Safety, Immunogenicity, and Efficacy of Therapeutic Mycobacterium Bovis BCG (BOOST)

Official title

Safety, Immunogenicity, and Efficacy of Therapeutic Mycobacterium Bovis BCG in Patients With Mycobacterium Avium Complex Lung Disease (BOOST)

Overview

The purpose of this study is to find out if the Mycobacterium bovis Bacillus Calmette Guerin (BCG) vaccine can be used safely to treat Mycobacterium avium complex (MAC) lung disease. Researchers will compare responses from patients with MAC lung disease after receiving an injection of BCG or placebo (a look-alike substance that contains no drug) Participants in the study: * Receive a BCG or placebo injection at UVA study center on Day 0 * Come to UVA study center on Day 60 * Come to UVA study center at the end of the study * Answer surveys and questionnaires about how you are doing * Have blood drawn 3 times, on injection day, day 60, and at end of study * Give the study team personal and demographic information * Discuss any new symptoms with the study team * Provide monthly sputum samples per usual care

Detailed description

Mycobacterium avium complex (MAC) lung disease (LD) is an increasingly prevalent condition in the United States. Treatment involves administration of multiple antibiotics for at least 12 months and many patients still fail, or infection recurs. New therapeutic strategies are needed. We hypothesize that Mycobacterium bovis Bacillus Calmette Guerin (BCG) will have microbiologic activity against MAC during lung disease, because of

* Its mycobacterium antigens shared with MAC (1). * In vitro evidence that BCG stimulates MAC-specific immune responses in mice and humans (2, 3). * In vivo evidence that BCG reduces MAC in mice with established infection (4). Clinical evidence for BCG protection against MAC infection in HIV patients and in children (5, 6).

Objectives:

The primary objective is to determine the safety and immunogenicity of BCG against MAC lung disease after intradermal vaccination with BCG or placebo.

The secondary objectives include:

* the microbiologic efficacy of BCG compared to placebo. * to determine if BCG is superior to placebo in reducing all-cause respiratory illness requiring additional antibiotics, healthcare assessment, or admission.

Endpoints:

Primary endpoints:

* Safety and tolerability of intradermal BCG (TICE®) in this patient population, compared to placebo, assessed by weekly questionnaire of adverse events over 12 weeks. * Serious adverse events related to the intradermal BCG over 12 months. * Immunogenicity of BCG as measured by the change in BCG-induced IFN-γ production in PBMCs 60 days after vaccination, compared to placebo.

Secondary endpoints:

* Proportion of monthly sputum cultures positive for MAC after BCG vaccine or placebo over 24 months. * Immunogenicity of BCG on MAC-specific IFN-γ responses. * Proportion of patients with MAC culture conversion and MAC recurrence within 24 months. * Rates of all-cause respiratory illness requiring additional antibiotics, healthcare assessment, or admission over 24 months. * Symptom scores using the Quality of Life- Bronchiectasis Respiratory (QOL-BR) questionnaire over 24 months. * Adverse Events of Special Interest (local/systemic M. bovis BCG infection) over 24 months.

Exploratory endpoints:

* Assess the efficacy of BCG versus placebo on chest imaging score. * While the study is not powered to detect differences among subgroups, we will enumerate whether above endpoints are modified among these patient subgroups: cavitary versus non-cavitary disease, age, gender, the species of MAC infection, and those with higher IFN-γ responses. * Assess PBMC cytokine responses beyond IFN-γ. * Assess durability of immune responses at 24 months.

Study Population:

We aim to enroll a total of 48 participants with MAC, of which 24 will be randomized to receive each of BCG and placebo.

Interventions

• Biological Mycobacterium bovis Bacillus Calmette Guerin (BCG) vaccine
  Subjects will be randomized to a single intradermal injection of BCG or placebo vaccine. Participants randomized to the BCG arm will receive TICE® BCG. Freeze-dried vaccine is produced in vials, each containing 1 to 8 x\^108 colony forming units (CFU). A vial will be reconstituted in 20 mL of preservative-free saline. Administration of 0.1 mL will contain \~2x\^106 CFU, which accounts for approximately 0.25 mg of the attenuated Mycobacterium bovis. Administration of 0.1 mL of diluted vaccine wi
• Drug preservative-free saline
  Patients randomized to the placebo arm will receive 0.1 mL preservative-free saline alone.

Primary outcome measures

• Adverse events [Time frame: 12 weeks after intervention]
• Serious adverse events [Time frame: 12 months]
• Immunogenicity [Time frame: 24 months]

Secondary outcome measures (1)

• Sputum cultures [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Male or female aged ≥18 years
• Mycobacterium avium complex lung disease as evidenced by diagnosis or treatment for MAC lung disease by pulmonologist or infectious disease physician in the medical record. The following data will be extracted from the medical record:

• History of at least 2 MAC positive respiratory cultures, one of which is within 1 year of enrollment. In the event a MAC positive culture is from bronchial lavage or biopsy, one culture rather than 2 will meet criteria.
• Respiratory and/or constitutional symptoms consistent with MAC lung disease
• Nodular or cavitary opacities on chest radiograph or bronchiectasis with multiple small nodules on high-resolution computed tomography
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures
• Women of childbearing potential (WOCBP) (i.e., fertile following menarche and until becoming postmenopausal unless permanently sterile) agree to practice a highly effective method of birth control from Day 0 to at least 90 days after study intervention. Some examples of acceptable birth controls are:

• True abstinence (refraining from heterosexual intercourse during the entire study),
• Copper intrauterine device (IUD),
• Hormonal methods (levonorgestrel-releasing intrauterine system, progestogen implant, combined oral contraceptive pill \[combined with barrier method\]), exclusive homosexual relationship) sole male partner who has undergone surgical sterilization

Exclusion criteria

Selection of study participants will be equitable, but an individual who meets any of the following criteria will be excluded from participation in this study:

• Currently receiving antibiotics prescribed for their MAC lung disease
• Having received any antibacterial antibiotics within the past 14 days prior to study vaccination, day 0
• Known allergy, intolerance or other contraindication to isoniazid or rifampin or ethambutol
• Expectation of starting anti-MAC lung disease antibiotics in the next 2 months per patient or their physician
• Persons with congenital or acquired immune deficiencies (e.g., HIV infection; leukemia, lymphoma, or cancer therapy within the past 2 years; immunosuppressive therapy such as anti B cell depleting therapies, corticosteroids (>20 mg/day for > 14 days), dupilumab, elivaldogene, etrasimod, cytotoxic chemotherapy, miscellaneous oncologic agents, therapeutic immunosuppressant agents, methotrexate, teplizumab, tezepelumab, tildrakizumab, tralokinumab, ustekinumab). Persons with lung and other solid organ transplants/hematologic stem cell transplants who may be contraindicated to receive a live vaccine. Point of care HIV testing must be negative at baseline.
• Prior BCG Vaccination. If unknown Bcgatlas.org shall be consulted for local vaccination administration policies.
• Known pregnancy at the time of screening or breastfeeding at the time of enrollment (pregnancy test negative at baseline if applicable)
• Cystic fibrosis
• Active tuberculosis: Active tuberculosis (respiratory AFB culture growing Mycobacterium tuberculosis complex within the past 4 months).
• Known exposure to a case of active pulmonary tuberculosis within 10 weeks of enrollment
• Known prior hypersensitivity reaction to BCG or any component of the BCG vaccine
• Received live injectable vaccine within 28 days of day 0 study vaccination
• Any condition in the opinion of the investigator that may confound the study endpoints Note that colonization or co-infection with other nontuberculous mycobacteria is not exclusionary, as MAC will be the endpoint.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Virginia Health — Charlottesville

Publications

• Blazevic A, Edwards RL, Xia M, Eickhoff CS, Hamzabegovic F, Meza KA, Ning H, Tennant J, Mosby KJ, Ritchie JC, Girmay T, Lai L, McCullough M, Beck A, Kelley C, Edupuganti S, Kabbani S, Buchanan W, Makhene MK, Voronca D, Cherikh S, Goll JB, Rouphael NG, Mulligan MJ, Hoft DF. Phase 1 Open-Label Dose Escalation Trial for the Development of a Human Bacillus Calmette-Guerin Challenge Model for Assessmen PMID 38019956
• Allen HF, Klingensmith GJ, Jensen P, Simoes E, Hayward A, Chase HP. Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study. Diabetes Care. 1999 Oct;22(10):1703-7. doi: 10.2337/diacare.22.10.1703. PMID 10526739
• Bricks LF. [Percutaneous or intradermal BCG vaccine?]. J Pediatr (Rio J). 2004 Mar-Apr;80(2):93-8. Portuguese. PMID 15079177
• Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, Snell L, Mangtani P, Adetifa I, Lalvani A, Abubakar I. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. 2014 Aug 5;349:g4643. doi: 10.1136/bmj.g4643. PMID 25097193
• Koekenbier EL, Fohse K, van de Maat JS, Oosterheert JJ, van Nieuwkoop C, Hoogerwerf JJ, Grobusch MP, van den Bosch MAAJ, van de Wijgert JHH, Netea MG, Rosendaal FR, Bonten MJM, Werkhoven CHHV; BCG-PRIME study group. Bacillus Calmette-Guerin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial. Clin Microbiol Inf PMID 36736662
• Pittet LF, Messina NL, Orsini F, Moore CL, Abruzzo V, Barry S, Bonnici R, Bonten M, Campbell J, Croda J, Dalcolmo M, Gardiner K, Gell G, Germano S, Gomes-Silva A, Goodall C, Gwee A, Jamieson T, Jardim B, Kollmann TR, Lacerda MVG, Lee KJ, Lucas M, Lynn DJ, Manning L, Marshall HS, McDonald E, Munns CF, Nicholson S, O'Connell A, de Oliveira RD, Perlen S, Perrett KP, Prat-Aymerich C, Richmond PC, Rodr PMID 37099341
• Dionato FAV, Jalalizadeh M, Buosi K, Visacri MB, Dal Col LSB, Giacomelli CF, Leme PAF, Maia CL, Moriel P, Reis LO. BCG vaccine safety in COVID-19 convalescent adults: BATTLE a randomized controlled trial. Vaccine. 2022 Jul 30;40(32):4603-4608. doi: 10.1016/j.vaccine.2022.06.039. Epub 2022 Jun 20. PMID 35738969
• Tsilika M, Taks E, Dolianitis K, Kotsaki A, Leventogiannis K, Damoulari C, Kostoula M, Paneta M, Adamis G, Papanikolaou I, Stamatelopoulos K, Bolanou A, Katsaros K, Delavinia C, Perdios I, Pandi A, Tsiakos K, Proios N, Kalogianni E, Delis I, Skliros E, Akinosoglou K, Perdikouli A, Poulakou G, Milionis H, Athanassopoulou E, Kalpaki E, Efstratiou L, Perraki V, Papadopoulos A, Netea MG, Giamarellos-B PMID 35865520

Identifiers

NCT: NCT07094711 · 302296Boost

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗