Infectious DiseasePhase 4EPAACNCT04084106
Effects of Phenoximethylpenicillin, Amoxicillin and Amoxicillin-clavulanic Acid on the Gut Microbiota
A Phase 4 study testing Phenoxymethylpenicillin, Amoxicillin and Amoxicillin-clavulanic acid in people with Infectious Disease, run by Uppsala University at 1 site in Sweden.
Trial summary
The overall aim of the project is to fill an important knowledge gap on the ecological effects of selected antibiotics. The results will be used to guide treatment decisions for common infections to as much as possible reduce the negative impact on the intestinal microbiota and consequently the risks of side effect… Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Infectious Disease
- What is being tested?
- Phenoxymethylpenicillin, Amoxicillin and Amoxicillin-clavulanic acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 104 participants
- Where
- 1 siteSweden
- Study dates
- 10 Sep 2019to 11 Nov 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Signed written informed consent
- Age ≥ 18 years
Who cannot join
- Chronic disease, allergy, asthma, recurrent infections
- Ongoing antibiotic treatment
- Antibiotic treatment the past 12 months
- Pregnancy or planned pregnancy within the study period
- Known allergy to phenoximethylpenicillin, amoxicillin and amoxicillin- clavulanic acid
- Planned travel outside Europe within one year from inclusion
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effects of Phenoximethylpenicillin, Amoxicillin and Amoxicillin-clavulanic Acid on the Gut Microbiota of Healthy Volunteers: a Randomized Clinical Trail
The overall aim of the project is to fill an important knowledge gap on the ecological effects of selected antibiotics. The results will be used to guide treatment decisions for common infections to as much as possible reduce the negative impact on the intestinal microbiota and consequently the risks of side effect and resistance development during therapy.
Specific aims for this study are to determine (1) the composition of intestinal microbiota and prevalence of resistant bacteria and resistance genes prior to and up to 1 year after antibiotic treatment, and (2) the relative effects on the microbiota after treatment with three antibiotics used for lower respiratory tract infections; phenoximethylpenicillin, amoxicillin and amoxicillin-clavulanic acid, or no treatment (control).
A total of 120 healthy volunteers will be recruited to the study. They are randomised to 5 days' treatment with phenoximethylpenicillin, amoxicillin or amoxicillin-clavulanic acid, or to no antibiotic treatment. Subjects submit faecal samples at eight different time-points; at the start of the study (before treatment), immediately, one week and 1, 3, 6, 12 and 24 months after completion of the treatment. The samples will be delivered to Scilifelab for metagenomic sequencing to detect antibiotic resistant genes and analysis of the intestinal microbiota and to the Microbiology ward for analysis with phenotypic methods (culturomics) to detect resistant genes and resistant bacteria.
Read the detailed description
Background: The rationale behind this project is that different antibiotics have varying effects on the intestinal microbiota, which has clinical implications. To investigate the relative collateral damage during treatment with different antibiotics a randomized trial is needed. Repeated sampling during a 1-year period is required to capture prolonged disturbance and the time to a restored microbiota. To readily examine the antibiotic effects healthy volunteers are ideal for the study as their microbiota is most likely to be normal at inclusion. They also have a low risk of encountering other factors during follow-up that will affect the composition of the intestinal bacteria.
Aim: The purpose of the study is to determine: (1) composition of intestinal microbiota and prevalence of resistant bacteria and resistance genes prior to and up to 1 year after antibiotic treatment, and (2) differences in the microbiota after treatment with antibiotics; phenoximethylpenicillin, amoxicillin and amoxicillin-clavulanic acid respectively compared to no treatment.
Method: The study is a conducted within the Department of Infectious Diseases at Uppsala University Hospital. A total of 120 healthy volunteers will be recruited to the study. They are randomised to 5 days' treatment with phenoximethylpenicillin, amoxicillin or amoxicillin-clavulanic acid, or to no antibiotic treatment. Subjects submit faecal samples at eight different time-points; at the start of the study (before treatment), immediately, one week and 1, 3, 6, 12 and 24 months after completion of the treatment. Altogether, the subjects will provide 8 faecal samples during the course of the study. A total of 960 faecal samples will be collected and analysed.
Each subject will submit two faecal samples at each time-point. One sample will be frozen in DNA-shield and delivered to Scilifelab for analysis of the intestinal microbiota and metagenomic sequencing to detect antibiotic resistant genes.The other faecal sample will be delivered to the Microbiology department for analysis with phenotypic methods (culturomics) to detect resistant genes and resistant bacteria.
Statistics: The compilation of data and statistics will primarily be descriptive. We will analyse the intestinal microbiota and the prevalence of resistance genes in the subjects prior to and immediately after antibiotic treatment, and then monitor the composition (diversity) of the intestinal microbiota, resistant bacteria and resistance genes 1 week, 1, 3, 6, 12 and 24 months after completion of the treatment. Diversity will be analysed using metagenomics (shotgun) and is used as a variable to compare the degree of collateral damage on the intestinal microbiota with different antibiotics, and to compare the intestinal microbiota before and after antibiotic treatment in the same individual. The diversity of the intestinal microbiota in faecal sample 1 will constitute the baseline. Targeted statistical calculations on differences between treatment groups and gender as regards intestinal microbiota, resistance and side effects will be carried out depending on outcomes, which cannot be predicted in advance.
Endpoints and outcomes: The primary endpoint is the diversity and composition of the intestinal microbiota, the prevalence of multidrug-resistant Gram-negative bacteria in screening cultures and the prevalence of antibiotic resistance genes in faeces prior to and up to 2 year after antibiotic treatment.
The results may be used as a basis for targeting the choice of antibiotic for pulmonary infections (pneumonia) towards those antibiotics that have the least risk of disrupting the intestinal microbiota and leading to resistance.
- Conditions
- Infectious Disease
- Being tested
- Phenoxymethylpenicillin, Amoxicillin, Amoxicillin-clavulanic acid
- Keywords
- randomized trial, antibiotic resistant genes, gut microbiota, healthy volunteers, metagenomics
- Medical subject headings
- Communicable Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhenoxymethylpenicillinDrug
Oral administration
AmoxicillinDrug
Oral administration
Amoxicillin-clavulanic acidDrug
Oral administration
| Study group | Role | What they receive |
|---|---|---|
| phenoximethylpenicillin | Experimental | phenoximethylpenicillin, tablet, 1 g 3 times daily for 5 days. Receives: Drug: Phenoxymethylpenicillin |
| amoxicillin | Active comparator | amoxicillin, tablet, 500 mg 3 times daily for 5 days. Receives: Drug: Amoxicillin |
| amoxicillin-clavulanic acid | Active comparator | amoxicillin-clavulanic acid tablet, 500/125 mg 3 times daily for 5 days. Receives: Drug: Amoxicillin-clavulanic acid |
| No intervention | No intervention | No intervention |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diversity of the intestinal microbiota prior to and after (any) antibiotic treatment as determined with metagenomics on repeated faecal samples.
The diversity of the intestinal microbiota prior to and up to 2 year after antibiotic treatment will be determined by sequencing with shotgun metagenomics.
Measured: 2 year
Comparison of the diversity of the intestinal microbiota with three different antibiotics - phenoxymethylpenicillin (reference), amoxicillin and amoxicillin-clavulanic acid - as determined with metagenomics on repeated faecal samples.
The relative effects of on the diversity of the intestinal microbiota prior to and up to 2 year after antibiotic treatment will be determined by sequencing with shotgun metagenomics.
Measured: 2 years
Prevalence of resistance genes in the intestinal microbiota prior to and after (any) antibiotic treatment as determined with metagenomics on repeated faecal samples.
The prevalence of resistant bacteria and resistance genes prior to and up to 2 year after antibiotic treatment will be determined by sequencing with shotgun metagenomics.
Measured: 2 years
Comparison of the prevalence of resistance genes in the intestinal microbiota with different antibiotics - phenoxymethylpenicillin, amoxicillin and amoxicillin-clavulanic acid - as determined with metagenomics on repeated faecal samples.
The relative effects of on the prevalence of resistant bacteria and resistance genes prior to and up to 2 year after treatment with phenoxymethylpenicillin (reference), amoxicillin or amoxicillin-clavulanic acid will be determined by sequencing with shotgun metagenomics.
Measured: 2 years
Prevalence of multidrug-resistant bacteria in the intestinal microbiota prior to and after (any) antibiotic treatment as determined with phenotypic analyses on repeated faecal samples.
Multidrug-resistant gram-negative bacteria will be isolated and characterized by incubation in selective media, MIC determination using conventional methods and PCR/whole-genome sequencing to determine the presence of resistance genes.
Measured: 2 years
Comparison of the prevalence of resistant bacteria in the intestinal microbiota with three different antibiotics - phenoxymethylpenicillin, amoxicillin and amoxicillin-clavulanic acid - as determined with phenotypic analyses on repeated faecal samples.
Multidrug-resistant gram-negative bacteria producing will be isolated and characterized by incubation in selective media, MIC determination using conventional methods and PCR/whole-genome sequencing to determine the presence of resistance genes.
Measured: 2 years
Secondary outcomes (2)
Prevalence of adverse events with (any) antibiotic treatment.
Information on side effects during and following antibiotic treatment will be collected using diaries and questionnaires.
Measured: 1 year
Comparison of prevalence of adverse events with three different antibiotics - phenoxymethylpenicillin (reference), amoxicillin and amoxicillin-clavulanic acid.
Information on side effects during and following antibiotic treatment will be collected using diaries and questionnaires.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Sep 2019
- Study start10 Sep 2019
- Primary completion11 Nov 2022
- Study completion11 Nov 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Infectious DiseaseStudies of the same condition, open and under way.
- More trials run by Uppsala UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized clinical trail
- Masking
- None (open label)
- Enrolment
- 104 participants (actual)
Sponsor and investigators
- Lead sponsor
- Uppsala University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Thomas Tängdén, Uppsala University
- Investigators
- Thomas Tängdén, MD, PhD, Principal investigator, Uppsala University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04084106
- Sponsor's protocol ID
- 2019-03300
- Other IDs
- 2019
- Acronym
- EPAAC
- Status last verified
- Dec 2022
- First submitted
- 30 Aug 2019
- Last updated
- 2 Dec 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Phenoximethylpenicillin, Amoxicillin and Amoxicillin-clavulanic Acid on the Gut Microbiota of Healthy Volunteers: a Randomized Clinical Trail
- ClinicalTrials.gov ID
- NCT04084106
- Acronym / sponsor ID
- EPAAC / 2019-03300
- Conditions
- Infectious Disease
- Keywords
- randomized trial, antibiotic resistant genes, gut microbiota, healthy volunteers, metagenomics
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 104 participants (actual)
- Lead sponsor
- Uppsala UniversityUniversity, hospital or other
- Study start
- 10 Sep 2019 (actual)
- Primary completion
- 11 Nov 2022 (actual)
- Study completion
- 11 Nov 2022 (actual)
- First posted
- 10 Sep 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The overall aim of the project is to fill an important knowledge gap on the ecological effects of selected antibiotics. The results will be used to guide treatment decisions for common infections to as much as possible reduce the negative impact on the intestinal microbiota and consequently the risks of side effect and resistance development during therapy.
Specific aims for this study are to determine (1) the composition of intestinal microbiota and prevalence of resistant bacteria and resistance genes prior to and up to 1 year after antibiotic treatment, and (2) the relative effects on the microbiota after treatment with three antibiotics used for lower respiratory tract infections; phenoximethylpenicillin, amoxicillin and amoxicillin-clavulanic acid, or no treatment (control).
A total of 120 healthy volunteers will be recruited to the study. They are randomised to 5 days' treatment with phenoximethylpenicillin, amoxicillin or amoxicillin-clavulanic acid, or to no antibiotic treatment. Subjects submit faecal samples at eight different time-points; at the start of the study (before treatment), immediately, one week and 1, 3, 6, 12 and 24 months after completion of the treatment. The samples will be delivered to Scilifelab for metagenomic sequencing to detect antibiotic resistant genes and analysis of the intestinal microbiota and to the Microbiology ward for analysis with phenotypic methods (culturomics) to detect resistant genes and resistant bacteria.
Detailed description
Background: The rationale behind this project is that different antibiotics have varying effects on the intestinal microbiota, which has clinical implications. To investigate the relative collateral damage during treatment with different antibiotics a randomized trial is needed. Repeated sampling during a 1-year period is required to capture prolonged disturbance and the time to a restored microbiota. To readily examine the antibiotic effects healthy volunteers are ideal for the study as their microbiota is most likely to be normal at inclusion. They also have a low risk of encountering other factors during follow-up that will affect the composition of the intestinal bacteria.
Aim: The purpose of the study is to determine: (1) composition of intestinal microbiota and prevalence of resistant bacteria and resistance genes prior to and up to 1 year after antibiotic treatment, and (2) differences in the microbiota after treatment with antibiotics; phenoximethylpenicillin, amoxicillin and amoxicillin-clavulanic acid respectively compared to no treatment.
Method: The study is a conducted within the Department of Infectious Diseases at Uppsala University Hospital. A total of 120 healthy volunteers will be recruited to the study. They are randomised to 5 days' treatment with phenoximethylpenicillin, amoxicillin or amoxicillin-clavulanic acid, or to no antibiotic treatment. Subjects submit faecal samples at eight different time-points; at the start of the study (before treatment), immediately, one week and 1, 3, 6, 12 and 24 months after completion of the treatment. Altogether, the subjects will provide 8 faecal samples during the course of the study. A total of 960 faecal samples will be collected and analysed.
Each subject will submit two faecal samples at each time-point. One sample will be frozen in DNA-shield and delivered to Scilifelab for analysis of the intestinal microbiota and metagenomic sequencing to detect antibiotic resistant genes.The other faecal sample will be delivered to the Microbiology department for analysis with phenotypic methods (culturomics) to detect resistant genes and resistant bacteria.
Statistics: The compilation of data and statistics will primarily be descriptive. We will analyse the intestinal microbiota and the prevalence of resistance genes in the subjects prior to and immediately after antibiotic treatment, and then monitor the composition (diversity) of the intestinal microbiota, resistant bacteria and resistance genes 1 week, 1, 3, 6, 12 and 24 months after completion of the treatment. Diversity will be analysed using metagenomics (shotgun) and is used as a variable to compare the degree of collateral damage on the intestinal microbiota with different antibiotics, and to compare the intestinal microbiota before and after antibiotic treatment in the same individual. The diversity of the intestinal microbiota in faecal sample 1 will constitute the baseline. Targeted statistical calculations on differences between treatment groups and gender as regards intestinal microbiota, resistance and side effects will be carried out depending on outcomes, which cannot be predicted in advance.
Endpoints and outcomes: The primary endpoint is the diversity and composition of the intestinal microbiota, the prevalence of multidrug-resistant Gram-negative bacteria in screening cultures and the prevalence of antibiotic resistance genes in faeces prior to and up to 2 year after antibiotic treatment.
The results may be used as a basis for targeting the choice of antibiotic for pulmonary infections (pneumonia) towards those antibiotics that have the least risk of disrupting the intestinal microbiota and leading to resistance.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- Randomized clinical trail
| Arm | Type | Receives |
|---|---|---|
| phenoximethylpenicillin | Experimental | Drug: Phenoxymethylpenicillinphenoximethylpenicillin, tablet, 1 g 3 times daily for 5 days. |
| amoxicillin | Active comparator | Drug: Amoxicillinamoxicillin, tablet, 500 mg 3 times daily for 5 days. |
| amoxicillin-clavulanic acid | Active comparator | Drug: Amoxicillin-clavulanic acidamoxicillin-clavulanic acid tablet, 500/125 mg 3 times daily for 5 days. |
| No intervention | No intervention | –No intervention |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Signed written informed consent
- Age ≥ 18 years
Key exclusion criteria (6 listed)
- Chronic disease, allergy, asthma, recurrent infections
- Ongoing antibiotic treatment
- Antibiotic treatment the past 12 months
- Pregnancy or planned pregnancy within the study period
- Known allergy to phenoximethylpenicillin, amoxicillin and amoxicillin- clavulanic acid
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PhenoxymethylpenicillinOral administration | Drug | phenoximethylpenicillin |
| AmoxicillinOral administration | Drug | amoxicillin |
| Amoxicillin-clavulanic acidOral administration | Drug | amoxicillin-clavulanic acid |
Primary outcome
Diversity of the intestinal microbiota prior to and after (any) antibiotic treatment as determined with metagenomics on repeated faecal samples.
Time frame: 2 year
The diversity of the intestinal microbiota prior to and up to 2 year after antibiotic treatment will be determined by sequencing with shotgun metagenomics.
Comparison of the diversity of the intestinal microbiota with three different antibiotics - phenoxymethylpenicillin (reference), amoxicillin and amoxicillin-clavulanic acid - as determined with metagenomics on repeated faecal samples.
Time frame: 2 years
The relative effects of on the diversity of the intestinal microbiota prior to and up to 2 year after antibiotic treatment will be determined by sequencing with shotgun metagenomics.
Prevalence of resistance genes in the intestinal microbiota prior to and after (any) antibiotic treatment as determined with metagenomics on repeated faecal samples.
Time frame: 2 years
The prevalence of resistant bacteria and resistance genes prior to and up to 2 year after antibiotic treatment will be determined by sequencing with shotgun metagenomics.
Comparison of the prevalence of resistance genes in the intestinal microbiota with different antibiotics - phenoxymethylpenicillin, amoxicillin and amoxicillin-clavulanic acid - as determined with metagenomics on repeated faecal samples.
Time frame: 2 years
The relative effects of on the prevalence of resistant bacteria and resistance genes prior to and up to 2 year after treatment with phenoxymethylpenicillin (reference), amoxicillin or amoxicillin-clavulanic acid will be determined by sequencing with shotgun metagenomics.
Prevalence of multidrug-resistant bacteria in the intestinal microbiota prior to and after (any) antibiotic treatment as determined with phenotypic analyses on repeated faecal samples.
Time frame: 2 years
Multidrug-resistant gram-negative bacteria will be isolated and characterized by incubation in selective media, MIC determination using conventional methods and PCR/whole-genome sequencing to determine the presence of resistance genes.
Comparison of the prevalence of resistant bacteria in the intestinal microbiota with three different antibiotics - phenoxymethylpenicillin, amoxicillin and amoxicillin-clavulanic acid - as determined with phenotypic analyses on repeated faecal samples.
Time frame: 2 years
Multidrug-resistant gram-negative bacteria producing will be isolated and characterized by incubation in selective media, MIC determination using conventional methods and PCR/whole-genome sequencing to determine the presence of resistance genes.
2 secondary outcomes
Prevalence of adverse events with (any) antibiotic treatment.
Time frame: 1 year
Comparison of prevalence of adverse events with three different antibiotics - phenoxymethylpenicillin (reference), amoxicillin and amoxicillin-clavulanic acid.
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Tängdén, MD, PhD principal investigator
Uppsala University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Phenoxymethylpenicillin, Amoxicillin and Amoxicillin-clavulanic acid in people with Infectious Disease, run by Uppsala University at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diversity of the intestinal microbiota prior to and after (any) antibiotic treatment as determined with metagenomics on repeated faecal samples. (time frame: 2 year). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2022.