Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Tuberculosis, MDR, Tuberculosis, Drug-Resistant Tuberculosis
Conditions
Keywords
tuberculosis, TB, DR-TB, pretomanid (PA), PA-824, XDR TB, Pa
Brief summary
Pretomanid is being used in an antimicrobial combination regimen(s) to treat patients with pulmonary tuberculosis (TB). The primary purpose of the Male Reproductive Safety - BPaMZ/SEM- clinical study is to evaluate the potential effect of pretomanid on human testicular function whilst being used in a 26 weeks antimicrobial combination regimen consisting of bedaquiline (B) plus pretomanid (Pa) plus moxifloxacin (M) and pyrazinamide (Z) (BPaMZ).
Detailed description
The primary objective of this study is to assess the male reproductive safety of pretomanid in the regimen (BPaMZ) of bedaquiline 200mg (200mg daily for 8 weeks then 100 mg daily for 18 weeks), together with pretomanid 200 mg (1x daily) + moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1 x daily) for 26 weeks in participants with drug-resistant pulmonary tuberculosis (DR-TB). The secondary objective of the study is to evaluate the tuberculosis (TB) treatment efficacy, safety and tolerability after 26 weeks of active treatment for TB and follow up until 52 weeks after end of the above-described treatment regimen in participants with DR-TB.
Interventions
DRUGPretomanid
pretomanid 200 mg (once daily) for 26 weeks (with meal)
DRUGBedaquiline
bedaquiline 200 mg (once daily) for 8 weeks (with meal), then bedaquiline 100mg (once daily) for 18 weeks (with meal)
DRUGmoxifloxacin
moxifloxacin 400 mg (once daily) for 26 weeks (with meal)
DRUGpyrazinamide
pyrazinamide 1500 mg (once daily) for 26 weeks (with meal)
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 2 single arm multi-center, open-label clinical trial in DR-TB participants. Participants will receive bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks together with pretomanid 200 mg \+ moxifloxacin 400 mg + pyrazinamide 1500 mg once daily (BPaMZ) for 26 weeks. Participants will be followed for 52 weeks after end of treatment
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures. 2. Male gender 18 years or over 3. Body weight (in light clothing and no shoes) ≥ 45kg. 4. A positive molecular test for tuberculosis in sputum either at screening or within one month prior to enrolment. 5. Disease Characteristics: * Participants must have been diagnosed with TB prior to or at screening * Participants' TB should be resistant to rifampicin and/or isoniazid, and susceptible to fluoroquinolones by rapid sputum-based tests. * Participants who have had previous treatment for DR-TB for more than 3 months at start of screening should be discussed with the medical monitor. 6. A chest x-ray, within 26 weeks prior to or at the screening visit, which in the opinion of the Investigator is compatible with pulmonary TB
Exclusion criteria
1. Resistant to fluoroquinolones by rapid molecular test 2. History of male infertility or vasectomy 3. Unable to produce semen sample 4. Evidence at screening of azoospermia 5. Known erectile dysfunction that would prevent ejaculation. 6. Historical or active disease process of the male reproductive tract that would compromise sperm production. e.g. tuberculous epididymitis. 7. History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study. 8. For HIV infected participants any of the following: 1. CD4+ count \<100 cells/μL 2. Received intravenous antifungal medication within the last 90 days 9. Participants with newly diagnosed tuberculosis and HIV that require initiation of appropriate HIV therapy before participants has received at least 2 weeks of an antituberculosis regimen. 10. Received pretomanid and/or delamanid to treat TB 11. Known chronic hepatitis B or C 12. For HIV infected participants: 1. The following antiretroviral therapy (ART) should not be used: 1\. Stavudine 2. Zidovudine 3. Didanosine 4. Triple NRTI regimen is not considered optimal for HIV treatment (poor efficacy) 13\. Participants with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft November 2007) where applicable: 1. Platelets \<75,000/mm3 2. Creatinine \>1.5 times upper limit of normal (ULN) 3. eGFR ≤ 60 mL/min 4. Haemoglobin \<8.0 g/dL 5. Serum potassium less than the lower limit of normal for the laboratory. This may be repeated once 6. AST: * ≥3.0 x ULN to be excluded * results between 1.5 x ULN and 3 x ULN must be discussed with and approved by the Sponsor Medical Monitor 7. ALT: * ≥3.0 x ULN to be excluded * greater than ULN must be discussed with and approved by the Sponsor Medical Monitor 8. ALP: * ≥3.0 x ULN to be excluded * 2.0 - \<3.0 x ULN must be discussed with and approved by the Sponsor Medical Monitor 9. Total bilirubin: * \>1.5 x ULN to be excluded * Greater than ULN must be discussed with and approved by the Sponsor Medical Monitor 10. Direct bilirubin: • greater than 1x ULN to be excluded 11. Positive hepatitis B surface Ag, or hepatitis C antibody
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Form Baseline Total Sperm Count | Week 26 | Change from baseline in total sperm number at 26 weeks of therapy. Total sperm count is calculated by multiplying the sperm cell concentration by the ejaculate volume. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Total Sperm Count at 44 Weeks | Baseline through 44 weeks | Change from baseline in total sperm number at 44 weeks (18 months post treatment completion). Total sperm count is calculated by multiplying the sperm cell concentration by the ejaculate volume. |
| Luteinizing Hormone (LH) | Baseline to Week 78 | (LH) at baseline, 26, 44, and 78 weeks. |
| Change From Baseline in Total Sperm Count at 12 Weeks | Baseline to Week 12 | Change from baseline in total sperm number at 12 weeks of therapy. Total sperm count is calculated by multiplying the sperm cell concentration by the ejaculate volume. |
| Testosterone | Baseline to 78 weeks | testosterone level at baseline, 26, 44 and 78 weeks. |
| Inhibin B | Baseline to 78 weeks | inhibin B at baseline, weeks 26, 44 and 78 |
| FSH | Baseline to week 78 | FSH at baseline, weeks 26, 44 and 78 |
Countries
Georgia, South Africa
Participant flow
Pre-assignment details
No pre-assignment events occurred.
Participants by arm
| Arm | Count |
|---|---|
| BPaMZ Participants will receive bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg once daily (BPaMZ) for 26 weeks.
Pretomanid: pretomanid 200 mg (once daily) for 26 weeks (with meal)
Bedaquiline: bedaquiline 200 mg (once daily) for 8 weeks (with meal), then bedaquiline 100mg (once daily) for 18 weeks (with meal)
moxifloxacin: moxifloxacin 400 mg (once daily) for 26 weeks (with meal)
pyrazinamide: pyrazinamide 1500 mg (once daily) for 26 weeks (with meal) | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment | Adverse Event | 2 |
| Treatment | pyrazinamide resistance | 1 |
| Treatment | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | BPaMZ |
|---|---|
| Age, Continuous | 35.4 years STANDARD_DEVIATION 10.8 |
| Alcohol use Current | 12 Participants |
| Alcohol use Former | 10 Participants |
| Alcohol use Never | 4 Participants |
| Body Mass Index (BMI) | 20 Kg/m^2 STANDARD_DEVIATION 3 |
| Height | 175.8 cm STANDARD_DEVIATION 7.3 |
| HIV Status Negative | 18 Participants |
| HIV Status Positive | 8 Participants |
| Previous Tuberculosis (TB) diagnoses DS-TB | 7 Participants |
| Previous Tuberculosis (TB) diagnoses INH Mono-resistant TB | 2 Participants |
| Previous Tuberculosis (TB) diagnoses MDR-TB | 9 Participants |
| Previous Tuberculosis (TB) diagnoses RIF mono-resistant TB | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment Georgia | 8 participants |
| Region of Enrollment South Africa | 18 participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) 1+ | 3 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) 2+ | 3 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) 3+ | 10 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) No AFB seen | 6 Participants |
| Screening smear microscopy for Acid Fast Bacilli (AFB) Scanty Positive | 4 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 26 Participants |
| Smoking Current | 12 Participants |
| Smoking Former | 8 Participants |
| Smoking Never | 6 Participants |
| Time to positivity at baseline | 9.9 Days STANDARD_DEVIATION 6.6 |
| Weight | 62.2 kg STANDARD_DEVIATION 11.7 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 26 |
| other Total, other adverse events | 21 / 26 |
| serious Total, serious adverse events | 2 / 26 |
Outcome results
Primary
Change Form Baseline Total Sperm Count
Change from baseline in total sperm number at 26 weeks of therapy. Total sperm count is calculated by multiplying the sperm cell concentration by the ejaculate volume.
Time frame: Week 26
Population: Excludes participants not meeting definition of having received adequate treatment (80% of allocated doses) or with major protocol deviations including participants who did not satisfy entry criteria but were entered anyway; participants who developed withdrawal criteria during the study but were not withdrawn; and participants who received the wrong treatment or incorrect dose..
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPaMZ | Change Form Baseline Total Sperm Count | 20 10^6 sperm cells/ejaculate | Standard Deviation 97.3 |
Secondary
Change From Baseline in Total Sperm Count at 12 Weeks
Change from baseline in total sperm number at 12 weeks of therapy. Total sperm count is calculated by multiplying the sperm cell concentration by the ejaculate volume.
Time frame: Baseline to Week 12
Population: Excludes participants not meeting definition of having received adequate treatment (80% of allocated doses)or with major protocol deviations including participants who did not satisfy entry criteria but were entered anyway; participants who developed withdrawal criteria during the study but were not withdrawn; and participants who received the wrong treatment or incorrect dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPaMZ | Change From Baseline in Total Sperm Count at 12 Weeks | 4.2 10^6 sperm cells/ejaculate | Standard Deviation 56.8 |
Secondary
Change From Baseline Total Sperm Count at 44 Weeks
Change from baseline in total sperm number at 44 weeks (18 months post treatment completion). Total sperm count is calculated by multiplying the sperm cell concentration by the ejaculate volume.
Time frame: Baseline through 44 weeks
Population: All enrolled participants who completed the 44-week visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BPaMZ | Change From Baseline Total Sperm Count at 44 Weeks | 4.4 10^6 sperm cells/ejaculate | Standard Deviation 95.9 |
Secondary
FSH
FSH at baseline, weeks 26, 44 and 78
Time frame: Baseline to week 78
Population: Total assessable. (Excludes participants who were lost to follow-up or with missing data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BPaMZ | FSH | 6.6 IU/mL |
| BPaMZ 26 Weeks | FSH | 6.2 IU/mL |
| BPaMZ 44 Weeks | FSH | 5.2 IU/mL |
| BPaMZ 78 Weeks | FSH | 4.6 IU/mL |
Secondary
Inhibin B
inhibin B at baseline, weeks 26, 44 and 78
Time frame: Baseline to 78 weeks
Population: Total assessable. (Excludes participants who were lost to follow-up or with missing data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BPaMZ | Inhibin B | 122 pg/mL |
| BPaMZ 26 Weeks | Inhibin B | 137 pg/mL |
| BPaMZ 44 Weeks | Inhibin B | 162.5 pg/mL |
| BPaMZ 78 Weeks | Inhibin B | 172 pg/mL |
Secondary
Luteinizing Hormone (LH)
(LH) at baseline, 26, 44, and 78 weeks.
Time frame: Baseline to Week 78
Population: Total assessable. (Excludes participants who were lost to follow-up or with missing data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BPaMZ | Luteinizing Hormone (LH) | 5.8 IU/mL |
| BPaMZ 26 Weeks | Luteinizing Hormone (LH) | 4.6 IU/mL |
| BPaMZ 44 Weeks | Luteinizing Hormone (LH) | 3.6 IU/mL |
| BPaMZ 78 Weeks | Luteinizing Hormone (LH) | 4.0 IU/mL |
Secondary
Testosterone
testosterone level at baseline, 26, 44 and 78 weeks.
Time frame: Baseline to 78 weeks
Population: Total assessable. (Excludes participants who were lost to follow-up or with missing data)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BPaMZ | Testosterone | 547 ng/dL |
| BPaMZ 26 Weeks | Testosterone | 600 ng/dL |
| BPaMZ 44 Weeks | Testosterone | 646 ng/dL |
| BPaMZ 78 Weeks | Testosterone | 615.5 ng/dL |