- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02052934
Safety of Sublingual dmLT for ETEC
A Phase 1 Dose Escalating Study of Double Mutant Heat-Labile Toxin LTR192G/L211A (dmLT) From Enterotoxigenic Escherichia Coli (ETEC) by Sublingual or Oral Immunization to Determine Safety and Immunogenicity of a Multi-dose Regimen in Adult Humans
Study Overview
Status
Conditions
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Ohio
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Cincinnati, Ohio, United States, 45229-3026
- Cincinnati Children's Hospital Medical Center - Gastroenterology, Hepatology and Nutrition
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male or female ages 18-45, inclusive. - Provide written informed consent before initiation of any study procedures. - General good health, without (a) significant medical illness, (b) clinically significant physical examination findings, including vitals, as determined by the PI, and (c) screening laboratory values outside the site's normal limits. - Within 46 days of vaccination, have normal screening laboratories, per Appendix B for white blood cells (WBCs), hemoglobin (Hgb), platelets, absolute neutrophil count (ANC), sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST). - Have normal screening laboratories for urine protein Trace protein is acceptable. - HgbA1C <6.5% at screening. - Demonstrate comprehension of the protocol procedures and knowledge of study by passing a written examination (passing grade is at least 70 percent). - Agrees to complete all study visits and procedures. - Female subjects must be of non-childbearing potential (as defined as surgically sterile or postmenopausal for more than 1 year), or if of childbearing potential, must be using an effective method of birth control (e.g., use hormonal or barrier birth control such as implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], cervical sponges, diaphragms, condoms with spermicidal agents must have a vasectomized partner) within 2 months of vaccination, or practice abstinence and must agree to continue such precautions during the study and for 30 days after the Day 29 study visit. Male subjects must agree not to father a child for 30 days after the Day 29 study visit. A woman is eligible if she is monogamous with a vasectomized male. - Agrees not to participate in another clinical trial during the study period. - Agrees not to donate blood to a blood bank for 12 months after receiving the vaccine. - Potential subjects must be willing to adhere to the following prohibitions and restrictions during the course of the study to be eligible for participation: - Strenuous exercise (e.g., long distance running > 5km/day, weight lifting, or any physical activity to which the subject is not accustomed) is to be avoided during the overnight stay and for at least 72 hours prior to each study drug administration (and the Follow-up visit). - Subjects should not have donated blood in the 8 weeks prior to study entry.
Exclusion Criteria:
- Women who are pregnant or lactating or have a positive serum pregnancy test at screening or positive urine pregnancy test prior to vaccination. - Abnormal vital signs, defined as: -- Hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg) at rest on 2 separate days; or -- Palpated heart rate <55 or >100 beats/minute at rest on 2 separate days*; or *If heart rate between 45 and 55, subjects may be enrolled with an EKG that demonstrates normal sinus rhythm and does not document conduction disorders. --Temperature >/= 38.0 degrees C (100.4 degrees F) - Symptoms of an acute self-limited illness, including a temperature >/= 38.0 degrees C (100.4 degrees F), such as an upper respiratory infection or gastroenteritis within 7 days of administration of dmLT. - Positive hepatitis C, or HIV serology or positive hepatitis B serology not consistent with prior hepatitis B immunization. - Have a positive urine drug screen for opiates. - Subjects who are unwilling or unable to cease smoking for the duration of the overnight stay. - History of antimicrobial treatment in the 2 weeks before administration of dmLT. - Received previous experimental E. coli, LT, or cholera vaccines or live E. coli or Vibrio cholera challenges; or previous infection with cholera or diarrheagenic E. coli. - Abnormal routine bowel habits as defined by fewer than three stools per week or more than two stools per day in the past 6 months. - History of chronic gastrointestinal illness, including severe dyspepsia (mild or moderate heartburn or epigastric pain occurring no more than three times per week is permitted), or other significant gastrointestinal tract disease. - Regular use (weekly or more often) of laxatives, anti-diarrheal, anti-constipation, or antacid therapy. - History of major gastrointestinal surgery, excluding uncomplicated appendectomy or cholecystectomy. - Long-term use, defined as longer than 14 days, of oral steroids, parenteral steroids, or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months. (Nasal and topical steroids are allowed). - Have a diagnosis of schizophrenia or other major psychiatric diagnosis. - Are receiving the following psychiatric drugs: aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene, chlorpromazine, perphenazine, trifluopromazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate, or lithium citrate. NOTE: Subjects who are receiving a single antidepressant drug and are stable for at least 3 months before enrollment without de-compensating symptoms are allowed to be enrolled in the study. - History of receiving Ig or other blood product within the 3 months before enrollment in this study. - Traveled to ETEC-endemic areas, defined as Africa, Middle East, South Asia, or Central or South America within the past 3 years or raised in a cholera or ETEC endemic area. - Received any licensed vaccine within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) before enrollment in this study or plans to receive any licensed vaccine within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) after any study vaccination. - An acute or chronic medical condition that, in the opinion of the investigator, would render administration of dmLT unsafe or would interfere with the evaluation of responses. This includes, but is not limited to: known or suspected immunodeficiency, known chronic liver disease, significant renal disease, unstable or pr ogressive neurological disorders, history of diabetes, cancer (other than a healed skin lesion), heart disease (in the hospital for a heart attack, history of irregular heart beat or fainting caused by an irregular heartbeat), unconsciousness (other than a single brief "concussion"), seizures (other than with fever when subject was a child <5 years old), asthma requiring treatment with inhaler or medication in the prior 2 years, autoimmune disease or eating disorder, and transplant recipients. - Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month before enrollment in this study or expects to receive an experimental agent during the study. - History of alcohol or drug abuse in the last 5 years. - Plans to travel outside of the USA in the time between study vaccination and 28 days following the final vaccination. - Unable to spend up to 48 hours at an overnight facility following the administration of Dose 1. - Any condition that would, in the opinion of the Site Investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. - Use of prescription or over-the-counter (OTC) medications that contain acetaminophen, aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs within 48 hours prior to receiving the investigational product. - Use of prescription acid suppression medication or OTC antacids within 72 hours of investigational product administration. - Subjects with autoimmune disorders, chronic inflammatory disorders or neurological disorders with a potential autoimmune correlation. - Subjects who planned to travel to an ETEC-endemic area, defined as Africa, Middle East, South Asia, or Central or South America, during the long-term safety follow-up period (6 months) of the study. - Known allergies to study compound. - Special populations, e.g., non-English speakers, children, illiterate or non-writing individuals, vulnerable populations. - Any abnormality of the palate.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Cohort 1
Three sublingual (SL) doses of dMLT, 1 microgram (mcg), on Days 1, 15 and 29, 8 subjects
|
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5 cohorts receive 3 doses ranging from 1 mcg to 50 mcg.
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5b cohort receive 3 doses of 25 mcg.
|
EXPERIMENTAL: Cohort 2
Three SL doses of dMLT, 5 mcg, on Days 1, 15 and 29, 8 subjects
|
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5 cohorts receive 3 doses ranging from 1 mcg to 50 mcg.
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5b cohort receive 3 doses of 25 mcg.
|
EXPERIMENTAL: Cohort 3
Three SL doses of dMLT, 25 mcg, on Days 1, 15 and 29, 11 subjects
|
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5 cohorts receive 3 doses ranging from 1 mcg to 50 mcg.
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5b cohort receive 3 doses of 25 mcg.
|
EXPERIMENTAL: Cohort 4
Three SL doses of dMLT, 50 mcg, on Days 1, 15 and 29, 11 subjects
|
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5 cohorts receive 3 doses ranging from 1 mcg to 50 mcg.
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5b cohort receive 3 doses of 25 mcg.
|
EXPERIMENTAL: Cohort 5a
Three SL doses of dMLT,25 mcg on Days 1, 15 and 29, 13 subjects.
|
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5 cohorts receive 3 doses ranging from 1 mcg to 50 mcg.
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5b cohort receive 3 doses of 25 mcg.
|
EXPERIMENTAL: Cohort 5b
Three oral doses of dMLT, 25 mcg on Days 1, 15and 29, 13 subjects
|
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5 cohorts receive 3 doses ranging from 1 mcg to 50 mcg.
Attenuated, Recombinant Double Mutant Heat-Labile Toxin (dmLT) from Enterotoxigenic Escherichia coli (ETEC), LT(R192G/L211A); lot 1575.
Subjects in 5b cohort receive 3 doses of 25 mcg.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Occurrence of solicited reactogenic side effects through Day 8 following each vaccination.
Time Frame: Day 0 to Day 8
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Day 0 to Day 8
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Occurrence of vaccine-related, non-solicited adverse events (AEs) for facial nerve disturbance through 75 days post third vaccination.
Time Frame: Day 29 through Day 104
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Day 29 through Day 104
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Occurrence of vaccine-related, non-solicited adverse events (AEs) through Day 36 following first vaccination.
Time Frame: Day 0 to Day 36
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Day 0 to Day 36
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Occurrence of vaccine-related serious adverse events (SAEs) through 7 months following first vaccination.
Time Frame: Day 0 through Day 210
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Day 0 through Day 210
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Proportion of subjects with =4-fold rise from the baseline in LT toxin neutralization titers.
Time Frame: Days 0, 8, 15, 22, 29, 36, 64 and 85
|
Days 0, 8, 15, 22, 29, 36, 64 and 85
|
Proportion of subjects with >/= 2-fold rise from the baseline in dmLT-specific IgA- and IgG-ALS at any time after vaccination.
Time Frame: Days 0, 8, 15, 22, 29, 36, 64, and 85
|
Days 0, 8, 15, 22, 29, 36, 64, and 85
|
Proportion of subjects with >/= 4-fold rise from the baseline in dmLT-specific fecal IgA or >/= 4-fold rise for the ratio of specific over total IgA after vaccination.
Time Frame: Days 0, 8, 15, 22, 29, 36, and 64
|
Days 0, 8, 15, 22, 29, 36, and 64
|
Proportion of subjects with >/= 4-fold rise from the baseline in dmLT-specific IgA- and IgG-ALS after vaccination.
Time Frame: Days 0, 8, 15, 20, 22, 29, 34, and 36
|
Days 0, 8, 15, 20, 22, 29, 34, and 36
|
Proportion of subjects with >/= 4-fold rise from the baseline in dmLT-specific saliva IgA or >/= 4-fold rise for the ratio of specific over total IgA after vaccination.
Time Frame: Days 0, 8, 15, 22, 29, 36, and 64
|
Days 0, 8, 15, 22, 29, 36, and 64
|
Proportion of subjects with >/= 4-fold rise from the baseline in dmLT-specific serum IgA or IgG at any time after vaccination.
Time Frame: Days 0, 8, 15, 22, 29, 36, 64, and 85
|
Days 0, 8, 15, 22, 29, 36, 64, and 85
|
Proportion of subjects with >8 IgA- or IgG-ASC/10^6 peripheral blood mononuclear cells (PBMCs) after vaccination.
Time Frame: Days 0, 8, 15, 20, 22, 29, 34, and 36
|
Days 0, 8, 15, 20, 22, 29, 34, and 36
|
Proportion of subjects with IgG and IgA dmLT-specific circulating ASC expressing gut homing receptors.
Time Frame: Days 0 8, 15, 20, 22, 29, 34, and 36
|
Days 0 8, 15, 20, 22, 29, 34, and 36
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 12-0023
- HHSN272201300016I
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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