- To evaluate the single-dose PK and pivotal bioequivalence of 3 compounds darunavir (DRV) 675 mg, FTC 200 mg, and tenofovir alafenamide (TAF) 10 mg in the presence of cobicistat (COBI)150 mg when administered as an fixed-dose combination (FDC) (D/C…
ID
Source
Brief title
Condition
- Immunodeficiency syndromes
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The following PK parameters for Darunavir, Cobicistat, Emtricitabine, and
Tenofovir alafenamide will be determined for each treatment period:
- Cmax maximum observed analyte concentration;
- tmax the actual sampling time to reach the maximum observed analyte
concentration;
- AUClast area under the analyte concentration-time curve (AUC) from time 0 to
the time of
the last measurable (non-below quantification limit [non-BQL]) concentration,
calculated by linear-linear trapezoidal summation;
- AUC* AUC from time 0 to infinity, calculated as AUClast + Clast/*z, where
Clast is the last observed measurable (non- BQL) concentration; extrapolations
of more than 20.00% of the total AUC are reported as approximations;
- Clast last observed measurable (non-below quantification limit [BQL]) analyte
concentration;
- tlast the actual sampling time of the last measurable (non-BQL) analyte
concentration
- *z apparent terminal elimination rate constant, determined by linear
regression using the terminal log-linear phase of the log-transformed
concentration vs. time curve;
- t1/2 apparent terminal elimination half-life, defined as 0.693/*z.
Secondary outcome
The study will include the following evaluations of safety and tolerability:
• Adverse events
• Clinical laboratory
• Vital signs
• ECG
• Physical examination
Background summary
During this study the participant will receive 4 different study compounds that
can be used for the treatment of infection with Human Immunodeficiency Virus
type 1 (HIV-1). HIV targets immune cells (T-cells) and kills them. This type of
immune cell is important for coordinating the immune response to infections.
Therefore, the body is more susceptible to new infections when there are not
enough T-cells. The reduced effectiveness of the immune system may over time
develop in AIDS. It is estimated that in 2018 approximately 38 million people
worldwide were living with HIV and that it resulted in about 770 000
HIV-related deaths. Treating HIV requires a combination of drugs, which makes
it harder for patients to follow directions.
Therefore a combination tablet that contains multiple drugs is under
investigation.
A short description of each compound is given below:
- Darunavir is a drug that is used for the treatment of HIV. It works by
blocking the activity of a HIV-related protein (HIV-1 protease) that is
important to generate new viruses. This prevents other cells from being
infected by the virus.
- Cobicistat is a medication that reduces the activity of a group of liver
proteins (CYP3A) that are important for breaking down chemicals (such as drugs)
in the body. Cobicistat can thereby prolong the activity of other administered
drugs.
- Emtricitabine is a drug that inhibits the growth of the virus that causes
HIV. It works by slowing down the copying of virus DNA and thereby prevents the
virus from multiplying.
-Tenofovir alafenamide is a medication that will be broken down in the body to
its active form: tenofovir. Tenofovir works in a similar way as emtricitabine
and slows down the multiplication of the virus on DNA level.
Study objective
- To evaluate the single-dose PK and pivotal bioequivalence of 3 compounds
darunavir (DRV) 675 mg, FTC 200 mg, and tenofovir alafenamide (TAF) 10 mg in
the presence of cobicistat (COBI)150 mg when administered as an fixed-dose
combination (FDC) (D/C/F/TAF) compared to the co-administration as the separate
commercial formulations (DRV 1×600 mg and 1×75 mg tablet and F/TAF 1×200 mg/10
mg tablet and COBI 1×150 mg tablet), under fed conditions, in healthy adult
participants.
-To evaluate the single-dose PK and relative bioavailability of COBI 150 mg in
the presence of DRV 675 mg, FTC 200 mg, and TAF 10 mg when administered as an
FDC (D/C/F/TAF) compared to co-administration as the separate commercial
formulations (COBI 1×150 mg tablet in the presence of DRV 1×600 mg and 1×75 mg
tablet and F/TAF 1×200 mg/10 mg tablet), under fed conditions, in healthy adult
participants.
-To evaluate the short-term safety and tolerability of co-administration of DRV
675 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg, under fed conditions, in
healthy adult participant.
Study design
The study will consist of 4 periods during each the participants will stay in
the research center for 5 days (4 nights).
Day 1 is the first day of administration of the study compounds. The
participants are expected at the research center at 10:00 AM in the morning
prior to each day of administration of the study compounds, so on Day -1 of
each period. In each period, the participant will leave the research center
after staying 4 nights (so on Day 4). There will be at least 7 days between
treatments in each period. The participant will be asked to return to the
research center approximately 7 - 10 days after the last administration of the
study compound (Period 4) to check their health for the last time.
Intervention
During the course of this study the participant will receive 2 treatments
twice, for a total of 4 treatments. They will receive the following doses of
the study compounds: 675 mg Darunavir, 200 mg Emtricitabine, 10 mg Tenofovir
alafenamide and 150 mg Cobicistat, composed as follows:
Treatment A:
• 1 single tablet combining 675 mg darunavir, 200 mg emtricitabine, 10 mg
tenofovir alafenamide and 150 mg cobicistat
Treatment B:
• 1 tablet containing 600 mg darunavir
• 1 tablet containing 75 mg darunavir
• 1 tablet combining 200 mg emtricitabine and 10 mg tenofovir alafenamide
• 1 tablet containing 150 mg cobicistat
The order of treatments is determined by randomization (ABBA or BAAB).
The study compounds will be given in the morning as oral tablets with 240
milliliters (mL) of (tap) water.
Study burden and risks
Four clinical studies have been completed with the Darunavir (D) /Cobicistat
(C) /Emtricitabine (F) /Tenofovir alafenamide (TAF) fixed dose combination
(FDC) tablet in 199 healthy volunteers. The most frequently observed side
effects (seen in more than 10 percent of research participants) of D/C/F/TAF
were diarrhea, headache, and skin rash, mostly mild or moderate in severity.
Skin rash, when it occurs, may be accompanied with fever and/or an increase in
liver enzymes. It usually develops within the first 4 weeks of treatment with
D, is often mild or moderate in severity, often resolves within one week and
does not necessarily lead to treatment interruption. In some cases, the rash
has been severe or life-threatening. Rare cases of Stevens-Johnson syndrome and
very rare cases of other severe skin reactions have been reported in patients
taking D in combination with other anti-HIV drugs, as well as other
medications. The signs and symptoms of severe rash may include mouth and lips
sores or ulcers, fever, itching, weakness, fatigue, malaise, muscle or joint
pain, skin conditions (blisters, hives, boils and peels), swollen eyelids or
red or inflamed eyes (conjunctivitis), trouble swallowing or breathing,
inflammation of the liver (hepatitis) and/or increase of white cells in the
blood (eosinophilia).
Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising. In total, no more than than 500
milliliters (mL) of blood from will be taken from the subjects over the entire
course of the study.
To make a heart tracing (ECG), electrodes (small, plastic patches) will be
pasted at specific locations on your arms, chest and legs. Prolonged use of
these electrodes can cause skin irritation (rash and itching).
Samples for the coronavirus test will be taken from the back of the nose and
throat using swabs. Taking the samples only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
the throat may cause the volunteer to gag. When the sample is taken from the
back of the nose, the volunteer may experience a stinging sensation and the
eyes may become watery
Janssen Infectious Disease BVNA - Turnhoutseweg 30
Beerse 2340
BE
Janssen Infectious Disease BVNA - Turnhoutseweg 30
Beerse 2340
BE
Listed location countries
Age
Inclusion criteria
1. Must be a man or woman between 18 and 55 years of age, extremes included, at
screening.
2. Must have a body mass index (BMI; weight [kg]/height2 [m]2) between 18.5 and
30.0 kg/m2 (extremes included), and a body weight of not less than 50 kg at
screening.
3. Must sign an ICF indicating that he or she understands the purpose of, and
procedures required for, the study and is willing to participate in the study,
before any study-related procedures take place.
4. Must be healthy on the basis of physical examination, medical history, vital
signs, and ECG performed at screening (results must be available on Day -1). If
there are abnormalities (other than those listed in inclusion criterion 10 [for
blood pressure]), the participant may be included only if the investigator
judges the abnormalities or deviations from normal to be not clinically
significant. This determination must be recorded in the participant's source
documents and initialed by the investigator.
5. Participant must be healthy on the basis of clinical laboratory test
performed at screening (results must be available on Day -1). If the results of
the serum chemistry panel, hematology, or urinalysis are outside the normal
reference ranges (other than those listed in exclusion criterion 2), the
participant may be included only if the investigator judges the abnormalities
or deviations from normal to be not clinically significant. This determination
must be recorded in the participant's source documents and initialed by the
investigator.
Further criteria apply.
Exclusion criteria
1. Has history or current clinically significant medical illness including (but
not limited to) cardiac arrhythmias or other cardiac disease, hematologic
disease, coagulation disorders (including any abnormal bleeding or blood
dyscrasias), lipid abnormalities, significant pulmonary disease (including
bronchospastic respiratory disease), diabetes mellitus, hepatic or renal
insufficiency (eg, estimated creatinine clearance below <90 mL/min at
screening), gastrointestinal disease (such as significant diarrhea, gastric
stasis, or constipation that in the investigator*s opinion could influence drug
absorption or bioavailability), thyroid disease, neurologic or psychiatric
disease,
infection, or any other illness that the investigator considers should exclude
the participant or that could interfere with the interpretation of the study
results.
2. Had one or more of the following laboratory abnormalities at screening as
defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult
and Pediatric Adverse Events and in accordance with the normal ranges of the
clinical laboratory:
- Serum creatinine Grade 1 or greater (>=1.1 x upper limit of laboratory normal
range [ULN]) or creatinine clearance (using the CKD-EPI formula) <90 mL/min.
- Lipase Grade 1 or greater (>=1.1 x ULN), and/or total amylase Grade 2 or
greater (>=1.5 x ULN).
- Hemoglobin (Hb) Grade 1 or greater (Female: <=7.2 mmol/L and Male: <=8.3
mmol/L).
- Platelet count Grade 1 or greater (<124.999 x 109/L).
- Absolute neutrophil count Grade 1 or greater (<=1.0 x 109/L).
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) Grade 1 or
greater (>=1.25 x ULN).
- Total bilirubin Grade 2 or greater (>=1.6 x ULN).
- Note: Participants with documented Gilbert*s syndrome could have total
bilirubin up to 5 x ULN.
- For proteinuria (spot urine) >=2+.
- Microscopic hematuria (>=5 red blood cells [RBC]/hpf); if a female participant
is menstruating at the time of screening a urine retest is to be performed
after the menstrual period.
- Any other laboratory abnormality of grade 2 or greater. For low-density
lipoprotein (LDL) cholesterol values corresponding to DAIDS grade 2 or greater,
participants will not to be excluded as long as the value is not higher than
ULN of the local lab.
3. Clinically significant abnormalities during physical examination, vital
signs, or 12-lead electrocardiogram (ECG) at screening or at admission to the
study center as deemed appropriate by the investigator.
4. With any history of clinically significant skin disease such as, but not
limited to, dermatitis, eczema, drug rash, psoriasis, food allergy, or
urticaria.
5. Has taken any disallowed therapies as noted in Section 5.5 of the protocol
before the planned first intake of study drug.
Further criteria apply.
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 | EUCTR2020-003396-18-NL |
| CCMO | NL75670.056.20 |