A Phase ⅠStudy of the Recombinant Mycobacterium Tuberculosis Vaccine Freeze-dried (AEC/BC02)

A Phase ⅠStudy of the Human Body Tolerance Research of the Recombinant Mycobacterium Tuberculosis Vaccine Freeze-dried

Shanghai Public Health Clinical Center, Beijing Simoonrecord Pharmaceutical Information Consulting Co.,Ltd

There are four populations in Recombinant Mycobacterium tuberculosis Vaccine Freeze-dried (AEC/BC02) phase I clinical research. The clinical study adopt open research design. Population I have 25 subjects who received Tuberculin purified protein derivative(TB-PPD) skin test and specific gamma-interferon (γ-IFN)detection whose results are both negative ;Population II have 30 subjects who received Tuberculin purified protein derivative(TB-PPD) and ESAT6-CFP10 skin test in different arms , specific gamma-interferon (γ-IFN) detection whose results are all negative.We call polulation III as uninfected TB PPD positve population.This group screened 30 subjects whose ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN)detection results are both negative,but Tuberculin purified protein derivative(TB-PPD) skin test positive.50 subjects whose three kinds of detection results are all positive γ-IFN,TB-PPD and ESAT6-CFP10 ) are named as population IV. After filtrating, injecting of population I start firstly.After ensure the safety of the population I,the population II～polulation IV carry out in turn the implementation at the same time.

Consider the safety of the inoculation,the trial is conducted in the following order: Population I start firstly, polulation II～population IV is sarted when population I is finished the entire immune and observation safety.Population II and population III should proceed simultaneously,and these two kinds of population finish injecting the first doses of placebo group after 4weeks,population IV start. All participants of the placebo group and adjuvant group complete the first needle intramuscular injection.5 subjects of Low-dose vaccine group are injected after being sure of the security of placebo and adjucant groups after 3 days. When these low-dose vaccine subjects is sure of safety in 2h,the rest of 5 subjects are injected.Each participant immune one type of placebo, adjuvant or vaccination every two weeks, totally six stitches. In the research, each subject receives only one dose of drug and cannot be subjected to experiments about dose escalation. The population Ⅰ subjects are received 6 needle times of placebo or low-dose adjuvant or low-dose vaccine by haunch deep intramuscular injection to provide security basis. The subjects should accept some physical examination during the clinical research. Vital signs (breathing, pulse, blood pressure, body temperature) of each volunteer before each needle injection and 30min; and local reaction of each volunteer at 30min after injection;routine blood, routine urine, liver and kidney function, and ECG before first-dose, third-dose,forth-dose and sixth-dose,7 days after the sixth needle injection; Female HCG is tested before each needle injection and 7days after the sixth dose injected; chest X-ray detection before the first injection and 7 days after the sixth needle injection. All subjects should assess the changes of immunological indexes before the first injection, the fourth time before injection and 7 days after the sixth needle injection. The specific injection orders are as follows: ①All the subjects of placebo group(5 cases) and low-dose adjuvant group(10 cases) will be injected on the same day, the adjuvant group subjects should be injected after all the placebo group completed and observed two hours safety; ② All the subjects of low-dose vaccine (10 cases) will be injected on the third day if the placebo group and adjuvant group subjects are observed safety. ③The clinical study of population Ⅱ and population Ⅲ will be carried out 3 days later if the low-dose vaccine group subjects of the population Ⅰ are observed safety; Each subject inoculates a dose of drug every two weeks, a total of six agents. In conclusion, the result of the Phase I Clinical Study of population I evaluate safety of different dose of Recombinant Mycobacterium tuberculosis Vaccine Freeze-dried(AEC/BCO2) in different population, but also provide a safe basis for the Phase I Clinical Study. The populationⅠsubjects are injected the first needle injection and observe safety after 3 days and then conducted clinical research population Ⅱ and Ⅲ in Phase I Clinical. The study population Ⅱ/Ⅲ will be injected to a placebo or adjuvant or vaccination and collect any adverse events and serious adverse events to evaluate its safety during the period of clinical research.When the above two kinds of population are injected first doses of placebo after 4 weeks,the low-dose group of population IV proceed.High-dose group of population IV conduct trial after the low-dose group injected first dose of placebo later 1 week. The 30 subjects of study population Ⅱand 30 subjects of population III who meet the inclusion criteria and do not accord with standard of exclusion are divided into placebo group,high-dose adjuvant group and high-dose vaccine group, each group has 10 participants.The 50 subjects of population IV are invidided into low-dose group and high-dose group,each group of 25 subjects.The Low-dose group consiste of 5 placebo subjects,10 adjuvant subjects and 10 vaccine subjects.The high-dose grouping is same as low-dose group.Every subject must accept some physical examination during the clinical research,and all the items of physical examination are as same as population I. Specific injection orders are as follows: ①Population II and population III should proceed simultaneously,and these two kinds of population finish injecting the first doses of placebo group after 4weeks,population IV start; ②High-dose group of population IV conduct trial after the low-dose group injected first dose of placebo later 1 week; ③Every pupolation are injected placebo and adjuvant firstly;5 subjects of Low-dose vaccine group are injected after being sure of the security of placebo and adjucant groups after 3 days. When these low-dose vaccine subjects is sure of safety in 2h,the rest of 5 subjects are injected. All subjects are vaccinated once every two weeks, a total of six times vaccination.

Population I has 25 subjects,and it is considered as Tuberculin purified protein derivative(TB-PPD) skin test and specific gamma-interferon (γ-IFN) detection result all negative.Population I are coxal muscle injection of placebo or low dose adjuvant or low dose vaccine.

Population II is considered as Tuberculin purified protein derivative(TB-PPD) skin test , ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result all negative.It has 30 subjects.Population II are coxal muscle injection of placebo or high dose adjuvant or high dose vaccine.

Population III is considered as ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result negive,but Tuberculin purified protein derivative(TB-PPD) skin test positive.Population IV is needed 30 subjects.These subjects are coxal muscle injection of placebo or high dose adjuvant or high dose vaccine.This arm is uninfected TB PPD positve population.

Population IV is considered as Tuberculin purified protein derivative(TB-PPD) skin test and ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result all positive.We are called latent infection population,and need to screen 50 subjects through these three selection method.Population III are coxal muscle injection of placebo or adjuvant( including low dose adjuvant or high dose adjuvant) or vaccine(including low dose vaccine high dose vaccine).

The placebo drug contains 20mg mannitol and 10 millimole(mM) phosphate buffer(PB).population I～population IV are coxal muscle injection of placebo.

The adverse events observed mainly from laboratory examination(including vital signs/routine blood/routingurine/Liver and kidney fuction/Electrocardiograghy and Chest X-ray detection),skin reactivity and local reaction after drug injection.Vital signs(breathing,pulse,blood pressure,body temperature) of each volunteer before each dose injection,and 30min after injection.Routine blood,routine urine,liver and kidney function,and ECG before first dose,third dose,sixth dose,and 7 days after the sixth time injection;skin reactivity and local reaction of rach volunteer at 30min before and after every injection.

Evaluation of IFN-γand antibody level of before and after the immune,intracellular cytokine staining in blood .

Inclusion Criteria: Agreed to participate in the test and sign the informed consent; Subjects should comply with the requirements of the clinical trial protocol and be followed; Aged form 18-45 years old . Body mass index should be in the range of 18-30. Body Mass Index BMI: weight (Kg)/ [height (m)*height (m)]; Physical condition: body temperatue, blood pressure, heart rate and respiratory status are normal minor abnormalities but no abnormal symptoms and signs; Lab test including blood, urine, liver and kidney function are normal minor abnormalities but no abnormal symptoms and signs; ECG,X-ray chest radiograph are normal minor abnormalities but no abnormal symptoms and signs; Subjects have no history of tuberculosis; Subjects have no acute or chronic disease, acute infectious diseases, dermatoses or skin allergy caused by various reasons; Subject have not participated in other clinical drug trials or inoculated against other prophylactic and immune globulin in the nearly 3 months. Exclusion Criteria: Suffering from other serious disease, e.g. tumor, autoimmune disease, progressive atherosclerosis, diabetes accompanied with complications, chronic obstructive pulmonary disease(COPD) needing oxygen therapy, acute or progressive liver or kidney disease, congestive heart failure, etc; Subjects were a history of TB; Subjects are immune dysfunction or abnormal, e.g. patients receive immunosuppressive agents or immunosuppressive agents, receive immunoglobulin preparations outsider the gastrointestinal or blood products within 3 months, extracted plasma or infected by immunodeficiency virus or related disease; Mentally or physically disabled,and have family history of convulsions, epilepsy, encephalopathy or mental illness. Subjects have took part in other clinical trials in the nearly 3 months,or vacinated any prophylactic; Allergic constitution, e.g. patients have allergic history to two or more kinds of drugs or food, or drug components; Substance abuse， drug or alcohol abuse; Pregnant or breast feeding female; people have birth plan during study or in six moons after entire immune; Any other cases that may influence the test evaluation.

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