Clinical Trial to Investigate the Safety, Tolerability, and Immunogenicity of the Novel Antituberculous Vaccine RUTI® Following One Month of Isoniazid Treatment in Subjects With Latent Tuberculosis Infection

Study Overview
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Brief Summary
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The aim of the trial is to assess the safety, tolerability and immunogenicity of two doses of RUTI® vaccine administered four weeks apart after one month pre-treatment with INH. The trial will be double-blinded, randomized and placebo-controlled with 96 subjects (48 HIV- and 48 HIV+ subjects). Three different RUTI® doses and placebo will be tested, randomizing assigned both in HIV+ and HIV- subjects. Each subject will be randomized to receive one of the four treatments (placebo, 5, 25, 50 μg), after completion of one month INH pre-treatment (one tablet of 300mg/day, vp.o.). Each subject will receive two administrations of the same treatment, 28 days apart. Subjects will be monitored until one month after the second inoculation with RUTI®.

Detailed Description
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RUTI is a therapeutic vaccine made from virulent M.tuberculosis bacteria, grown in stressful conditions, fragmented, detoxified, heat inactivated (FCMtb) and liposomed. RUTI provides a strong humoral and cellular immune response against antigens from active growing and latent bacilli but also against structural antigens, as it has been proved in animal models of latent tuberculosis infection and in phase I clinical trial of Healthy Volunteers. The vaccine has been designed to be used against Latent Tuberculosis Infection as a therapeutic vaccine after 1-month of chemotheraputic treatment, instead the current treatment based on 6-9 months of chemotherapy.

Official Title
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Double-Blind, Randomized, Placebo-Controlled Phase II Clinical Trial to Investigate the Safety, Tolerability, and Immunogenicity of the Novel Antituberculous Vaccine RUTI® Following One Month of Isoniazid Treatment in Subjects With Latent Tuberculosis Infection

Conditions
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Latent Tuberculosis Infection, Tuberculosis

Intervention / Treatment
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* Biological: RUTI
* Biological: RUTI
* Biological: RUTI
* Biological: RUTI Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asymptomatic adult aged 18 up to 50 years. No evidence of active TB (Section 8). No clinically significant finding at the discretion of the investigator. Willingness to undergo an HIV test. Resident in or near trial site for the duration of the trial. Willingness to allow the investigators to discuss the patient's medical history with his usual doctor or HIV physician. No donation of blood for 56 days prior to screening and agreement to refrain from blood donation during the trial. Willing and able to provide written informed consent. Positive tuberculin skin test (TST +), (≥5 mm induration) and Quantiferon TB Gold positive result (according to manufacturers instructions). Reliable contraception to be used by female subjects during the clinical trial. Additional inclusion criteria for HIV+ groups: HIV antibody positive. CD4 count ≥350 cells/mL3 on a single CD4 count at the period of screening. Subjects on anti-retroviral treatment can be included if clinically stable. Exclusion Criteria: Any deviation from the normal range in biochemistry or haematology blood tests or in urine analysis that is considered to be clinically significant at the discretion of the investigator. Values of Hb, WCC, platelet count, AST/ALT and creatinine should be in a normal range accordingly to the normal laboratory values. Use of any investigational or non-registered drug, vaccine, or medical device other than the trial vaccine within 30 days prior to dosing of trial vaccine, or planned use during the trial period. Administration of chronic (defined as more than 14 days) immunosuppressive drugs within six months of vaccination and required throughout the duration of the trial (for corticosteroids this means prednisolone or equivalent at ≥ 0.5 mg/kg/day). Female of child bearing potential who intends to become pregnant during the trial. Females who are pregnant, lactating, or of child bearing potential with a blood HCG positive result 24-48 hours at the screening period, or prior to every injection of RUTI®. Any AIDS defining illness according to the CDC classification system for HIV infection. Presence of active (previously undiagnosed) TB or being on TB treatment. Suspected or known current alcohol abuse (alcohol intake questionnaire. Suspected or known substance abuse. Presence of any underlying disease, specifically autoimmune disease, asthma, angioedema, bleeding disorders, uncontrolled hypertension and diabetes, and any other disease that compromises the diagnosis and evaluation of response to the vaccine, excluding HIV. Administration of immunoglobulins and/or any blood products within three months prior to the planned administration of the vaccine. Any history of anaphylaxis in reaction to vaccination and/or other medication. Investigator assessment of lack of understanding or willingness to participate and comply with all requirements of the trial protocol. Any other finding which in the opinion of the investigator would significantly increase the risk of having an adverse outcome from participating in the trial. Exclusion criteria relating to INH pre-treatment Weight less than 40 kg. Known or suspected hypersensitivity to INH. Self reported chronic liver disease or symptoms suggesting active hepatitis (jaundice, nausea, vomiting, right upper quadrant pain, dark urine, pale stools). Alcohol use exceeding 28 units per week (men) or 21 units per week (women) (see alcohol intake questionnaire, Appendix 17.2). History of convulsions. History of psychosis. Peripheral neuropathy grade 2 or greater. Three months post-partum. Concomitant medication with phenytoin, carbamazepine; warfarin; theophylline; disulfiram; selective serotonin re-uptake inhibitor antidepressants (e.g. citalopram, fluoxetine, paroxetine, sertraline); oral ketoconazole or itraconazole. Additional exclusion criterion for HIV negative groups: • Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia. Additional exclusion criterion for HIV+ groups • CD4 count < 350 cells/mL3.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RUTI 5 micrograms of FCMtb in HIV -<br>n=12 | Biological: RUTI<br>* dose:5 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.<br>|
| Experimental: RUTI 25 micrograms of FCMtb in HIV -<br>n=12 | Biological: RUTI<br>* dose:25 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.<br>|
| Experimental: RUTI 50 micrograms of FCMtb in HIV -<br>n=12 | Biological: RUTI<br>* dose:50 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.<br>|
| Placebo Comparator: RUTI Matching Placebo in HIV -<br>n=12 | Biological: RUTI Matching Placebo<br>* Placebo of the vaccine RUTI; given subcutaneously twice, on days 28 and 56.<br>|
| Experimental: RUTI 5 micrograms of FCMtb in HIV +<br>n=12 | Biological: RUTI<br>* dose:5 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.<br>|
| Experimental: RUTI 25 micrograms of FCMtb in HIV +<br>n=12 | Biological: RUTI<br>* dose:25 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.<br>|
| Experimental: RUTI 50 micrograms of FCMtb in HIV +<br>n=12 | Biological: RUTI<br>* dose:50 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.<br>|
| Placebo Comparator: RUTI Matching Placebo in HIV +<br>n=12 | Biological: RUTI Matching Placebo<br>* Placebo of the vaccine RUTI; given subcutaneously twice, on days 28 and 56.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local tolerability | The investigator will evaluate the site of injection for redness, pain, swelling, and induration and functional limitation. Redness, swelling and induration will be evaluated and recorded on the CRF as: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. If present, the extent of the reaction will be measured in mm. Pain will be recorded, after questioning the subjects, by means of a Visual Analogue Scale (VAS from 0 to 100). The presence of abscess, ulceration or necrosis will also be evaluated, measured and adequately documented. | 84 days | 
| Focal Tolerability | Evaluation of the hilar lymph nodes for inflammation: An un-contrasted thoracic computerised tomographic scan will be performed to evaluate the change in size of the hilar lymph nodes. | 84 days | 
| Systemic tolerability | Body temperature ≥38ºC, asthenia, sweating, malaise, headache, dizziness, nausea, myalgia, arthralgia, rash and generalised pruritus | 84 days | 
| Vital Signs and physical examination | Blood pressure (systolic and diastolic), pulse, respiratory rate, body temperature and full physical examination will be assessed | 84 days | 
| ECG | The following ECG parameters will be measured: Bits Frequency Heart rate, PR, QRS, QT and QTc (Bazett) intervals. Any other anomaly on the ECG (such as U wave, ischaemia, rhythm and conduction disturbances) will be evaluated by the investigator | 84 days | 
| Laboratory Tests | Blood samples for serum chemistry and haematology and urine sample for urinalysis will be taken under fasting conditions for evaluation of laboratory safety parameters | 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity | Samples to perform immunogenicity testing will be collected at specified visits. Cellular mediated immunity (ELISPOT and ELISA techniques), IFN-gama Spot Forming Units after stimulation for 18 hours with five stimuli, WHO assay (stimulating whole blood 7days with PPD) and TIGRA (TSPOT TB assay). Peripheral blood mononuclear cells will be frozen for future immune assays. Sera will be frozen to be further tested for the antibody-mediated immunity against M.tuberculosis antigens | 63 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LTBI (Latent Tuberculosis Infection), TB (Tuberculosis), Vaccine