Safety of RUTI® Vaccination in MDR-TB Patients
Safety of RUTI® Vaccination in MDR-TB Patients
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 12 weeks upon start of standard MDR-TB treatment (cohort B).
 All the patients will be followed up 8 weeks after vaccination.
Inclusion Criteria:

 -  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 enrollment 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,

 -  MDR-TB patients with Mycobacterium tuberculosis (or Mycobacterium africanum) by
 culture, at least also present in sputum;

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

 -  Having successfully completed 16 or 12 weeks (depending on the cohort) of MDR-TB
 treatment, fully supervised, and

 -  with beneficial initial response to therapy, evidenced by

 -  clinical response criteria: in patients initially presenting with three classical
 symptoms (weight loss, chronic cough, fever or night sweats), clinical
 improvement should be recorded in at least two of three symptoms at least 4 weeks
 apart; in patients with only two of these symptoms present initially, patients
 should show improvement in at least one symptom, at least 4 weeks apart; and in
 addition, patients should not develop clinical deterioration - i.e., on-going
 weight loss, or increased cough, or new-onset fever or night sweats. In addition,
 the attending physician should ascertain an overall clinical beneficial response
 to treatment. 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 Data Safety Monitoring Board; evidence of improvement on chest
 x-ray.

 -  Microbiological response criteria: as evidenced by improvement in at least 2
 measurements at least 4 weeks apart, using Mycobacterial Growth Indicator Tube
 (liquid culture microbiological assay read at 10 days)

 Exclusion Criteria:

 -  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 New York Heart Association class 2; a
 diagnosis of metastasized malignancy; renal failure in excess of creatinine clearance
 < 30 mls/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 (Body Mass Index >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 bilirubin > 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 < 350 copies/mL; those with >350 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.