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

NCT04873063 | Completed Phase 1

• 1 other identifier: PSC DS BDP-Once 1
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Adult Male Volunteers

Outcome Measures

Primary Outcomes (9)

• Pharmacokinetics - Cmax, morning;

  Peak exposure after the morning dose (Cmax, morning)

  Day 1 and Day 7 of each Period

• Pharmacokinetics - Cmax, evening;

  Peak exposure after the evening dose (Cmax, evening)

  Day 1 and Day 7 of each Period

• Pharmacokinetics - AUC0-24

  • Total exposure over 24 hours (AUC0-24)

  Day 1 and Day 7 of each Period

• Pharmacokinetics - AUC0-12

  • Total exposure during dosing interval - morning (AUC0-12)

  Day 1 and Day 7 of each Period

• Pharmacokinetics - AUC12-24

  • Total exposure during dosing interval - evening (AUC12-24)

  Day 1 and Day 7 of each Period

• HPA-axis: 24-hour plasma cortisol - AUC0-24, cortisol

  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.

  Baseline and Day 7 of each Period

• HPA-axis: 24-hour plasma cortisol - AUC0-12, cortisol

  Area under the cortisol level-time curve over 12 hours after the morning dose (AUC0-12, cortisol). As above.

  Baseline and Day 7 of each Period

• HPA-axis: 24-hour plasma cortisol - AUC12-24, cortisol

  Area under the cortisol level-time curve over 12 hours after the evening dose (AUC12-24, cortisol). As above.

  Baseline and Day 7 of each Period

• HPA-axis: 24-hour plasma cortisol - pAUC2-8, cortisol

  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.

  Baseline and Day 7 of each Period

Secondary Outcomes (9)

• Pharmacokinetics - trough concentrations

  Day 1 and Day 7 of each Period

• Pharmacokinetics - Cmax morning/AUC0-12 ratio

  Day 1 and Day 7 of each Period

• Pharmacokinetics - Tmax, morning

  Day 1 and Day 7 of each Period

• Pharmacokinetics - Percent fluctuation (%PTF12)

  Day 7 of each Period

• Pharmacokinetics - Percent fluctuation (%PTF24)

  Day 7 of each Period

Other Outcomes (2)

• Safety - Adverse Events

  From screening to follow up (approximately 59 days)

• Safety - Laboratory values

  At screening, before each period and at follow-up (+21 days after the end of Period 2)

Study Arms (2)

Reference/Test

EXPERIMENTAL

* 3 mg BDP suppositories (R product) delivered twice daily for 7 days * Washout period (at least 7-day and preferably no more than 9 days) * 6 mg BDP suppositories (T product) delivered once daily in the morning for 7 days. Matching placebo suppository will be applied rectally once daily in the evening, on same days as the T product.

Drug: Beclomethasone dipropionate

Test/Reference

EXPERIMENTAL

* 6 mg BDP suppositories (T product) delivered once daily in the morning for 7 days. Matching placebo suppository will be applied rectally once daily in the evening, on same days as the T product. * Washout period (at least 7-day and preferably no more than 9 days) * 3 mg BDP suppositories (R product) delivered twice daily for 7 days

Drug: Beclomethasone dipropionate

Interventions

Beclomethasone dipropionate DRUG

BDP 3 mg bid (R product) BDP 6 mg qd (T product)

Also known as: Beclomethasone 17,21-dipropionate, BDP

Reference/Test; Test/Reference

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• SOFAR S.p.A.: lead

Study Sites (1)

Centro Ricerche Cliniche AOU Integrata di Verona - Policlinico Universitario G.B. Rossi

Verona, 37134, Italy

Location

MeSH Terms

Interventions

Beclomethasone

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Chlorinated

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: April 26, 2021
• First Posted: May 5, 2021
• Study Start: October 22, 2021
• Primary Completion: April 28, 2022
• Study Completion: April 28, 2022
• Last Updated: May 4, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR

Locations

IT (1)