Clinical trial NCT05012033: Evaluation of High Dose Prednisolone Pharmacokinetics in the Acute and Chronic Setting
Official title: Evaluation of High Dose Prednisolone Pharmacokinetics in the Acute and Chronic Setting
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Thyroid Eye Disease
Vasculitis
COPD Exacerbation Acute
Asthma
Inflammatory Disease
Lead sponsor: Imperial College London
Sponsor class: OTHER
First posted: 2021-08-19
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients receiving high dose prednisolone for any inflammatory disorder.

Brief summary: This is a pilot study to investigate serum prednisolone profiles in:

* Patients on high doses of prednisolone for any inflammatory disorder, both in the acute and chronic setting.
* Patients stepping up from or down to prednisolone therapy in association with a course of high dose methyl-prednisolone or dexamethasone.

The study will comprise 3 groups, including those started on high doses of prednisolone acutely in an inpatient or outpatient setting, participants on chronically high doses, and those receiving a several week course of high dose methylprednisolone or dexamethasone.

The study aims to measure prednisolone levels at a number of time points to investigate serum profile differences in those receiving prednisolone acutely compared with longer term steroid use. Further samples will be taken to characterise additional metabolic changes.

Detailed description: Prednisolone is an anti-inflammatory drug widely used to reduce inflammation and immune activation in a number of medical conditions, including asthma, allergy, inflammatory and auto-immune conditions. Its therapeutic actions, however, are accompanied by several adverse side effects, which are more frequent following high doses and long term treatments. The aim is therefore to use the lowest effective dose or highest dose for the shortest treatment required.

It has been observed in a select number of patients on replacement prednisolone doses for adrenal insufficiency (AI) that serum prednisolone levels change over time, despite patients remaining on the same dose. It is currently unclear whether serum levels of prednisolone match the doses in patients taking high dose prednisolone, both in the acute and chronic setting, and whether the way in which prednisolone is metabolised is altered after receiving high doses for prolonged periods of time.

The rationale for the use of particular doses for particular conditions is not clear, and has been developed historically in the absence of individual patient data. It is possible that more tailored dosing of prednisolone will result in reduced side effects, and that the minimum possible dose may be weight related.

In addition, genetic and epigenetic factors may also play a role in the efficacy of prednisolone and in the risk of developing side effects, accounting for some of the inter-individual variation in drug response.

Further characterising this may help to create an evidence base to tailor anti-inflammatory doses and weaning regimens of synthetic glucocorticoids that avoid deleterious effects.

Eligibility criteria: Inclusion Criteria:

* Aged 18 - 75 years
* Male or female
* Participants who are otherwise healthy enough to participate, as determined by pre-study medical history
* Participants who are able and willing to give written informed consent to participate in the study
* Group A only: Patients requiring acute (\<5 days) high dose (minimum 30mg) oral prednisolone therapy for antiinflammatory purposes in either an inpatient or outpatient setting.
* Group B only: Minimum of 1 month duration of high dose prednisolone (\>30mg) if in the chronic use group.
* Group C only: Patients started on high dose methylprednisolone (\>3 day course) or prolonged courses of dexamethasone.

Exclusion Criteria:

* Participants with a diagnosis of Type 1 or Type 2 diabetes mellitus.
* Unable to give informed consent.
* Taking supplements or herbal medications that the participant is unwilling or unable to stop prior to and during the study period e.g. St John's Wort (may decrease prednisolone levels), Cat's claw, Echinacea (immunomodulatory properties).
* Currently taking medications that alter CYP3A4 metabolism of glucocorticoids that the participant is unwilling or unable to stop prior to and during the study period e.g. phenytoin, phenobarbital, rifampicin, rifabutin, carbamazepine, primidone, aminogluethimide, itraconazole, ketoconazole, ciclosporin or ritonavir.
* Pregnancy. Females of child-bearing age will be asked to provide a urine sample for a pregnancy test at each visit.
* History of any medical, psychological or other condition, or use of any medications, including over-the-counter products, which, in the opinion of the investigators, would either interfere with the study or compromise the safety of the participant.

Primary outcomes:
measure: To elucidate differences in prednisolone pharmacokinetics (in patients receiving high dose prednisolone acutely and in the chronic setting).
timeFrame: Pharmacokinetics measurements taken at the first and second visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
measure: To elucidate differences in prednisolone pharmacokinetics (in patients receiving high dose
timeFrame: Pharmacokinetics measurements taken at the first and second visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
measure: To elucidate differences in prednisolone pharmacokinetics (in patients receiving high dose
timeFrame: Pharmacokinetics measurements taken at the first and second visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
measure: To elucidate differences in prednisolone pharmacokinetics (in patients receiving high dose
timeFrame: Pharmacokinetics measurements taken at the first and second visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
Secondary outcomes:
measure: To elucidate further differences in metabolic profiles and glucocorticoid axis
timeFrame: Time points post prednisolone dose at 1st and 2nd visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
measure: Exploratory Outcomes
timeFrame: Time points post prednisolone dose at 1st and 2nd visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
measure: Surrogate markers and risk factors for cardiovascular disease
timeFrame: On 1st and 2nd visits
measure: Surrogate markers and risk factors for cardiovascular disease
timeFrame: On 1st and 2nd visits
measure: Surrogate markers and risk factors for cardiovascular disease
timeFrame: On 1st and 2nd visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
measure: Surrogate markers and risk factors for cardiovascular disease
timeFrame: On 1st and 2nd visits. This will be of variable duration depending on duration of steroid treatment (5 days up to 2 years)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
affiliation: Imperial College London
name: Karim Meeran, MBBS BSc MD
role: PRINCIPAL_INVESTIGATOR
References: