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Safety of RUTI® Vaccination in MDR-TB Patients

Primary Purpose

Tuberculosis, Multidrug Resistant

Status
Terminated
Phase
Phase 2
Locations
Ukraine
Study Type
Interventional
Intervention
RUTI® Therapeutic vaccine
Matching RUTI® Placebo
Sponsored by
Archivel Farma S.L.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis, Multidrug Resistant

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • "Chernivtsi Regional Clinical TB Dispensary", II tuberculosis department of multidrug-resistant tuberculosis
  • "Ivano-Frankivsk Regional Phthisiopulmonology Center of Ivano-Frankivsk Regional Council", Center for Pulmonary Diseases
  • Medical Department #2 (resistant tuberculosis) of Kharkiv Regional Antituberculosis Dispensary No1

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

RUTI® vaccine

Matching RUTI® Placebo

Arm Description

Intervention: Patients randomized to receive RUTI® vaccine will receive one injection of RUTI® vaccine in their right or left deltoid muscle.

Intervention: Patients randomized to receive Placebo will receive one injection of Placebo in their right or left deltoid muscle.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)
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.

Full Information

First Posted
February 25, 2016
Last Updated
June 30, 2022
Sponsor
Archivel Farma S.L.
Collaborators
London School of Hygiene and Tropical Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT02711735
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.
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Terminated
Why Stopped
Lack of recruitment
Study Start Date
March 18, 2020 (Actual)
Primary Completion Date
September 9, 2020 (Actual)
Study Completion Date
September 9, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Archivel Farma S.L.
Collaborators
London School of Hygiene and Tropical Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Multidrug Resistant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RUTI® vaccine
Arm Type
Active Comparator
Arm Description
Intervention: Patients randomized to receive RUTI® vaccine will receive one injection of RUTI® vaccine in their right or left deltoid muscle.
Arm Title
Matching RUTI® Placebo
Arm Type
Placebo Comparator
Arm Description
Intervention: Patients randomized to receive Placebo will receive one injection of Placebo in their right or left deltoid muscle.
Intervention Type
Biological
Intervention Name(s)
RUTI® Therapeutic vaccine
Intervention Description
Participants randomised to this arm will receive one single dose of RUTI® vaccine in the right/left deltoid muscle.
Intervention Type
Biological
Intervention Name(s)
Matching RUTI® Placebo
Intervention Description
Participants randomised to this arm will receive aone single dose of matching RUTI® placebo in the right / left deltoid
Primary Outcome Measure Information:
Title
Clinical safety parameters related to vaccination
Description
Safety Evaluation: Physical examination, SAEs, routine laboratory, chest radiography, between the intervention and control group within 8 weeks after vaccination.
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
IFN-y release of PBMCs in response to antigen stimulation
Description
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)
Time Frame
8 weeks
Title
Mycobacterial Growth Inhibition Assay
Description
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.
Time Frame
8 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tjip S van der Werf, MD PhD
Organizational Affiliation
University Medical Center Groningen, The Netherlands
Official's Role
Principal Investigator
Facility Information:
Facility Name
"Chernivtsi Regional Clinical TB Dispensary", II tuberculosis department of multidrug-resistant tuberculosis
City
Chernivtsi
ZIP/Postal Code
58000
Country
Ukraine
Facility Name
"Ivano-Frankivsk Regional Phthisiopulmonology Center of Ivano-Frankivsk Regional Council", Center for Pulmonary Diseases
City
Ivano-Frankivs'k
ZIP/Postal Code
76018
Country
Ukraine
Facility Name
Medical Department #2 (resistant tuberculosis) of Kharkiv Regional Antituberculosis Dispensary No1
City
Kharkiv
ZIP/Postal Code
61096
Country
Ukraine

12. IPD Sharing Statement

Plan to Share IPD
Yes
Citations:
PubMed Identifier
19853680
Citation
Vilaplana C, Montane 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.
Results Reference
background
PubMed Identifier
24586912
Citation
Nell AS, D'lom E, Bouic P, Sabate 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.
Results Reference
background

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Safety of RUTI® Vaccination in MDR-TB Patients

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