Primary objectives:To assess the bioequivalence of a single-dose TRI as a whole tablet (reference) compared to a crushed and suspended tablet (intervention I).To assess the bioequivalence of a single-dose TRI as a whole tablet (reference) compared…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary aim of this study is to assess the bioequivalence of dolutegravir,
abacavir and lamivudine administered as a whole tablet (reference) compared to
a crushed and suspended tablet in a fasted state (intervention I) or after a
standardized amount of drip feed (intervention II).
Geometric Mean Ratios and the 90% confidence interval of the pharmacokinetic
parameters AUC0-*, Cmax, and T* of intervention I compared to the reference
treatment.
Geometric Mean Ratios and the 90% confidence interval of the pharmacokinetic
parameters AUC0-*, Cmax, and T* of intervention II compared to the reference
treatment.
Secondary outcome
The secondary aim of this study is to assess the bioequivalence of
dolutegravir, abacavir and lamivudine after dosing as a crushed and suspended
tablet in a fasted state (intervention I) compared to a crushed and suspended
tablet after a standardized amount of drip feed (intervention II).
Geometric Mean Ratios and the 90% confidence interval of the pharmacokinetic
parameters AUC0-*, Cmax, and T* of intervention I compared to intervention II.
Adverse events after administration of a single-dose TRI in the different
treatment arms will be described and compared (including clinically relevant
laboratory abnormalities).
Background summary
Dolutegravir is an HIV-1 integrase inhibitor which is marketed as a single
tablet (Tivicay®) and in a fixed dose combination tablet with abacavir and
lamivudine (Triumeq®, referred to as TRI). For patients with swallowing
difficulties, administration of whole tablets can be problematic and tablets
are cut or crushed to ease administration. In addition, if HIV patients develop
opportunistic infections, patients can become severely ill and may end up on
the intensive care. Patients at the intensive care might not be able to swallow
medication. Therefore it is useful to know if it is possible to administer TRI
through a different route, like a feeding tube. If TRI can be crushed or
dissolved and given through a catheter it is also useful to know if it can be
given with drip feed.
Currently there is no information about crushing TRI tablets. Depending on the
biopharmaceutical characteristics of a drug formulation, crushing tablets can
lead to altered pharmacokinetics of drugs. This has been shown for some of the
antiretroviral drugs, such as ritonavir, lopinavir, efavirenz and tenofovir.
It is important to know whether pharmacokinetics are influenced by crushing of
tablets as low concentrations are associated with virologic failure. Therefore
higher doses or switching to other HIV-drugs might be needed. In addition,
higher Cmax and/or exposure can lead to toxicity. As a result therapeutic drug
monitoring is advised, or crushing the drug is a contra-indication based on the
available data.
It has been shown that simultaneous oral ingestion of antacids and
dolutegravir gives a decrease in Cmax and AUC of dolutegravir. This interaction
is not shown for co-ingestion with omeprazole, which makes it unlikely that
this interaction is caused by a pH-lowering effect influencing the absorption
of dolutegravir. It is probably a local gastrointestinal complexation
phenomenon, similar to what has been observed with other HIV integrase
inhibitors. A possible pharmacokinetic interaction between dolutegravir and
complexation formers may be expected. Especially considering the active binding
sites of dolutegravir which bind magnesium metal ion cofactors. It is currently
unclear if certain foods or liquids containing high amounts of magnesium or
other cations can cause this same interaction.
Therefore this study will be conducted to investigate whether crushed and
suspended TRI and crushed and suspended TRI with drip feed are bioequivalent to
taking TRI as a whole.
Study objective
Primary objectives:
To assess the bioequivalence of a single-dose TRI as a whole tablet (reference)
compared to a crushed and suspended tablet (intervention I).
To assess the bioequivalence of a single-dose TRI as a whole tablet (reference)
compared to a standardized amount of drip feed followed by a crushed and
suspended tablet (intervention II).
• To assess bioequivalence of the different ways of administration, the
pharmacokinetics (AUC0-*, Cmax, Tmax, T*) of dolutegravir, abacavir, and
lamivudine will be obtained and the geometric mean ratios of the AUC0-* and
Cmax of the test versus reference treatment.
Secondary objective:
To assess the bioequivalence of a single-dose TRI as a crushed and suspended
tablet (intervention I) compared to a standardized amount of drip feed followed
by a crushed and suspended tablet (intervention II).
• To assess bioequivalence of the different ways of administration, the
pharmacokinetics (AUC0-*, Cmax, Tmax, T*) of dolutegravir, abacavir, and
lamivudine will be obtained and the geometric mean ratios of the AUC0-* and
Cmax of intervention I versus intervention II.
Tertiary objective:
To evaluate the safety and tolerability of co-administration of dolutegravir,
abacavir and lamivudine in healthy adult subjects after administration of whole
tablets and crushed and suspended tablets.
Study design
Open-label, 3 period, randomized, cross-over, single-center, phase I,
single-dose study in 24 healthy adult subjects.
The 24 subjects will be divided into one of the following treatment sequences:
ABC; ACB; BCA; BAC; CAB; CBA .
Treatment period:
• A: Single-dose TRI as a whole tablet in a fasted state
• B: Single-dose crushed and suspended TRI in a fasted state
• C: 250 ml drip feed (Nutrison) followed by a single-dose crushed and
suspended TRI
Between the different treatment periods a wash-out period of 7 days is
scheduled.
On the day of administration, day 1, 8 and 15, a pharmacokinetic curve is
recorded.
Intervention
See study design.
3 different ways of administration of Triumeq:
- whole tablet
- crushed and suspended tablet
- standard amount of drip feed followed by a crushed and suspended tablet
Study burden and risks
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, and 3 full days. The duration of the entire trial (excluding
screening period) is 17 days. Duration of treatment with study medication is 3
days.
Triumeq has a good benefit/risk ratio. The most common adverse events are
generally transient, self-limiting and mild-to moderate in severity. The most
frequently reported adverse reactions in clinical trials of chronic use of
Triumeq were nausea, insomnia, dizziness and headache.
For pharmacokinetic purposes 45 blood samples will be taken in total. For
safety assessment (haematology and clinical chemistry), hCG blood tests and
blood glucose, serology and pharmacogenetic testing, a total of 16 blood
samples will be collected. The total blood volume taken will be approximately
330 ml. During the days that blood samples will be collected for a PK-curve, an
intravenous cannula will be inserted to facilitate blood sampling and limit the
amount of venous punctures.
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 (see Appendix A). 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. Positive HLA-B*5701 status;
4. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients;
5. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion;
6. Inability to understand the nature and extent of the study and the procedures required;
7. 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;
8. Therapy with any drug (including herbal remedies, multivitamins, magnesium- and calcium-containing supplements, etc.) (for two weeks preceding day 1), except for acetaminophen;
9. 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;
10. History of or current abuse of drugs, alcohol or solvents;
11. Participation in a drug study within 60 days prior to day 1;
12. Donation of blood within 60 days prior to day 1;
13. Febrile illness within 3 days before day 1;
14. 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 | EUCTR2015-002280-42-NL |
| CCMO | NL54232.091.15 |