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

• Sponsor: Biofabri, S.L (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02013245
• Collaborator: Universidad de Zaragoza (Other), Centre Hospitalier Universitaire Vaudois (Other), TuBerculosis Vaccine Initiative (Other)
• Enrollment: 36
• Location: 1
• Arms: 4
• Duration (Months): 22
• Patients Per Site Per Month: 1.6

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis; Healthy	Biological: MTBVAC live vaccine; Biological: Commercially available BCG live vaccine	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• 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 Start Date: Jan 1, 2013
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MTBVAC group 1 Intervention: MTBVAC live vaccine (low dose 5 x 10E03 CFU/0.1mL)	Biological: MTBVAC live vaccine; Live-attenuated Mycobacterium tuberculosis vaccine
Experimental: MTBVAC Group 2 Intervention: MTBVAC live vaccine (middle dose 5 x 10E04 CFU/0.1mL)	Biological: MTBVAC live vaccine; Live-attenuated Mycobacterium tuberculosis vaccine
Experimental: MTBVAC Group 3 Intervention: MTBVAC live vaccine (high dose 5 x 10E05 CFU/0.1mL)	Biological: MTBVAC live vaccine; Live-attenuated Mycobacterium tuberculosis vaccine
Active Comparator: BCG Control Group Intervention: Commercially available BCG live vaccine (dose 5 x 10E05 CFU/0.1mL)	Biological: Commercially available BCG live vaccine; Live-attenuated Mycobacterium bovis vaccine

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events up to 210 Days After Vaccination [7 months follow up]

   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

1. Number of Participants With Three-cytokine-positive CD4+ T-cell Response [Day 28]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre Hospitalier Universitaire Vaudois	Lausanne	Canton of Vaud	Switzerland	1011

Sponsors and Collaborators

• Biofabri, S.L
• Universidad de Zaragoza
• Centre Hospitalier Universitaire Vaudois
• TuBerculosis Vaccine Initiative

Investigators

• Principal Investigator: François Spertini, MD, Centre Hospitalier Universitaire Vaudois

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• Gonzalo-Asensio J, Mostowy S, Harders-Westerveen J, Huygen K, Hernández-Pando R, Thole J, Behr M, Gicquel B, Martín 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.
• 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.
• Pérez E, Samper S, Bordas Y, Guilhot C, Gicquel B, Martín C. An essential role for phoP in Mycobacterium tuberculosis virulence. Mol Microbiol. 2001 Jul;41(1):179-87.
• 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.

• Responsible Party: Biofabri, S.L
• ClinicalTrials.gov Identifier: NCT02013245
• Other Study ID Numbers: MTBVAC-01
• First Posted: Dec 17, 2013
• Last Update Posted: Mar 24, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Tuberculosis; Vaccines

Study Results

Participant Flow

Arm/Group Title	MTBVAC Group 1	MTBVAC Group 2	MTBVAC Group 3	BCG Control Group
Arm/Group Description	Intervention: MTBVAC live vaccine (low dose 5 x 10^3 CFU)	Intervention: MTBVAC live vaccine (middle dose 5 x 10^4 CFU)	Intervention: MTBVAC live vaccine (high dose 5 x 10^5 CFU)	Intervention: Commercially available BCG live vaccine (dose 5 x 10^5 CFU)
Period Title: Overall Study
STARTED	9	9	9	9
COMPLETED	9	8	9	9
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Group 3	BCG Control Group	Total
Arm/Group Description	MTBVAC low dose group (5 x 10^3 CFU MTBVAC)	MTBVAC intermediate dose group (5 x 10^4 CFU MTBVAC)	MTBVAC high dose group (5 x 10^5 CFU MTBVAC)	BCG standard dose group (5 x 10^5 CFU BCG)	Total of all reporting groups
Overall Participants	9	9	9	9	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	9 100%	9 100%	9 100%	9 100%	36 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28 (9.6)	28.2 (3.2)	27.1 (6.1)	25.6 (3.4)	27.2 (6.0)
Sex: Female, Male (Count of Participants)
Female	3 33.3%	6 66.7%	7 77.8%	6 66.7%	22 61.1%
Male	6 66.7%	3 33.3%	2 22.2%	3 33.3%	14 38.9%
Region of Enrollment (participants) [Number]
Switzerland	9 100%	9 100%	9 100%	9 100%	36 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events up to 210 Days After Vaccination
Description	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
Time Frame	7 months follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MTBVAC Group 1	MTBVAC Group 2	MTBVAC Group 3	BCG Control Group
Arm/Group Description	Intervention: MTBVAC live vaccine (low dose 5 x 10^3 CFU)	Intervention: MTBVAC live vaccine (middle dose 5 x 10^4 CFU)	Intervention: MTBVAC live vaccine (high dose 5 x 10^5 CFU)	Intervention: Commercially available BCg live vaccine (standard dose 5 x 10^5 CFU)
Measure Participants	9	9	9	9
Number [participants]	9 100%	9 100%	9 100%	9 100%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Number of Participants with Three-cytokine-positive CD4+ T-cell Response (per protocol analysis)

Arm/Group Title	MTBVAC Group 1	MTBVAC Group 2	MTBVAC Group 3	BCG Control Group
Arm/Group Description	Intervention: MTBVAC live vaccine (low dose 5 x 10^3 CFU)	Intervention: MTBVAC live vaccine (middle dose 5 x 10^4 CFU)	Intervention: MTBVAC live vaccine (high dose 5 x 10^5 CFU)	Intervention: Commercially available BCg live vaccine (standard dose 5 x 10^5 CFU)
Measure Participants	9	8	9	9
Number [participants]	0 0%	0 0%	4 44.4%	1 11.1%

Adverse Events

Time Frame	Solicited local and systemic adverse events: within 7 days of vaccination (diary card). Unsolicited local and systemic adverse events at days 0, 7, 28, 56, 90, 150 and 210
Adverse Event Reporting Description	Safety was assessed based on a collection of solicited local (injection site pain, erythema, induration, pruritus and discharges) and systemic (fever, headache, fatigue, musculoskeletal pains, gastrointestinal symptoms) adverse events (AEs) within 7 days of vaccination (diary card). Unsolicited local and systemic AEs as well as serious AEs (SAEs) were collected during the entire study period.
Arm/Group Title	MTBVAC Group 1		MTBVAC Group 2		MTBVAC Group 3		BCG Control Group
Arm/Group Description	Intervention: MTBVAC live vaccine (low dose 5 x 10^3 CFU)		Intervention: MTBVAC live vaccine (middle dose 5 x 10^4 CFU)		Intervention: MTBVAC live vaccine (high dose 5 x 10^5 CFU)		Intervention: Commercially available BCG live vaccine (standard dose 5 x 10^5 CFU)
All Cause Mortality
	MTBVAC Group 1		MTBVAC Group 2		MTBVAC Group 3		BCG Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MTBVAC Group 1		MTBVAC Group 2		MTBVAC Group 3		BCG Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)		0/9 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	MTBVAC Group 1		MTBVAC Group 2		MTBVAC Group 3		BCG Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		9/9 (100%)		9/9 (100%)		9/9 (100%)
Gastrointestinal disorders
Digestive	1/9 (11.1%)		3/9 (33.3%)		2/9 (22.2%)		3/9 (33.3%)
General disorders
Headache	5/9 (55.6%)		4/9 (44.4%)		3/9 (33.3%)		3/9 (33.3%)
Fatigue	7/9 (77.8%)		4/9 (44.4%)		3/9 (33.3%)		4/9 (44.4%)
Fever	1/9 (11.1%)		4/9 (44.4%)		3/9 (33.3%)		1/9 (11.1%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	5/9 (55.6%)		2/9 (22.2%)		5/9 (55.6%)		2/9 (22.2%)
Skin and subcutaneous tissue disorders
Pain at injection site	3/9 (33.3%)		5/9 (55.6%)		5/9 (55.6%)		8/9 (88.9%)
Erythema	5/9 (55.6%)		8/9 (88.9%)		8/9 (88.9%)		7/9 (77.8%)
Induration	5/9 (55.6%)		7/9 (77.8%)		8/9 (88.9%)		9/9 (100%)
Pruritis	3/9 (33.3%)		3/9 (33.3%)		1/9 (11.1%)		2/9 (22.2%)
Discharge	0/9 (0%)		0/9 (0%)		2/9 (22.2%)		4/9 (44.4%)

Limitations/Caveats

This is a first-in-human Phase 1 trial designed to evaluate the safety and tolerability profile of MTBVAC in comparison to BCG.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.