Clinical trial NCT02329730: Phase IIa Clinical Study of Recombinant Mycobacterium Tuberculosis Allergen ESAT6-CFP10
Official title: Phase IIa Clinical Study of Recombinant Mycobacterium Tuberculosis Antigen ESAT6-CFP10
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: diagnosis of Tuberculosis (TB)
ESAT6
CFP10
Phase IIa Clinical Trial
Lead sponsor: Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Shanghai Public Health Clinical Center
name: Tianjin Haihe Hospital
name: Air Force Military Medical University, China
name: Proswell Medical Corporation
First posted: 2015-01-01
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: Choose healthy subjects and patients with TB, distribute them into different dose groups according to the recombinant EC allergen dose from low to high average. Conducting clinical trials of TB-PPD or placebo as controlled arms intradermal injection. Do specific interferon gamma detection before the skin test，after the test 72h±2h and 144h±2h. Evaluate the safety of the recombinant EC allergy , and provide the appropriate dose range for phase IIb clinical trials.

Detailed description: First, 56 healthy subjects are distributed into different dose groups according to the recombinant EC allergen dose from low to high.Conducting clinical trials of TB-PPD as controlled arms intradermal injection.Do specific interferon gamma detection before the skin test，after the test 72h±2h and 144h±2h. The vital signs (breathing, heart rate, blood pressure and temperature), skin reaction at injection site (flush and induration) , local reactions (rash, pain, itching and skin mucous membrane) and a variety of adverse events; The vital signs, blood routine, urine routine, liver and kidney function, electrocardiogram （before the skin test,after skin test 144h ）are the main test items,Evaluate the safety of the recombinant EC allergy in the expansion of the healthy people , and provide the appropriate dose range for phase IIb clinical trials.

Second，56 patients of TB are distributed different dose groups according to the recombinant EC allergen dose from low to high. Conducting clinical trials of TB-PPD as controlled arms intradermal injection.Do specific interferon gamma detection before the skin test，after the test 72h±2h and 144h±2h. The vital signs (breathing, heart rate, blood pressure and temperature),skin reaction at injection site (flush and induration) , local reactions (rash, pain, itching and skin mucous membrane) and a variety of adverse events; The vital signs, blood routine, urine routine, liver and kidney function, electrocardiogram （before the skin test,after skin test 144h ）are the main test items,Evaluate the safety of the recombinant EC allergy in patients of TB,and provide the appropriate dose range for phase IIb clinical trials.

Third，32 patients of TB are distributed into different dose groups according to the recombinant EC allergen dose from low to high. Conducting clinical trials of placebo as controlled arms intradermal injection.Do specific interferon gamma detection before the skin test，after the test 72h±2h and 144h±2h. The vital signs (breathing, heart rate, blood pressure and temperature), skin reaction at injection site (flush and induration), local reactions (rash, pain, itching and skin mucous membrane) and a variety of adverse events; The vital signs, blood routine, urine routine, liver and kidney function, electrocardiogram （before the skin test,after skin test 144h ）are the main test items,Evaluate the safety of the recombinant EC allergy in patients of TB on safety.

Eligibility criteria: Inclusion Criteria of healthy subjects:

1. 18 to 65 years old
2. Consent and signed ICF(informed consent forms)
3. Comply with follow-up
4. No history or family history of TB(tuberculosis)
5. Without the internal and external of pulmonary tuberculosis ; no symptoms of respiratory tract and other body parts for TB
6. The examination such as X-ray chest radiograph, sputum bacteria confirmed non-tuberculosis (TB)
7. No uncontrolled kinds of acute or chronic disease or acute infectious diseases or skin disease or skin allergies due to a variety of causes
8. Physical condition : No obvious heart, liver, kidney, gastrointestinal tract, nervous system, mental disorder and metabolic abnormalities and other medical history from signed informed consent to the injection within four weeks prior to delivery ;by the comprehensive physical examination showed electrocardiogram, blood pressure, heart rate, breathing and laboratory tests, including blood, urine routine, liver, kidney and other various biochemical test all without exception or slightly unusual but does not affect our research
9. Did not attend any other new drug clinical trials and not vaccinate prevention products and immunoglobulin for nearly 3 months
10. Normal axillary temperature(quiet condition ≤37.0 ℃)
11. No smoking, no alcohol and drinking caffeinated beverages during the study

Exclusion Criteria of Healthy volunteers:

1. Has the following serious disease, such as advanced cancer, diabetes, chronic obstructive pulmonary disease (copd) in acute episodes, acute/ progressive liver disease or kidney disease, congestive heart failure, etc
2. Have seizures, epilepsy, brain and nervous system symptoms or signs of history
3. Has known or suspected (or risk possible) immune damaged or abnormal functional , accept glucocorticoid and immunosuppressants or immunopotentiator treatment, outside the gastrointestinal tract protein or blood products or plasma extraction in 3 months, immunodeficiency virus infection or related diseases
4. Has acute febrile diseases and infectious diseases
5. Participate in other new drug clinical trials
6. Participated in any other new drug clinical trials in 3 months
7. Allergic people who have histories of allergy to two or more drugs/food allergy and physical scars, are allergic to alcohol or drugs known to the group of points
8. Women who are in pregnancy or lactation
9. People with mental or physical disabilities
10. Researchers consider that any conditions may affect the trial evaluation

Inclusion Criteria of TB (tuberculosis)subjects:

1. Diagnosis TB according to the health of the People's Republic of China industry standard WS 288-2008 tuberculosis diagnostic criteria
2. Aged 18 to 65 years old
3. Consent and signed ICF to participate in this study
4. Comply with the requirements of the clinical research plan for follow-up

Exclusion Criteria of TB volunteers:

1. Have the following serious disease, such as advanced cancer, diabetes, chronic obstructive pulmonary disease (copd) in acute episodes, acute/ progressive liver disease or kidney disease, congestive heart failure, etc
2. Have seizures, epilepsy, brain and nervous system symptoms or signs of history;
3. Have known or suspected (or risk possible) immune damaged or abnormal functional , accept glucocorticoid and immunosuppressants or immunopotentiator treatment, outside the gastrointestinal tract protein or blood products or plasma extraction in 3 months, immunodeficiency virus infection or related diseases
4. People in the pyrogenic stage with febrile diseases or infectious diseases (non tuberculosis)
5. Participate in other new drug clinical trials
6. Participated in any other new drug clinical trials in 3 months;
7. Allergic people who have histories of allergy to two or more drugs/food allergy and physical scars, are allergic to alcohol or drugs known to the group of points;
8. Women who are in pregnancy or lactation;
9. People with mental or physical disabilities;
10. Researchers consider that any conditions may affect the trial evaluation.

Primary outcomes:
measure: Number of Healthy Participants Negative for Reaction at 24 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 24 hours after intradermal injection
measure: Number of Tuberculosis (TB) Participants Positive for Reaction at 24 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 24 hours after intradermal injection
measure: Number of Healthy Participants Negative for Reaction at 48 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 48 hours after intradermal injection
measure: Number of Tuberculosis (TB) Participants Positive for Reaction at 48 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 48 hours after intradermal injection
measure: Number of Healthy Participants Negative for Reaction at 72 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 72 hours after intradermal injection
measure: Number of Tuberculosis (TB) Participants Positive for Reaction at 72 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 72 hours after intradermal injection
measure: Number of Healthy Participants Negative for Reaction at 96 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 96 hours after intradermal injection
measure: Number of Tuberculosis (TB) Participants Positive for Reaction at 96 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 96 hours after intradermal injection
Secondary outcomes:
measure: the Number of Participants With Adverse Events
timeFrame: before injection to 144 hours (plus or minus 2 hours) after injection
measure: the Number of Healthy Participants Negative for IFN-γ(Gamma Interferon ) Before Injection
timeFrame: before injection and after signed ICF(informed consent forms)
measure: the Number of Tuberculosis (TB) Participants Positive for IFN-γ(Gamma Interferon ) Before Injection
timeFrame: 4 hours before injection and after signed ICF(informed consent forms)
measure: the Number of Healthy Participants Negative for IFN-γ(Gamma Interferon ) at 72 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 72 hours after injection
measure: the Number of Tuberculosis (TB) Participants Positive for IFN-γ(Gamma Interferon ) at 72 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 72 hours after injection
measure: the Number of Healthy Participants Negative for IFN-γ(Gamma Interferon ) at 144 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 144 hours after injection
measure: the Number of Tuberculosis (TB) Participants Positive for IFN-γ(Gamma Interferon ) at 144 Hours After Intradermal Injection With ESAT6-CFP10
timeFrame: 144 hours after injection
Other outcomes:
Locations:
Study officials:
affiliation: Shanghai Public Health Clinical Center
name: Shuihua Lu, Bachelor
role: PRINCIPAL_INVESTIGATOR
affiliation: Tianjin Haihe Hospital
name: Qi Wu, Master
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Pinxteren LA, Ravn P, Agger EM, Pollock J, Andersen P. Diagnosis of tuberculosis based on the two specific antigens ESAT-6 and CFP10. Clin Diagn Lab Immunol. 2000 Mar;7(2):155-60. doi: 10.1128/CDLI.7.2.155-160.2000.
citation: Ravn P, Munk ME, Andersen AB, Lundgren B, Lundgren JD, Nielsen LN, Kok-Jensen A, Andersen P, Weldingh K. Prospective evaluation of a whole-blood test using Mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10 for diagnosis of active tuberculosis. Clin Diagn Lab Immunol. 2005 Apr;12(4):491-6. doi: 10.1128/CDLI.12.4.491-496.2005.
citation: Brusasca PN, Colangeli R, Lyashchenko KP, Zhao X, Vogelstein M, Spencer JS, McMurray DN, Gennaro ML. Immunological characterization of antigens encoded by the RD1 region of the Mycobacterium tuberculosis genome. Scand J Immunol. 2001 Nov;54(5):448-52. doi: 10.1046/j.1365-3083.2001.00975.x.
citation: Weldingh K, Andersen P. ESAT-6/CFP10 skin test predicts disease in M. tuberculosis-infected guinea pigs. PLoS One. 2008 Apr 23;3(4):e1978. doi: 10.1371/journal.pone.0001978.
citation: Aagaard C, Govaerts M, Meikle V, Vallecillo AJ, Gutierrez-Pabello JA, Suarez-Guemes F, McNair J, Cataldi A, Espitia C, Andersen P, Pollock JM. Optimizing antigen cocktails for detection of Mycobacterium bovis in herds with different prevalences of bovine tuberculosis: ESAT6-CFP10 mixture shows optimal sensitivity and specificity. J Clin Microbiol. 2006 Dec;44(12):4326-35. doi: 10.1128/JCM.01184-06. Epub 2006 Sep 27.