Clinical trial NCT03895567: Study to Compare Blood Levels of Ceftriaxone Given by Suppository or Injection.
Official 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 type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Healthy
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Biopharma (Orofino Pharmaceuticals Group)
First posted: 2019-03-29
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 46
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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


Eligibility criteria: 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.

Primary outcomes:
measure: Bioavailablity of rectal formulation
timeFrame: Approximately 9 months
Secondary outcomes:
measure: Description of Exposure (AUC0-∞)
timeFrame: Approximately 9 months
measure: Description of Peak concentration (Cmax)
timeFrame: Approximately 100 days
measure: Description of Absorption rate (Tmax)
timeFrame: Approximately 9 months
measure: 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)
timeFrame: Approximately 9 months
measure: 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.
timeFrame: Approximately 9 months
measure: Occurrence of all adverse events from the date of the first dose to 28 days after the final dose, according to the MedDRA classification.
timeFrame: Approximately 9 months
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: Faculty of Tropical Medicine, Mahidol University
Study officials:
affiliation: Mahidol Oxford Tropical Medicine Research Unit
name: Elizabeth Ashley, MD
role: PRINCIPAL_INVESTIGATOR
References: