Safety of RUTI® Vaccination in MDR-TB Patients

Tuberculosis, Multidrug Resistant Clinical Trial

Official title:

Double-Blind, Randomized, Placebo-Controlled Phase IIa Clinical Trial to Investigate the Safety and Immunogenicity of RUTI® Therapeutic Vaccination in Patients With MDR-TB After Successful Intensive-phase Treatment.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02711735
• Other study ID #: 201600136
• Secondary ID: 2016-000850-36
• Status: Terminated
• Phase: Phase 2
• Start date: March 18, 2020
• Est. completion date: September 9, 2020

Study information

• Verified date: June 2022
• Source: Archivel Farma S.L.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Prospective, randomized, double-blind, multicentre, placebo-controlled clinical phase IIa trial to evaluate safety and immunogenicity of RUTI® vaccine in Multidrug-resistant Tuberculosis (MDR-TB) patients favourably responding to standard MDR-TB treatment. Time point of vaccination starts at 16 weeks upon start of standard MDR-TB treatment (cohort A), and if clinically safe as evaluated by an independent panel of experts (DSMB), another cohort of patients will be vaccinated at 2 weeks upon start of standard MDR-TB treatment (cohort B), All the patients will be followed up 8 weeks after vaccination.

Description:

Prospective, randomized, double-blind, multicentre, placebo-controlled clinical phase IIa trial to evaluate safety and immunogenicity of RUTI® vaccine in Multidrug-resistant Tuberculosis (MDR-TB) patients favourably responding to standard MDR-TB treatment. Time point of vaccination starts at 16 weeks upon start of standard MDR-TB treatment (cohort A), and if clinically safe as evaluated by an independent panel of experts (DSMB), another cohort of patients will be vaccinated at 2 weeks upon start of standard MDR-TB treatment (cohort B)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: September 9, 2020
• Est. primary completion date: September 9, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria

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

• Diagnosed with pulmonary MDR-TB, and therefore managed with second line TB drugs;

• Admitted in a TB unit / hospital routinely diagnosed with pulmonary MDR-TB with clinical status = 6 with Bandim TB score combined with chest radiography; and microbiological criteria according to the medical history), using rapid genetic testing (GeneXpert TB test) and MGIT to confirm or Line Probe Assay; or classical diagnostic tools including sputum microscopy and culture followed by phenotypic drug susceptibility testing. All of this medical information will be in the medical history;

• Females and males aged = 18; females of non-childbearing potential: at least 2 years post-menopausal or surgically sterile (e.g. tubal ligation); females of childbearing potential (including females less than 2 years post-menopausal) must have a negative pregnancy test at enrolment and must agree to use highly effective methods of birth control (i.e. diaphragm plus spermicide or male condom plus spermicide, oral contraceptive in combination with a second method, contraceptive implant, injectable contraceptive, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in the study and for 30 days after end of the study for each group; males must agree to use a double barrier method of contraception (condom plus spermicide or diaphragm plus spermicide) while participating in the study and for 30 days after end of the study for the respective group; or the male patient or his female partner must be surgically sterile (e.g. vasectomy, tubal ligation) or the female partner must be post-menopausal;

• The patient must provide written informed consent;

• The patient must be willing and able to attend all study visits and comply with all study procedures.

Inclusion criteria for vaccination

• Having successfully completed 16, 8 or 4 weeks (depending on the cohort) of MDR-TB treatment, fully supervised, and

• With beneficial initial response to therapy, evidenced by:

Clinical response criteria: patients admitted in a TB unit / hospital routinely diagnosed with pulmonary MDR-TB (according to clinical status = 5 with Bandim TB score) (33).

Transient deterioration of chest radiographic abnormalities might be explained by a paradoxical inflammatory response, and this may therefore not necessarily be interpreted as treatment failure; such decision depends on consensus with the DSMB; evidence of improvement on chest x-ray.

• Microbiological response criteria: It has to be reported a reduction of the bacillary load in the sputum by means of the reduction of bacillary counts in GeneXpert TB test and liquid culture (MGIT) to confirm (diagnosis week 0 collected in the medical history) at week 4 in CohortsC, week 8 in both Cohorts (A-B) and week 12 and 16 in Cohort A.

Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Inability to provide written informed consent;

• Women reported, or detected, or willing to be pregnant during the trial period;

• Severity of illness precluding full evaluation: expected early death, evidenced by respiratory failure, low blood pressure, WHO performance score 3-4; Central Nervous System involvement of TB (TB meningitis, intra-cranial tuberculomas) as there is too little evidence for effective drug penetration for second-line TB drugs;

• Major co-morbid conditions precluding full evaluation, i.e., active lung cancer, acute coronary syndrome, heart failure exceeding NYHA class 2; a diagnosis of metastasized malignancy; renal failure in excess of creatinine clearance < 30 mL/min calculated by the Cockcroft-Gault formula, which would severely complicate administration of aminoglycosides and capreomycin, considered as the major second-line TB drugs; obesity (BMI>30 kg/m2); chronic liver disease - Child-Pugh class C;

• Any of the following laboratory parameters:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) Total bilirubine > 2 x ULN Neutrophil count = 500 neutrophils / mm3 Platelet count < 50,000 cells / mm3

• Receiving or anticipated to receive a daily dose of = 10 mg of systemic prednisone or equivalent within the period starting 14 days prior to enrolment. Note: patients are allowed to receive an acute, short course of methylprednisolone or prednisone or equivalent for management of an acute exacerbation of COPD or reactive airway disease in asthmatics;

• Cytotoxic chemotherapy or radiation therapy within the previous 3 months;

• HIV co-infection, if CD4 count < 250 cells/mm3 at the diagnosis of HIV; those with > 250 copies/mL are expected to be able to mount a sufficient cellular immune response and will therefore be eligible;

• Blood transfusion in the last three weeks prior to the trial;

• Documented allergy to TB vaccines, notably, to the RUTI® vaccine.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Multidrug Resistant
• Tuberculosis, Multidrug-Resistant

Intervention

Biological:
• RUTI® Therapeutic vaccine
Participants randomised to this arm will receive one single dose of RUTI® vaccine in the right/left deltoid muscle.
• Matching RUTI® Placebo
Participants randomised to this arm will receive aone single dose of matching RUTI® placebo in the right / left deltoid

Locations

Country	Name	City	State
Ukraine	"Chernivtsi Regional Clinical TB Dispensary", II tuberculosis department of multidrug-resistant tuberculosis	Chernivtsi
Ukraine	"Ivano-Frankivsk Regional Phthisiopulmonology Center of Ivano-Frankivsk Regional Council", Center for Pulmonary Diseases	Ivano-Frankivs'k
Ukraine	Medical Department #2 (resistant tuberculosis) of Kharkiv Regional Antituberculosis Dispensary No1	Kharkiv

Sponsors (2)

Lead Sponsor	Collaborator
Archivel Farma S.L.	London School of Hygiene and Tropical Medicine

Country where clinical trial is conducted

Ukraine, 

References & Publications (2)

Nell AS, D'lom E, Bouic P, Sabaté M, Bosser R, Picas J, Amat M, Churchyard G, Cardona PJ. Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection. PLoS One. 2014 Feb 26;9(2):e89612. doi: 10.1371/journal.pone.0089612. eCollection 2014. — View Citation

Vilaplana C, Montané E, Pinto S, Barriocanal AM, Domenech G, Torres F, Cardona PJ, Costa J. Double-blind, randomized, placebo-controlled Phase I Clinical Trial of the therapeutical antituberculous vaccine RUTI. Vaccine. 2010 Jan 22;28(4):1106-16. doi: 10.1016/j.vaccine.2009.09.134. Epub 2009 Oct 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical safety parameters related to vaccination	Safety Evaluation: Physical examination, SAEs, routine laboratory, chest radiography, between the intervention and control group within 8 weeks after vaccination.	8 weeks
Secondary	IFN-y release of PBMCs in response to antigen stimulation	Immunogenicity Evaluation: Immunogenic properties of RUTI® vaccine (before vaccination and at week 2 and 8 after vaccination) compared to placebo assessed by i) IFN-? production of ex vivo stimulated peripheral blood mononuclear cells (PBMC)	8 weeks
Secondary	Mycobacterial Growth Inhibition Assay	Immunogenicity Evaluation: Immunogenic properties of RUTI® vaccine (before vaccination and at week 2 and 8 after vaccination) compared to placebo assessed by the summative ability of PBMCs to control mycobacterial growth in an ex vivo system.	8 weeks