Primary objectives:- To assess the relative bioavailability of TAF and TFV after a single-dose FTC/TAF 3x60/7.5 mg DT (reference TAF) compared to TAF and TFV after a single-dose FTC/TAF 3x 60/7.5mg DT in combination with a single dose of DTG 30mg as…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameters of this study are to assess:
- The relative bioavailability of TAF and TFV after a single-dose FTC/TAF 3x
60/7.5mg DT (reference TAF) compared to TAF and TFV after a single-dose FTC/TAF
3x 60/7.5mg DT in combination with a single dose of DTG 30mg as 6 tablets of
5mg DT (test).
- The relative bioavailability of FTC after a single-dose FTC/TAF 3x 60/7.5mg
DT (reference FTC) compared to FTC after a single-dose FTC/TAF 3x 60/7.5mg DT
in combination with a single dose of DTG 30 mg as 6 tablets of 5 mg DT (test).
- The relative bioavailability of DTG after a single-dose DTG 30mg as 6 tablets
of 5mg DT (reference DTG) compared to DTG after a single-dose FTC/TAF 3x
60/7.5mg DT in combination with a single dose of DTG 30mg as 6 tablets of 5mg
DT (test).
- The relative bioavailability of the potential interaction, the
pharmacokinetics (AUC0-*, Cmax, Tmax, T*) of DTG, FTC, TAF and TFV and the
geometric mean ratios of the AUC0-tlast (TAF), AUC0-* (DTG, FTC and TFV) and
Cmax of the test versus reference treatment.
Secondary outcome
The safety and tolerability of (co-)administration of DTG, FTC/TAF in healthy
adult subjects.
Background summary
This is a study that will inform another project: UNIVERSAL. Within the
UNIVERSAL project paediatric fixed dose combination tablets will be developed
for children living with HIV, one of the products to be developed is a
dispersible tablet (DT) combination of dolutegravir/tenofovir alafenamide
fumarate/emtricitabine (DTG/FTC/TAF). In the UNIVERSAL 1 trial PK of existing
DTG DT tablets and existing FTC/TAF DT tablets will be evaluated in children in
the dose combinations suggested for the fixed dose tablet. The dose
combinations will be evaluated by in silico modelling. If modelling project
suggests dose strengths that are not approved, then new tablet strengths will
be developed.
Potentially there is an interaction between DTG and TAF when given as
dispersible tablets, based on experience with the bictegravir/FTC/TAF DT
tablets developed by Gilead. A 30% increase in TAF exposure and a 31% increase
in bictegravir (BIC) exposure was observed when combining these drugs in
different fixed dose combinations. (1) BIC and DTG are similar in structure,
which raises the question whether this may be the case between TAF and DTG as
well.
Drug-drug-interaction studies with the adult film coated tablets DTG and
FTC/TAF showed no effect of FTC/TAF on DTG, but 17% higher TAF and 25% higher
tenofovir (TFV) concentrations in combination with DTG were observed. (2)
These increases were not clinically relevant, but point in the same direction
as FTC/TAF DT versus BIC/FTC/TAF DT.
Therefore, this study will be conducted to investigate whether there is a
drug-drug-interaction between paediatric DTG 5 mg scored DT (30mg) and the 3x
60/7.5 mg FTC/TAF DT tablet. The dose is similar to the adult dose, because, a
single tablet of the pediatric TAF/FTC tablet would generate almost
unmeaserable TAF levels.
Study objective
Primary objectives:
- To assess the relative bioavailability of TAF and TFV after a single-dose
FTC/TAF 3x60/7.5 mg DT (reference TAF) compared to TAF and TFV after a
single-dose FTC/TAF 3x 60/7.5mg DT in combination with a single dose of DTG
30mg as 6 x 5 mg DT tablets (test).
- To assess the relative bioavailability of FTC after a single-dose FTC/TAF
60/7.5mg DT (reference FTC) compared to FTC after a single-dose FTC/TAF 3x
60/7.5mg DT in combination with a single dose of DTG 30 mg as 6 x 5 mg DT
tablets (test).
- To assess the relative bioavailability of DTG after a single-dose DTG 30mg as
6 x 5 mg DT tablets (reference DTG) compared to DTG after a single-dose FTC/TAF
3x 60/7.5mg DT in combination with a single dose of DTG 30mg as 6 x 5 mg DT
tablets (test).
- To assess relative bioavailability of the potential interaction, the
pharmacokinetics (AUC0-*, Cmax, Tmax, T*) of DTG, FTC, TAF and TFV will be
obtained and the geometric mean ratios of the AUC0-tlast (TAF), AUC0-* (DTG,
TFC and TFV) and Cmax of the test versus reference treatment.
Secondary objective:
- To evaluate the safety and tolerability of (co-)administration of DTG,
FTC/TAF in healthy adult subjects.
Study design
Open-label, 3 period, randomized, cross-over, single-center, single-dose study
in 16 healthy adult subjects.
Intervention
The 16 subjects will be divided into one of the following treatment sequences:
ABC; ACB; BCA; BAC; CAB; CBA.
Treatment:
- A: Single-dose FTC/TAF 3x 60/7.5mg DT as a dispersed suspension in a fasted
state
- B: Single-dose DTG 30mg as 6 x 5mg DT as a dispersed suspension in a fasted
state
- C: Single-dose FTC/TAF 3x 60/7.5mg DT + DTG 30mg as 6 x 5mg DT as a
co-dispersed suspension in a fasted state
Study burden and risks
This study will be conducted considering COVID-19 safety precaution for both
staff and participants.
The study participants are healthy adult subjects and will not benefit from the
participation in this clinical trial.
Participants will visit the clinical research centre for a screening visit, 9
short visits (10 minutes), and 3 full days (13 hours). The duration of the
entire trial (excluding screening period) is 17 days. Duration of treatment
with study medication is 3 days (days 1, 8 and 15).
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 and not older than 55 years of age at the day of
screening.
2. Subject weighs at least 40 kg.
3. Subject has a BMI of 18.5-30 kg/m2, extremes included.
4. Subject is able and willing to sign the Informed Consent Form prior to
screening evaluations.
5. Subject is in good age-appropriate health condition as established by
medical history, physical examination, electrocardiography, results of
biochemistry, haematology and urinalysis testing within four weeks prior to day
1. Results of biochemistry, haematology and urinalysis testing should be within
the laboratory's reference ranges. If laboratory results are not within the
reference ranges, the subject is included based on the Investigator*s judgment
that the observed deviations are not clinically relevant. This should be
clearly recorded.
6. Subject has a normal blood pressure and pulse rate, according to the
Investigator*s judgment.
7. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day
for at least 3 months prior to day 1.
Exclusion criteria
1. Positive HIV test.
2. Positive hepatitis B or C test.
3. Documented history of sensitivity/idiosyncrasy to medicinal products or
excipients.
4. Relevant history or current condition that might interfere with drug
absorption, distribution, metabolism or excretion.
5. Inability to understand the nature and extent of the study and the
procedures required.
6. Pregnant female (as confirmed by an hCG test performed less than 4 weeks
before day 1) or breast-feeding female. Female subjects of childbearing
potential without adequate contraception, e.g. hysterectomy, bilateral tubal
ligation, (non-hormonal) intrauterine device, total abstinence, double barrier
methods, or two years post-menopausal. They must agree to take precautions in
order to prevent a pregnancy throughout the entire conduct of the study.
7. Therapy with any drug (including herbal remedies, multivitamins, iron
supplements and calcium supplements) for two weeks preceding day 1, except for
acetaminophen.
8. Relevant history or presence of pulmonary disorders (especially COPD),
cardiovascular disorders, neurological disorders (especially seizures and
migraine), psychiatric disorders, gastro-intestinal disorders, renal disorders
(renal failure determined as an estimated Glomerular Filtration Rate (eGFR)
below 50 ml/min (MDRD-based)), hepatic disorders (Child-Pugh B or C), hormonal
disorders (especially diabetes mellitus), coagulation disorders.
9. History of or current abuse of drugs, alcohol or solvents.
10. Participation in a drug study within 60 days prior to day 1.
11. Donation of blood within 60 days prior to day 1.
12. Febrile illness within 3 days before day 1.
13. Co-worker of Radboud university medical center.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-005069-41-NL |
| CCMO | NL79111.091.22 |