Safety of RUTI® Vaccination in MDR-TB Patients

• ClinicalTrials.gov Identifier: NCT02711735
• Recruitment Status: Terminated
• First Posted: March 17, 2016
• Last Update Posted: July 5, 2022
• Sponsor: Archivel Farma S.L.
• Collaborator: London School of Hygiene and Tropical Medicine
• Information provided by (Responsible Party): Archivel Farma S.L.

Tracking Information

• First Submitted Date: February 25, 2016
• First Posted Date: March 17, 2016
• Last Update Posted Date: July 5, 2022
• Actual Study Start Date: March 18, 2020
• Actual Primary Completion Date: September 9, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 16, 2016)

Clinical safety parameters related to vaccination [ Time Frame: 8 weeks ]

Safety Evaluation: Physical examination, SAEs, routine laboratory, chest radiography, between the intervention and control group within 8 weeks after vaccination.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 16, 2016)

• IFN-y release of PBMCs in response to antigen stimulation [ Time Frame: 8 weeks ]
  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)
• Mycobacterial Growth Inhibition Assay [ Time Frame: 8 weeks ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety of RUTI® Vaccination in MDR-TB Patients
• 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.
• Brief 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.
• Detailed 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)
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: 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.
• Biological: Matching RUTI® Placebo
  Participants randomised to this arm will receive aone single dose of matching RUTI® placebo in the right / left deltoid

Study Arms

• Active Comparator: RUTI® vaccine
  Intervention: Patients randomized to receive RUTI® vaccine will receive one injection of RUTI® vaccine in their right or left deltoid muscle.
  Intervention: Biological: RUTI® Therapeutic vaccine
• Placebo Comparator: Matching RUTI® Placebo
  Intervention: Patients randomized to receive Placebo will receive one injection of Placebo in their right or left deltoid muscle.
  Intervention: Biological: Matching RUTI® Placebo

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 30, 2022): 9
• Original Estimated Enrollment (submitted: March 16, 2016): 27
• Actual Study Completion Date: September 9, 2020
• Actual Primary Completion Date: September 9, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Ukraine

Administrative Information

• NCT Number: NCT02711735
• Other Study ID Numbers: 201600136; 2016-000850-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol

• Current Responsible Party: Archivel Farma S.L.
• Original Responsible Party: Tjip van der Werf, University Medical Center Groningen, Prof dr Tjip S van der Werf
• Current Study Sponsor: Archivel Farma S.L.
• Original Study Sponsor: University Medical Center Groningen
• Collaborators: London School of Hygiene and Tropical Medicine

Investigators

• Principal Investigator: Tjip S van der Werf, MD PhD; University Medical Center Groningen, The Netherlands

• PRS Account: Archivel Farma S.L.
• Verification Date: June 2022