Effect of Tebipenem on Normal Human Intestinal Microbiota

NCT04376554 | Completed Phase 1 FDA Drug

• 1 other identifier: SPR994-103
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The overall purpose of this study is to support the development of an oral formulation of TBPM-PI-HBr by assessing the potential ecological effects of tebipenem on the normal intestinal microbiota as compared to the effects of oral amoxicillin-clavulanate.

Conditions

Healthy Volunteers

Keywords

intestinal microbiota; safety; pharmacokinetics; TBPM-PI-HBr; tebipenem

Outcome Measures

Primary Outcomes (2)

• Changes in the number of microorganisms in the intestinal flora of healthy subjects during and after 10 days of oral administration of TBPM-PI-HBr or amoxicillin-clavulanate

  Changes in the number of microorganisms identified in feces

  Change from baseline (Day-1), at Days 2, 4, 7, 10, 14, 21, 90, and 180

• Changes in the types of microorganisms in the intestinal flora of healthy subjects during and after 10 days of oral administration of TBPM-PI-HBr or amoxicillin-clavulanate

  Changes in the types of microorganisms identified in feces

  Change from baseline (Day-1), at Days 2, 4, 7, 10, 14, 21, 90, and 180

Secondary Outcomes (7)

• To explore the potential for development of resistance by measuring the number of new colonizing bacterial isolates

  Change from baseline (Day-1), at Days 2, 4, 7, 10, 14, 21, 90, and 180

• To assess the plasma concentrations of tebipenem over 10 days of oral administration of TBPM-PI-HBr.

  Day 1 through Day 14

• To assess the fecal concentrations of tebipenem over 10 days of oral administration of TBPM-PI-HBr.

  Day 1 through Day 14

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  Incidents of treatment-emergent adverse events from Day 1 through last follow-up visit (180 days after last dose)

• Incidence of abnormal safety laboratory assessments [Safety and Tolerability]

  Incidents of abnormal safety laboratory assessments from Day 1 through last follow-up visit (180 days after last dose)

Other Outcomes (1)

• Correlation of intestinal microbiota patterns with tebipenem concentrations measured in feces.

  Day 1 through last follow-up visit (180 days after last dose)

Study Arms (2)

TBPM-PI-HBr

EXPERIMENTAL

Healthy subjects meeting eligibility criteria will be sequentially randomized to receive either 600mg TBPM-PI-HBr every 8 hours (PO q8h \[±1 hour\]) or 500/125mg amoxicillin-clavulanate PO q8h (±1 hour) for 10 days.

Drug: TBPM-PI-HBr

amoxicillin-clavulanate

ACTIVE COMPARATOR

Healthy subjects meeting eligibility criteria will be sequentially randomized to receive either 500/125mg amoxicillin-clavulanate PO q8h (±1 hour) or 600mg TBPM-PI-HBr every 8 hours (PO q8h \[±1 hour\]) or for 10 days.

Drug: amoxicillin-clavulanate

Interventions

TBPM-PI-HBr DRUG

TBPM-PI-HBr (2 x 300mg tablets) PO q8h \[±1 hour\] for 10 days

Also known as: TBPM-PI-HBr oral tablet

TBPM-PI-HBr

amoxicillin-clavulanate DRUG

amoxicillin-clavulanate (1 × 500mg/125mg tablet) PO q8h \[±1 hour\] for 10 days

Also known as: amoxicillin-clavulanate oral tablets

amoxicillin-clavulanate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adult males and/or females, ≥18 years of age at the time of screening;
• Medically healthy without clinically significant abnormal values for hematology, clinical chemistry, urinalysis, physical examination, vital signs, or ECG as determined by the investigator during the screening period. Discussion is encouraged between the Investigator and the Sponsor Medical Monitor regarding the clinical relevance of any abnormal laboratory value during the pre-dose period;
• Willing and able to provide written informed consent;
• Willing and able to comply with all study assessments and adhere to the protocol schedule, including all scheduled post-therapy visits;
• Have suitable venous access for blood sampling;
• Women of childbearing potential (WOCBP\*) must use a highly effective form of birth control (confirmed by the Investigator). Rhythm methods will not be considered as highly effective methods of birth control. WOCBP must agree to use a highly effective method of birth control, as defined above, from signing the Informed Consent Form (ICF), throughout the study duration and until 30 days after the last dose of study drug;
• Non-vasectomized male volunteers must use an adequate method of contraception (condom or condom with spermicide, depending on local regulations) from the time of signing the ICF, throughout the study duration and until 30 days after the last dose of study drug. Men with a partner who is (are) not of childbearing potential are exempt from these requirements;
• Male volunteers must not donate sperm for time of signing the ICF until at least 30 days after the last dose of the study drug

You may not qualify if:

• History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past 3 months determined by the Investigator to be clinically relevant;
• History or presence of known or suspected gastrointestinal disorder, including but not limited to Clostridioides difficile infection, inflammatory bowel disease, recent history of food poisoning or other stomach/intestinal disorders including gastroenteritis (within 6 months);
• History of systemic antibiotic treatment during the last three months prior to randomization;
• Use of any systemic prescription medication or any systemic over-the-counter medication, including herbal products and vitamins or probiotics within 7 days prior to randomization; except for hormonal contraceptives and the intermittent use of paracetamol, ibuprofen, and antihistamines;
• Alanine transaminase (ALT) or aspartate transaminase (AST) \>5 × upper limit of normal and CrCl of ≤50 mL/min, as estimated by the Lund-Malmö revised formula;
• History of seizure disorders, except for febrile seizures in childhood;
• History of substance or alcohol abuse and positive urine drug testing at screening. History of substance or alcohol abuse and negative urine drug testing at screening can be enrolled in study based on the Investigator's discretion;
• Positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV);
• Documented or suspected hypersensitivity reaction or anaphylaxis to β-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems), product excipients (Mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and film coating systems \[Opadry\]) or any contraindication to the use of amoxicillin- clavulanate;
• Participation in another investigational clinical study within 3 months prior to Day 1;
• Current or anticipated need for systemic antibiotics, probiotics, or laxatives during the study;
• Any other condition or prior therapy, which, in the opinion of the Investigator, would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements.

Sponsors & Collaborators

• Spero Therapeutics: lead
• Iqvia Pty Ltd: collaborator

Study Sites (1)

Karolinska University Hospital

Huddinge, Stockholm County, Sweden

Location

Related Publications (1)

• Sewunet T, Razavi M, Rosenborg S, Camporeale A, Nowak M, Melnick D, Gasink LB, Eckburg PB, Critchley IA, Nord CE, Giske CG. Effect of tebipenem pivoxil hydrobromide on the normal gut microbiota of a healthy adult population in Sweden: a randomised controlled trial. Lancet Microbe. 2024 Apr;5(4):e355-e365. doi: 10.1016/S2666-5247(23)00360-9. Epub 2024 Feb 29.

  PMID: 38432233 DERIVED

MeSH Terms

Interventions

Amoxicillin-Potassium Clavulanate Combination

Intervention Hierarchy (Ancestors)

Clavulanic Acid; Clavulanic Acids; beta-Lactams; Lactams; Amides; Organic Chemicals; Amoxicillin; Ampicillin; Penicillin G; Penicillins; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Steffan Rosenborg

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Subjects will be randomized by gender to 1:1 ratio to receive TBPM-PI-HBr or amoxicillin-clavulanate using a SAS ® generated randomization code and the treatment allocation will be performed using a block randomization algorithm.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single-Center, Open-Label, Randomized, Parallel-Group, Active Control, Phase 1 Study

Study Record Dates

• First Submitted: March 16, 2020
• First Posted: May 6, 2020
• Study Start: February 10, 2020
• Primary Completion: April 6, 2021
• Study Completion: April 6, 2021
• Last Updated: May 4, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)