Evaluating the Early Bactericidal Activity, Safety and Tolerability of Nebulised RESP301 in Adults With Tuberculosis

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase 2 Study to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Nebulised RESP301 in Adults With Newly Diagnosed, Rifampicin Susceptible Pulmonary Tuberculosis

Conditions
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Rifampicin Susceptible Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: RESP301
* Drug: HRZE


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel control arm, randomised clinical study in two sequential stages, with no stratification
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 (Active)<br>Inhaled RESP301 6ml via nebulisation three times daily | Drug: RESP301<br>* Nitric Oxide agent<br>|
| Active Comparator: 2 (Control)<br>HRZE taken orally once daily | Drug: HRZE<br>* isoniazid 75 mg (H), rifampicin 150 mg (R), pyrazinamide 400 mg (Z), ethambutol 275 mg (E)<br>|
| Experimental: 3 (Active)<br>Inhaled RESP301 6 ml via nebulisation once daily | Drug: RESP301<br>* Nitric Oxide agent<br>|
| Experimental: 4 (Active)<br>Inhaled RESP301 6 ml via nebulisation twice daily | Drug: RESP301<br>* Nitric Oxide agent<br>|
| Experimental: 5 (Active)<br>Inhaled RESP301 6 ml via nebulisation three times daily plus HRZE taken orally once dialy | Drug: RESP301<br>* Nitric Oxide agent<br>Drug: HRZE<br>* isoniazid 75 mg (H), rifampicin 150 mg (R), pyrazinamide 400 mg (Z), ethambutol 275 mg (E)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 14 days | 
| Safety and tolerability of inhaled RESP301 measured as incidence 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. | 1.5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Bactericidal Activity (EBA)