Study to Compare Blood Levels of Ceftriaxone Given by Suppository or Injection. (CefREC)

A Randomised Crossover Study of the Pharmacokinetics, Safety and Tolerability of Two Rectal Formulations of Ceftriaxone Compared to Parenteral Ceftriaxone, in Healthy Thai Adults.

Phase 1, three-way cross-over, randomised, open label comparison of intravenous versus two rectal dosage forms of ceftriaxone in 37 healthy Thai adults.

The following regimens will be evaluated in random order in all participants:

A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) B. Ceftriaxone rectal dosage form test formulation 1-hard-shell gelatin capsule (1 x 500mg) C. Ceftriaxone rectal dosage form test formulation 2-rectodispersible mannitol-based tablet (1 x 500mg)

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 predetermined by a computer generated randomisation list. This will be a constrained randomization which ensures approximately balanced proportions for all six schedules (either 6 or 7 participants per schedule). There will be 7-28 days washout period between doses. The last follow up visit is 28 (+ 2) days after 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 dataset is compromised.

This study is funded by the Medical Research Council. The grant reference number is MR/W021560/1

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy
• Intervention / Treatment: Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg)

• Study Type: Interventional
• Enrollment (Estimated): 37
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Elizabeth A Ashley, MD; Phone Number: +95(0)1544537; Email: liz@tropmedres.ac

Study Locations

• Thailand
  • Bangkok, Thailand, 10400
    • Faculty of Tropical Medicine, Mahidol University
    • Contact: Kittiyod Poovorawan, MD; Phone Number: +66831496864; Email: Kittiyod@tropmedres.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 46 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy male or non-pregnant female, aged 18 to 46 years (inclusive)
• Willing and able to give informed consent to participate in the trial
• Able, in the investigators opinion, and willing to comply with the study requirements and followup.

Exclusion Criteria:

• Female participant who is pregnant, lactating or planning pregnancy during the course of the study.
• 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
• Irritable bowel syndrome (IBS) or diarrhoea in the 24 hours prior to study drug administration
• 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).
• Seropositive for HIV at screening
• Hepatitis B surface antigen (HBsAg) detected in serum at screening.
• Seropositive for hepatitis C virus (antibodies to HCV) at screening
• 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.
• Any medical condition that in the judgment of the investigator would make the administration of the study treatments unsafe.
• 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.
• Known 27-hydroxylase deficiency (presenting as cerebrotendinous xanthomatosis)
• 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).
• 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.
• Serious chronic illness.

• Abnormal baseline laboratory screening test as defined below:

  • AST > 2 x upper normal limit
  • ALT > 2 x upper normal limit
  • Anaemia (Hb < 11 g/dL for female and Hb < 12 g/dL for male),
  • Platelets < 150,000
  • Total bilirubin > 2 x upper normal limit
• Hepatomegaly, right upper quadrant abdominal pain or tenderness.
• Body Mass Index> 35
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ABC; A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) B. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500mg) C. Ceftriaxone rectal dosage form test formulation 2- rectodispersible mannitol-based tablet (1 x 500mg)	Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Parenteral ceftriaxone Intravenous injection of 500mg of ceftriaxone sodium (Rocephin®; Roche).; Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Rectal ceftriaxone formulations Formulation 1 ceftriaxone 500mg + Na-CDC 125mg hard-shell gelatin capsule; Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg); Rectal ceftriaxone formulations Formulation 2 ceftriaxone 500mg + Na-CDC 125mg rectodispersible mannitol-based tablet
Experimental: ACB; A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) C. Ceftriaxone rectal dosage form test formulation 2- rectodispersible mannitol-based tablet (1 x 500mg) B. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500mg)	Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Parenteral ceftriaxone Intravenous injection of 500mg of ceftriaxone sodium (Rocephin®; Roche).; Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Rectal ceftriaxone formulations Formulation 1 ceftriaxone 500mg + Na-CDC 125mg hard-shell gelatin capsule; Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg); Rectal ceftriaxone formulations Formulation 2 ceftriaxone 500mg + Na-CDC 125mg rectodispersible mannitol-based tablet
Experimental: BAC; B. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500mg) A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) C. Ceftriaxone rectal dosage form test formulation 2- rectodispersible mannitol-based tablet (1 x 500mg)	Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Parenteral ceftriaxone Intravenous injection of 500mg of ceftriaxone sodium (Rocephin®; Roche).; Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Rectal ceftriaxone formulations Formulation 1 ceftriaxone 500mg + Na-CDC 125mg hard-shell gelatin capsule; Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg); Rectal ceftriaxone formulations Formulation 2 ceftriaxone 500mg + Na-CDC 125mg rectodispersible mannitol-based tablet
Experimental: BCA; B. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500mg) C. Ceftriaxone rectal dosage form test formulation 2- rectodispersible mannitol-based tablet (1 x 500mg) A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection)	Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Parenteral ceftriaxone Intravenous injection of 500mg of ceftriaxone sodium (Rocephin®; Roche).; Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Rectal ceftriaxone formulations Formulation 1 ceftriaxone 500mg + Na-CDC 125mg hard-shell gelatin capsule; Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg); Rectal ceftriaxone formulations Formulation 2 ceftriaxone 500mg + Na-CDC 125mg rectodispersible mannitol-based tablet
Experimental: CAB; C. Ceftriaxone rectal dosage form test formulation 2- rectodispersible mannitol-based tablet (1 x 500mg) A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection) B. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500mg)	Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Parenteral ceftriaxone Intravenous injection of 500mg of ceftriaxone sodium (Rocephin®; Roche).; Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Rectal ceftriaxone formulations Formulation 1 ceftriaxone 500mg + Na-CDC 125mg hard-shell gelatin capsule; Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg); Rectal ceftriaxone formulations Formulation 2 ceftriaxone 500mg + Na-CDC 125mg rectodispersible mannitol-based tablet
Experimental: CBA; C. Ceftriaxone rectal dosage form test formulation 2- rectodispersible mannitol-based tablet (1 x 500mg) B. Ceftriaxone rectal dosage form test formulation 1- hard-shell gelatin capsule (1 x 500mg) A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection)	Drug: A. Ceftriaxone (Roche ®) 500mg (slow intravenous injection); Parenteral ceftriaxone Intravenous injection of 500mg of ceftriaxone sodium (Rocephin®; Roche).; Drug: B. Ceftriaxone rectal dosage form test formulation 1 (1 x 500mg); Rectal ceftriaxone formulations Formulation 1 ceftriaxone 500mg + Na-CDC 125mg hard-shell gelatin capsule; Drug: C. Ceftriaxone rectal dosage form test formulation 2 (1 x 500mg); Rectal ceftriaxone formulations Formulation 2 ceftriaxone 500mg + Na-CDC 125mg rectodispersible mannitol-based tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bioavailablity of rectal formulation	Approximately 9 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Description of Exposure (AUC0-∞)	Approximately 9 months
Description of Peak concentration (Cmax)	Approximately 100 days
Description of Absorption rate (Tmax)	Approximately 9 months
Time above a plasma concentration of 1µg/mL (this concentration is above the MIC90 for major neonatal pathogens and is the lower limit of detection of the assay)	Approximately 9 months
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.	Approximately 9 months
Occurrence of all adverse events from the date of the first dose to 28 days after the final dose, according to the MedDRA classification.	Approximately 9 months

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Biopharma (Orofino Pharmaceuticals Group)
• Investigators: Principal Investigator: Elizabeth Ashley, MD, Mahidol Oxford Tropical Medicine Research Unit

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: March 27, 2019
• First Submitted That Met QC Criteria: March 27, 2019
• First Posted (Actual): March 29, 2019

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Ceftriaxone
• Other Study ID Numbers: BAC18003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: With participant's consent, participant's clinical data and results from blood analyses stored in our database may be shared with Biopharma Orofino Pharmaceuticals Group, regulatory authorities, or other researchers to use in the future. However, the other researchers will not be given any information that could identify the participant.
• IPD Sharing Access Criteria: Requests to share data will be considered by the MORU data access committee in line with the MORU data sharing policy
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No