Healthy Adult Male Volunteers
Conditions
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.
Interventions
DRUGBeclomethasone dipropionate
BDP 3 mg bid (R product) BDP 6 mg qd (T product)
Sponsors
SOFAR S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Single-centre, randomized, double-blind, two-period, two-sequence, cross-over 7-day study.
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HPA-axis: 24-hour plasma cortisol - pAUC2-8, cortisol | Baseline and Day 7 of each Period | Partial area under the cortisol level-time curve covering 3rd, 4th, 5th, 6th, 7th and 8th hour post morning dose (i.e., between 10:00 and 16:00 hours, that is, between sampling times at 2 and 8 hours post-dose) - a time period during which normal cortisol levels are still relatively high and the strongest suppression after morning dose could be expected (pAUC2-8, cortisol). As above. |
| HPA-axis: 24-hour plasma cortisol - AUC12-24, cortisol | Baseline and Day 7 of each Period | Area under the cortisol level-time curve over 12 hours after the evening dose (AUC12-24, cortisol). As above. |
| Pharmacokinetics - Cmax, morning; | Day 1 and Day 7 of each Period | Peak exposure after the morning dose (Cmax, morning) |
| Pharmacokinetics - Cmax, evening; | Day 1 and Day 7 of each Period | Peak exposure after the evening dose (Cmax, evening) |
| Pharmacokinetics - AUC0-24 | Day 1 and Day 7 of each Period | • Total exposure over 24 hours (AUC0-24) |
| Pharmacokinetics - AUC0-12 | Day 1 and Day 7 of each Period | • Total exposure during dosing interval - morning (AUC0-12) |
| Pharmacokinetics - AUC12-24 | Day 1 and Day 7 of each Period | • Total exposure during dosing interval - evening (AUC12-24) |
| HPA-axis: 24-hour plasma cortisol - AUC0-24, cortisol | Baseline and Day 7 of each Period | Area under the cortisol level-time curve over 24 hours (AUC0-24, cortisol). AUC will be determined for each subject/treatment at baseline and at Day 7 by the linear trapezoidal rule and ln-transformed. Ln(AUCs) will be used to determine intra-subject difference Day 7 - baseline that will be subject to analysis. |
| HPA-axis: 24-hour plasma cortisol - AUC0-12, cortisol | Baseline and Day 7 of each Period | Area under the cortisol level-time curve over 12 hours after the morning dose (AUC0-12, cortisol). As above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HPA axis - 24-hour cortisol profile | Baseline and Day 7 of each Period | 24-hour cortisol profile: time-point-by-time-point differences Day 7 vs. baseline |
| HPA axis - Number (proportion) of subjects with cortisol <10 μg/dL | Day 8 and 9 of each Period | ACTH stimulation test results on the morning of Day 9 (first post-dosing day) dichotomized as normal or abnormal |
| Pharmacokinetics - trough concentrations | Day 1 and Day 7 of each Period | Trough concentrations for R (C12) and T (C24) dosing on Day 1 and Day 7 as well as morning pre-dose (C0) |
| Pharmacokinetics - Cmax morning/AUC0-12 ratio | Day 1 and Day 7 of each Period | Ratio of the peak exposure after the morning dose to exposure over the subsequent 12 hours (illustrates absorption rate) (Cmax,morning/AUC0-12) |
| Pharmacokinetics - Tmax, morning | Day 1 and Day 7 of each Period | Time to peak exposure after the morning dose (Tmax,morning) |
| Pharmacokinetics - Percent fluctuation (%PTF12) | Day 7 of each Period | Day 7 - percent fluctuation over 12 hours after morning dose (%PTF12) |
| Pharmacokinetics - Percent fluctuation (%PTF24) | Day 7 of each Period | Day 7 - percent fluctuation over 24 hours (%PTF24) |
| Pharmacokinetics - Accumulation ratio | Day 1 and Day 7 of each Period | Accumulation ratio (Cmax,morning Day 7/Day 1; AUC0-24 Day 7/Day 1). Accumulation ratio will be estimated based on two outcomes: peak exposure after the morning dose (Cmax, morning) and total exposure over 24 hours (AUC0-24). |
| HPA axis - Number/proportion of subjects with abnormal ACTH stimulation test. | Day 8 and 9 of each Period | Number (proportion) of subjects with cortisol levels \<10 μg/dL at 08:00 a.m. on Day 8 and number (proportion) of subjects with abnormal ACTH stimulation test results in the morning of Day 9 (should any subject be submitted). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety - Adverse Events | From screening to follow up (approximately 59 days) | Adverse events reporting |
| Safety - Laboratory values | At screening, before each period and at follow-up (+21 days after the end of Period 2) | Incidence of abnormal laboratory test results (Urinalysis, biochemical and haematological tests performed) |
Countries
Italy
Outcome results
None listed