Primary endpoint: Evaluation of the safety of the novel anti-TB vaccine RUTI® (25*g FCMtb) in patients with MDR-TB favourably responding to second-line, standard MDRTB treatment through clinical, microbiological, and radiological response criteria.…
ID
Source
Brief title
Condition
- Mycobacterial infectious disorders
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoint of this study is safety. This will be assessed using
clinical, routine laboratory, and radiographic data obtained during follow-up.
- Local tolerability (limited function, swelling, redness, pain, itch) will be
examined daily during the first week and weekly in the remaining 7 weeks of
follow up.
- Systemic tolerability (body temperature, generalized pruritus, rashes,
arthralgia, myalgia, nausea, malaise, headache) will be assessed daily during
the first week and weekly in the remaining 7 weeks of follow up.
- Vital signs (blood pressure, heart rate, respiratory rate, and pulse
oxymetry) will be taken at screening, immediately before vaccination and at
weeks 1, 2, 3, 4, 6 and 8 during the follow-up.
- Adverse Events raised by patients spontaneously or observed by the study
doctor or attending physician during the study
- Chest X-Rays will be taken before vaccination and at week 8 follow up for
assessment of nature and extent of lung lesions
- Laboratory tests at screening and at weeks 2 and 8 after vaccination:
o full blood count, haematology;
o serum chemistry (liver and kidney function);
o ESR, CRP;
o Glucose
Secondary outcome
Immunogenicity is the secondary study endpoint and the assays will be performed
at the London School of Hygiene and Tropical Medicine, UK. It will be assessed
using
i) IFN-* responses of stimulated Peripheral Blood Mononuclear Cells (PBMCs)
upon stimulation with a panel of antigens comparing placebo and intervention
group at three time points (before vaccination, 2 and 8 weeks
post-vaccination). The technique used is ELISPOT (Enzyme-linked immunosorbent
spot)
ii) Mycobacterial growth inhibition assay (MGIA). This functional
immunogenicity assay measures the summative ability of the patient derived
PBMCs to control the mycobacterial growth in an ex vivo system. Mycobacterial
growth inhibition will be assessed using a BACTEC MGIT (mycobacterial growth
indicator tube; as used for liquid culture) system as well as plate counting to
measure the decrease of bacterial load upon vaccination in the presence of
PBMCs. The assessment will be performed after 4 days of PBMC co-culture with
Mycobacterium bovis BCG as immune target. This is a novel tool to measure
immunogenicity, which has not been used with PBMCs from clinical vaccine trials
before.
Exploratory endpoint: Effect on a clinically relevant endpoint
Difference between the intervention and control group in time to sputum culture
positivity immediately before vaccination and at 8 weeks post-vaccination grown
in liquid culture (MGIT) read at 10 days.
Background summary
The threat and emergence of multidrug-resistant tuberculosis (MDR-TB) is a
European public health priority. While the treatment of MDR-TB can be reduced
to 9-12 months under strict circumstances most of the cases of MDR-TB require
20-24 months of chemotherapy with toxic and expensive second/third-line drugs
and treatment success. Worldwide this treatment is successful in only 50% of
the cases (WHO, Global Tuberculosis Report, 2015, Geneva, Switzerland). Apart
from antibiotic development, alternative therapeutic options are therefore
needed. MDR-TB is caused by strains of M. tuberculosis that have become drug
resistant. With anti TB drugs, most organisms are killed but a sub-population
turns into a persister state under antimicrobial pressure. This phenotype is
similar to the latent form of TB that infects 23% of the worlds population. Due
to their very low metabolism, these persister bacilli cannot be reached by
conventional drug therapy and that is why log-lasting treatment is required to
prevent failure, relapse and reactivation of disease. This equally represents
the key problem why TB is so difficult to eradicate; if immunotherapy should
seem to work in eradicating these persister bacilli this would open
unprecedented opportunities for the elimination of TB and its latent form
worldwide.
The RUTI® vaccine has been developed to evoke an immune response directed at
the molecular signature and antigens expressed by these persister bacilli. It
consists of fragmented and inactivated M. tuberculosis cells grown under stress
conditions to express persister antigens. RUTI® vaccine has been proven
clinically safe and immunogenic in Phase I and II studies in healthy volunteers
and latently TB infected individuals, also in HIV co-infected individuals.
The hypothesis of using RUTI® vaccine as adjunct during standard antibiotic
therapy is that it stimulates host immune effector cells directed at bacilli
that persist under antimicrobial therapy. The ultimate aim is to shorten the
(currently 20-months lasting) treatment duration, and to reduce the chances of
failure and relapse. The first step is assuring that the RUTI® vaccine is safe
in patients with multidrug-resistant (MDR-) TB at two different time points of
vaccination.
Study objective
Primary endpoint: Evaluation of the safety of the novel anti-TB vaccine RUTI®
(25*g FCMtb) in patients with MDR-TB favourably responding to second-line,
standard MDRTB treatment through clinical, microbiological, and radiological
response criteria. The safety will be assessed through standard blood testing
and physical examination.
Secondary endpoint: Evaluation of the immunogenicity of the novel anti-TB
vaccine RUTI® (25*g FCMtb) in patients with MDR-TB favourably responding to
second-line, standard MDRTB treatment as evidenced by i) an ex-vivo IFN-y
ELISPOT assay and ii) a novel Mycobacterial Growth Inhibition Assay (MGIA).
Exploratory endpoint:
To explore the efficacy as the reduction of bacillary load in the sputum of the
novel anti-TB vaccine RUTI® (25*g FCMtb) in patients with MDRTB favourably
responding to TB treatment as evidenced by an increase in time-to-positivity of
liquid culture.
Study design
Prospective, randomized, double-blind, multicentre, placebo-controlled clinical
phase IIa trial to evaluate the safety and immunogenicity of RUTI® vaccine in
MDR-TB patients favourably responding to standard MDR-TB treatment. Cohort A
will receive the experimental vaccination treatment at time point 16 weeks
after start of standard MDR-TB treatment. If clinically safe, as evaluated by
an independent panel of experts (DSMB), the second cohort (cohort B) will be
vaccinated at time point 12 weeks after start of standard MDR-TB treatment. All
the patients will be followed up 8 weeks after vaccination.
Intervention
Study participants will receive once one dose of 25*g of either RUTI® vaccine
or Matching RUTI® Placebo that will be injected subcutaneously at the deltoid
muscle by the attending pulmonologist at 16 weeks upon start of MDR-TB
treatment for Cohort A, and at 12 weeks upon start of MDR-TB treatment for
Cohort B.
Study burden and risks
In previous clinical studies, local adverse events such as swelling, itch, and
redness have been reported. We prevent the unlikely event of an exacerbated
immune response by ensuring that vaccination will be given only when successful
antibiotic therapy is guaranteed by clinical, laboratory, microbiological, and
Chest X-Ray evaluation.
Clinical evaluation: patients will be assessed daily in the first week
post-vaccination and once in week 2, 3, 4, 6 and 8. Each visit will take
between 10-30 minutes. For immunogenicity read-out 40 ml (equal to 8 spoons)
will be drawn before vaccination and at time points 2 and 8 weeks post
vaccination; blood sampling will be combined with routine blood testing
whenever possible.
Participants will benefit from state-of-the-art diagnostics, optimized
treatment, and possibly boosted immune response directed at persistent and
latent bacilli. According to WHO guidelines MDR-TB treatment lasts for 9-20
months, and second line TB drugs cause many unpleasant side effects. Only half
the patients qualify for a treatment shortening to 9-12 months, for the
remaining patients treatment will take 20-24 months. In less than 50% of the
cases this treatment is successful; many fail, die or relapse shortly upon
finalizing the treatment. Ever more drug resistances are being recorded and
only very few promising new drugs are at the last steps of the development
pipeline. Therefore we urgently need to assess novel ways to help these
patients. All in all, this patient group will benefit from this investigation
with the potential to shorten this lengthy treatment, and to increase treatment
success.
C/ Fogars de Todera 61
Badalona, Barcelona 08916
ES
C/ Fogars de Todera 61
Badalona, Barcelona 08916
ES
Listed location countries
Age
Inclusion criteria
- Female or Male patients (aged * 18);- Females of childbearing potential must have a negative pregnancy test at enrolment and must agree to use highly effective methods of birth control during and 30 days after the study;- 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;- diagnosed with active MDR-TB and therefore treated with second-line TB drugs;- MDR-TB patients with Mycobacterium tuberculosis (or Mycobacterium africanum) confirmed by sputum culture;- having successfully completed 16 (Cohort A) or 12 weeks (Cohort B) of MDR-TB treatment, fully supervised, with beneficial initial response to therapy, evidenced by:;1) 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 DSMB. ;2) Microbiological response criteria: as evidenced by improvement in at least 2 measurements at least 4 weeks apart, using MGIT (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 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; ;- 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.;-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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 201600136 |
| EudraCT | EUCTR2016-000850-36-NL |
| CCMO | NL56995.000.16 |