A Clinical Study Investigating Rifampicin and Dolutegravir in Combination in Healthy Volunteers (RADIO)

Phase One, Open Lab Study to Investigate the Impact of Rifampicin Administration on the PK of Dolutegravir When Dosed Once Daily at 50 or 100 mg in Healthy Volunteers

The purpose of the study is to see how the drug Dolutegravir is broken down by your body, when taken with another drug called Rifampicin. Dolutegravir is given to people as a treatment for HIV. Rifampicin is given to people as a treatment for tuberculosis.

Study Overview

• Status: Unknown
• Conditions: Tuberculosis; HIV-1-infection
• Intervention / Treatment: Drug: Dolutegravir; Drug: Rifampicin

Detailed Description

The integrase inhibitor under investigation in this study, Dolutegravir (DTG), is relatively new to the market only having been approved in 2014. DTG is now being used on a large scale to treat HIV-1 positive patients, therefore robust drug-drug interaction data is required for medications that are prescribed with DTG.

Tuberculosis is biggest killer of patients that are co-infected with the HIV-1 virus, killing over 25% of the population. There is an unmet need for data concerning DTG once daily dosing in the presence of rifampicin (RIF), the widely used anti-tuberculosis antibiotic. This is the main purpose of this investigative study.

The design of the study is an open label, single site pharmacokinetic (PK) study to measure the blood plasma concentration of DTG in the presence of RIF.

The study will recruit 18-63 years old healthy volunteers, either male or non-pregnant females. Subjects will be recruited at the single study site. A site in the United Kingdom will be selected based on its past experience in the HIV field, and its ability to recruit 16 subjects from their healthy volunteer database.

The study period is expected to be 43 days, excluding screening and follow-up. The most significant procedures in terms of study data will be pharmacokinetic (PK) sampling days 7, 14, 35 and 42. On these days PK sampling will occur over a 24 hour period, mapping out the blood concentrations of DTG in the presence of RIF.

There will also be a pharmacogenomic sub-study included in the study design. Researchers have included this because the HIV investigator community agrees that a pharmacogenomic approach to HIV treatment is important to understand why patients show different degrees of virological responses or drug toxicity.

This research is funded by Wits Health Consortium, and sponsored by St Stephens Clinical Research.

• Study Type: Interventional
• Enrollment (Anticipated): 16
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Project manager; Phone Number: 0203 828 0593; Email: radio@ststcr.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements
2. Male or non-pregnant, non-lactating females.
3. Between 18 to 60 years, inclusive
4. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive (with weight ≥50kg).
5. Alanine aminotransferase, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A single repeat is allowed for eligibility determination.

6. Women of childbearing potential (WOCBP - definition in Appendix 4) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 3 months after the study.

   A female may be eligible to enter and participate in the study if she:

   1. is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
   2. is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
   3. True abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 4 weeks after discontinuation of all study medications. (When this is in line with the preferred and usual lifestyle of the subject.) (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), and withdrawal are not acceptable methods of contraception].
   4. Any non-hormonal intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see protocol appendix 4 for an example listing of approved IUDs);
   5. Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject; Any contraception method must be used consistently, in accordance with the approved product label and for at least 4 weeks after discontinuation of IP.

7. Men who have partners who are women of childbearing potential (WOCBP - definition in Appendix 4 must be using an adequate method of contraception to avoid pregnancy in their partner throughout the study and for a period of at least 4 weeks after the study (see inclusion criteria 6);

   • True abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 4 weeks after discontinuation of all study medications (When this is in line with the preferred and usual lifestyle of the subject.) (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), and withdrawal are not acceptable methods of contraception].
   • Any non-hormonal intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see Appendix 4 for an example listing of approved IUDs);
   • Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject; Any contraception method must be used consistently, in accordance with the approved product label and for at least four weeks after discontinuation of IMP.
8. Willing to consent to their personal details being entered onto the TOPS database
9. Willing to provide proof of identity by photographic ID at screen and any subsequent visit
10. Registered with a GP in the UK

Exclusion Criteria:

1. Any clinically significant acute or chronic medical illness
2. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations
3. Positive blood screen for hepatitis B surface antigen or C antibody
4. Positive blood screen for HIV-1 or 2 by antibody/antigen assay
5. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
6. Current or recent (within three months) gastrointestinal disease.
7. Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study
8. Exposure to any investigational drug (or placebo) or participation in a clinical study involving the donation of blood samples within three months of first dose of study drug
9. Use of any other drugs (unless approved by the Investigator), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs.
10. Females of childbearing potential without the use of effective birth control methods, or not willing to continue practising these birth control methods for at least 4 weeks after the end of the treatment period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single arm; Single arm trial design based on the dosing regimen below: Day 1 - 7 - Dolutegravir 50 mg once daily with food Day 8 - 14 - Dolutegravir 100 mg once daily with food Day 15 - 28 - Rifampicin 600 mg once daily Day 29 - 35 - Rifampicin 600 mg once daily & Dolutegravir 50 mg once daily Day 36 - 42 - Rifampicin 600 mg once daily & Dolutegravir 100 mg once daily	Drug: Dolutegravir; Antiviral (integrase inhibitor); Other Names: Tivicay; Drug: Rifampicin; Antibiotic; Other Names: Rifidan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the pharmacokinetics of DTG 50 or 100 mg OD in the presence of RIF 600 mg OD in healthy volunteers as measured by trough concentration (Ctrough)	Ctrough is defined as the concentration at 24 hours after the observed drug dose.	43 days
To investigate the pharmacokinetics of DTG 50 or 100 mg OD in the presence of RIF 600 mg OD in healthy volunteers as measured by maximum observed plasma concentration (Cmax)	Maximum observed plasma concentration (Cmax).	43 days
To investigate the pharmacokinetics of DTG 50 or 100 mg OD in the presence of RIF 600 mg OD in healthy volunteers as measured by elimination half-life (t1/2)	Elimination half-life (t1/2)	43 days
To investigate the pharmacokinetics of DTG 50 or 100 mg OD in the presence of RIF 600 mg OD in healthy volunteers as measured by time point at Cmax (Tmax)	Time point at Cmax (Tmax)	43 days
To investigate the pharmacokinetics of DTG 50 or 100 mg OD in the presence of RIF 600 mg OD in healthy volunteers as measured by total drug exposure.	Total drug exposure, expressed as the area under the plasma concentration-time curve from 0-24 hours after dosing (AUC0-24h).	43 days

Collaborators and Investigators

• Sponsor: St. Stephens Clinical Research

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2017
• Primary Completion (Anticipated): March 1, 2018
• Study Completion (Anticipated): March 1, 2018

Study Registration Dates

• First Submitted: June 20, 2017
• First Submitted That Met QC Criteria: June 23, 2017
• First Posted (Actual): June 27, 2017

Study Record Updates

• Last Update Posted (Actual): October 23, 2017
• Last Update Submitted That Met QC Criteria: October 20, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin; Dolutegravir
• Other Study ID Numbers: SSCR103

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No