Pharmacokinetics of Antituberculosis Drugs in Breastfeeding Women (PRiMe)

McGill University

Status and phase: Begins enrollment in 1 month; Phase 1

Conditions: Breastfeeding; Healthy Volunteer; Tuberculosis Infection

Treatments: Drug: Standard dose levofloxacin; Drug: Standard dose rifapentine; Drug: Standard dose bedaquiline; Drug: High dose rifampicin; Drug: Standard dose isoniazid; Drug: Standard dose rifampicin

Study type: Interventional

Funder types: Other

Identifiers

NCT07069582

PRIME_V.2.0

Details and patient eligibility

About

This study is a sub-study of the SSTARLET trial (NCT06498414). The overall aim is to assess the pharmacokinetic profiles after taking a single dose of rifampicin, isoniazid, levofloxacin, rifapentine, and bedaquiline in breastfeeding women and the excretion of these drugs in breast milk, with the hope of including breastfeeding women in future clinical trials of TPT, including expanding the inclusion criteria of the SSTARLET trial. In this study, healthy breastfeeding women who fulfill the eligibility criteria will be enrolled from several primary health care centers in Bandung, which will be referred to the TB Research Clinic of the Universitas Padjadjaran, Bandung, Indonesia. Ten participants will be randomized to each of the following six study arms:

• Arm A: Single-dose rifampicin at 10 mg/kg body weight (RIF10).
• Arm B: Single-dose rifampicin at 20 mg/kg body weight (RIF20).
• Arm C: Single-dose isoniazid at 5 mg/kg body weight (INH5).
• Arm D: Single-dose levofloxacin at 10-15 mg/kg body weight (LFX10-15).
• Arm E: Single-dose rifapentine at 10 mg/kg body weight (RPT10).
• Arm F: Single-dose bedaquiline at 400 mg (BDQ400).

Full description

Pregnant and breastfeeding women have been largely excluded from recent and ongoing clinical trials due to ethical concerns, limiting their access to the latest advancements in tuberculosis (TB) therapy. To support the development of short, effective tuberculosis preventive treatment (TPT) regimens lasting 1-2 months, a phase 2 adaptive clinical trial (SSTARLET trial) is being planned. This trial will evaluate three experimental regimens: two months of daily double-dose rifampicin; one month of daily levofloxacin and rifapentine; and either one month of daily isoniazid and rifapentine or a bedaquiline-containing regimen. The comparator will be the current standard of four months of daily rifampicin. The safest and shortest regimen will be selected for progression to a phase 3 trial. Inclusion of breastfeeding women in future trials of these regimens is intended; however, limited pharmacokinetic (PK) and safety data exist regarding the excretion of these drugs into breast milk, which is necessary to support their use in this population.

The current study aims to establish the PK profiles of rifampicin, isoniazid, levofloxacin, rifapentine, and bedaquiline in breastfeeding women and the excretion of these drugs in breast milk, with the hope of including breastfeeding women in future clinical trials of TPT. The specific objective of the study is to describe the PK profiles after a single dose of rifampicin, isoniazid, levofloxacin, rifapentine, and bedaquiline in plasma and breast milk of breastfeeding women.

In this study, healthy breastfeeding women who fulfill the eligibility criteria will be enrolled from several primary health care centers in Bandung, which will be referred to the TB Research Clinic of the Universitas Padjadjaran, Bandung, Indonesia.

The primary outcomes in this study are the total drug exposure, i.e., the area under the concentration-time curve from 0 to 24 hours after drug administration (AUC0-24) and peak concentration (Cmax) of single doses of rifampicin, isoniazid, levofloxacin, rifapentine, and bedaquiline in plasma and breastmilk of breastfeeding women, including the breast milk/plasma ratios for AUC0-24 and Cmax to estimate the external exposure of the drugs to breastfed infants. The secondary outcomes are PK measures of rifampicin, isoniazid, levofloxacin, rifapentine, and bedaquiline other than AUC0-24 and Cmax, including time to Cmax (Tmax), elimination rate constant (Ke), elimination half-life (t1/2), apparent clearance (CL/F), and apparent volume of distribution (Vd/F) in plasma and breast milk of breastfeeding women.

The study design is an open-label, randomized, six-arm, single-dose, intensive PK study, that will be performed at the TB Research Clinic of the Universitas Padjadjaran, Bandung, Indonesia. Six oral drug dosages will be evaluated: rifampicin 10 mg/kg (RIF10), rifampicin 20 mg/kg (RIF20), levofloxacin 10-15 mg/kg (LFX10-15), rifapentine 10 mg/kg (RPT10), isoniazid 5 mg/kg (INH5), and bedaquiline 400 mg (BDQ400). Simple randomization will be performed, with a ratio of 1:1:1:1:1:1 for RIF10, RIF20, LFX10-15, RPT10, INH5, and BDQ400. Venous blood and breastmilk samples will be collected for PK assessments of each of the study drugs. Ten participants will be assigned to each arm, with a total participants of 60.

Enrollment: 60 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

Participants may enter the study if all of the following apply:

1. Healthy breastfeeding women aged 18 years or older, with a minimum of 3 months and a maximum of 24 months after delivery of a healthy baby, and are not currently diagnosed with either TB infection or TB disease.
2. Have a body weight between 25 and 100 kg.
3. Provide written informed consent.

Exclusion criteria

Participants may not enter the study if any of the following criteria apply:

1. Grade 3-4 abnormalities on baseline blood chemistry tests, including serum alanine aminotransferase (ALT), creatinine, or blood glucose.
2. Grade 3-4 abnormalities on baseline hematological tests, including white blood count, platelets, or hemoglobin.
3. Contraindications or history of hypersensitivity/intolerance to rifampicin, isoniazid, levofloxacin, rifapentine, or bedaquiline.
4. Taking concomitant medications for TB disease, TB infection, diabetes mellitus, hypertension, HIV, cardiac disease or any other chronic diseases.
5. Having a breastfed infant who was diagnosed with TB infection or TB disease and is currently on treatment.
6. Pregnancy
7. Have an active, acute illness at the time of study enrolment.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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60 participants in 6 patient groups

10 mg/kg rifampicin (RIF10)

Experimental group

Description:

Single-dose rifampicin at 10 mg/kg body weight

Treatment:

Drug: Standard dose rifampicin

20 mg/kg rifampicin (RIF20)

Experimental group

Description:

Single-dose rifampicin at 20 mg/kg body weight

Treatment:

Drug: High dose rifampicin

5 mg/kg isoniazid (INH5)

Experimental group

Description:

Single-dose isoniazid at 5 mg/kg body weight

Treatment:

Drug: Standard dose isoniazid

10-15 mg/kg levofloxacin (LFX10-15)

Experimental group

Description:

Single-dose levofloxacin at 10-15 mg/kg body weight

Treatment:

Drug: Standard dose levofloxacin

10 mg/kg rifapentine (RPT10)

Experimental group

Description:

Single-dose rifapentine at 10 mg/kg body weight

Treatment:

Drug: Standard dose rifapentine

400 mg bedaquiline (BDQ400)

Experimental group

Description:

Single-dose bedaquiline at 400 mg

Treatment:

Drug: Standard dose bedaquiline