A Phase I Study of the Safety and Immunogenicity of MVA85A in Healthy Gambian Volunteers
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      A Phase I study of the Safety and immunogenicity of MVA85A in healthy Gambian volunteers
    

Detailed description: 
      Study Design: The study is a non-randomized clinical trial. Twelve volunteers will be
      recruited. They would be given 5x107 pfu of the MVA85A vaccine intradermally. The subjects
      will be required to stay in the unit for an hour after the vaccination. Local and systemic
      adverse events would be recorded. Blood samples will be taken at the screening visit, day of
      immunisation, 1 week after the vaccination, then at 2, 4, 8, 12 and 24 weeks after the
      vaccination.

      Screening:

      Details of the study will be carefully discussed with the subjects and informed consent
      approved by the combined MRC/Gambian government ethics committee prior to any study-related
      evaluations being performed. The subjects that agree to enroll and have signed consent
      documentation will be assessed at the AFTBVAC clinic at MRC.

      Entry

      Subjects will be recruited at the MRC AFTBVAC clinic. Subjects will be screened in the eight
      weeks prior to entering the study. The screen will consist of checking subject eligibility
      and a full physical examination. The following will be carried out: height, weight, vital
      signs, haematology (haemoglobin, packed cell volume, white cell counts, platelets, blood film
      for malaria parasites), serum chemistry (electrolytes and creatinine, liver enzymes, serum
      bilirubin and proteins), Mantoux test, ELISPOT, Chest X-ray, anti-vaccinia antibodies,
      anti-HBV antibodies, , anti-HIV antibodies, urinalysis. All chest X-rays will be reviewed by
      two clinicians to confirm no radiological sign of Tuberculosis.

      Evaluations during study: Scheduled follow-up:

      Vaccination Day 0: after a pysician has confirmed that the volunteers are ESAT-6 and CFP-10
      nagative. The following assessments will be performed pre-dosing: vital signs (20 minutes
      pre-dose) and blood samples collected for heamatology (haemoglobin, packed cell volume, white
      cell counts, platelets, blood film for malaria parasites), serum chemistry (electrolytes and
      creatinine, liver enzymes, serum bilirubin and proteins) and immunological assays. Provided
      vital signs are is satisfactory, subjects will receive the first vaccination. Subjects will
      have a dressing applied over the injection site, which will remain for at least one hour
      after the vaccination. Post vaccination vital signs will be taken at 30 and 60 minutes. Any
      adverse events (AEs) noted by the study personnel or described by the volunteer will be
      documented. Concomitant medication given will be documented. The volunteer will remain at the
      clinical area for one hour following vaccination and will then be allowed to return home.

      Day 1 and 2: On the first and second day after vaccination subjects will be visited at home
      by a field worker or they will return to the clinical area. The injection site will be
      examined and the subjects will be questioned for AEs and use of any concomitant medications.

      Day 7: Subjects will be visited at home by a field worker or they will return to the clinical
      area. Vital sign assessments will be performed. Blood samples will be taken for
      haematology(haemoglobin, packed cell volume, white cell counts, platelets, blood film for
      malaria parasites), serum chemistry (electrolytes and creatinine, liver enzymes, serum
      bilirubin and proteins) and immunological assays. The injection site will be examined and the
      subjects will be questioned for AEs and concomitant medications.

      At day 14, 28, 56, 84 and 189, subjects will return to the clinical area. Vital sign
      assessments will be performed. Blood samples will be taken prior to dosing for haematology
      (haemoglobin, packed cell volume, white cell counts, platelets, blood film for malaria
      parasites), serum chemistry (electrolytes and creatinine, liver enzymes, serum bilirubin and
      proteins) and immunological assays. The injection site will be examined and the subjects will
      be questioned for AEs and concomitant medications. Day 22 and 23: On the first and second day
      after vaccination a field worker will visit subjects at home or they will return to the
      clinical area. The injection site will be examined and the subjects will be questioned for
      AEs and concomitant medications.

      Post study Evaluations:

      The injection site will be examined and the subjects asked about AEs. It is possible that
      they will be asked in the future to provide samples for genetic studies.

      DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE REPORTING

      Records to be kept and a regulatory folder will contain:

      SCC document Project Management plan Protocol with appendices Letter of ethical approval
      Information sheets and blank forms Signed consent forms for each subject

      All filled in paper forms will be filed. Individual medical records will be filed together.

      All data on the Case Report Forms (CRF) must be legibly recorded in blue or black ink or
      typed. A correction should be made by striking through the incorrect entry with a single line
      and entering the correct information adjacent to it. The correction must be initialed and
      dated by the investigator or a designated, qualified individual.

      Any requested information that is not obtained as specified in the protocol should have an
      explanation noted on the CRF as to why the required information was not obtained.

      Role of Data Management

      The Data manager will be responsible for receiving, entering, querying, analysing, and
      storing the data which accrues from the study. He will be responsible for linking the
      epidemiological and clinical data from the field and the clinic with the laboratory data from
      the immunology, microbiology, haematology and genetics laboratories.

      Adverse Events (AE) Reporting

      Adverse events, however minor, will be recorded as observed by the Investigators or as
      volunteered by the subject. Full details will be documented in the CRF whether or not the
      Investigator or his deputies consider the event to be related to the trial substance.

      Serious Adverse Events (SAE) Reporting

      Serious adverse events (SAEs) that occur during the study or within six months of the final
      vaccination will be notified immediately (within 24 hours) by telephone to the Safety
      Monitor, Ethics Committee, collaborators and funding agency.

      Serious adverse event are defined as an event that:

        -  results in death;

        -  is life-threatening (i.e., the subject was at risk of death at the time of the event);

        -  requires or prolongs in-patient hospitalization;

        -  results in persistent or significant disability/incapacity;

        -  is a congenital anomaly/birth defect;

        -  is a cancer.

      Note:

      Proven malaria events will not be included as an SAE.

      Minimum details to be given in a telephone report are:

        -  Name of reporting doctor and contact telephone number.

        -  Study number.

        -  Nature of adverse event.

        -  Subject details (number, initials, sex, date of birth, weight and age).

        -  Date and time of event.

        -  Date and time of MVA85A administration and dose.

        -  Other drug history.

        -  Other relevant history.

        -  Outcome.

        -  Causality.

      The event will be documented on the SAE page of the CRF and reported to the Safety Monitor,
      Ethics Committee, Collaborators and funding agency as appropriate. Other adverse events will
      be graded. After the ethics committee's response to the SAE is received, the Principal
      Investigator, Clinical Monitor and available co-investigators will meet to determine the
      future plan for the study, which could involve amending the protocol, discontinuing the
      vaccinations, or continuing unchanged for the other volunteers.

      STATISTICAL CONSIDERATIONS

      General Design Issues

      A total of 12 subjects will be sufficient to provide descriptive data. As some of the
      subjects may drop out of the study, 12 subjects. However, only 10 individuals will be given
      the vaccine.

      Outcomes of interest

      Safety of the Vaccine

      This will be determined by the degree and number of adverse events reported.

      Immunogenicity of this vaccine

      It is expected that the vaccine will stimulate T cell responses, which will be measured by
      interferon -gamma Elispot assays.

      Sample Size and Accrual

      Formal sample sizing calculations have not been performed but it is believed that the sample
      size of 10 subjects will be sufficient for this purpose.

      No attempt will be made in the study to conceal the allocation group of the subjects either
      from the subjects themselves, the investigators or laboratory personnel.

      Monitoring and Analysis

      The data manager will be responsible for monitoring the trial. This will include confirming
      the existence of the appropriate documents in the regulatory folder and of source documents
      for all entered data. He would also assess the consistency of data. The data manager will be
      responsible for data entry and for initial analysis of the results.

      The main analyses will be descriptive and comparative.

      HUMAN SUBJECTS

      Institutional Review Board (IRB) Review and Informed Consent

      The study has been approved by the joint MRC/ Gambia government ethical committee. Written
      informed consent will be obtained from the subject (or parent, legal guardian, or person with
      power of attorney for subjects who cannot consent for themselves, such as, those below the
      legal age). The subject's assent must also be obtained if he or she is able to understand the
      nature, significance and risks associated with the study. The informed consent will describe
      the purpose of the study, the procedures to be followed, and the risks and benefits of
      participation. A signed copy of the consent form will be given to the subject (or parent or
      legal guardian).

      Subject Confidentiality

      All records will be kept in a secure place. All data on computer files will have restricted
      access. Clinical information will not be released without written permission of the subject,
      except as necessary for monitoring.
    

Intervention name(s): MVA85A (Tuberculosis vaccine)
Intervention type(s): Biological
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Mycobacterium tuberculosis; Antigen 85A; Modified Vaccinia Virus Ankara (MVA).