Clinical Trial to Study 4 Different Doses of the Vaccine RUTI in Healthy Volunteers

• Sponsor: Germans Trias i Pujol Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00546273
• Collaborator: Archivel Farma S.L. (Industry)
• Enrollment: 24
• Locations: 3
• Arms: 5
• Duration (Months): 14
• Patients Per Site: 8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The aim of this study is to evaluate the safety of a new vaccine against Tuberculosis (RUTI) when administered to healthy adult volunteers, compared to placebo; and determine its safe dosage range. An initial evaluation of immune responses to the vaccine compared to placebo will also be undertaken.

In the present Phase I clinical trial, four increasing doses of RUTI will be tested, the groups composed by 6 volunteers each. (Total of 24 volunteers). The escalation to a new dose to test will be done after the safety of the previous dose has been ensured.

For each dose of FCMtb to test, each volunteer will be inoculated twice (at day 0 and day 28) with RUTI (4 volunteers) or placebo (2 volunteers) and will be followed-up up to 25 weeks from the first inoculation. The global length of the study will be approximately 15 months.

Condition or Disease	Intervention/Treatment	Phase
Latent Tuberculosis Infection; Tuberculosis	Biological: RUTI; Biological: RUTI; Biological: RUTI; Biological: RUTI; Biological: placebo of the vaccine RUTI	Phase 1

Detailed Description

RUTI is a therapeutic vaccine made from virulent M.tuberculosis bacteria, grown in stressful conditions, fragmented, detoxified, heat inactivated (FCMtb) and liposomed. RUTI provides a strong humoral and cellular immune response against antigens from active growing and latent bacilli but also against structural antigens, as it has been proved in animal models of latent tuberculosis infection. The vaccine has been designed to be used against Latent Tuberculosis Infection as a therapeutic vaccine after 1-month of chemotheraputic treatment, instead the current treatment based on 6-9 months of chemotherapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double-Blind, Randomized, Placebo-Controlled Phase I Study, to Study the Tolerability and Immunogenicity of 4 RUTI Antituberculous Vaccine Different Doses (5, 25, 100 y 200µg of FCMtb) in Healthy Volunteers
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RUTI 5 micrograms of FCMtb RUTI dose: 5 micrograms of FCMtb (for fragmented cells of M. tuberculosis) (n=4)	Biological: RUTI; dose: 5 micrograms of FCMtb; given subcutaneously twice, on days 0 and 28; Other Names: FCMtb is the active compound of the vaccine RUTI
Experimental: RUTI 25 micrograms of FCMtb RUTI dose: 25 micrograms of FCMtb (for fragmented cells of M. tuberculosis) (n=4)	Biological: RUTI; dose: 25 micrograms of FCMtb; given subcutaneously twice, on days 0 and 28; Other Names: FCMtb is the active compound of the vaccine RUTI
Experimental: RUTI 100 micrograms of FCMtb RUTI dose: 100 micrograms of FCMtb (for fragmented cells of M. tuberculosis) (n=4)	Biological: RUTI; dose: 100 micrograms of FCMtb; given subcutaneously twice, on days 0 and 28; Other Names: FCMtb is the active compound of the vaccine RUTI
Experimental: RUTI 200 micrograms of FCMtb RUTI 200 micrograms of FCMtb (for fragmented cells of M. tuberculosis) (n=4)	Biological: RUTI; dose: 200 micrograms of FCMtb; given subcutaneously twice, on days 0 and 28; Other Names: FCMtb is the active compound of the vaccine RUTI
Placebo Comparator: placebo placebo of the vaccine RUTI (total n=8, n=2 for each period)	Biological: placebo of the vaccine RUTI; placebo of the vaccine RUTI given subcutaneously twice, on days 0 and 28; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. VAS Pain Score (Visual Analogic Scale, That Ranges From 0 to 100) to Evaluate Each Volunteer Subjective Pain Intensity at the Inoculation Point [at protocol defined timepoints: days 0, 1, 3, 7, 21, 28, 29, 31, 35, 56]

2. Occurrence, Intensity and Relationship to Vaccination of Local and Systemic Events [during the whole study]

3. Number of Clinically Relevant Abnormalities in the Laboratory Tests According to the Doctors' Impression [at protocol defined timepoints: days 0, 7, 21, 28, 35, 56, 112 & 156]

   haematological and biochemical laboratory tests

Secondary Outcome Measures

1. Evaluation of the Immunogenicity of the Different Doses of the Vaccine Tested [at protocol defined timepoints: days 0, 7, 21, 28, 35, 56, 112 & 156]

   Immunological assays are performed at all timepoints to determine vaccine immunogenicity

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Signed informed consent

• Healthy, based on medical examination at inclusion

• Male Caucasian subjects, aged between 18 and 40 years

• Willing and likely to be able to comply with the trial procedures

Exclusion Criteria:

• Evidence of previous, current or latent tuberculosis, as radiological findings on chest X ray compatible with previous or current infection with tuberculosis

• Positive T-SPOT TB result

• BCG-vaccinated subjects

• History of severe organ-system diseases, including

• History of allergic disorders or known hypersensitivity to any drug or vaccine, or to any of the vaccine to be studied components

• Personal or familiar history of autoimmune diseases, or Positive Antinuclear Antibodies

• HIV, HBV and HCV sero-positive

• Suspected or known current drug and/or alcohol abuse (as defined by an alcohol intake of > 50 g a day

• Lost of more than 400 mL of blood within 12 weeks, or more than 250 mL within 4 weeks, before the recruitment

• Laboratory parameters outside of normal ranges considered clinically significant

• Intake of trial medication in other clinical trials within 1 month of the first vaccination

• Intake of any other drugs that could not be eliminated of the body before the first vaccination, especially anti-inflammatory nonsteroid and corticosteroid drugs

• Acute disease with > 37ºC temperature within 72 hours before the first vaccination

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Experimental Tuberculosis Unit. Fundació Institut per la Investigació Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
2	Hospital Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
3	Pharmacology Department. Hospital Universitari Germans Trias i Pujol.	Badalona	Barcelona	Spain	08916

Sponsors and Collaborators

• Germans Trias i Pujol Hospital
• Archivel Farma S.L.

Investigators

• Principal Investigator: Pere-Joan Cardona, MD, PhD, Unitat de Tuberculosi Experimental. Fundació Institut per la Investigació en Ciències de la Salut Germans Trias i Pujol.
• Principal Investigator: Joan Costa, MD, PhD, Pharmacology Department. Hospital Universitari "Germans Trias i Pujol"

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol homepage

Publications

• Cardona PJ, Amat I, Gordillo S, Arcos V, Guirado E, Díaz J, Vilaplana C, Tapia G, Ausina V. Immunotherapy with fragmented Mycobacterium tuberculosis cells increases the effectiveness of chemotherapy against a chronical infection in a murine model of tuberculosis. Vaccine. 2005 Feb 3;23(11):1393-8.
• Cardona PJ, Amat I. [Origin and development of RUTI, a new therapeutic vaccine against Mycobacterium tuberculosis infection]. Arch Bronconeumol. 2006 Jan;42(1):25-32. Review. Spanish.
• Cardona PJ. RUTI: a new chance to shorten the treatment of latent tuberculosis infection. Tuberculosis (Edinb). 2006 May-Jul;86(3-4):273-89. Epub 2006 Mar 20. Review.
• Gil O, Vilaplana C, Guirado E, Díaz J, Cáceres N, Singh M, Cardona PJ. Enhanced gamma interferon responses of mouse spleen cells following immunotherapy for tuberculosis relapse. Clin Vaccine Immunol. 2008 Nov;15(11):1742-4. doi: 10.1128/CVI.00255-08. Epub 2008 Sep 30.
• Guirado E, Gil O, Cáceres N, Singh M, Vilaplana C, Cardona PJ. Induction of a specific strong polyantigenic cellular immune response after short-term chemotherapy controls bacillary reactivation in murine and guinea pig experimental models of tuberculosis. Clin Vaccine Immunol. 2008 Aug;15(8):1229-37. doi: 10.1128/CVI.00094-08. Epub 2008 Jun 4.
• Vilaplana C, Ruiz-Manzano J, Gil O, Cuchillo F, Montané E, Singh M, Spallek R, Ausina V, Cardona PJ. The tuberculin skin test increases the responses measured by T cell interferon-gamma release assays. Scand J Immunol. 2008 Jun;67(6):610-7. doi: 10.1111/j.1365-3083.2008.02103.x. Epub 2008 Apr 4.

• ClinicalTrials.gov Identifier: NCT00546273
• Other Study ID Numbers: FA/MI/01; EudraCT Number: 2006-000690-29
• First Posted: Oct 18, 2007
• Last Update Posted: May 27, 2009
• Last Verified: May 1, 2009

• Keywords provided by , ,: LTBI (Latent tuberculosis infection); TB(Tuberculosis); Vaccine
• Additional relevant MeSH terms: Tuberculosis; Latent Tuberculosis; Vaccines

Study Results

Participant Flow

Recruitment Details	Four RUTI doses were tested, in a sequencial way (n=6 each). 14 days before starting each level of treatment, subjects, after signing the informed consent, were screened in the Phase 1 Unit (Hospital Germans Trias i Pujol) in order to decide if they were elegible to be part of the study.
Pre-assignment Detail	24 volunteers were enrolled and distributed in 4 groups, one group for every period (each period: 6 new volunteers). There was one period per dose tested, and doses were tested increasingly, not beginning to test one dose until clinically ensured the safety of the previous dose. The double blind was opened at the end of the study.

Arm/Group Title	RUTI 5 Micrograms of FCMtb	RUTI 25 Micrograms of FCMtb	RUTI 100 Micrograms of FCMtb	RUTI 200 Micrograms of FCMtb	Placebo
Arm/Group Description	RUTI dose: 5 micrograms of FCMtb	RUTI dose: 25 micrograms of FCMtb	RUTI dose: 100 micrograms of FCMtb	RUTI dose: 200 micrograms of FCMtb	placebo of the vaccine RUTI, given subcutaneously twice, on days 0 and 28
Period Title: I
STARTED	4	0	0	0	2
COMPLETED	4	0	0	0	2
NOT COMPLETED	0	0	0	0	0
Period Title: I
STARTED	0	4	0	0	2
COMPLETED	0	4	0	0	2
NOT COMPLETED	0	0	0	0	0
Period Title: I
STARTED	0	0	4	0	2
COMPLETED	0	0	4	0	2
NOT COMPLETED	0	0	0	0	0
Period Title: I
STARTED	0	0	0	4	2
COMPLETED	0	0	0	4	2
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	RUTI 5 Micrograms of FCMtb	RUTI 25 Micrograms of FCMtb	RUTI 100 Micrograms of FCMtb	RUTI 200 Micrograms of FCMtb	Placebo	Total
Arm/Group Description	RUTI dose: 5 micrograms of FCMtb	RUTI dose: 25 micrograms of FCMtb	RUTI dose: 100 micrograms of FCMtb	RUTI dose: 200 micrograms of FCMtb	placebo of the vaccine RUTI, given subcutaneously twice, on days 0 and 28	Total of all reporting groups
Overall Participants	4	4	4	4	8	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	4 100%	4 100%	4 100%	4 100%	8 100%	24 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.25 (2.87)	26 (2.94)	23 (2.16)	22.25 (2.22)	24 (4.75)	24.08 (3.46)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	4 100%	4 100%	4 100%	4 100%	8 100%	24 100%
Region of Enrollment (participants) [Number]
Spain	4 100%	4 100%	4 100%	4 100%	8 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	VAS Pain Score (Visual Analogic Scale, That Ranges From 0 to 100) to Evaluate Each Volunteer Subjective Pain Intensity at the Inoculation Point
Time Frame	at protocol defined timepoints: days 0, 1, 3, 7, 21, 28, 29, 31, 35, 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

2. Secondary Outcome

Title	Evaluation of the Immunogenicity of the Different Doses of the Vaccine Tested
Description	Immunological assays are performed at all timepoints to determine vaccine immunogenicity
Time Frame	at protocol defined timepoints: days 0, 7, 21, 28, 35, 56, 112 & 156

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Primary Outcome

Title	Occurrence, Intensity and Relationship to Vaccination of Local and Systemic Events
Time Frame	during the whole study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Primary Outcome

Title	Number of Clinically Relevant Abnormalities in the Laboratory Tests According to the Doctors' Impression
Description	haematological and biochemical laboratory tests
Time Frame	at protocol defined timepoints: days 0, 7, 21, 28, 35, 56, 112 & 156

Outcome Measure Data

Analysis Population Description

All the participants of the study were analyzed for this specific outcome measure.

Arm/Group Title	RUTI 5 Micrograms of FCMtb	RUTI 25 Micrograms of FCMtb	RUTI 100 Micrograms of FCMtb	RUTI 200 Micrograms of FCMtb	Placebo
Arm/Group Description	RUTI dose: 5 micrograms of FCMtb	RUTI dose: 25 micrograms of FCMtb	RUTI dose: 100 micrograms of FCMtb	RUTI dose: 200 micrograms of FCMtb	placebo of the vaccine RUTI, given subcutaneously twice, on days 0 and 28
Measure Participants	4	4	4	4	8
Number [number of abnormalities]	0	0	0	0	0

Adverse Events

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The disclosure of the results has to be previously arranged if mutually agreeable to both investigators and the company manufacturer of the vaccine RUTI: Archivel Farma S.L.