maximum concentration [Tmax], elimination rate constant, area under the concentration-time curve [AUCinf, AUClast] and half-life (t½) of remdesivir
Endpoint to secondary objective
A population pharmacokinetic model of remdesivir
Endpoints to exploratory objectives
Pharmacogenomic characterization of metabolic enzymes involved in remdesivir metabolism
Participant timeline {13}
Study A
Table 1: Sequence 1
Protocol Activity
|
Day -14
|
Day-3
|
Day 1
|
Day 2
|
Day
3-7
|
Day 8
|
Day
9-13
|
Day 14
|
Day 15
|
Day 18
|
Day 22
|
Day 29
EOS
|
Informed consent
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Screening
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Enrolment and Randomisation
|
|
X
|
|
|
|
|
|
|
|
|
|
|
Remdesivir
|
|
|
X
|
|
|
|
|
X
|
|
|
|
|
TDF/3TC
|
|
|
|
|
|
X
|
X
|
X
|
|
|
|
|
Rich PK Visit
|
|
|
X
|
|
|
|
|
X
|
|
|
|
|
Single PK sample
|
|
|
|
X
|
|
|
|
|
X
|
|
|
|
Washout period
|
|
|
|
|
|
|
|
|
|
|
|
|
Clinical review
|
X
|
|
X
|
|
XT
|
X
|
XT
|
X
|
|
XT
|
|
X
|
Vital Signs
|
X
|
|
X
|
|
|
|
|
X
|
|
|
|
X
|
HBV serology
|
X
|
|
|
|
|
|
|
|
|
|
|
|
HIV serology
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Malaria RDT
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Safety bloods
|
X
|
|
|
X
|
|
X
|
|
X
|
X
|
|
X
|
|
Urinalysis
|
X
|
|
X
|
|
|
|
|
X
|
|
|
|
|
Pregnancy Test
|
X
|
|
X
|
|
|
X
|
|
|
|
|
|
|
ECG
|
X
|
|
X
|
|
|
|
|
X
|
|
|
|
|
Pharmacogenomic sample
|
|
|
|
|
|
X
|
|
|
|
|
|
|
XT telephone visit, RDT Rapid Diagnostic Test
Study A
Table 2: Sequence 2
Protocol Activity
|
Day -14
|
Day-3
|
Day 1
|
Day
2-6
|
Day 7
|
Day 8
|
Day
9-14
|
Day 15
|
Day 16
|
Day 18
|
Day 22
|
Day 29
EOS
|
Informed consent
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Screening
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Enrolment and Randomisation
|
|
X
|
|
|
|
|
|
|
|
|
|
|
Remdesivir
|
|
|
|
|
X
|
|
|
X
|
|
|
|
|
TDF/3TC
|
|
|
X
|
X
|
X
|
|
|
|
|
|
|
|
Rich PK Visit
|
|
|
|
|
X
|
|
|
X
|
|
|
|
|
Single PK sample
|
|
|
|
|
|
X
|
|
|
X
|
|
|
|
Washout period
|
|
|
|
|
|
|
|
|
|
|
|
|
Clinical review
|
X
|
|
X
|
XT
|
|
|
XT
|
X
|
|
XT
|
|
X
|
Vital Signs
|
X
|
|
X
|
|
|
|
|
X
|
|
|
|
X
|
HBV serology
|
X
|
|
|
|
|
|
|
|
|
|
|
|
HIV serology
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Malaria RDT
|
X
|
|
|
|
|
|
|
|
|
|
|
|
Safety bloods
|
X
|
|
|
|
X
|
X
|
|
X
|
X
|
|
X
|
|
Urinalysis
|
X
|
|
|
|
X
|
|
|
|
|
|
|
|
Pregnancy Test
|
X
|
|
X
|
|
|
|
|
X
|
|
|
|
|
ECG
|
X
|
|
|
|
X
|
|
|
X
|
|
|
|
|
Pharmacogenomic sample
|
|
|
|
|
|
X
|
|
|
|
|
|
|
XT telephone visit, RDT Rapid Diagnostic Test
Table 3: Study B
Protocol Activity
|
Day -14
|
Day-3
|
Day 1
|
Day 2-6
|
Day 7
|
Day 8
|
Day 11
|
Day 15
|
Day 22
EOS
|
Informed consent
|
X
|
|
|
|
|
|
|
|
|
Screening
|
X
|
|
|
|
|
|
|
|
|
Enrolment and Randomisation
|
|
X
|
|
|
|
|
|
|
|
Remdesivir
|
|
|
|
|
X
|
|
|
|
|
TDF/3TC plus ATVr
|
|
|
X
|
X
|
X
|
|
|
|
|
Rich PK Visit
|
|
|
|
|
X
|
|
|
|
|
Single PK sample
|
|
|
|
|
|
X
|
|
|
|
Washout period
|
|
|
|
|
|
|
|
|
|
Clinical review
|
X
|
|
X
|
XT
|
|
|
XT
|
|
X
|
Vital Signs
|
X
|
|
X
|
|
|
|
|
|
X
|
HBV serology
|
X
|
|
|
|
|
|
|
|
|
HIV serology
|
X
|
|
|
|
|
|
|
|
|
Malaria RDT
|
X
|
|
|
|
|
|
|
|
|
Safety bloods
|
X
|
|
|
|
X
|
X
|
|
X
|
|
Urinalysis
|
X
|
|
|
|
X
|
|
|
|
|
Pregnancy Test
|
X
|
|
|
|
X
|
|
|
|
|
ECG
|
X
|
|
|
|
X
|
|
|
|
|
Pharmacogenomic sample
|
|
|
|
|
|
X
|
|
|
|
XT telephone visit, RDT Rapid Diagnostic Test
Sample size {14}
The primary objective will evaluate drug exposure of remdesivir in a uniform population with subjects acting as their own controls. A formal power calculation based on differences in exposure between two different groups is therefore not applicable in this situation. Intensive pharmacokinetic studies aim to estimate the pharmacokinetic parameters with precision, and therefore for studies with an intensive sampling schedule, as in this case, a sample size of 24 participants is considered sufficient.
Recruitment {15}
Healthy volunteer participants will be identified and recruited from communities that are within close proximity of the IDI CTU. Input from the IDI Community Advisory Board (CAB) whose members are solicited from within communities where research is undertaken will be sought when sensitizing the community on the objectives of the trial.
IRB approved study flyers will be displayed on notice boards and other easily accessible locations. Administrative clearance will be obtained from responsible authorities to display study flyers within the community. Contact information including the physical address of the clinical team will be provided on the flyers. An informed consent form will be provided to potential participants who contact the clinical team and wish to get information regarding the study. Potential participants will be given adequate time to review the Informed consent form and an opportunity to ask any questions about the study.
Eligibility will be confirmed by a medical practitioner prior to enrolment into the study.
Assignment of interventions: allocation
Sequence generation {16a}
Eligible participants will be assigned to study groups in accordance with a computer-generated randomisation schedule. The randomisation schedule will be generated using permuted block randomisation by the study statistician.
Concealment mechanism {16b}
Enrolled participants will be allocated sequentially to treatment groups using concealed envelopes. Only the study statistician will have access to the treatment allocation concealment log (TCL). Following the TCL, a set of sequentially numbered, opaque and sealed envelopes for allocation concealment and treatment allocation will be prepared. Sealed and tamper-evident treatment allocation envelopes (TAE) will be prepared by the study statistician. One envelope will be created for each particular trial subject. Each envelope will have the study identification, e.g. the subject number to identify the particular subject recruited. The envelopes will be secured in a lockable drawer kept by the study pharmacist. Each envelope will contain a piece of white paper printed clearly with the subject number and the allocation given either as “Study A Sequence 1”, “Study A Sequence 2”, or “Study B”. When a particular trial subject has signed the written consent form and is eligible for randomization, the study clinician will assign a subject number chronologically to the subject. The chronological process will be maintained to make sure that the allocation is not subverted. Each allocation code will be verified with the central record kept with the study statistician.
Implementation {16c}
Eligible participants will be enrolled into the study by a medical practitioner.
Assignment of interventions: Blinding
Who will be blinded {17a}
Not applicable
Procedure for unblinding if needed {17b}
Not applicable
Data collection and management
Plans for assessment and collection of outcomes {18a}
Copies of the data collection tools are available upon request from the corresponding author.
Plans to promote participant retention and complete follow-up {18b}
Participants may voluntarily withdraw from the study for any reason at any time. They may be considered withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to follow-up for any other reason. If a participant withdrawal occurs for any reason, the Investigator must make every effort to determine the primary reason for a subject’s withdrawal from the study and record this information in the CRF.
For participants who are lost to follow-up (i.e., those participants whose status is unclear because they fail to appear for study visits without stating an intention to withdraw), the study team will document in source documents steps taken to contact the participant, e.g., telephone calls, short message service (SMS), home visits, letters/emails etc.
Participants who are withdrawn from the study for reasons other than safety may be replaced by an equal number of newly enrolled subjects.
Any participant who is discontinued for any of the above reasons and does not withdraw consent, should return to the site to complete their end of study assessments.
If a participant withdraws from the study, and also withdraws consent for disclosure of future information, no further evaluations will be performed, and no additional data will be collected. The sponsor may retain and continue to use any data collected before such withdrawal of consent.
Data management {19}
Data will be entered into a study specific electronic database by designated staff on a regular basis from completed Case Report Forms (CRFs) and stored securely on a server at Infectious Diseases Institute. Study records, including the identity of all participating participants, all original signed informed consent documents, copies of all CRFs, safety reporting forms, source documents, and detailed records of treatment disposition, and adequate documentation of relevant correspondence (eg, letters, meeting minutes, telephone calls reports) will be kept securely in a locked cabinet with access granted only to authorized study staff. Upon study competition, study records will be transferred and stored at IDI’s secure archival site for at least 20 years in accordance with Uganda National Drug Authority (NDA) guidance.
Confidentiality {27}
Clinical data will be entered into a study specific electronic database by designated staff on a regular basis from completed Case Record Forms (CRFs). Access to the database will be given to authorized personnel only (members of the immediate study team) and a log of authorized personnel will be stored in the trial master file. Case Report Forms and trial documents will be kept in locked cabinets. No participant identifying information will be disclosed in any publication or at any conference activities arising from the study.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Whole blood will be obtained and collected into vacutainers containing anticoagulant or cell preparation tubes and delivered within 30 minutes to the laboratory. Samples will be centrifuged to separate plasma and PBMCs. To inactivate the esterase responsible for remdesivir degradation, plasma samples will be heat inactivated at 58oC for 35 minutes and aliquoted into cryovials. Plasma and PBMC cryovials will be stored at -80OC until analysis. Whole blood or nucleate cell aliquots will be analysed for DNA biomarkers related to the effect of treatment. Detailed descriptions of the assays will be included in a bioanalytical data report.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The study aims to evaluate the safety, tolerability, and pharmacokinetics of single dose remdesivir in healthy volunteers. The number and percentage 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.
Pharmacokinetic parameters in plasma and PBMCs including the area under the concentration-time curve to the last measurable time point (AUC0-t), terminal elimination half-life (t1/2 ), maximum concentration (Cmax) and time to Cmax (Tmax) will be estimated using non-compartmental analysis (WinNonlin, Phoenix, version 6.1 or higher, Pharsight, Mountain View, CA). Remdesivir pharmacokinetic parameters with and without antiretroviral therapy will be compared by calculating geometric mean ratios and 90% confidence intervals. Coefficient of variation (CV=mean/SD*100) will be calculated at all timepoints and for the measured parameters. Only subjects with evaluable remdesivir pharmacokinetic parameters data will be included in the primary analysis.
Descriptive statistics (including mean, SD, CV% mean, geometric mean, CV%, median, minimum and maximum) will be provided for all pharmacokinetic parameters of remdesivir.
Analysis of Secondary Endpoints
The pharmacokinetic data collected in the study will be interpreted using population pharmacokinetic modelling (pop-PK). A pop-PK model will be developed to describe remdesivir pharmacokinetics pooling the clinical trial pharmacokinetic data from each subject and each sequential treatment condition in a single analysis. Nonlinear mixed effects will be used to define remdesivir pharmacokinetic parameters and their relationships with covariates such as weight, age, sex (fixed effects) and to determine interindividual (and potentially interoccasion) variability in parameters and residual variably (random effects). Simulations will be used to predict dosing for patients across the data range, for example, by weight, sex, and age groups. This will provide a quantitative evaluation of pharmacokinetic variability that could facilitate evaluation of potential dosing strategies for patients with special characteristics in this setting.
Interim analyses {21b}
A safety monitor will perform Interim review of the trial’s safety data. The safety monitor will review safety data after the first five participants have been enrolled into the study and every two weeks thereafter. Further reviews may be convened at the discretion of the safety monitor, or upon request from the Principal Investigator if unexpected data emerge, or if the study stopping criteria is met.
Study Stopping Rules
Enrolment in the study will be placed on hold if any of the following occurs cumulatively across all of the cohorts:
- One or more treatment-emergent SAEs, except those that are clearly and incontrovertibly due to extraneous causes;
- At least two or more subjects experience a similar AE which is assessed as severe in intensity, and is considered as potentially related to study drugs;
- The principal investigator, and the safety monitor consider that the number and/or severity of AEs, abnormal safety monitoring tests or abnormal laboratory findings justify putting the study on hold.
The study may resume if it is safe to proceed following a safety review of participant clinical and laboratory data.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Analysis of Exploratory Endpoints
Stored samples will be used for optional genetic research which may include genome-wide association studies. As the numbers of participants enrolled in the study are too small to complete proper statistical analyses, additional data from other similar clinical trials, maybe combined, as appropriate, with those from other studies to enlarge the data set for analysis.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
No imputation of missing data will be considered for safety and tolerability analysis.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The full protocol, participant-level dataset, and statistical code will be made available upon request from the corresponding author.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Dr. Mohammed Lamorde (principal investigator), Dr. Stephen I Walimbwa, Julian P Kaboggoza, Dr. Catriona Waitt, and Dr. Pauline Byakika-Kibwika will oversee the day to day activities of the trial.
Composition of the data monitoring committee, its role and reporting structure {21a}
A safety monitor will make data safety and monitoring recommendations about the study. The safety monitor is a clinical trial research-experienced infectious diseases clinician without direct involvement in the study. The safety monitor will review safety data after the first five subjects have been enrolled into the study. Further reviews may be convened (at the discretion of the safety monitor, or upon request from the Principal investigator) if unexpected data emerge, or if the study stopping criteria is met. Any Serious Adverse Events (SAEs) or Suspected Unexpected Serious Adverse Reaction (SUSARs) will also be reported to the safety monitor in a timely manner. A charter describing the functioning of the safety monitor has been developed.
Adverse event reporting and harms {22}
Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal relationship will be reported.
For all AEs, the investigators will pursue and obtain information adequate both to determine the outcome of the AE and to assess whether it meets the criteria for classification as an SAE requiring immediate notification. For all AEs, sufficient information will be obtained by the investigators to determine the causality of the AE. The investigators will assess causality. Follow-up by the investigators will be until the event or its sequelae resolve or stabilize at a level acceptable to the investigators.
During each study visit the study clinician will assess AEs which may have occurred since the previous visit. The investigators will generate and submit annual reports summarizing these adverse events.
Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:
Results in death; Is life-threatening (immediate risk of death); Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); Results in congenital anomaly/birth defect
Severity Assessment
The severity of adverse events will be graded according to the Common Terminology Criteria for Adverse Effects (CTCAE) V.5.
Causality Assessment
The relationship to study drug of each adverse event will be assessed using the following definitions:
DEFINITE: distinct temporal relationship with drug treatment. Known reaction to agent or chemical group, or predicted by known pharmacology. Event cannot be explained by subject’s clinical state or other factors.
PROBABLE: reasonable temporal relationship with drug treatment. Likely to be known reaction to agent or chemical group, or predicted by known pharmacology. Event cannot easily be explained by subject’s clinical state or other factors.
POSSIBLE: reasonable temporal relationship with drug treatment. Event could be explained by subject’s clinical state or other factors.
UNLIKELY: poor temporal relationship with drug treatment. Event easily explained by subject’s clinical state or other factors.
UNRELATED: the event occurs prior to dosing. Event or intercurrent illness is due wholly to factors other than drug treatment.
Reporting Requirements
Each AE will be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, expedited reporting will follow IRB, local and international regulations, as appropriate. All SAEs will be reported to IDI Scientific Review Committee, the IRB, the Uganda National Council of Science and Technology (UNCST), the Uganda National Drug Authority (NDA). All SAEs will be reported to the sponsor within 24 hours of becoming aware of the event and to the ethics committee, UNCST and NDA within seven days of knowing about the event. Further relevant follow-up information will be given when available and follow-up will continue until the event resolves.
All AEs will be tabulated and reported to the IRB in annual study reports.. AEs and SAEs will be reported using concise medical terminology.
Frequency and plans for auditing trial conduct {23}
Periodic monitoring will be conducted independent of the investigators by internal monitors at the Infectious Diseases Institute. The frequency and procedures for monitoring the trial are outlined in a monitoring plan.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Protocol deviations will be communicated to the appropriate authorities within seven days. Amendments to the protocol will be implemented following local ethics and regulatory approvals and updated in ClinicalTrials.org.
Dissemination plans {31a}
Information will be developed in modalities appropriate to the target audience. Input from Community Advisory Boards (CAB) will be sought from study set-up to dissemination. Through regular meetings between CAB and the study team, key updates on study progress, new evidence external to the study and study results will be communicated and presented in a format which is accessible to members of the community. Other communication activities may include a trial website, study Twitter account and newsletters.
Data will be shared with consortium partners and other research groups according to data transfer agreements, with all originating RemTLAR data remaining the property of the sponsor. Access to study data will be granted to qualified individuals for research and educational purposes after approval by the relevant regulatory bodies.
A whole or part of this study results will be communicated, orally presented, and/or published in appropriate scientific journals and research forums including the IDI Research Forum and Journal Club. In addition, participants wanting to see the results of the trial can request a copy of the article from the investigators once it has been published. Full anonymity of participant’s details will be maintained throughout.