The Pharmacokinetics of Dolutegravir, Darunavir/Cobocistat When Co-administered in Healthy Volunteers
Condition: HIV
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to look at the levels of three HIV medications: dolutegravir,
      darunavir and cobicistat in the blood after drug intake has been stopped, in order to
      understand how long these drugs persist in the blood. The study will specifically look at
      blood levels of these three drugs after taking them every day for 14 days.

      There will be two groups. Participants in Group 1 will take dolutegravir everyday for 14
      days, then nothing for 7 days, then dolutegravir and darunavir/cobicistat together for 14
      days, nothing for 7 days, and then darunavir/cobicistat alone for 14 days. If participants go
      into Group 2 they will begin with darunavir/cobicistat everyday for 14 days, then nothing for
      7 days, then dolutegravir and darunavir/cobicistat together for 14 days, nothing for 7 days,
      and then dolutegravir alone for 14 days. Drug levels for both groups will be measured on days
      14, 35 and 56. If the participants decide to take part, the duration of the study will be up
      to 57 days plus a screening visit which will take place up to 28 days prior to the start of
      the study, and a follow up visit, which takes place 15 to 22 days after the last dose of
      study medication. Eligible participants will be randomized (1:1 ratio) to group 1 or group 2.
      Participants and the study doctor will know which study medications the participant is taking
      at all times during the study.
    

Detailed description: 
      This is a randomised, cross-over, open label study, which means that the participants will be
      randomly assigned to the different arms of the study which receive different medications. The
      participants and the study doctor will know which study medications the participant is taking
      at all times during the study.This study will be conducted in a single site, in London.

      The total duration of the participant's involvement in the study will be up to 57 days plus a
      screening visit up to 28 days prior to the start of the study, and a follow up visit 27 to 33
      days after the last blood measurement.

      The participants will be asked to visit the clinic on up to 14 occasions, of which three
      visits involve staying in the unit for approximately 12 hours (day 14,35 and 56).

      Blood samples will be taken from the participants throughout the study to measure the levels
      of dolutegravir, darunavir and cobicistat in blood. Blood and urine will also be collected
      throughout the study for safety analysis; this is to ensure the participants are healthy to
      take part or to continue taking part in the study. The total amount of blood collected from
      each participant during the study will be approximately 500ml (just below a pint).

      Participants will be provided with written information about the study in the form of a
      participant information sheet and will be allowed adequate time for questions and to consider
      the study before agreeing to participate. It will be the responsibility of the investigator
      or the co-investigator to obtain written informed consent prior to undertaking any procedure
      detailed in the protocol. As part of the consent procedure, participants will also be asked
      consent to their personal details being entered into TOPS (the over-volunteering protection
      system).

      The investigator or designee will provide adequate explanation of the aims, methods,
      objectives and potential hazards of the study. They will also be explaining to the
      participants that they are free to refuse or withdraw from the study for any reason without
      detriment to their future care or treatment.

      A detailed description of each study visit follows below:

        1. Screening visit If the participant agrees to take part, they will firstly be asked to
           sign the informed consent form and they will be given a copy to keep.

           During the visit the following assessments will be carried out:

           • Demographic details

           • Full medical, drug and social history

           • Physical examination including weight, height, and vital signs (temperature, blood
           pressure, heart rate, and respiratory rate)

           • ECG

           • Chemistry panel

           • Haematology with a differential and clotting screen

           • HIV antibody testing

           • Hepatitis B and C screening

           • Urinalysis (macro analysis)

           • Drug screen (urine)

           • Pregnancy test (urine) for WOCBP (women of child-bearing potential)

           • Registration of TOPS database

           • Concomitant medications

           GP verification of medical history: A medical history questionnaire will be sent to all
           participants' GPs for verification of medical history. This information will be reviewed
           by the Investigator as part of the medical history evaluation. If the completed
           questionnaire is not received from the GP, then the available information regarding the
           participant will be reviewed by the Investigator. The Investigator will assess this
           information and decide whether they are sufficiently confident that the inclusion and
           exclusion criteria are met and whether the participant may be enrolled into the study.
           This decision must be documented in writing BEFORE the participant is dosed. Copies of
           sent GP letters and returned confirmation of medical history will be filed in each
           participant's source documentation.

        2. Baseline Visit, Day 1

           Participants will attend the Unit in the morning and will be asked to fast for 8 hours
           overnight prior to attending. The following evaluations will be performed in the morning
           of Day 1, before study medication dosing:

           • Vital signs (temperature, blood pressure, heart rate, and respiratory rate)

           • Haematology with a differential and clotting screen

           • Chemistry panel

           • Urinalysis (macro analysis)

           • Pregnancy test for WOCBP (urine)

           • Drug screen (urine)

           • Concomitant medications

           • Review of adverse events (AEs) Blood samples will be collected for:

           - Laboratory tests for safety

           - Pharmacogenetics if they have agreed to this part of the study

           - Platelets function (to investigate how clotting works in people taking anti-HIV
           medication).

           Group1:

           A Tivicay® (dolutegravir) tablet will be administered with a standard breakfast, made up
           according to instructions along with 240 ml of water. This will set the nominal time of
           dosing. Subjects will be instructed to administer Tivicay® at home in the morning on all
           other days (14 days in total) (with the exception of days 7, and 14, when the drug will
           be administered in the PK Unit). Participants will be instructed to administer study
           drugs in the morning within 15 min of standard breakfast.Participants will be given a
           diet sheet giving examples of a standardised breakfast for them to have at home with the
           study drug. They will be also reminded to take their study drug to the unit on day 14 as
           they will take their last dose in the unit on that day.

           Group2:

           A Rezolsta® (darunavir plus cobicistat) tablet will be administered with a standard
           breakfast, made up according to instructions along with 240 ml of water. This will set
           the nominal time of dosing. Subjects will be instructed to administer Rezolsta® at home
           in the morning on all other days (14 days in total) (with the exception of days 7, and
           14, when the drug will be administered in the PK Unit). Subjects will be instructed to
           administer study drugs in the morning within 15 min of standard breakfast.Participants
           will be given a diet sheet giving examples of a standardised breakfast for them to have
           at home with the study drug. They will be also reminded to take their study drug to the
           unit on day 14 as they will take their last dose in the unit on that day.

        3. Wash out periods (Days 15 to 21 and Days 36 to 42):Group 1 and 2

      From days 15 to 21 and days 36 to 42, participants will be asked to stop taking their study
      medication for a total of 7 days each time. These are the washout periods. 7) Intensive
      Pharmacokinetic Visits (Days 14, 35 and 56) Participants will be admitted to the unit in the
      morning on days 14, 35 and 56 and will remain in the Unit for approximately 12 hours. They
      will be asked to fast for 8 hours overnight prior to attending.

      The following evaluations will be performed in the morning of Days 14, 35 and 56, before
      study medication dosing: Vital signs (temperature, blood pressure, heart rate, and
      respiratory rate) • Physical Examination (symptom directed)

      • Adherence questioning

        -  Review of AEs

        -  Concomitant medication check

        -  Haematology with a differential and clotting screen

        -  Chemistry panel

        -  Urinalysis (macro analysis)

        -  Drug screen (urine)

        -  Pregnancy test for WOCBP (urine)

        -  Pill count

        -  Blood samples will be collected for:Platelets function (to investigate how clotting
           works in people taking anti-HIV medication).

      Serial blood samples will be taken on 6 occasions over the day (pre-dose (within 10 minutes
      before dosing), then 2, 4, 6, 8, and 12 hrs later) to measure the levels of study drugs in
      their blood. A cannula will be placed in a vein in the participant's forearm to allow
      repeated blood samples to be taken without having to repeatedly use a needle.

      The exact time of intake of study medication will be recorded on the CRF. Participants should
      remain in a semi- recumbent position until four hours post dose.

      Patients will be able to leave the unit after the 12 hour sample to return the following
      morning.

      • Tail Pharmacokinetic Visits (Day 15, 36 and 57)

      Participants will be required to attend the unit for plasma drug concentration sampling. This
      will occur at 24 hours post dose.

      Participants will attend on days 5, 36 and 57.

      • Follow up visit (day 84 to 90)

      Participants will return to the unit on one occasion between days 80 to 90 inclusive and
      undergo the following evaluations:

        -  Vital signs (temperature, blood pressure, heart rate, and respiratory rate)

        -  Haematology with a differential and clotting screen

        -  Chemistry panel.

        -  Concomitant medications

        -  Review of AEs

           10) Early termination visit In case of early termination, participants will attend the
           unit for an early termination visit within one week (or otherwise as the investigator
           believes appropriate).

      During this visit the following evaluations will be performed:

        -  Vital signs (temperature, blood pressure, heart rate, and respiratory rate)

        -  Haematology with a differential and clotting screen

        -  Chemistry panel

        -  Concomitant medications and adverse event check The reason for the early termination of
           the participant will be clearly documented on the participant's CRF. The participant
           will not then be required to attend for a follow up visit unless deemed necessary in the
           opinion of the investigator (e.g. due to adverse event follow up).
    

Intervention name(s): Tivicay; Rezolsta
Intervention type(s): Drug; Drug
Intervention description(s): 50 mg once daily; darunavir 800 mg/cobicistat 150 mg once daily
Other intervention name(s): Dolutegravir; darunavir/cobicistat
Intervention MeSH terms: Dolutegravir; Darunavir; Cobicistat; Cobicistat mixture with darunavir
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment