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Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine. (MTBVAC)

Primary Purpose

Tuberculosis, Healthy

Status

Completed

Phase

Phase 1

Locations

Switzerland

Study Type

Interventional

Intervention

MTBVAC live vaccine

Commercially available BCG live vaccine

About this trial

This is an interventional prevention trial for Tuberculosis

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Subjects who the Investigator believes that they can and will comply with the requirements of the protocol
Subjects who have no evidence of exposition to BCG as demonstrated by a ELISPOT PPD assay along with no history of BCG vaccination and no BCG scar
A male or female between, and including, 18 and 45 years of age at the time of the vaccination.
Written informed consent obtained from the subject prior to any study procedure.
If the subject is female, she must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception
Clinically acceptable laboratory values for blood tests.
Seronegative for human immunodeficiency virus 1 and -2 (HIV-1/2) antibodies, p24 antigen, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibodies.
No evidence of pulmonary pathology as confirmed by chest X-ray.
No history of extrapulmonary TB.
No history of previous contact with M. tuberculosis (latent tuberculosis) as demonstrated by a negative ELISPOT Tb (ESAT-6, CFP10) assay.

Exclusion Criteria:

History of allergic reactions (significant IgE-mediated events) or anaphylaxis to previous immunisations (any vaccine).
History of allergic disease or reactions
History of previous administration of experimental Mycobacterium tuberculosis vaccines.
Use of any investigational or non-registered product (drug or vaccine) in another experimental protocol other than the study vaccines within 30 days preceding the vaccination, or planned use during the study period.
Any chronic drug therapy to be continued during the study period.
Chronic administration of immunosuppressors or other immune-modifying drugs.
Administration of any immunoglobulins, any immunotherapy and/or any blood products within the three months preceding the vaccination, or planned administrations during the study period.
Any confirmed or suspected immunosuppressive or immunodeficient condition (including HIV) based on medical history and physical examination.
Any condition or history of any acute or chronic illness or medication which, in the opinion of the Investigator, may interfere with the evaluation of the study objectives.
A family history of congenital or hereditary immunodeficiency.
A stay of more than 2 months in a highly endemic area (e.g. Eastern Europe (Romania, Bulgaria) and low-income countries) within 6 months prior to the screening visit or travel of more than 2 months foreseen in an area of high endemicity after the enrolment into the study.
History of any neurologic disorders or seizures.
History of chronic alcohol consumption and/or drug abuse.
Major congenital defects.
Pregnant or lactating female.
Female planning to become pregnant or planning to discontinue contraceptive precautions.

Sites / Locations

Centre Hospitalier Universitaire Vaudois

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Arm Label

MTBVAC group 1

MTBVAC Group 2

MTBVAC Group 3

BCG Control Group

Arm Description

Intervention: MTBVAC live vaccine (low dose 5 x 10E03 CFU/0.1mL)

Intervention: MTBVAC live vaccine (middle dose 5 x 10E04 CFU/0.1mL)

Intervention: MTBVAC live vaccine (high dose 5 x 10E05 CFU/0.1mL)

Intervention: Commercially available BCG live vaccine (dose 5 x 10E05 CFU/0.1mL)

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events up to 210 Days After Vaccination

Safety and reactogenicity for all subjects as determined by: Occurrence of solicited symptoms during the 7-day follow-up period following vaccination and occurrence of unsolicited symptoms during the 210-day follow-up period following vaccination. Occurrence of grade 3 vaccine related local and general symptoms during the 210-day follow-up period following vaccination and occurrence of serious adverse events throughout the entire study period. Haematological and biochemical safety test levels prior and after vaccination

Secondary Outcome Measures

Number of Participants With Three-cytokine-positive CD4+ T-cell Response

Measure of the kinetics of CD4+ T-cell responses to MTBVAC or BCG vaccination by tracking the expression of IFNγ, TNFα and IL-2 upon stimulation with live MTBVAC or BCG

Full Information

NCT ID

NCT02013245

First Posted

December 3, 2013

Last Updated

February 6, 2017

Sponsor

Biofabri, S.L

Collaborators

Universidad de Zaragoza, Centre Hospitalier Universitaire Vaudois, TuBerculosis Vaccine Initiative

1. Study Identification

Unique Protocol Identification Number

NCT02013245

Brief Title

Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine.

Acronym

MTBVAC

Official Title

Phase I Double Blind, Randomized, Controlled, Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC in Comparison With BCG in Elispot TB(ESAT-6, CFP10, PPD)- and HIV- Negative Volunteers

Study Type

Interventional

2. Study Status

Record Verification Date

February 2017

Overall Recruitment Status

Completed

Study Start Date

January 2013 (undefined)

Primary Completion Date

June 2014 (Actual)

Study Completion Date

November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Biofabri, S.L

Collaborators

Universidad de Zaragoza, Centre Hospitalier Universitaire Vaudois, TuBerculosis Vaccine Initiative

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to test the safety and immunogenicity of MTBVAC as a potential substitute for BCG vaccination. BCG vaccination has indeed demonstrated its major limitation in inducing protection against tuberculosis (TB). Novel vaccines are essential to fight against the current world epidemics in tuberculosis and resistance to anti-TB drugs.

Detailed Description

A randomized, double-blind, controlled Phase I study conducted at CHUV, Lausanne, Switzerland, to compare MTBVAC to licensed BCG in healthy, PPD-negative adult male and female volunteers. The study involves random allocation of up to 36 subjects (4 vaccine groups of 9 volunteers fulfilling the inclusion criteria) to MTBVAC (tested at three separate doses) or standard dose BCG (on a 3 verum : 1control basis) in a dose-escalation manner to one of three cohorts. Each cohort includes 9 subjects set to receive MTBVAC lowest dose 5x10E03, or MTBVAC intermediate dose 5x10E04, or high dose 5x10E05 colony forming units (CFU) in 0.1 mL and 3 subjects set to receive standard dose BCG (5x10E05 CFU in 0.1 mL). A single intradermal injection is given in the non-dominant arm of each volunteer starting with the lowest MTBVAC dose. Each MTBVAC vaccine dose is administered staggered by cohort, starting with the cohort with the lowest MTBVAC dose level. After at least 35 days of follow-up within each cohort a safety review and evaluation by Independent Data Safety Monitoring Board provides go/no-go for vaccination of the subsequent cohorts if no safety issues as defined by preset stopping rules.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis, Healthy

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MTBVAC group 1

Arm Type

Experimental

Arm Description

Intervention: MTBVAC live vaccine (low dose 5 x 10E03 CFU/0.1mL)

Arm Title

MTBVAC Group 2

Arm Type

Experimental

Arm Description

Intervention: MTBVAC live vaccine (middle dose 5 x 10E04 CFU/0.1mL)

Arm Title

MTBVAC Group 3

Arm Type

Experimental

Arm Description

Intervention: MTBVAC live vaccine (high dose 5 x 10E05 CFU/0.1mL)

Arm Title

BCG Control Group

Arm Type

Active Comparator

Arm Description

Intervention: Commercially available BCG live vaccine (dose 5 x 10E05 CFU/0.1mL)

Intervention Type

Biological

Intervention Name(s)

MTBVAC live vaccine

Intervention Description

Live-attenuated Mycobacterium tuberculosis vaccine

Intervention Type

Biological

Intervention Name(s)

Commercially available BCG live vaccine

Intervention Description

Live-attenuated Mycobacterium bovis vaccine

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events up to 210 Days After Vaccination

Description

Time Frame

7 months follow up

Secondary Outcome Measure Information:

Title

Number of Participants With Three-cytokine-positive CD4+ T-cell Response

Description

Measure of the kinetics of CD4+ T-cell responses to MTBVAC or BCG vaccination by tracking the expression of IFNγ, TNFα and IL-2 upon stimulation with live MTBVAC or BCG

Time Frame

Day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subjects who the Investigator believes that they can and will comply with the requirements of the protocol Subjects who have no evidence of exposition to BCG as demonstrated by a ELISPOT PPD assay along with no history of BCG vaccination and no BCG scar A male or female between, and including, 18 and 45 years of age at the time of the vaccination. Written informed consent obtained from the subject prior to any study procedure. If the subject is female, she must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception Clinically acceptable laboratory values for blood tests. Seronegative for human immunodeficiency virus 1 and -2 (HIV-1/2) antibodies, p24 antigen, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibodies. No evidence of pulmonary pathology as confirmed by chest X-ray. No history of extrapulmonary TB. No history of previous contact with M. tuberculosis (latent tuberculosis) as demonstrated by a negative ELISPOT Tb (ESAT-6, CFP10) assay. Exclusion Criteria: History of allergic reactions (significant IgE-mediated events) or anaphylaxis to previous immunisations (any vaccine). History of allergic disease or reactions History of previous administration of experimental Mycobacterium tuberculosis vaccines. Use of any investigational or non-registered product (drug or vaccine) in another experimental protocol other than the study vaccines within 30 days preceding the vaccination, or planned use during the study period. Any chronic drug therapy to be continued during the study period. Chronic administration of immunosuppressors or other immune-modifying drugs. Administration of any immunoglobulins, any immunotherapy and/or any blood products within the three months preceding the vaccination, or planned administrations during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition (including HIV) based on medical history and physical examination. Any condition or history of any acute or chronic illness or medication which, in the opinion of the Investigator, may interfere with the evaluation of the study objectives. A family history of congenital or hereditary immunodeficiency. A stay of more than 2 months in a highly endemic area (e.g. Eastern Europe (Romania, Bulgaria) and low-income countries) within 6 months prior to the screening visit or travel of more than 2 months foreseen in an area of high endemicity after the enrolment into the study. History of any neurologic disorders or seizures. History of chronic alcohol consumption and/or drug abuse. Major congenital defects. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

François Spertini, MD

Organizational Affiliation

Centre Hospitalier Universitaire Vaudois

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centre Hospitalier Universitaire Vaudois

City

Lausanne

State/Province

Canton of Vaud

ZIP/Postal Code

1011

Country

Switzerland

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

23965219

Citation

Arbues A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, Fernandez C, Parra A, Cardona PJ, Vilaplana C, Ausina V, Williams A, Clark S, Malaga W, Guilhot C, Gicquel B, Martin C. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine. 2013 Oct 1;31(42):4867-73. doi: 10.1016/j.vaccine.2013.07.051. Epub 2013 Aug 17.

Results Reference

background

PubMed Identifier

19367339

Citation

Verreck FA, Vervenne RA, Kondova I, van Kralingen KW, Remarque EJ, Braskamp G, van der Werff NM, Kersbergen A, Ottenhoff TH, Heidt PJ, Gilbert SC, Gicquel B, Hill AV, Martin C, McShane H, Thomas AW. MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques. PLoS One. 2009;4(4):e5264. doi: 10.1371/journal.pone.0005264. Epub 2009 Apr 15. Erratum In: PLoS One. 2011;6(2). doi:10.1371/annotation/e599dafd-8208-4655-a792-21cb125f7f66.

Results Reference

background

PubMed Identifier

18946503

Citation

Gonzalo-Asensio J, Mostowy S, Harders-Westerveen J, Huygen K, Hernandez-Pando R, Thole J, Behr M, Gicquel B, Martin C. PhoP: a missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence. PLoS One. 2008;3(10):e3496. doi: 10.1371/journal.pone.0003496. Epub 2008 Oct 23.

Results Reference

background

PubMed Identifier

16564606

Citation

Martin C, Williams A, Hernandez-Pando R, Cardona PJ, Gormley E, Bordat Y, Soto CY, Clark SO, Hatch GJ, Aguilar D, Ausina V, Gicquel B. The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs. Vaccine. 2006 Apr 24;24(17):3408-19. doi: 10.1016/j.vaccine.2006.03.017.

Results Reference

background

PubMed Identifier

11454210

Citation

Perez E, Samper S, Bordas Y, Guilhot C, Gicquel B, Martin C. An essential role for phoP in Mycobacterium tuberculosis virulence. Mol Microbiol. 2001 Jul;41(1):179-87. doi: 10.1046/j.1365-2958.2001.02500.x.

Results Reference

background

PubMed Identifier

26598141

Citation

Spertini F, Audran R, Chakour R, Karoui O, Steiner-Monard V, Thierry AC, Mayor CE, Rettby N, Jaton K, Vallotton L, Lazor-Blanchet C, Doce J, Puentes E, Marinova D, Aguilo N, Martin C. Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. Lancet Respir Med. 2015 Dec;3(12):953-62. doi: 10.1016/S2213-2600(15)00435-X. Epub 2015 Nov 17.

Results Reference

result

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Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine.

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