rTSST-1 Variant Vaccine Phase 1 First-in-man Trail

Study Overview
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Brief Summary
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Toxic Shock Syndrome (TSS) a severe condition with high morbidity and mortality results from the hosts overwhelming inflammatory response and cytokine storm. Staphylococcal superantigen toxins are the main causative agents. Toxic shock syndrome toxin (TSST-1) being responsible for almost all of menstruation associated and more than 50% of all other cases. There is no specific therapy. The aim of this study is to demonstrate the safety and tolerability of the BioMed recombinant toxic shock syndrome toxin (rTSST-1) Variant Vaccine in healthy adults. The second aim of the study is to measure antibodies in the blood of these healthy volunteers which have been produced in response to treatment with the BioMed rTSST-1 Variant Vaccine. These antibodies are expected to be important in resistance against the diseases. 46 healthy adults, male and female, age 18-64 years will be assigned to 6 dose groups of the vaccine at the Department of Clinical Pharmacology of the Medical University of Vienna. The patients will be monitored for vital signs, hematology, clinical chemistry, blood cytokine level and antibodies against TSST-1. Immunization will be repeated 4 weeks after the first with the same dose.

Detailed Description
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The BioMed rTSST-1 Variant Vaccine has been developed by Biomedizinische ForschungsgmbH as one component of a polyvalent staphylococcal vaccine for the prevention of toxic shock and hyperimmunization of donors for the production of TSST-1 immunoglobulin. This is a prospective, partly randomized, parallel control, dose escalation study of the safety and immunogenicity of the BioMed rTSST1 Variant Vaccine compared to adjuvant in healthy adults. 28 - 3 days prior to entry into the study, 50 male and female subjects 18 - 64 years in age will be screened for eligibility , screening criteria to include physical examination, medical history, pregnancy/ adequate contraception in females, HIV Ab, hepatitis C virus antibodies (HCV Ab), hepatitis B antigen (HBs Ag) and TSST-1 Ab. 46 of these subjects will be entered into the study. In a first step, two subjects will receive the adjuvanted Vaccine containing 100 ng rTSST-1 Ag and one subject will receive the adjuvant containing 0.2 mg Al(0H)3 only (Group 1). The subjects will be seen four times after immunization in a period of 14 days (6 h, 48 h + 2 hrs, 7 + 1 days and 14 + 2 days).Tests and examinations will include vital signs, hematology and clinical chemistry parameters, C-reactive protein, cytokines, TSST-Ab , local reactions and adverse events. In the absence of clinically relevant adverse events , another three subjects will be entered into the study one week later, two of them to receive the adjuvanted Vaccine containing 300 ng rTSST-1 Ag, one receiving the adjuvant containing 0.6 mg Al(0H)3 (Group 2) and be followed for a period of 14 days as described above. In the absence of clinically relevant adverse events , four more subjects will be entered into the study one week thereafter, three of them to receive the adjuvanted Vaccine containing 1 µg rTSST-1 Ag , one to receive adjuvant containing 1 mg Al(0H)3 alone (Group 3), and be followed for a period of 14 days in the manner described above. Immunization will be repeated at the same dose level in each group one to two months after the first. Follow-up will be the same. If immunogenicity can be shown after the second administration of the Vaccine containing 1 µg of rTSST-1 Ag, doses and sample sizes will be increased to Vaccine containing 3 µg , 10 µg, and 30 µg and adjuvant containing 1 mg Al(0H)3 in nine and three subjects in Groups 4 - 6, respectively. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. Subjects in Groups 4 - 6 will receive a second immunization at the respective dose level one to two months after the first, follow-up being the same as in Groups 1 - 3. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 - 8 weeks thereafter in dose groups of 1 µg (Groups 3 - 6) and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer. Subjects to receive vaccine containing 3 µg rTSST-1 Ag or more will be randomized.

Official Title
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Phase 1 Clinical Trial of the BioMed rTSST-1 Variant Vaccine in Healthy Adults

Conditions
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Toxic Shock Syndrome, Vaccination; Sepsis

Intervention / Treatment
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* Biological: rTSST-1 Variant Candidate Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male and female 18 - 64 years written informed consent physical exam: no abnormal findings unless considered irrelevant by the investigator uneventful medical history females: adequate contraception Exclusion Criteria: pregnancy positive virology markers signs and symptoms of relevant autoimmunity TSST-1 Ab titer > 1:2000

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Group 1<br>Treatment: rTSST-1 Variant Candidate Vaccine 100 ng | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|
| Experimental: Dose Group 2<br>Treatment: rTSST-1 Variant Candidate Vaccine 300 ng | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|
| Experimental: Dose Group 3<br>Treatment: rTSST-1 Variant Candidate Vaccine 1 µg | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|
| Experimental: Dose Group 4<br>Treatment: rTSST-1 Variant Candidate Vaccine 3 µg | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|
| Experimental: Dose Group 5<br>Treatment: rTSST-1 Variant Candidate Vaccine 10 µg | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|
| Experimental: Dose Group 6<br>Treatment: rTSST-1 Variant Candidate Vaccine 30 µg | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|
| Placebo Comparator: Dose Group 0<br>Control: Al(OH)3 Adjuvant | Biological: rTSST-1 Variant Candidate Vaccine<br>* In the absence of adverse events classified as clinically relevant, interval between dose escalations 1 week. Immunization to be repeated at the same dose level 1 - 2 months later. If immunogenicity can be shown after the second administration of 1 µg, the sample size will be increased from 3 + 1 to 9 + 3. Otherwise, the sample size of 3 + 1 will continue until immunogenicity is seen at a higher dose level. If there is no immune response in any dose group after the second immunization, a third injection will be given 4 -8 weeks thereafter in dose groups of 1 µg and above. Immunogenicity is defined by seroconversion from a TSST-1 Ab titer of < 20 to > 40 or a 4-fold increase in TSST-1 Ab titer . Patients 3 µg or more will be randomized.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Clinical observations and clinical laboratory values | through day 70 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Seroconversion | ELISA IgG against rTSST-1 | through day 70 |