Rifampicin Susceptible Pulmonary Tuberculosis
Conditions
Keywords
Early Bactericidal Activity (EBA)
Brief summary
A Phase 2, Single-Centre, Open-Label, Parallel Control Arm, Randomised Clinical Study to Evaluate the Early Bactericidal Activity (EBA), Safety and Tolerability of Nebulised RESP301 in Adults with Newly Diagnosed, Rifampicin Susceptible Pulmonary Tuberculosis
Detailed description
A total of approximately 15 participants will be recruited per treatment arm (total of approximately 75 participants in the study). Control arm participants will be split across sequential stages stages 1 and 2, with no stratification. Stage 1: To determine the EBA of * Treatment Arm 1 (Active; n = 15) - inhaled RESP301 6 ml dosed via nebulisation administered three times daily over 14 days * Treatment Arm 2 (Control; n= 5) - HRZE taken orally once daily On completion of Stage 1, recruitment will be paused and an interim analysis performed to determine whether the study should proceed to Stage 2. Stage 2: To determine the EBA of * Treatment Arm 2 (Control; n= 10) - HRZE taken orally once daily * Treatment Arm 3 (Active; n = 15) - inhaled RESP301 6 ml dosed via nebulisation administered once daily over 14 days * Treatment Arm 4 (Active; n = 15) - inhaled RESP301 6 ml dosed via nebulisation administered twice daily over 14 days * Treatment Arm 5 (Active; n = 15) - inhaled RESP301 6 ml dosed via nebulisation administered three times daily in combination with HRZE taken orally once daily over 14 days
Interventions
Sponsors
Thirty Respiratory Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Microbiology staff will be blinded to treatment allocation.
Intervention model description
Parallel control arm, randomised clinical study in two sequential stages, with no stratification
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Provide written, informed consent prior to all study-related procedures and agree to undergo all study procedures * Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive * Newly diagnosed pulmonary TB * Rifampicin susceptible pulmonary TB as determined by molecular testing * Ability to produce an adequate volume of sputum as estimated from a pre-treatment overnight sputum collection sample (estimated 10 ml or more) * Spirometry performed during screening with a FEV1 of ≥ 40% * Be of non-childbearing potential or willing to use effective methods of contraception
Exclusion criteria
* HIV positive AND CD4 \< 350 cells/mm3 OR are receiving antiviral therapy (ART) * Methaemoglobin saturation (SpMet) \>3% * Female participant who is pregnant or breast-feeding * Participants planning to conceive a child within the anticipated period of study participation and for at least 90 days after the last dose of IMP in the study * Participation in other clinical studies with investigational agents within 8 weeks prior to screening * Treatment received for this episode of TB with any drug active against M.tb * Treatment with immunosuppressive medications such as TNF-alpha inhibitors within 2 weeks prior to screening, or systemic corticosteroids for more than 7 days within 2 weeks prior to screening. * Treatment with nitric oxide and other nitric oxide donor agents, phosphodiesterase inhibitors and lung surfactant drugs, within 30 days prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-2, 0-7, 0-14, 0-15 and 14-15 days | Overnight sputum collection from which viable mycobacteria in the sample is quantified as TTP Observed EBA for 0-2, 0-7, 0-14, 0-15 and 14-15 days in TTP (hours) for treatment in each of the treatment groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-2, 0-7, 0-14, 0-15 and 14-15 days | Overnight sputum collection from which viable mycobacteria in the sample is quantified as CFU Observed EBA for 0-2, 0-7, 0-14, 0-15 and 14-15 days in CFU (Log10 CFU/mL) for treatment in each of the treatment groups |
| Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Stage 1: Dosing period 14 days + Follow-up period 14 days. Stage 2: Participants did not enter the treatment phase due to early study termination | Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by severity, drug relatedness, seriousness, leading to early withdrawal and leading to death. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 (Active) Inhaled RESP301 6ml via nebulisation three times daily
RESP301: Nitric Oxide agent | 15 |
| 2 (Control) HRZE taken orally once daily
HRZE: isoniazid 75 mg (H), rifampicin 150 mg (R), pyrazinamide 400 mg (Z), ethambutol 275 mg (E) | 5 |
| 3 (Active) Inhaled RESP301 6 ml via nebulisation once daily
RESP301: Nitric Oxide agent | 0 |
| 4 (Active) Inhaled RESP301 6 ml via nebulisation twice daily
RESP301: Nitric Oxide agent | 0 |
| 5 (Active) Inhaled RESP301 6 ml via nebulisation three times daily plus HRZE taken orally once daily
RESP301: Nitric Oxide agent
HRZE: isoniazid 75 mg (H), rifampicin 150 mg (R), pyrazinamide 400 mg (Z), ethambutol 275 mg (E) | 0 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | At the request of the investigator or the sponsor | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 1 (Active) | 2 (Control) | Total |
|---|---|---|---|
| Age, Continuous | 31.00 years STANDARD_DEVIATION 10.09 | 31.20 years STANDARD_DEVIATION 5.93 | 31.05 years STANDARD_DEVIATION 9.08 |
| BMI | 18.70 kg/m^2 STANDARD_DEVIATION 3.58 | 18.34 kg/m^2 STANDARD_DEVIATION 1.7 | 18.61 kg/m^2 STANDARD_DEVIATION 3.17 |
| Height | 1.69 m STANDARD_DEVIATION 0.07 | 1.65 m STANDARD_DEVIATION 0.05 | 1.68 m STANDARD_DEVIATION 0.07 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 5 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 13 Participants | 4 Participants | 17 Participants |
| Weight | 53.05 kg STANDARD_DEVIATION 9.83 | 50.08 kg STANDARD_DEVIATION 6.76 | 52.31 kg STANDARD_DEVIATION 8.85 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 5 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 15 / 15 | 4 / 5 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 15 | 0 / 5 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP)
Overnight sputum collection from which viable mycobacteria in the sample is quantified as TTP Observed EBA for 0-2, 0-7, 0-14, 0-15 and 14-15 days in TTP (hours) for treatment in each of the treatment groups
Time frame: 0-2, 0-7, 0-14, 0-15 and 14-15 days
Population: Decision was made by the sponsor not to progress to Stage 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-7 | 2 Hours |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-15 | 6.2 Hours |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-2 | 3.5 Hours |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 14-15 | 7.5 Hours |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-14 | 2.5 Hours |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 14-15 | 2 Hours |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-2 | 63.5 Hours |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-7 | 140.2 Hours |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-14 | 167.8 Hours |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Time to Positivity (TTP) | 0-15 | 225 Hours |
Secondary
Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU)
Overnight sputum collection from which viable mycobacteria in the sample is quantified as CFU Observed EBA for 0-2, 0-7, 0-14, 0-15 and 14-15 days in CFU (Log10 CFU/mL) for treatment in each of the treatment groups
Time frame: 0-2, 0-7, 0-14, 0-15 and 14-15 days
Population: Decision was made by the sponsor not to progress to Stage 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-7 | 0.2 Log10 CFU/mL |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-15 | 0.3 Log10 CFU/mL |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-14 | 0.4 Log10 CFU/mL |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 14-15 | 0 Log10 CFU/mL |
| 1 (Active) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-2 | 0.3 Log10 CFU/mL |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 14-15 | 0.1 Log10 CFU/mL |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-2 | -0.9 Log10 CFU/mL |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-7 | -1.2 Log10 CFU/mL |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-14 | -2.9 Log10 CFU/mL |
| 2 (Control) | Early Bactericidal Activity (EBA) of Inhaled RESP301 Measured as Colony Forming Units (CFU) | 0-15 | -2.4 Log10 CFU/mL |
Secondary
Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs)
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by severity, drug relatedness, seriousness, leading to early withdrawal and leading to death.
Time frame: Stage 1: Dosing period 14 days + Follow-up period 14 days. Stage 2: Participants did not enter the treatment phase due to early study termination
Population: Decision was made by the sponsor not to progress to Stage 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1 (Active) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 1 (Mild) TEAEs | 38 events |
| 1 (Active) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 2 (Moderate) TEAEs | 13 events |
| 1 (Active) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 3 (Severe) TEAEs | 2 events |
| 1 (Active) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 4 (Life-threatening) TEAEs | 0 events |
| 1 (Active) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Unrelated TEAEs | 27 events |
| 1 (Active) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Related TEAEs | 26 events |
| 2 (Control) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Unrelated TEAEs | 8 events |
| 2 (Control) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 1 (Mild) TEAEs | 7 events |
| 2 (Control) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 4 (Life-threatening) TEAEs | 0 events |
| 2 (Control) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 2 (Moderate) TEAEs | 2 events |
| 2 (Control) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Related TEAEs | 1 events |
| 2 (Control) | Safety and Tolerability of Inhaled RESP301 Measured as Number of Treatment Emergent Adverse Events (TEAEs) | Number of Grade 3 (Severe) TEAEs | 0 events |