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

• ClinicalTrials.gov Identifier: NCT02013245
• Recruitment Status: Completed
• First Posted: December 17, 2013
• Results First Posted: March 24, 2017
• Last Update Posted: March 24, 2017
• Sponsor: Biofabri, S.L
• Collaborators: Universidad de Zaragoza; Centre Hospitalier Universitaire Vaudois; TuBerculosis Vaccine Initiative
• Information provided by (Responsible Party): Biofabri, S.L

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Conditions: Tuberculosis; Healthy
• Interventions: Biological: MTBVAC live vaccine; Biological: Commercially available BCG live vaccine
• Enrollment: 36

Participant Flow

Recruitment Details
Pre-assignment Details

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 Number of Baseline Participants		9	9	9	9	36
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	9 participants	9 participants	36 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	9 100.0%	9 100.0%	9 100.0%	9 100.0%	36 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	9 participants	9 participants	9 participants	9 participants	36 participants
		28 (9.6)	28.2 (3.2)	27.1 (6.1)	25.6 (3.4)	27.2 (6.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	9 participants	9 participants	36 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; Measure Type: Number; Unit of measure: Participants
Switzerland	Number Analyzed	9 participants	9 participants	9 participants	9 participants	36 participants
		9	9	9	9	36

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)
Overall Number of Participants Analyzed	9	9	9	9
Measure Type: Number; Unit of Measure: participants
	9	9	9	9

2. Secondary Outcome

Title	Number of Participants With Three-cytokine-positive CD4+ T-cell Response
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)
Overall Number of Participants Analyzed	9	8	9	9
Measure Type: Number; Unit of Measure: participants
	0	0	4	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 (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	MTBVAC Group 1	MTBVAC Group 2	MTBVAC Group 3	BCG Control Group
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/9 (0.00%)	0/9 (0.00%)	0/9 (0.00%)	0/9 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	MTBVAC Group 1	MTBVAC Group 2	MTBVAC Group 3	BCG Control Group
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	9/9 (100.00%)	9/9 (100.00%)	9/9 (100.00%)	9/9 (100.00%)
Gastrointestinal disorders
Digestive †	1/9 (11.11%)	3/9 (33.33%)	2/9 (22.22%)	3/9 (33.33%)
General disorders
Headache † [1]	5/9 (55.56%)	4/9 (44.44%)	3/9 (33.33%)	3/9 (33.33%)
Fatigue †	7/9 (77.78%)	4/9 (44.44%)	3/9 (33.33%)	4/9 (44.44%)
Fever †	1/9 (11.11%)	4/9 (44.44%)	3/9 (33.33%)	1/9 (11.11%)
Musculoskeletal and connective tissue disorders
Musculoskeletal † [2]	5/9 (55.56%)	2/9 (22.22%)	5/9 (55.56%)	2/9 (22.22%)
Skin and subcutaneous tissue disorders
Pain at injection site † [3]	3/9 (33.33%)	5/9 (55.56%)	5/9 (55.56%)	8/9 (88.89%)
Erythema † [4]	5/9 (55.56%)	8/9 (88.89%)	8/9 (88.89%)	7/9 (77.78%)
Induration † [5]	5/9 (55.56%)	7/9 (77.78%)	8/9 (88.89%)	9/9 (100.00%)
Pruritis † [6]	3/9 (33.33%)	3/9 (33.33%)	1/9 (11.11%)	2/9 (22.22%)
Discharge † [7]	0/9 (0.00%)	0/9 (0.00%)	2/9 (22.22%)	4/9 (44.44%)
† Indicates events were collected by systematic assessment; [1] General headache related or unrelated to vaccination; [2] Musculoskeletal pain; [3] Pain at injection site; [4] Erythema at injection site; [5] Induration at injection site; [6] Pruritis at site of injection; [7] Discharge from site of injection

Limitations and 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.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. François Spertini, Associate Professor, Division Immunology & Allergy
• Organization: Centre Hospitalier Universitaire Vaudois (CHUV)
• Phone: +41 21 31 40 799
• EMail: Francois.Spertini@chuv.ch

Publications of Results:

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.

Other 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.

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.

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.

• Responsible Party: Biofabri, S.L
• ClinicalTrials.gov Identifier: NCT02013245
• Other Study ID Numbers: MTBVAC-01
• First Submitted: December 3, 2013
• First Posted: December 17, 2013
• Results First Submitted: March 15, 2016
• Results First Posted: March 24, 2017
• Last Update Posted: March 24, 2017