Dose Escalating Study of Intramuscular Invaplex[AR-DETOX]

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety of a Shigella flexneri 2a detoxified artificial invasin complex (Invaplex[AR-Detox]) vaccine candidate administered by intramuscular immunization.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, Phase 1 clinical trial in which a total of 60 volunteers will receive one of three doses of Invaplex[AR-DETOX] or placebo (saline). The vaccine will be administered via intramuscular (IM) injection on study days 1, 22, and 43. Each participant will receive the same formulation at each vaccination dependent upon group assignment. The study will be initiated with the lowest dose level (2.5 μg) and will proceed to the next highest dose in an escalating fashion. All safety data will be summarized and reviewed by the Protocol Safety Review Team (PSRT) prior to dose-escalation. Specimens will be collected at prescribed intervals to examine systemic and mucosal immune responses. Vaccine safety will be actively monitored during vaccination and for 28 days following the third vaccine dose.

Official Title
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A Phase 1 Double-blind, Placebo-controlled, Dose Escalating Study of Intramuscular Detoxified Shigella Flexneri 2a Artificial Invasin Complex (Invaplex[AR-DETOX]) Vaccine

Conditions
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Diarrhea

Intervention / Treatment
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* Biological: Invaplex[AR-DETOX]
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, adult, male or female, age 18 to 50 years (inclusive) at the time of enrollment. Completion and review of comprehension test (achieved ≥ 70% accuracy, two attempts allowed). Provide written informed consent before initiation of any study procedures. Agrees to complete all study visits and procedures and to provide a screening stool sample. Women of childbearing capacity: Negative pregnancy test with understanding (through informed consent process) to not become pregnant during the study or within three (3) months following the last vaccine dose. Exclusion Criteria: Health problems (for example, chronic medical conditions such as psychiatric conditions, diabetes mellitus, hypertension, or any other conditions that might place the subjects at increased risk of adverse events) - study clinicians, in consultation with the Principal Investigator (PI), will use clinical judgment on a case-by-case basis to assess safety risks under this criterion. The PI will consult with the Research Monitor as appropriate. History of autoimmune disorders, cardiovascular and renal disease. Use of immunosuppressive medications (systemic corticosteroids or chemotherapeutics that may influence antibody development), or immunosuppressive illness, including immunoglobulin A (IgA) deficiency (defined by serum IgA < 7 mg/dL). Women who are pregnant or planning to become pregnant during the study period plus 3 months beyond the last vaccine dose and currently nursing women. Participation in research involving another investigational product (defined as receipt of an investigational product or exposure to an invasive investigational device) 30 days before planned date of first vaccination or anytime throughout the duration of the study until the last in-clinic study safety visit. Positive blood test for hepatitis B surface antigen (HBsAG), hepatitis C virus antibody (HCV Ab), human immunodeficiency virus (HIV)-1/HIV-2 antibody. Clinically significant abnormalities on basic laboratory screening tests. Systemic antimicrobial treatment (i.e., topical treatments are not an exclusion) within 1 week before administration of the first vaccine dose. Allergies that may increase the risk of adverse events (AEs). Regular use (weekly or more often) of antidiarrheal, anti-constipation, or antacid therapy. Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis. Personal or family history of an inflammatory arthritis. Positive blood test for human leukocyte antigen (HLA) B27 (associated with increased risk of reactive arthritis secondary to Shigella infection) History of allergy to any vaccine. Exclusionary skin disease history/findings that would confound assessment or prevent appropriate local monitoring of AEs, or possibly increase the risk of a local AE. Serum immunoglobulin G (IgG) titer > 2500 to Shigella flexneri 2a lipopolysaccharide antigen (LPS). History of microbiologically confirmed Shigella infection. Received previous licensed or experimental Shigella vaccine or live Shigella challenge. Travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within two years prior to dosing (clinician judgement). Occupation involving handling of Shigella bacteria currently, or in the past 3 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Invaplex[AR-Detox] 2.5 μg<br>Participants received an intramuscular injection of 2.5 μg Invaplex[AR-DETOX] vaccine on Days 1, 22, and 43. | Biological: Invaplex[AR-DETOX]<br>* Detoxified Shigella flexneri 2a Artificial Invasin Complex (Invaplex[AR-Detox]) Vaccine<br>|
| Experimental: Invaplex[AR-Detox] 10 μg<br>Participants received an intramuscular injection of 10 μg Invaplex[AR-DETOX] vaccine on Days 1, 22, and 43. | Biological: Invaplex[AR-DETOX]<br>* Detoxified Shigella flexneri 2a Artificial Invasin Complex (Invaplex[AR-Detox]) Vaccine<br>|
| Experimental: Invaplex[AR-Detox] 25 μg<br>Participants received an intramuscular injection of 25 μg Invaplex[AR-DETOX] vaccine on Days 1, 22, and 43. | Biological: Invaplex[AR-DETOX]<br>* Detoxified Shigella flexneri 2a Artificial Invasin Complex (Invaplex[AR-Detox]) Vaccine<br>|
| Placebo Comparator: Placebo<br>Participants received an intramuscular injection of placebo solution on Days 1, 22, and 43. | Other: Placebo<br>* Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events | All adverse events (AEs) were assessed for severity by the investigator according to the following scale: Grade 1 (Mild): Does not interfere with routine activities, minimal level of discomfort; Grade 2 (Moderate): Interferes with routine activities, moderate level of discomfort; Grade 3 (Severe): Unable to perform routine activities, significant level of discomfort; Grade 4 (Potentially life-threatening): Hospitalization or ER visit for potentially life-threatening event. An AE was considered serious if it resulted in any of the following outcomes: Death Life-threatening AE Inpatient hospitalization or prolongation of existing hospitalization Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Congenital anomaly/birth defect. The Investigator assessed the relationship of each adverse event to study drug. | From first dose up to 28 days following the third immunization (71 days) | 
| Number of Participants With Solicited Adverse Events Up to 7 Days After Dose 1 | The solicited AEs for this study included: Site pain Site tenderness Swelling Induration (determined by investigator exam) Site redness Pruritus Fever Nausea Vomiting Abdominal pain Diarrhea (loose stools) Appetite change Fatigue Headache Myalgias (general pain or soreness in muscles) Arthralgias (general pain in joints) Malaise | 7 days after the first immunization (Days 1 to 7) | 
| Number of Participants With Solicited Adverse Events Up to 7 Days After Dose 2 | The solicited AEs for this study included: Site pain Site tenderness Swelling Induration (determined by investigator exam) Site redness Pruritus Fever Nausea Vomiting Abdominal pain Diarrhea (loose stools) Appetite change Fatigue Headache Myalgias (general pain or soreness in muscles) Arthralgias (general pain in joints) Malaise | 7 days after the second immunization (Days 22 to 28) | 
| Number of Participants With Solicited Adverse Events After Dose 3 | The solicited AEs for this study included: Site pain Site tenderness Swelling Induration (determined by investigator exam) Site redness Pruritus Fever Nausea Vomiting Abdominal pain Diarrhea (loose stools) Appetite change Fatigue Headache Myalgias (general pain or soreness in muscles) Arthralgias (general pain in joints) Malaise | 7 days after the third immunization (Days 43 to 49) | 
| Number of Participants With Unsolicited Adverse Events After Each Dose |  | Dose 1: Days 1 to 21; Dose 2: Days 22 to 42; Dose 3: Days 43 to 71 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titer (GMT) of Serum Immunoglobulin A (IgA) Antibodies to Invaplex |  | Days 1 (Baseline), 22, 43, 50, 57 and 71. | 
| Geometric Mean Titer (GMT) of Serum Immunoglobulin G (IgG) Antibodies to Invaplex |  | Days 1 (Baseline), 22, 43, 50, 57 and 71. | 
| Geometric Mean Titer (GMT) of Immunoglobulin A Antibodies to Invaplex in α4β7+ Antibody in Lymphocyte Supernatant (ALS) |  | Days 1 (Baseline), 8, 29, and 50 | 
| Geometric Mean Titer of Immunoglobulin G Antibodies to Invaplex in α4β7+ Antibody in Lymphocyte Supernatant |  | Days 1 (Baseline), 8, 29, and 50 | 
| Percentage of Participants With a ≥ 4-fold Increase in Serum IgA Antibodies From Baseline | Seroconversion was defined as ≥ 4-fold increase in antibody titer from Baseline. | Days 1 (Baseline), 22 43, 50, 57 and 71 | 
| Percentage of Participants With a ≥ 4-fold Increase in Serum IgG Antibodies From Baseline | Seroconversion was defined as ≥ 4-fold increase in antibody titer from Baseline. | Days 1 (Baseline), 22 43, 50, 57 and 71 | 
| Percentage of Participants With a ≥ 4-fold Increase in ALS IgA From Baseline | Seroconversion was defined as ≥ 4-fold increase in antibody titer from Baseline. | Days 1 (Baseline), 8, 29, and 50 | 
| Percentage of Participants With a ≥ 4-fold Increase in ALS IgG From Baseline | Seroconversion was defined as ≥ 4-fold increase in antibody titer from Baseline. | Days 1 (Baseline), 8, 29, and 50 | 
| Geometric Mean Fold-rise (GMFR) in Serum IgA From Baseline |  | Days 1 (Baseline), 22, 43, 50, 57 and 71. | 
| Geometric Mean Fold-rise in Serum IgG From Baseline |  | Days 1 (Baseline), 22, 43, 50, 57 and 71. | 
| Geometric Mean Fold-rise in ALS IgA From Baseline |  | Days 1 (Baseline), 8, 29, and 50 | 
| Geometric Mean Fold-rise in ALS IgG From Baseline |  | Days 1 (Baseline), 8, 29, and 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Shigella flexneri 2a, Enteric, Shigella