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

Phase 2, Double-blind, Randomized, Placebo-Controlled Study to Evaluate Safety and Efficacy of H56:IC31 in Reducing the Rate of TB Disease Recurrence in HIV Negative Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03512249

Enrollment

831

Registered

2018-04-30

Start date

2019-01-31

Completion date

2023-03-20

Last updated

2026-02-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Tuberculosis, Pulmonary

Keywords

tuberculosis, prevention of recurrence, relapse, reinfection, subunit vaccine, whole-genome sequencing

Brief summary

Detailed description

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.

Interventions

BIOLOGICALH56:IC31

5ug H56/500 nmol IC31

BIOLOGICALPlacebo

Sterile saline for injection

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

TRIPLE (Subject, Caregiver, Investigator)

Masking description

The unblinded persons in the study are the study vaccine manager (and designee) who manages the participant inventory log(s) at the trial site, the unblinded site staff, and the unblinded clinical trial site monitor(s) responsible for monitoring the investigational product at the trial site. All unblinded persons must take care to not reveal individual participant treatment assignments to any blinded member of the study team. There is an unblinded contact person at the sponsor's site in order to manage queries from the unblinded site staff or the unblinded monitors in the trial. The study vaccine manager (and designee) should be a designated site team member, such as the study pharmacist. Unblinded site staff must not participate in the evaluation of adverse events. The randomization list will be provided by the unblinded statistician and will be implemented as a module in the eCRF.

Intervention model description

2 Cohorts - H56:IC31 and Placebo. First 150 participants will be in a safety group with additional scheduled evaluations.

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Rate of TB Disease Recurrence (Relapse or Reinfection), Defined as TB Diagnosed by Confirmation of Mtb by Culture of Sputum.	During the period starting 14 days after the 2nd vaccination (V6= Day 70) and ending 12 months after the 2nd vaccination	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).

Secondary

Measure	Time frame	Description
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	Day 0 through Day 70	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.
Summary of the Number of Participants Reporting All Adverse Events Within the 14 Days After Each of the 1st and 2nd Vaccinations	Day 0 through Day 70	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.
Number of Participants With Serious Adverse Events Including Medically Important Events Occurring After the 1st Vaccination Through the End of the Trial	Day 0 through Day 421	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.
Efficacy of H56:IC31 Compared to Placebo in Reducing the Rate of TB Disease Relapse	Day 70 through Day 421	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
Efficacy of H56:IC31 Compared to Placebo in Reducing the Rate of TB Disease Reinfection	Day 70 through Day 421	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.
Antigen-specific Cell-mediated Immune Responses to H56:IC31 by Whole Blood (Absolute Values)	Day 0 through Day 70	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)
Humoral Immune Responses to H56:IC31 by Immunoglobulin G ELISA (Absolute Values)	Day 0 through Day 70	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.
Antigen-specific Cell-mediated Immune Responses to H56:IC31 by Whole Blood (Fold Increase)	Day 0 through Day 70	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)
Humoral Immune Responses to H56:IC31 by Immunoglobulin G ELISA (Fold Increase From Baseline to Visit 6 [Day 70])	Day 0 through Day 70	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.

Countries

South Africa, Tanzania

Contacts

STUDY_DIRECTORMarissa Russell

IAVI (previously Aeras)

Participant flow

Recruitment details

Various methods of recruitment were used i.e., advertising, referrals, or proposition. All recruitment materials were approved by IRB and/or IEC. Interested TB patients from local TB clinics were invited to participate in the informed consent process. Recruitment commenced on 31 Jan 2019 and ended on 03 Sep 2021.

Baseline characteristics

Characteristic	—
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	831 Participants
Age, Continuous	34.7 years STANDARD_DEVIATION 11.1
Age, Customized Age group 18-35 years	480 Participants
Age, Customized Age group 36-60 years	351 Participants
Anaemia No	378 Participants
Anaemia Yes	37 Participants
BMI group 13 to 25 kg/m^2	374 Participants
BMI group 25 kg/m^2 and above	51 Participants
Body Mass Index (BMI)	21.17 kg/m^2 STANDARD_DEVIATION 3.41
Comorbidity No	302 Participants
Comorbidity Yes	114 Participants
Diabetes mellitus No	398 Participants
Diabetes mellitus Yes	18 Participants
Enrollment per trial site A1	108 Participants
Enrollment per trial site A2	139 Participants
Enrollment per trial site A3	229 Participants
Enrollment per trial site A4	45 Participants
Enrollment per trial site A5	106 Participants
Enrollment per trial site A6	33 Participants
Height	166.22 cm STANDARD_DEVIATION 8.94
Race/Ethnicity, Customized Black or African American	273 Participants
Race/Ethnicity, Customized Mixed Cape Ancestry	274 Participants
Race/Ethnicity, Customized Other	7 Participants
Region of Enrollment South Africa	633 Participants
Region of Enrollment Tanzania	92 Participants
Sex: Female, Male Female	229 Participants
Sex: Female, Male Male	299 Participants
Smoking status Ex-smoker	61 Participants
Smoking status Non-smoker	324 Participants
Smoking status Smoker	180 Participants
Weight	58.67 kg STANDARD_DEVIATION 10.01

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	2 / 415	6 / 416
other Total, other adverse events	300 / 415	267 / 416
serious Total, serious adverse events	14 / 415	12 / 416

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Jul 23, 2026