Phase IIa Clinical Study of Recombinant Mycobacterium Tuberculosis Allergen ESAT6-CFP10

Tuberculosis Clinical Trial

Official title:

Phase IIa Clinical Study of Recombinant Mycobacterium Tuberculosis Antigen ESAT6-CFP10

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02329730
• Other study ID #: LTao-EC IIa
• Status: Completed
• Phase: Phase 2
• First received: December 23, 2014
• Last updated: March 26, 2015
• Start date: February 2014
• Est. completion date: August 2014

Study information

• Verified date: March 2015
• Source: Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 144
• Est. completion date: August 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Biological:
• 1µg/ml ESAT6-CFP10 and tuberculin purified protein derivative
Left arm intradermal injection of 0.1ml TB-PPD(50IU/ml) by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 1µg/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 Allergen and TB-PPD only one time in the healthy subjects and the first part of tuberculosis subjects respectively.
• 5µg/ml ESAT6-CFP10 and tuberculin purified protein derivative
Left arm intradermal injection of 0.1ml TB-PPD(50IU/ml) by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 5g/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 Allergen and TB-PPD only one time in the healthy subjects and the first part of tuberculosis subjects respectively.
• 10µg/ml ESAT6-CFP10 and tuberculin purified protein derivative
Left arm intradermal injection of 0.1ml TB-PPD(50IU/ml) by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 10g/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 Allergen and TB-PPD only one time in the healthy subjects and the first part of tuberculosis subjects respectively.
• 20µg/ml ESAT6-CFP10 and tuberculin purified protein derivative
Left arm intradermal injection of 0.1ml TB-PPD(50IU/ml) by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 20/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 Allergen and TB-PPD only one time in the healthy subjects and the first part of tuberculosis subjects respectively.
• 1µg/ml ESAT6-CFP10 and placebo
Left arm intradermal injection of the placebo of 1µg/ml ESAT6-CFP10 by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 1µg/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 and placebo only one time in the second part of tuberculosis subjects.
• 5µg/ml ESAT6-CFP10 and placebo
Left arm intradermal injection of the placebo of 5µg/ml ESAT6-CFP10 by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 5µg/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 and placebo only one time in the second part of tuberculosis subjects.
• 10µg/ml ESAT6-CFP10 and placebo
Left arm intradermal injection of the placebo of 10µg/ml ESAT6-CFP10 by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 10µg/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 and placebo only one time in the second part of tuberculosis subjects.
• 20µg/ml ESAT6-CFP10 and placebo
Left arm intradermal injection of the placebo of 20µg/ml ESAT6-CFP10 by a syringe(1ml).Observe 30 minutes , if without obvious adverse reaction then right arm intradermal injection 20µg/ml ESAT6-CFP10 by a syringe(1ml). Inject ESAT6-CFP10 and placebo only one time in the second part of tuberculosis subjects.

Locations

Country	Name	City	State
n/a

Sponsors (5)

Lead Sponsor	Collaborator
Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.	Fourth Military Medical University, Proswell Medical Corporation, Shanghai Public Health Clinical Center, Tianjin Haihe Hospital

References & Publications (5)

Aagaard C, Govaerts M, Meikle V, Vallecillo AJ, Gutierrez-Pabello JA, Suarez-Güemes 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. Epub 2006 Sep 27. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Healthy Participants Negative for Reaction at 24 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in healthy participants at 24 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the healthy participants' arm are positive reaction.; The percentage of negative(negative number/total number*100%) is the specificity of ESAT6-CFP10 .	24 hours after intradermal injection	No
Primary	Number of Tuberculosis (TB) Participants Positive for Reaction at 24 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in TB participants at 24 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the participants' arm are positive reaction.	24 hours after intradermal injection	Yes
Primary	Number of Healthy Participants Negative for Reaction at 48 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in healthy participants at 48 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the healthy participants' arm are positive reaction.	48 hours after intradermal injection	Yes
Primary	Number of Tuberculosis (TB) Participants Positive for Reaction at 48 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in TB participants at 48 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the participants' arm are positive reaction.	48 hours after intradermal injection	Yes
Primary	Number of Healthy Participants Negative for Reaction at 72 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in healthy participants at 72 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the healthy participants' arm are positive reaction.; The percentage of negative(negative number/total number*100%) is the specificity of ESAT6-CFP10	72 hours after intradermal injection	Yes
Primary	Number of Tuberculosis (TB) Participants Positive for Reaction at 72 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in TB participants at 72 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the participants' arm are positive reaction.	72 hours after intradermal injection	Yes
Primary	Number of Healthy Participants Negative for Reaction at 96 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in healthy participants at 96 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the healthy participants' arm are positive reaction.	96 hours after intradermal injection	Yes
Primary	Number of Tuberculosis (TB) Participants Positive for Reaction at 96 Hours After Intradermal Injection With ESAT6-CFP10	The investigators measure the longitudinal diameter and transverse diameter of induration and/or redness of ESAT6-CFP10 in TB participants at 96 hours after intradermal injection by vernier caliper . And at the same blisters and lymphangitis are the specificity of the positive reaction of ESAT6-CFP10 .So induration ,redness ,blisters and lymphangitis in the participants' arm are positive reaction.	96 hours after intradermal injection	Yes
Secondary	the Number of Participants With Adverse Events	evaluate specific time point of vital signs, skin test reaction, blood routine, urine routine, liver and kidney function, electrocardiogram and adverse events as the incidence of adverse events in the participants .; Skin test reaction observation time: at the end of the skin test, skin test after 15 minutes, 1 hour, 4 hours, 24 hours, 48 hours, 72 hours, 96 hours; Vital signs evaluation time: 0 minutes before the subjects were intradermal injection, intradermal injection after 15 minutes, 1 hour, 4 hours, 24 hours, 48 hours, 72 hours, 96 hours, 144 hours.; Blood routine, urine routine, liver and kidney function, electrocardiogram (ecg) evaluation time: skin test before and 144 h after injection; adverse events evaluation time: participants signed a written informed consent to finish all the follow-up.	before injection to 144 hours (plus or minus 2 hours) after injection	Yes
Secondary	the Number of Healthy Participants Negative for IFN-?(Gamma Interferon ) Before Injection	The investigator draw 5ml venous blood for detection of IFN-? four hours before injection with drug.The percentage of negative(negative number/total number*100%) is the specificity of IFN-? in healthy participants.	before injection and after signed ICF(informed consent forms)	No
Secondary	the Number of Tuberculosis (TB) Participants Positive for IFN-?(Gamma Interferon ) Before Injection	The investigator draw 5ml venous blood for detection of IFN-? four hours before injection with drug. The percentage of positive(positive number/total number*100%) is the sensitivity of IFN-? in TB Participants.	4 hours before injection and after signed ICF(informed consent forms)	No
Secondary	the Number of Healthy Participants Negative for IFN-?(Gamma Interferon ) at 72 Hours After Intradermal Injection With ESAT6-CFP10	The investigator draw 5ml venous blood for detection of IFN-? four hours before injection with drug.The percentage of negative(negative number/total number*100%) is the specificity of IFN-? in healthy participants.	72 hours after injection	No
Secondary	the Number of Tuberculosis (TB) Participants Positive for IFN-?(Gamma Interferon ) at 72 Hours After Intradermal Injection With ESAT6-CFP10	The investigator draw 5ml venous blood for detection of IFN-? 72 hours after injection with drug.The percentage of positive(positivenumber/total number*100%) is the sensitivity of IFN-? in in TB participants.	72 hours after injection	No
Secondary	the Number of Healthy Participants Negative for IFN-?(Gamma Interferon ) at 144 Hours After Intradermal Injection With ESAT6-CFP10	The investigator draw 5ml venous blood for detection of IFN-? 144 hours after injection with drug.The percentage of negative(negative number/total number*100%) is the specificity of IFN-? in healthy participants.	144 hours after injection	No
Secondary	the Number of Tuberculosis (TB) Participants Positive for IFN-?(Gamma Interferon ) at 144 Hours After Intradermal Injection With ESAT6-CFP10	The investigator draw 5ml venous blood for detection of IFN-? 144 hours before injection with drug.The percentage of positive(positive number/total number*100%) is the sensitivity of IFN-? in in TB participants.	144 hours after injection	No

External Links

•   Center for drug evaluation, CFDA ,China