studies

The purpose of this research study is see if taking medications to prevent tuberculosis (TB) affect the drug levels in blood of a commonly used HIV medication called dolutegravir (DTG) and if an extra dose of DTG is needed during this TB preventive treatment. The other medicines, rifapentine (RPT) and isoniazid (INH), are drugs used to prevent active TB in people who have been exposed to TB. This study will also help us make sure that people tolerate the medicines and that they are safe when given together. In many countries, DTG is the recommended first-line treatment for HIV. DTG, RPT, and INH are proven beneficial treatments for people living with HIV and latent TB, but it is unclear whether these treatments work differently when taken together. Understanding how DTG interacts with the short-term treatment for latent TB (1HP) is very important for delivering both treatments effectively.

Purpose of the Study:  To see if taking a medicine to treat TB called RPT, affects the levels of DTG (an HIV medicine) in the blood or not.

Requirements to Enter Study:  This study is for people living with HIV between the ages of 18-65 and who either tested positive for the bacteria that causes tuberculosis (TB) or live in a country where TB infection occurs frequently. Participants must be taking dolutegravir as part of a three drug regimen to treat HIV and must have a viral load < 50 copies/ml.  In addition to these criteria, blood samples will be drawn for lab tests to check general health.  Participants will also need to weigh at least 40 kilograms and have either a chest x-ray or CT scan of their lungs to check for active TB disease.

Treatment:  Participants will continue ART medications that include DTG and 2 nucleoside reverse transcriptase inhibitors for the entire study period.

TB medication to prevent active TB disease will begin at entry into the study and include the RPT and a second medication used to treat TB called isoniazid (INH) along with daily vitamin B6, to decrease the risk of side effects from INH.

The study will have two (2) groups. Group 2 will only open after the results from Group 1 are reviewed.

Below are the medicines that you will take during the study depending on which Group you are in:

Group 1

• DTG 50 mg orally twice daily – about 12 hours apart
  • 1^st dose will be taken in the morning; this will not be supplied by the study
  • 2^nd dose will be taken in the evening; this will be supplied by the study for 4 weeks
• 1HP: INH 300 mg + RPT 600 mg orally once daily (in the morning) for 4 weeks (supplied by the study)

Group 2 (upon opening)

• DTG 50 mg orally once daily (in the morning) (not supplied by the study)
• 1HP: INH 300 mg + RPT 600 mg orally once daily (in the morning) for 4 weeks (supplied by the study)

You will continue taking your existing ART drugs while on the study – your ART must include 2 NRTIs (excluding TAF) during the study. Your ART will not be provided by the study.

You will also receive pyridoxine (vitamin B6) 25 or 50 mg with each dose of INH based on the current local, national, or international dosing guidelines.

Because the blood draws on study visits will be dependent on the time you take the drugs, you will need to take your HIV drugs and drugs provided by the study (except second dose of DTG if you are in Arm 1) in the morning during the duration of the study. If you generally take your HIV drugs in the evening, you will need to switch to taking them in the morning for this study, including at least 3 days before the Day 0 visit. On the study visit days, you will hold on taking the drugs until you arrive at the clinic.

Duration of Study:  Most people will be on this study for six weeks (4 weeks on study treatment and two weeks of follow-up). You may be on study up to 11 weeks if you have to have additional follow-up visits to check your viral load. There are 7 or 8 scheduled visits during this time.

This study is for participants who have pulmonary tuberculosis (TB), a bacterial infection in their lungs. Isoniazid (INH) is a drug commonly used to treat TB. Sometimes, the bacteria that cause TB can become resistant to INH, and then INH does not work as well at fighting the bacteria. This study will treat people with INH-resistant TB with different doses of INH to see if INH can still fight the bacteria if we just increase the dose.

Purpose

We will compare how well the drug works at higher doses for participants who have resistant TB to how well the drug works at regular doses for participants who have TB that is sensitive to the drug. The study will also compare the safety and tolerability of the different doses of INH.

Study Stages

If you join this study, you will need to be admitted to the hospital for at least 9 days. If you have not stopped taking INH you may need to be admitted for longer (up to 16 days in total) so that there is time for the INH to wash out of your body. While you are in the hospital, you will be asked to collect the sputum that you cough up in a container. Seeing how many bacteria are in the sputum you cough up will help us to know how well the medicine is working. After you are discharged from the hospital, you will come to the clinic 14 days later for a final visit.

If you meet the eligibility requirements for the study, you will have a test to see if you have INH-resistant TB, and if it is low-level or high-level resistance. (With low-level resistance, the bacteria are not as resistant to INH as they are with high-level resistance.) You may also be asked to provide sputum for other types of resistance tests.

Depending on the test result, you will be assigned to one of 3 groups:

• If you have low-level INH resistance, you will either be referred to receive standard TB treatment outside of the study or be randomized (like a flip of a coin) to receive 5, 10 or 15 mg/kg INH once a day for 7 days. Randomized means that you have equal chance of being in any of these 3 groups. (Mg/kg, or milligrams per kilogram, means the amount of INH in milligrams you will receive for each kilogram you weigh.)
• If your test shows no INH resistance, you will either be referred to receive standard TB treatment outside the study or you will receive 5 mg/kg INH once a day for 7 days.
• If you have high-level resistance, you will either be referred to received standard TB treatment outside the study or you will be randomized to receive 15 or 20 mg/kg INH once a day for 7 days.

INH will be provided for you. In addition, you must also take vitamin B₆ once a day while taking INH, to help prevent possible side effects of INH. Vitamin B₆ will also be provided to you. When you are finished taking study drug, you will be referred for full TB treatment outside the study.

Inclusion Criteria:

• New or current pulmonary TB
• Adults between the ages of 18 and 65

Exclusion Criteria

• Known exposure to extensively resistant TB (XDR-TB)

Duration of Study: About 23 days

Total number of participants: Between 128 and 218

This is a randomized study, which means, by chance, you will be in one of three groups. You have an equal chance of being assigned to a group like flipping a coin. A5343 is an open label clinical trial, which means you will know which group you are in and what medications you will be taking.

This study will compare three treatment arms for people who have pulmonary multidrug resistant tuberculosis (MDR-TB). Pulmonary MDR-TB is a form of tuberculosis (TB) in the lung that is resistant to two or more of the primary drugs used for the treatment of TB (isoniazid and rifampin).

You will receive standard treatment for MDR-TB plus one or two new drugs for TB, called bedaquiline (BDQ) and delamanid (DLM). Throughout the study, you will be monitored to make sure that there are no safety concerns. Your heart will be monitored closely to make sure it is safe to give the drugs together.

Purposes of the Study:

This study looks at how the two new drugs fight MDR-TB when used alone with other TB drugs or used together. It looks at how the TB drugs work inside the body when you take them. It also looks at how safe and well tolerated these two drugs are in people.. Multiple times throughout the study, blood samples and an ECG, a test that measures the electrical activity in your heart, will be done to monitor the safety of the drugs.

Requirements to Enter Study:

Inclusion Criteria: To be in the study, you must:

• Be age 18 or older
• Have MDR-TB in your lungs and be on treatment less than 8 weeks
• Not be pregnant or breastfeeding
• Use an approved form of birth control for both men and women
• For persons with HIV : CD4 count above 100 cells/mm³ (CD4 cells are a kind of white blood cell that are a measure of the immune system)
• Taking treatment for MDR-TB before joining the study
• Willing to stay in hospital for at least 2 months
• Able to take pills by mouth
• Consent in writing to be in the study

Exclusion Criteria: You cannot be in the study if you:

• Have MDR-TB that does not involve the lungs
• Have received BDQ or DLM in the past
• Have any allergies to the study drugs
• Are actively drinking alcohol or using drugs
• Have heart problems or other serious illness
• Require or may require the use of certain drugs to treat HIV at the same time you are taking study drugs
• Require or may require the use of certain drugs, including, but not limited to, clofazimine and moxifloxacin, from 48 hours prior to study entry through 4 weeks after stopping study drugs

Study Treatment:

The treatment arms are:

• Arm 1: BDQ (comes as a tablet to take by mouth)
• Arm 2: DLM (comes as a tablet to take by mouth)
• Arm 3: Both BDQ and DLM (as above)

The duration and doses will be explained by the study nurse or study doctor.

Length of Study:

24 weeks on study treatment, followed by 104 weeks follow-up, for a total length of 128 weeks

Number of Participants:

Up to 84 people will enroll in this study