Study to Evaluate H56:IC31 in Preventing Rate of TB Recurrence

International AIDS Vaccine Initiative831 enrolled

Overview

This is a phase 2, double-blind, randomized (1:1), placebo-controlled trial with two parallel groups. * H56:IC31 (investigational vaccine) * Placebo 900 HIV-negative adults with a diagnosis of drug susceptible pulmonary TB are planned to be included, recruited from TB clinics with established relationships to the trial sites at the start of their TB treatment. 5 study sites in South Africa: 2 sites from the AURUM institute (Klerksdorp and Tembisa) and 3 in Cape Town at TASK Applied Science (TASK), the University of Cape Town Lung Institute (UCTLI)) and South African Tuberculosis Vaccine Initiative (SATVI) under UCT, respectively. 1 study site in Tanzania (TZ): 1 site at Mbeya Medical Research Centre (MMRC) under the National Institute for Medical Research (NIMR). Preclinical data suggest H56:IC31 may be more efficacious if administered while patients are still on treatment. Following the national guidelines for TB treatment in South Africa and Tanzania, we will obtain sputum samples from patients towards the end of treatment at about the same time they are obtained within the national TB control programmes, and if the sputum is smear negative, the criterion for successful treatment within TB programmes, the individual will be eligible for randomization and vaccination towards the end of their six-month treatment period. As this is a proof of concept TB vaccine study, HIV positive individuals have been excluded as it is not yet known what effect HIV infection may have on the immune response to the vaccine. However, HIV positive individuals are an important population to include in future studies should efficacy be demonstrated in this study.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Completed the written informed consent process. 2. Agrees to give access to medical records for trial related purposes. 3. Was HIV-negative (self-reported) with a diagnosis of drug susceptible pulmonary TB at the start of the TB treatment. 4. Able to provide 2 separate sputum samples within ≤ 7 days of starting TB treatment. Participants are not expected to provide sputum samples prior to starting TB treatment if their 1st screening visit (V1) is performed on the same day as their 2nd screening visit (V2). 5. Confirmed Mtb negative by smear AFB microscopy of 2 separate sputum samples taken at V2. Participants unable to produce sputum, but considered asymptomatic by the investigator, may be considered Mtb negative and eligible for inclusion. 6. Confirmed HIV negative at V2. 7. Completed ≥ 5 months (22 weeks) of TB treatment with treatment still ongoing at the time of the 1st vaccination and total treatment time not extended beyond 28 weeks. 8. Aged ≥ 18 years on the date of V1 and ≤ 60 years on the date of V3= Day 0. 9. Agrees to stay in contact with the clinical trial site for the duration of the trial, provide updated contact information as necessary, and has no current plans to move from the area for the duration of the trial. Exclusion Criteria: 1. Diagnosis or co-diagnosis of extra pulmonary TB. 2. Hospitalized for the current episode of drug susceptible pulmonary TB disease. 3. History of or ongoing severe disease that in the opinion of the investigator might affect the safety of the participant or the immunogenicity of the investigational product. 4. Insulin dependent diabetes. 5. History of allergic disease or reactions likely to be exacerbated by any component of the investigational product. 6. History or laboratory evidence of immunodeficiency, autoimmune disease or immunosuppression. 7. History of chronic hepatitis. 8. Severe anemia, defined as hemoglobin less than 10 g/dL or a hematocrit less than 30% based on most recent hematology obtained before randomization. 9. History of receipt of treatment against active TB, prior to the current treatment episode, within the last 5 years 10. Receipt of any investigational TB vaccine previously. 11. Receipt or planned receipt of any investigational drug or investigational vaccine from V1 through V8= Day 421. 12. Receipt or planned receipt of any licensed vaccine from V1 through V6= Day 70, except for SARS-Cov-2 vaccines recommended by national vaccination programs which will be allowed if given \> 28 days before and from the time of administration of clinical trial product. 13. Receipt of treatment likely to modify the immune response (e.g. blood products, immunoglobulins, immunosuppressive treatment) within 42 days before V3= Day 0 through V6= Day 70. Inhaled and topical corticosteroids are permitted. 14. Has a body mass index (BMI) \< 13 (weight, kg / height, m2) on the date of V1. 15. Female participants of childbearing potential (not sterilized, menstruating or within 1 year of last menses, if post-menopausal): if not willing to use an acceptable method to avoid pregnancy (sterile sexual partner, sexual abstinence, hormonal contraceptives (oral, injection, transdermal patch, or implant) or intrauterine device from 28 days before V3= Day 0 until 2 months after the 2nd vaccination. 16. Female participants: if lactating / nursing, or pregnant as per positive pregnancy test on V2. 17. Not suitable for inclusion in the opinion of the investigator.

Locations (6)

Task Clinical Research Centre

Bellville, Cape Town, South Africa

University of Cape Town Lung Institute

Mowbray, Cape Town, South Africa

The Aurum Institute: Tembisa Clinical Research Centre

Tembisa, Gauteng, South Africa

The Aurum Institute

Klerksdorp, North West, South Africa

South African Tuberculosis Vaccine Initiative , Project Office, Brewelskloof Hospital , Harlem Street, Worcester

Cape Town, Western Cape, South Africa

NIMR Mbeya Medical Research Centre

Mbeya, Tanzania

Outcomes

Primary Outcomes

Rate of TB Disease Recurrence (Relapse or Reinfection), Defined as TB Diagnosed by Confirmation of Mtb by Culture of Sputum.

To evaluate the following in HIV-negative participants who have completed at least 5 months (22 weeks) treatment for drug-susceptible pulmonary TB and who test negative for acid fast bacilli (AFB) on sputum smear microscopy prior to vaccination (participants unable to produce sputum, and considered asymptomatic by the investigator, may be considered Mtb negative): Efficacy of H56:IC31 compared to placebo in reducing the rate of recurrent TB disease (relapse or reinfection).

Time frame: During the period starting 14 days after the 2nd vaccination (V6= Day 70) and ending 12 months after the 2nd vaccination

Secondary Outcomes

Number of Participants With Adverse Events Occurring During the First 14 Days After Each of the 1st and 2nd Vaccinations by System Organ Class and Preferred Term

Solicited adverse events were infection site reactions (redness, swelling and tenderness/pain) and systemic adverse events (AEs) (fever, arthralgia, myalgia, fatigue, headache, rash, chills, and nausea). All participants were provided with a diary, a thermometer to record axillary temperature, a ruler to measure injection site redness and swelling, and instructions on using the diary for the first 7 days after each vaccination. In the period from 8 days after the vaccinations until the diary review at 14 days after each vaccination, the participants were instructed to fill in the diary only in case of an AE.

Time frame: Day 0 through Day 70

Summary of the Number of Participants Reporting All Adverse Events Within the 14 Days After Each of the 1st and 2nd Vaccinations

Treatment emergent AEs, AEs within 14 days after vaccination, solicited AEs and solicited SAEs occurring within the 7 days after each vaccination, and unsolicited AEs and SAEs occurring within the first 14 days after each vaccination are summarized.

Time frame: Day 0 through Day 70

Number of Participants With Serious Adverse Events Including Medically Important Events Occurring After the 1st Vaccination Through the End of the Trial

Number of participants with serious adverse events including medically important events occurring after the 1st vaccination through the end of the trial, comparing H56:IC31 to placebo.

Time frame: Day 0 through Day 421

Efficacy of H56:IC31 Compared to Placebo in Reducing the Rate of TB Disease Relapse

Rate of TB relapse defined as subjects meeting the primary endpoint of TB disease recurrence, AND determined by whole genome sequencing (WGS) of the Mtb isolate to be the same strain of Mtb as in the subject's original isolate from the time of diagnosis

Time frame: Day 70 through Day 421

Efficacy of H56:IC31 Compared to Placebo in Reducing the Rate of TB Disease Reinfection

Rate of TB disease reinfection defined as subjects meeting the primary endpoint of TB disease recurrence, AND determined by WGS of the Mtb isolate to be a different strain than in the subject's original isolate from the time of diagnosis.

Time frame: Day 70 through Day 421

Antigen-specific Cell-mediated Immune Responses to H56:IC31 by Whole Blood (Absolute Values)

Antigen-specific cell-mediated immune responses by whole blood intracellular cytokine staining (WB ICS) at baseline (V3= Day 0) and 14 days after the 2nd vaccination (V6= Day 70) in the immunogenicity cohort. Variables of interest for assessment of antigen specific cell mediated immune response to vaccination were the percentage of CD4+ and CD8+ cells that express IL-2, IFN-gamma, TNF, and IL-17 in the following combinations: H56 protein-specific CD4+ T cells expressing the total cytokine response, i.e., any combination of IL-2, IFN-gamma, TNF, and/or IL-17 H56 protein-specific CD4+ T cells co-expressing IL-2 and TNF H56 protein-specific CD4+ T cells co-expressing IL-2, IFN-gamma and TNF H56 protein-specific CD8+ T cells expressing any combination of IL-2, IFN-gamma, TNF, and/or IL-17 (total response)

Time frame: Day 0 through Day 70

Humoral Immune Responses to H56:IC31 by Immunoglobulin G ELISA (Absolute Values)

Antigen-specific antibody responses (anti-H56 IgG) assessed by IgG ELISA of plasma samples at baseline (V3= Day 0) and 14 days after the 2nd vaccination (V6= Day 70). Summary of immune response at Visit 3 (Day 0/Baseline) and Visit 6 (Day 70) as well as fold increase from Baseline to Day 70.

Time frame: Day 0 through Day 70

Antigen-specific Cell-mediated Immune Responses to H56:IC31 by Whole Blood (Fold Increase)

Time frame: Day 0 through Day 70

Humoral Immune Responses to H56:IC31 by Immunoglobulin G ELISA (Fold Increase From Baseline to Visit 6 [Day 70])

Time frame: Day 0 through Day 70

Study to Evaluate H56:IC31 in Preventing Rate of TB Recurrence

Overview

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Primary Outcomes

Secondary Outcomes