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Latent Tuberculosis InfectionPhase 2NCT01136161

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

A Phase 2 study testing RUTI in people with Latent Tuberculosis Infection and Tuberculosis, run by Archivel Farma S.L. at 3 sites in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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). Read more about this study

Who is it for?
Ages 18 to 50 years
Conditions the study is for
Latent Tuberculosis Infection, Tuberculosis
What is being tested?
RUTI
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
95 participants
Where
3 sitesSouth Africa
Study dates
Jun 2010to May 2011
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

3 sites in 1 country.

South Africa3 sites
  • Parexel Int. Bloemfontein

    Bloemfontein, 9301

  • Parexel Int. George

    George, 6529

  • Parexel Int. Port Elizabeth

    Port Elizabeth, 6045

Other trials in South Africa

About this study

Official title: 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

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®.

Read the detailed description

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.

Being tested
RUTI, RUTI Matching Placebo
Keywords
LTBI (Latent Tuberculosis Infection), TB (Tuberculosis), Vaccine
Medical subject headings
Latent Tuberculosis, Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RUTIBiological

    dose:5 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.

  • RUTIBiological

    dose:25 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.

  • RUTIBiological

    dose:50 micrograms of FCMtb (Fragmented cells of M. tuberculosis); given subcutaneously twice, on days 28 and 56.

  • RUTI Matching PlaceboBiological

    Placebo of the vaccine RUTI; given subcutaneously twice, on days 28 and 56.

Study groups in NCT01136161
Study groupRoleWhat they receive
RUTI 5 micrograms of FCMtb in HIV -Experimentaln=12
Receives: Biological: RUTI
RUTI 25 micrograms of FCMtb in HIV -Experimentaln=12
Receives: Biological: RUTI
RUTI 50 micrograms of FCMtb in HIV -Experimentaln=12
Receives: Biological: RUTI
RUTI Matching Placebo in HIV -Placebo comparatorn=12
Receives: Biological: RUTI Matching Placebo
RUTI 5 micrograms of FCMtb in HIV +Experimentaln=12
Receives: Biological: RUTI
RUTI 25 micrograms of FCMtb in HIV +Experimentaln=12
Receives: Biological: RUTI
RUTI 50 micrograms of FCMtb in HIV +Experimentaln=12
Receives: Biological: RUTI
RUTI Matching Placebo in HIV +Placebo comparatorn=12
Receives: Biological: RUTI Matching Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 84 days

  2. 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.

    Measured: 84 days

  3. Systemic tolerability

    Body temperature ≥38ºC, asthenia, sweating, malaise, headache, dizziness, nausea, myalgia, arthralgia, rash and generalised pruritus

    Measured: 84 days

  4. Vital Signs and physical examination

    Blood pressure (systolic and diastolic), pulse, respiratory rate, body temperature and full physical examination will be assessed

    Measured: 84 days

  5. 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

    Measured: 84 days

  6. 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

    Measured: 84 days

Secondary outcomes (1)
  1. 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

    Measured: 63 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jun 2010 (estimated)
  2. Study startJun 2010
  3. Primary completionMay 2011
  4. Study completionMay 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
95 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01136161
Sponsor's protocol ID
RUTISAPH2
Status last verified
Jan 2013
First submitted
31 May 2010
Last updated
24 Jan 2013
Results posted
No
Data monitoring committee
Yes

Publications

  • Gil O, Diaz I, Vilaplana C, Tapia G, Diaz J, Fort M, Caceres N, Pinto S, Cayla J, Corner L, Domingo M, Cardona PJ. Granuloma encapsulation is a key factor for containing tuberculosis infection in minipigs. PLoS One. 2010 Apr 6;5(4):e10030. doi: 10.1371/journal.pone.0010030.

    PubMed 20386605
  • Cardona PJ. Revisiting the natural history of tuberculosis. The inclusion of constant reinfection, host tolerance, and damage-response frameworks leads to a better understanding of latent infection and its evolution towards active disease. Arch Immunol Ther Exp (Warsz). 2010 Feb;58(1):7-14. doi: 10.1007/s00005-009-0062-5. Epub 2010 Jan 5.

    PubMed 20049645
  • 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.

    PubMed 19853680
  • Domingo M, Gil O, Serrano E, Guirado E, Nofrarias M, Grassa M, Caceres N, Perez B, Vilaplana C, Cardona PJ. Effectiveness and safety of a treatment regimen based on isoniazid plus vaccination with Mycobacterium tuberculosis cells' fragments: field-study with naturally Mycobacterium caprae-infected goats. Scand J Immunol. 2009 Jun;69(6):500-7. doi: 10.1111/j.1365-3083.2009.02251.x.

    PubMed 19439010
  • Cardona PJ. A dynamic reinfection hypothesis of latent tuberculosis infection. Infection. 2009 Apr;37(2):80-6. doi: 10.1007/s15010-008-8087-y. Epub 2009 Mar 23.

    PubMed 19308318
  • Gil O, Vilaplana C, Guirado E, Diaz J, Caceres N, Singh M, Cardona PJ. Enhanced gamma interferon responses of mouse spleen cells following immunotherapy for tuberculosis relapse. Clin Vaccine Immunol. 2008 Nov;15(11):1742-4. doi: 10.1128/CVI.00255-08. Epub 2008 Sep 30.

    PubMed 18827194
  • Guirado E, Gil O, Caceres N, Singh M, Vilaplana C, Cardona PJ. Induction of a specific strong polyantigenic cellular immune response after short-term chemotherapy controls bacillary reactivation in murine and guinea pig experimental models of tuberculosis. Clin Vaccine Immunol. 2008 Aug;15(8):1229-37. doi: 10.1128/CVI.00094-08. Epub 2008 Jun 4.

    PubMed 18524883
  • Vilaplana C, Ruiz-Manzano J, Gil O, Cuchillo F, Montane E, Singh M, Spallek R, Ausina V, Cardona PJ. The tuberculin skin test increases the responses measured by T cell interferon-gamma release assays. Scand J Immunol. 2008 Jun;67(6):610-7. doi: 10.1111/j.1365-3083.2008.02103.x. Epub 2008 Apr 4.

    PubMed 18397200
  • Cardona PJ. New insights on the nature of latent tuberculosis infection and its treatment. Inflamm Allergy Drug Targets. 2007 Mar;6(1):27-39. doi: 10.2174/187152807780077282.

    PubMed 17352686
  • Guirado E, Amat I, Gil O, Diaz J, Arcos V, Caceres N, Ausina V, Cardona PJ. Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice. Microbes Infect. 2006 Apr;8(5):1252-9. doi: 10.1016/j.micinf.2005.12.004. Epub 2006 Jan 27.

    PubMed 16702016
  • Cardona PJ. RUTI: a new chance to shorten the treatment of latent tuberculosis infection. Tuberculosis (Edinb). 2006 May-Jul;86(3-4):273-89. doi: 10.1016/j.tube.2006.01.024. Epub 2006 Mar 20.

    PubMed 16545981
  • Cardona PJ, Amat I, Gordillo S, Arcos V, Guirado E, Diaz J, Vilaplana C, Tapia G, Ausina V. Immunotherapy with fragmented Mycobacterium tuberculosis cells increases the effectiveness of chemotherapy against a chronical infection in a murine model of tuberculosis. Vaccine. 2005 Feb 3;23(11):1393-8. doi: 10.1016/j.vaccine.2004.09.008.

    PubMed 15661388
  • 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.

    PubMed 24586912

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing RUTI in people with Latent Tuberculosis Infection and Tuberculosis, run by Archivel Farma S.L. at 3 sites in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Local tolerability (time frame: 84 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01136161, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jan 2013.

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