Clinical trial NCT04176250: Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis
Official title: A Phase 2a, Dose Escalation, Controlled, Randomized Study to Evaluate Safety, Early Bactericidal Activity (EBA) and Pharmacokinetics of TBA-7371 in Adult Patients With Rifampicin-sensitive Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Keywords: Rifampicin-sensitive pulmonary tuberculosis
TBA-7371
Pulmonary tuberculosis
Lead sponsor: Bill & Melinda Gates Medical Research Institute
Sponsor class: OTHER
First posted: 2019-11-25
Enrollment: 93
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the safety, early bactericidal activity (EBA) and pharmacokinetics of TBA-7371 in adult participants with rifampicin-sensitive tuberculosis and select dose regimen(s) for future studies.


Eligibility criteria: Inclusion Criteria:

* Participants between 18 to 60 years of age inclusive at the time of signing the informed consent.
* Body weight within 40 and 100 kilogram (inclusive).
* Untreated, rifampicin-sensitive pulmonary tuberculosis, as defined by all of the following:

  1. isoniazid urine screen negativity
  2. sputum smear positivity on direct microscopy for acid-fast bacilli, defined as at least 1+ on the International Unit Against Tuberculosis and Lung Disease/ World Health Organization scale
  3. chest X-rays which in the opinion of the investigator is consistent with tuberculosis (TB).
  4. Mycobacterium tuberculosis (Mtb) positivity on molecular test (GeneXpert®)
  5. rifampicin sensitivity on molecular test (GeneXpert®).
* Participants must be able to produce at least 10 milliliter of sputum during the overnight sputum collection (day -7 to -3 or day -2 of the Screening Phase).
* Female and male participants should be of non-childbearing potential or using an effective method of birth control.

  * Non-childbearing potential is defined as follows:

    1. participant is not heterosexually active or practices sexual abstinence, OR
    2. female participant or sexual partner has undergone bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy, OR
    3. female participant or sexual partner has been postmenopausal with a history of no menses for at least 12 consecutive months, OR
    4. male participant or sexual partner has undergone vasectomy or bilateral orchidectomy at least three months prior to screening, OR
    5. male participant with pregnant sexual partner (for duration of the study) who does not have any other sexual partners.
  * An effective method of birth control is defined as follows:

    1. double barrier method, which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together), OR
    2. barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female participant or partner, AND
    3. participant willing to continue practicing one of the above-mentioned birth control methods throughout 14-day Study Treatment Phase and for 4 weeks after the last dose of study medication or discontinuation from study medication in case of early withdrawal.
* Participants must be capable of giving signed informed consent, which includes agreeing to compliance with the requirements and restrictions listed in the informed consent form and the protocol.

Exclusion Criteria:

* Need for immediate effective anti-TB treatment as judged by the investigator.
* Evidence and/or history of extra-thoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis, ocular TB), as judged by the investigator.
* Evidence and/or history in the last 5 years of one or any combination of the following:

  1. uveitis;
  2. color vision deficiency;
  3. amblyopia;
  4. visual acuity worse than 20/25 after correction in either eye;
  5. any known eye disease or prior eye surgery;
  6. any systemic condition with ocular manifestations (i.e. Marfan, syphilis, diabetes, Beçhet, Vogt-Koyanagi-Harada, Lyme, or chronic inflammatory condition such as sarcoidosis, rheumatoid arthritis, psoriatic arthritis)
* Evidence and/or history in the last 5 years of clinically significant medical condition(s) as judged by the investigator, including malignancies and unstable or uncontrolled hypertension.
* Any current medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the participant will comply with the protocol.
* For Human Immunodeficiency Virus infected participants:

  1. CD4+ count \<350 cells/microliter, OR
  2. Acquired Immune Deficiency Syndrome-defining opportunistic infection or malignancies (except pulmonary TB).
* Seated systolic/diastolic blood pressure assessed as vital sign \[i.e. not from electrocardiogram (ECG)\] is less than 95/40 millimeters of Mercury (mmHg) or greater than 145/95 mmHg at screening. Out-of-range blood pressure may be repeated twice with at least 5 minutes intervening.
* Seated heart rate assessed as vital sign (i.e. not from ECG) is lower than 40 beats per minute (bpm) or higher than 110 bpm at screening. Out-of-range heart rate may be repeated twice with at least 5 minutes intervening.
* A clinically significant ECG abnormality at screening. NOTE: The following can be considered not clinically significant:

  1. mild first-degree atrio-ventricular block (P-R interval \<0.23 seconds);
  2. right or left axis deviation;
  3. incomplete right bundle branch block;
  4. isolated left anterior fascicular block (left anterior hemiblock) in young athletic participants.
* A list of commonly used prohibited medications with the features described below are prohibited:

  * Use of medications active against Mtb within 3 months prior to the first dose of study drug.
  * Use of systemic immunosuppressive medications within 14 days prior to the first dose of study drug.
  * Use of strong inhibitors or strong inducers of cytochrome P450 (CYP) enzymes within 14 days prior to the first dose of study drug.
  * Use of inhibitors of phosphodiesterase (PDE) enzymes within 14 days prior to the first dose of study drug.
  * Use of medications known to affect the eye within 3 months prior to the first dose of study drug.
  * For Human Immunodeficiency Virus positive participants, use of medications listed in the protocol within 3 months prior to the first dose of study drug.
* Participation in other clinical study(-ies) with investigational agent(s) within 6 months prior to trial start.
* The following laboratory values from blood collected during the Screening Phase, which represent Grade 2 or higher abnormalities per Division of Acquired Immune Deficiency Syndrome (DAIDS) Toxicity Table Version 2.1, will be cause for exclusion:

  * Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≥ 2.5x upper limit of normal (ULN) for local laboratory values
  * Total bilirubin ≥ 1.6x ULN
  * Creatinine ≥ 1.3x ULN
  * Hemoglobin \< 10 grams per deciliter (g/dL) \[male\] or 9.5 g/dL \[female\]
  * White Blood Cells \< 2,000 /cubic millimeter (mm3)
  * Platelets ≤ 100,000 /mm3
  * International normalized ratio of prothrombin time (INR) ≥ 1.5x ULN
  * Partial thromboplastin time (PTT) ≥ 1.66 ULN
  * Prothrombin time (PT) ≥ 1.25x ULN
* Grade 2 or higher abnormalities in other laboratory parameters from blood or urine Grade 1 abnormalities, or abnormalities from laboratory parameters not included in the DAIDS Toxicity Table Version 2.1, may lead to exclusion if the investigator considers them clinically significant.
* History of allergy or hypersensitivity to any of the study drugs or related substances.
* Positive urine drug screening for cocaine AND/OR amphetamines AND/OR opiates AND/OR methamphetamines. Note: screening will also be conducted for cannabinoids and results documented in the case report form; however, a positive test for cannabinoids is not an exclusion criterion.
* Female participants currently pregnant or lactating/nursing; OR having positive serum pregnancy test during the Screening Phase OR planning a pregnancy within the 1 month after first dose of study drug.

Primary outcomes:
measure: Average Change Per Day (Slope) of Log Colony Forming Units (CFU) Counts From Day 0 to Day 14 (BACFU [0-14]) to Assess Bactericidal Activity
timeFrame: Day 0 to Day 14
measure: Number of Participants Reporting ≥Grade 3 Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 15
Secondary outcomes:
measure: Average Change Per Day (Slope) of Log CFU Counts From Day 0 to Day 2 (BACFU [0-2]) and From Day 2 to Day 14 (BACFU [2-14]) to Assess Bactericidal Activity
timeFrame: Day 0 to Day 2 and Day 2 to Day 14
measure: Average Change Per Day(Slope)of Time to Sputum Culture Positivity(TTP) in Mycobacteria Growth Indicator Tube (MGIT) System From Day0 to Day14 (BATTP[0-14]),From Day0 to Day2(BATTP[0-2]), and From Day2 to Day14(BATTP [2-14]) to Assess Bactericidal Activity
timeFrame: Day 0 to Day 14, Day 0 to Day 2 and Day 2 to Day 14
measure: Average Change Per Day (Slope) of the log10 Sputum Lipoarabinomannan (LAM) Measurements From Day 0 to Day 14 (BALAM [0-14]), From Day 0 to Day 2 (BALAM [0-2]) and From Day 2 to Day 14 (BALAM [2-14]) to Assess Bactericidal Activity
timeFrame: Day 0 to Day 14, Day 0 to Day 2 and Day 2 to Day 14
measure: Number of Participants Reporting Any Adverse Events (AEs)
timeFrame: Up to Day 15
measure: Number of Participants Reporting Grade >=3 AEs by Preferred Term
timeFrame: Up to Day 15
measure: Number of Participants Reporting AEs (Presented by Severity)
timeFrame: Up to Day 15
measure: Number of Participants Experiencing AEs Related to Study Intervention
timeFrame: Up to Day 15
measure: Number of Participants With Any New Eye Symptom in One or Both Eyes
timeFrame: Up to Day 15
measure: Average Duration of New Eye Symptom in One or Both Eyes
timeFrame: Up to Day 15
measure: Total Number of Days With New Eye Symptoms in One or Both Eyes
timeFrame: Up to Day 15
measure: Change From Baseline in Visual Acuity Score
timeFrame: Baseline and up to Day 15
measure: Number of Participants With Color Vision Abnormality in One or Both Eyes
timeFrame: Up to Day 15
measure: Change From Baseline in Heart Rate (HR)
timeFrame: Baseline and up to Day 15
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and up to Day 15
measure: Change From Baseline in HR as Measured by Electrocardiogram (ECG)
timeFrame: Baseline and at Day 15
measure: Number of Participants With ≥25% Intraday Increase in HR, ≥25% Intraday Decrease in SBP, ≥25% Intraday Decrease in DBP at Any Intraday Time
timeFrame: Day 1 and up to Day 15
measure: Mean Number of Days With ≥25% Increase in HR From Baseline
timeFrame: Baseline (Day 1) and up to Day 15
measure: Mean Number of Days With ≥25% Decrease in SBP and Decrease in DBP From Baseline
timeFrame: Baseline (Day 1) and up to Day 15
measure: Change From Baseline in Electrocardiogram (ECG) Parameters
timeFrame: Baseline and up to Day 15
measure: Change From Baseline in HR
timeFrame: Baseline (Day 1) and at Day 4, Day 7, Day 10 and Day 14
measure: Change From Baseline in SBP and DBP
timeFrame: Baseline (Day 1) and at Day 4, Day 7, Day 10 and Day 14
measure: Number of Participants With New Eye Symptoms in Any Eye
timeFrame: Day 1, Day 4, Day 7, Day 10, Day 14 and 15
measure: Change From Baseline in Visual Acuity Score
timeFrame: Baseline, Day 1, Day 4, Day 7, Day 10 and Day 14
measure: Number of Participants With Color Vision Abnormality in One or Both Eyes
timeFrame: Day 1, Day 4, Day 7, Day 10 and Day 14
measure: Change From Baseline in HR
timeFrame: Baseline and at Day 28 and Day 42
measure: Change From Baseline in SBP and DBP
timeFrame: Baseline and at Day 28 and Day 42
measure: Change From Baseline in Visual Acuity Score
timeFrame: Baseline and up to Day 42
measure: Number of Participants With Color Vision Abnormality in One or Both Eyes
timeFrame: Up to Day 42
measure: Number of Participants With Shift From Baseline in Hematology Parameters
timeFrame: Day 3, Day 7, Day 15 and Day 42
measure: Number of Participants With Shift From Baseline in Clinical Chemistry Parameters
timeFrame: Day 3, Day 7, Day 15 and Day 42
measure: Number of Participants With Shift From Baseline in Serum Coagulation Parameters
timeFrame: Day 3, Day 7, Day 15 and Day 42
measure: Change From Baseline in Urinalysis Parameter: Urine Specific Gravity
timeFrame: Baseline and at Day 3, Day 7 and Day 42
measure: Change From Baseline in Urinalysis Parameter: Urine Potential of Hydrogen (pH)
timeFrame: Baseline and at Day 3, Day 7 and Day 42
measure: Maximum Observed Serum Concentration (Cmax) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Time at Maximum Plasma Concentration (Tmax) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Last Quantifiable Concentration (Clast) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Time at Last Quantifiable Concentration (Tlast) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUCinf) After Administration of TBA7371
timeFrame: Day 1
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Last Quantifiable Concentration (AUClast) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Tau (AUCtau) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Minimum Observed Plasma Concentration (Cmin) After Administration of TBA7371
timeFrame: Days 7 and 14
measure: Half-life (T1/2) After Administration of TBA7371
timeFrame: Days 1, 7 and 14
measure: Accumulation Ratio After Administration of TBA7371
timeFrame: Days 7 and 14
Other outcomes:
Locations:
city: Bellville
country: South Africa
facility: TASK
state: Cape Town
city: Mowbray
country: South Africa
facility: University of Cape Town (UCT) Lung Institute
state: Cape Town
city: Pretoria
country: South Africa
facility: The Aurum Institute
state: Gauteng
city: Jouberton
country: South Africa
facility: Perinatal HIV Research Unit (PHRU)
state: North West Province
Study officials:
affiliation: Bill & Melinda Gates Medical Research Institute
name: Gates MRI
role: STUDY_DIRECTOR
References: