Clinical trial NCT04873063: Evaluation of Systemic Bioavailability and Effects on 24-Hour Plasma Cortisol Profile of 6 mg Delivered Once Daily Versus 3 mg Delivered Twice Daily in Healthy Adult Male Volunteers
Official title: Explorative Study of the Safety/Tolerability of Beclomethasone Dipropionate Suppositories: Evaluation of Systemic Bioavailability and Effects on 24-Hour Plasma Cortisol Profile of 6 mg Delivered Once Daily Versus 3 mg Delivered Twice Daily in Healthy Adult Male Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Adult Male Volunteers
Lead sponsor: SOFAR S.p.A.
Sponsor class: INDUSTRY
First posted: 2021-05-05
Enrollment: 28
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Single-centre, randomized, double-blind, two-period, two-sequence, cross-over 7-day study.
Primary purpose: OTHER

Brief summary: Single-centre, randomized, double-blind, two-period, two-sequence, cross-over 7-day study.

This study is the first safety/tolerability evaluation of a product -suppository formulation containing 6 mg BDP (once daily dosing), a second-generation oral or rectal corticosteroids with high topical anti-inflammatory efficacy in the gut and minimal systemic bioavailability (BA).

BDP is marketed in different pharmaceutical formulations, including 3 mg suppositories, and approved for ulcerative proctosigmoiditis in the first attack or exacerbation phase at the dosage of 3 mg twice a day. For these reasons, a 6 mg suppository (Test - "T" product) is a scale-up of the 3 mg formulation (Reference - "R" product).

For locally-applied-locally acting drug products that result in quantifiable systemic availability due to absorption from the administration site, relative systemic BA is informative for safety, but also with respect to efficacy. Therefore, safety/tolerability of T is evaluated through a comparison to R.

Detailed description: Primary objective is the evaluation of systemic safety of T, based on valid surrogate outcomes - systemic BA (relative BA) at the start of treatment (first 24 hours) and after 7 days of continuous treatment; effects on the hypothalamo-pituitary-adrenal axis (HPA) assessed based on 24-hour cortisol profile after 7 days of continuous treatment. This includes identification of subjects with cortisol levels \<10 μg/dL at the last sampling point in the 24-hour cortisol profile (08:00 a.m. on Day 8). In such cases, identified subjects will undergo ACTH stimulation test in the morning of Day 9.

Secondary objective is the evaluation of safety/tolerability based on clinical and laboratory adverse events.

Eligibility criteria: Inclusion Criteria:

* Healthy male, aged between 18 and 55 years. Healthy subjects are defined as individuals who are free from clinically significant illness or disease as determined by their medical history, physical examination, laboratory and other (e.g. ECG) tests.
* BMI 19.0 - 29.0 kg/m2;
* Signed and dated written informed consent of the subject to participate in the clinical study;
* The subject is willing to refrain from the use of illicit drugs and alcohol and to adhere to other protocol-stated restrictions while participating in the study;
* The subject is able to understand and comply with the protocol requirements and instructions and is likely to complete the study as planned;
* Non-smoker for at least 3 months.

Exclusion Criteria:

* Subject with a significant abnormality in the past and/or at the Screening that influences the present general health condition and requires pharmacological treatment during the study;
* History of serious allergic diseases, including allergy to medicinal products, which in opinion of the investigator, contraindicates participation to the trial;
* History of diseases of the alimentary tract, liver or kidneys that may influence absorption, distribution and elimination;
* History of average alcohol consumption;
* Hypersensitivity to BDP or study products inactive ingredients;
* Use of any pharmacological treatments (including high dose vitamins, lozenges, herbal and dietary supplements), with the exception of paracetamol ≤ 1 g/daily, within 15 days before the admission to the study Site in the Period 1;
* Use of steroids, anabolic or hormonal therapy within 3 months before the admission to the study Site in the Period 1;
* Laboratory indication of adrenocortical dysfunction;
* Blood loss exceeding 200 ml over the last 4 weeks before the day of Screening;
* Positive results to Sars Cov-2 nasopharyngeal swab;
* Positive results of HBsAg, anti-HCV, anti-HIV tests;
* Blood pressure: systolic \>140mmHg or \< 90mmHg, diastolic \<60 mmHg or \>90 mmHg during screening procedures;
* Subject who adhere to a special diet (e.g. low calories, vegetarian etc.);
* Consumption of products containing methylxanthines in the following average quantities: \> 3 cups of 200 ml of strong coffee a day;
* Presence of metabolites of illicit drugs (opioids, cannabis) during screening procedures;
* Participation in other clinical trials during the 6 months preceding the study, counting from the day of last product administration.

Primary outcomes:
measure: Pharmacokinetics - Cmax, morning;
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - Cmax, evening;
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - AUC0-24
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - AUC0-12
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - AUC12-24
timeFrame: Day 1 and Day 7 of each Period
measure: HPA-axis: 24-hour plasma cortisol - AUC0-24, cortisol
timeFrame: Baseline and Day 7 of each Period
measure: HPA-axis: 24-hour plasma cortisol - AUC0-12, cortisol
timeFrame: Baseline and Day 7 of each Period
measure: HPA-axis: 24-hour plasma cortisol - AUC12-24, cortisol
timeFrame: Baseline and Day 7 of each Period
measure: HPA-axis: 24-hour plasma cortisol - pAUC2-8, cortisol
timeFrame: Baseline and Day 7 of each Period
Secondary outcomes:
measure: Pharmacokinetics - trough concentrations
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - Cmax morning/AUC0-12 ratio
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - Tmax, morning
timeFrame: Day 1 and Day 7 of each Period
measure: Pharmacokinetics - Percent fluctuation (%PTF12)
timeFrame: Day 7 of each Period
measure: Pharmacokinetics - Percent fluctuation (%PTF24)
timeFrame: Day 7 of each Period
measure: Pharmacokinetics - Accumulation ratio
timeFrame: Day 1 and Day 7 of each Period
measure: HPA axis - Number (proportion) of subjects with cortisol <10 μg/dL
timeFrame: Day 8 and 9 of each Period
measure: HPA axis - Number/proportion of subjects with abnormal ACTH stimulation test.
timeFrame: Day 8 and 9 of each Period
measure: HPA axis - 24-hour cortisol profile
timeFrame: Baseline and Day 7 of each Period
Other outcomes:
measure: Safety - Adverse Events
timeFrame: From screening to follow up (approximately 59 days)
measure: Safety - Laboratory values
timeFrame: At screening, before each period and at follow-up (+21 days after the end of Period 2)
Locations:
city: Verona
country: Italy
facility: Centro Ricerche Cliniche AOU Integrata di Verona - Policlinico Universitario G.B. Rossi
Study officials:
References: