Safety of RUTI® Vaccination in MDR-TB Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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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.

Conditions
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Tuberculosis, Multidrug Resistant

Intervention / Treatment
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* Biological: RUTI® Therapeutic vaccine
* Biological: Matching RUTI® Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RUTI® vaccine<br>Intervention: Patients randomized to receive RUTI® vaccine will receive one injection of RUTI® vaccine in their right or left deltoid muscle. | Biological: RUTI® Therapeutic vaccine<br>* Participants randomised to this arm will receive one single dose of RUTI® vaccine in the right/left deltoid muscle.<br>|
| Placebo Comparator: Matching RUTI® Placebo<br>Intervention: Patients randomized to receive Placebo will receive one injection of Placebo in their right or left deltoid muscle. | Biological: Matching RUTI® Placebo<br>* Participants randomised to this arm will receive aone single dose of matching RUTI® placebo in the right / left deltoid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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-γ production of ex vivo stimulated peripheral blood mononuclear cells (PBMC) | 8 weeks | 
| 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 |