Study to compare blood levels of ceftriaxone given by suppository or injection
| ISRCTN | ISRCTN82660596 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN82660596 |
| ClinicalTrials.gov number | NCT03895567 |
| Secondary identifying numbers | BAC18003 |
- Submission date
- 22/11/2022
- Registration date
- 06/12/2022
- Last edited
- 20/09/2024
- Recruitment status
- Not yet recruiting
- Overall study status
- Ongoing
- Condition category
- Other
Plain English summary of protocol
Background and study aims
In remote areas, babies born at home who become sick from infections during the first week of life need to be referred to a hospital that may be several hours or days journey away. If there was a medicine that was as effective as the injectable treatment given in the hospital that could be given in the rural health post this might improve their chance of recovery. Ceftriaxone is an intravenous antibiotic that treats infection effectively. Researchers have developed two test formulations (one capsule and one tablet) of a well-known antibiotic called ceftriaxone as suppositories which could be given to sick babies. Before this is done, they need to show that they deliver enough medicine to the body to treat severe infections and that they are safe. This study is the first step. The researchers will compare how much medicine gets into the blood after giving the new suppositories compared to giving a standard injection of ceftriaxone and check for any side effects of the suppository in healthy adults.
Who can participate?
Healthy non-pregnant Thai adults aged 18-46 years
What does the study involve?
The following will be evaluated in a random order in all participants.
1. Ceftriaxone (Roche®) 500 mg (slow intravenous injection)
2. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500 mg)
3. Ceftriaxone rectal dosage form test formulation 2 - rectodispersible mannitol-based tablet (1 x 500 mg)
Each participant will receive a single treatment dose of each of the three formulations in an order pre-determined by a computer-generated randomisation list. This will ensure approximately balanced proportions for all six schedules (either 6 or 7 participants per schedule). There will be a 7-28 days washout period between doses. The last follow-up visit is 28 (+ 2) days after the final dose. Participants lost to follow-up or unevaluable for any reason before completion of blood sampling after the final dose will be replaced at the discretion of the investigators with another participant of the same population, if either the sample size or completeness of the dataset is compromised.
What are the possible benefits and risks of participating?
There are no anticipated direct benefits for participating in this study. Knowledge gained from this study may assist with the development of a rectal dosage form of ceftriaxone which could be used to treat children with severe infections in the community in the region in the future.
There may be minor bruising, local tenderness or pre-syncopal symptoms (the feeling that you are about to faint) associated with blood samples. This risk will be minimised by having the procedure performed by trained nurses.
As with any antibiotic, unexpected serious adverse events, including severe allergic reactions may occur. In order to mitigate this risk, participants will be treated in an in-patient clinical area where Advanced Life Support trained physicians, equipment and drugs are immediately available for the management of any immediate post-dose serious adverse reactions. Participants will be observed closely for at least 30 minutes following the administration of any dose of study medication.
Ceftriaxone is usually very well tolerated. Doses exceeding 2 g have been associated with ‘pseudocholelithiasis’ (sludging in the gall bladder) in sick patients some of whom have been on parenteral nutrition. Ultrasound evidence of sludging in the gall bladder may be seen in up to 50% of patients but 9% of patients may be symptomatic. This side effect is unlikely to occur in a healthy population dosed once.
Cephalosporins may cause mild maculopapular rashes (<2%), loose stools (<3%), and transient increases in creatinine (1%) and liver enzymes (<3%).
The active pharmaceutical ingredient is the same so the risks of rectal formulations of ceftriaxone are the same as those described above for parenteral ceftriaxone. In addition, participants may experience adverse events at the site of administration such as tenesmus (the feeling that you need to pass stools), proctalgia (rectal pain) or proctitis (rectal inflammation).
Where is the study run from?
Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University (Thailand)
When is the study starting and how long is it expected to run for?
March 2019 to August 2026
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Prof. Elizabeth A Ashley (Principal Investigator), Elizabeth.Ashley@tropmedres.ac
Contact information
Principal Investigator
Mahidol-Oxford Tropical Medicine Research Unit (MORU)
Faculty of Tropical Medicine
Mahidol University
420/6 Rajvithi Road
Bangkok
10400
Thailand
 ORCID ID |
0000-0002-7620-4822 |
|---|---|
| Phone | +95 (0)1544537 |
| Elizabeth.Ashley@tropmedres.ac |
Study information
| Study design | Randomized open-label single-centre Phase I crossover study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | A randomised crossover study of the pharmacokinetics, safety and tolerability of two rectal formulations of ceftriaxone compared to parenteral ceftriaxone, in healthy Thai adults |
| Study acronym | CefREC |
| Study objectives | Is the bioavailability of ceftriaxone administered by suppository (in two new formulations) greater than or equal to 15%? |
| Ethics approval(s) |
1. Approved 20/04/2023, Oxford Tropical Research Ethics Committee (University of Oxford, University Offices, Wellington Square, Oxford, OX1 2JD, United Kingdom; +44 (0) 1865 (2)82106; oxtrec@admin.ox.ac.uk), ref: 10-19 2. Approved 07/03/2023, Faculty of Tropical Medicine Ethics Committee (Mahidol University, Bangkok, 10400, Thailand; +66 (0)2 3549100; tmectropmed@mahidol.ac.th), ref: TMEC 22-083 |
| Health condition(s) or problem(s) studied | Healthy volunteers |
| Intervention | Current interventions as of 07/03/2023: The following regimens will be evaluated in random order in all participants: 1. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) 2. Ceftriaxone rectal dosage form test formulation 1 - hard-shell gelatin capsule (1 x 500 mg) 3. Ceftriaxone rectal dosage form test formulation 2 - rectodispersible mannitol-based tablet (1 x 500 mg) Possible schedules: ABC, ACB, BAC, BCA, CAB, CBA. Each recipient will receive a single treatment dose of each of the three formulations in an order pre-determined by a computer-generated randomisation list. This will be a constrained randomisation which ensures approximately balanced proportions for all six schedules (either 6 or 7 participants per schedule). There will be a 7-28 days washout period between doses. The last follow-up visit is 28 (+ 2) days after the final dose. Participants lost to follow-up or unevaluable for any reason before completion of pharmacokinetic sampling after the final dose will be replaced at the discretion of the investigators with another participant of the same population, if either sample size or completeness of the dataset is compromised. Previous interventions: The following regimens will be evaluated in random order in all participants: 1. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) 2. Ceftriaxone rectal dosage form test formulation 1 - hard-shell gelatin capsule (1 x 500 mg) 3. Ceftriaxone rectal dosage form test formulation 2 - rectodispersible mannitol-based tablet (1 x 500 mg) Possible schedules: ABC, ACB, BAC, BCA, CAB, CBA. Each recipient will receive a single treatment dose of each of the three formulations in an order pre-determined by a computer-generated randomisation list. This will be a constrained randomisation which ensures approximately balanced proportions for all six schedules (either 6 or 7 participants per schedule). There will be a minimum 7-day washout period between doses. The last follow-up visit is 28 (+ 2) days after the final dose. Participants lost to follow-up or unevaluable for any reason before completion of pharmacokinetic sampling after the final dose will be replaced at the discretion of the investigators with another participant of the same population, if either sample size or completeness of the dataset is compromised. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Ceftriaxone (Roche ®) 500 mg (slow intravenous injection), ceftriaxone rectal dosage form test formulation 1 - hard-shell gelatin capsule (1 x 500 mg), ceftriaxone rectal dosage form test formulation 2 - rectodispersible mannitol-based tablet (1 x 500 mg) |
| Primary outcome measure | Bioavailability of rectal formulations estimated from the pharmacokinetic data obtained following administration of parenteral and rectal formulations for each participant. |
| Secondary outcome measures | Current secondary outcome measures as of 07/03/2023: 1. Description of other key pharmacokinetic parameters measured using a validated LC-MS/MS bioanalytical method: 1.1. Exposure (AUC0-∞) 1.2. Peak concentration (Cmax) 1.3. Absorption rate (Tmax) 1.4. Time above a plasma concentration of 1 µg/ml (this concentration is above the MIC90 for major neonatal pathogens (Streptococcus agalactiae, Klebsiella spp., Escherichia coli, methicillin-sensitive Staphylococcus aureus) and is the lower limit of detection of the assay) 2. Safety and tolerability: 2.1. Occurrence of serious adverse events (SAEs) from the date of the first dose to 28 days after the final dose, according to the MedDRA classification 2.2. Occurrence of all adverse events from the date of the first dose to 28 days after the final dose, according to the MedDRA classification Previous secondary outcome measures: 1. Description of other key pharmacokinetic parameters measured using a validated LC-MS/MS bioanalytical method: 1.1. Exposure (AUC0-∞) 1.2. Peak concentration (Cmax) 1.3. Absorption rate (Tmax) 1.4. Time above a plasma concentration of 1 µg/ml (this concentration is above the MIC90 for major neonatal pathogens (Streptococcus agalactiae, Klebsiella spp., Escherichia coli, methicillin-sensitive Staphylococcus aureus) and is the lower limit of detection of the assay) 2. Safety and tolerability: 2.1. Occurrence of serious adverse events (SAEs) from the date of the first dose to 28 days after the final dose, according to the MedRA classification 2.2. Occurrence of all adverse events from the date of the first dose to 28 days after the final dose, according to the MedRA classification |
| Overall study start date | 20/03/2019 |
| Completion date | 01/08/2026 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 46 Years |
| Sex | Both |
| Target number of participants | 37 |
| Key inclusion criteria | 1. Healthy male or non-pregnant female, aged 18 to 46 years (inclusive) 2. Willing and able to give informed consent to participate in the trial 3. Able, in the investigator's opinion, and willing to comply with the study requirements and follow-up |
| Key exclusion criteria | Current participant exclusion criteria as of 07/03/2023: 1. Female participant who is pregnant, lactating or planning pregnancy during the course of the study 2. Presence of any condition which in the judgment of the investigator would affect the absorption of the rectal formulation e.g. previous surgery, haemorrhoids, inflammatory bowel disease 3. Irritable bowel syndrome (IBS) or diarrhoea in the 24 hours prior to the study drug administration 4. Presence of any condition which in the judgment of the investigator would place the participant at undue risk or interfere with the results of the study (e.g. serious underlying cardiac, renal, hepatic or neurological disease; severe malnutrition; congenital defects or febrile condition) 5. Seropositive for HIV at screening 6. Hepatitis B surface antigen (HBsAg) detected in serum at screening 7. Seropositive for hepatitis C virus (antibodies to HCV) at screening 8. Participation in a clinical trial and/or has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication and throughout the study period 9. Any medical condition that in the judgment of the investigator would make the administration of the study treatments unsafe 10. Use of medications known to have a potentially clinically significant interaction with ceftriaxone or with sodium chenodeoxycholate (Na-CDC) in the 28 days prior to the first dose and throughout the study period. This includes aluminium-containing antacids, colestipol, phenobarbital and the combined oral contraceptive pill. 11. Known 27-hydroxylase deficiency (presenting as cerebrotendinous xanthomatosis) 12. History of anaphylaxis and/or hypotension, laryngeal oedema, wheezing, angioedema or urticarial rash following treatment with ceftriaxone, another cephalosporin or any beta-lactam (e.g. penicillin) 13. History of any other clinically significant reaction to ceftriaxone, another cephalosporin or beta-lactam e.g. drug-induced nephritis, hepatitis, erythema multiforme that, in the opinion of the investigator, contraindicates participation in the study. 14. Serious chronic illness. 15. Abnormal baseline laboratory screening test as defined below: 15.1. AST > 2 x upper normal limit 15.2. ALT > 2 x upper normal limit 15.3. Anaemia (Hb < 11 g/dL for female and Hb < 12 g/dL for male) 15.4. Platelets < 150,000 15.5. Total bilirubin > 2 x upper normal limit 16. Hepatomegaly, right upper quadrant abdominal pain or tenderness. 17. Body Mass Index> 35 18. History of alcohol or substance abuse or dependence during the 6 months before study participation: History of regular alcohol consumption averaging >7 drinks/week for women or >14 drinks/week for men. One drink is equivalent to 12 g alcohol = 5 oz (150 ml) of wine or 12 oz (360 ml) of beer or 1.5 oz (45 ml) of 80-proof distilled spirits. Previous participant exclusion criteria: 1. Female participant who is pregnant, lactating or planning pregnancy during the course of the study 2. Presence of any condition which in the judgment of the investigator would affect the absorption of the rectal formulation e.g. previous surgery, haemorrhoids, inflammatory bowel disease 3. Irritable bowel syndrome (IBS) or diarrhoea in the 24 hours prior to the study drug administration 4. Presence of any condition which in the judgment of the investigator would place the participant at undue risk or interfere with the results of the study (e.g. serious underlying cardiac, renal, hepatic or neurological disease; severe malnutrition; congenital defects or febrile condition) 5. Seropositive for HIV at screening 6. Hepatitis B surface antigen (HBsAg) detected in serum at screening 7. Seropositive for hepatitis C virus (antibodies to HCV) at screening 8. Participation in a clinical trial and/or has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication and throughout the study period 9. Any medical condition that in the judgment of the investigator would make the administration of the study treatments unsafe 10. Use of medications known to have a potentially clinically significant interaction with ceftriaxone or with sodium chenodeoxycholate (Na-CDC) in the 28 days prior to the first dose and throughout the study period. This includes aluminium-containing antacids, colestipol, phenobarbital and the combined oral contraceptive pill. 11. Known 27-hydroxylase deficiency (presenting as cerebrotendinous xanthomatosis) 12. History of anaphylaxis and/or hypotension, laryngeal oedema, wheezing, angioedema or urticarial rash following treatment with ceftriaxone, another cephalosporin or any beta-lactam (e.g. penicillin) 13. History of any other clinically significant reaction to ceftriaxone, another cephalosporin or beta-lactam e.g. drug-induced nephritis, hepatitis, erythema multiforme that, in the opinion of the investigator, contraindicates participation in the study. 14. Serious chronic illness. 15. Abnormal baseline laboratory screening test as defined below: 15.1. AST > 2 x upper normal limit 15.2. ALT > 2 x upper normal limit 15.3. Anaemia (Hb < 10 g/dL) 15.4. Platelets < 150,000 15.5. Total bilirubin > 2 x upper normal limit 16. Hepatomegaly, right upper quadrant abdominal pain or tenderness. 17. Body Mass Index> 35 18. History of alcohol or substance abuse or dependence during the 6 months before study participation: History of regular alcohol consumption averaging >7 drinks/week for women or >14 drinks/week for men. One drink is equivalent to 12 g alcohol = 5 oz (150 ml) of wine or 12 oz (360 ml) of beer or 1.5 oz (45 ml) of 80-proof distilled spirits. |
| Date of first enrolment | 01/09/2025 |
| Date of final enrolment | 31/05/2026 |
Locations
Countries of recruitment
- Thailand
Study participating centre
Thung Phaya Thai
Ratchathewi
Bangkok
10400
Thailand
Sponsor information
University/education
Clinical Trials and Research Governance
Joint Research Office
Block 60
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
England
United Kingdom
| Phone | +44 (0)1865 572224 |
|---|---|
| rgea.sponsor@admin.ox.ac.uk | |
| Website | https://researchsupport.admin.ox.ac.uk/clinical-trials-research-governance |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/09/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a peer-reviewed journal. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Editorial Notes
20/09/2024: The following changes were made to the trial record:
1. The overall end date was changed from 01/08/2025 to 01/08/2026.
2. The recruitment start date was changed from 01/09/2024 to 01/09/2025.
3. The recruitment end date was changed from 31/05/2025 to 31/05/2026.
15/03/2024: The following updates have been made:
1. Ethics approval added.
2. The overall study end date was changed from 01/04/2025 to 01/08/2025.
3. The recruitment start date was changed from 01/03/2024 to 01/09/2024.
4. The recruitment end date was changed from 31/12/2024 to 31/05/2025.
07/03/2023: The following updates have been made to the study record and the plain English summary updated accordingly:
1. The interventions have been changed.
2. The secondary outcome measures have been changed.
3. The participant exclusion criteria have been changed.
25/01/2023: The sponsor email was updated.
05/12/2022: Trial's existence confirmed by MRC.
