CompletedNCT04873063Updated May 4, 2022

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

A Phase 1 interventional study of Beclomethasone dipropionate in Healthy Adult Male Volunteers, sponsored by SOFAR S.p.A.. Completed at 1 site in Italy. Open to male participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-05-04.

Sponsored by SOFAR S.p.A. · Phase 1, Interventional, and Other

Phase: Phase 1
Study type: Interventional
Enrollment: 28
Allocation: Randomized
Ages: 18 Years to 55 Years
Sex: Male

Study 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.

Read the 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.

Conditions studied

Healthy Adult Male Volunteers

Who can participate

Ages eligible: 18 Years to 55 Years
Sexes eligible: Male
Accepts 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

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.

Study design

Phase: Phase 1
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Double (Participant, Investigator)
Enrollment: 28 participants (actual)

Study arms

Experimental
Reference/Test
* 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
Experimental
Test/Reference
* 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

DrugBeclomethasone dipropionate
BDP 3 mg bid (R product) BDP 6 mg qd (T product)
Also known as: Beclomethasone 17,21-dipropionate, BDP

What researchers measure

Primary outcomes

Pharmacokinetics - Cmax, morning;
Peak exposure after the morning dose (Cmax, morning)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - Cmax, evening;
Peak exposure after the evening dose (Cmax, evening)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - AUC0-24
• Total exposure over 24 hours (AUC0-24)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - AUC0-12
• Total exposure during dosing interval - morning (AUC0-12)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - AUC12-24
• Total exposure during dosing interval - evening (AUC12-24)
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Day 7 of each Period

Secondary outcomes

Pharmacokinetics - trough concentrations
Trough concentrations for R (C12) and T (C24) dosing on Day 1 and Day 7 as well as morning pre-dose (C0)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - Cmax morning/AUC0-12 ratio
Ratio of the peak exposure after the morning dose to exposure over the subsequent 12 hours (illustrates absorption rate) (Cmax,morning/AUC0-12)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - Tmax, morning
Time to peak exposure after the morning dose (Tmax,morning)
Time frame: Day 1 and Day 7 of each Period
Pharmacokinetics - Percent fluctuation (%PTF12)
Day 7 - percent fluctuation over 12 hours after morning dose (%PTF12)
Time frame: Day 7 of each Period
Pharmacokinetics - Percent fluctuation (%PTF24)
Day 7 - percent fluctuation over 24 hours (%PTF24)
Time frame: Day 7 of each Period
Pharmacokinetics - Accumulation ratio
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).
Time frame: Day 1 and Day 7 of each Period
HPA axis - Number (proportion) of subjects with cortisol <10 μg/dL
ACTH stimulation test results on the morning of Day 9 (first post-dosing day) dichotomized as "normal" or "abnormal"
Time frame: Day 8 and 9 of each Period
HPA axis - Number/proportion of subjects with abnormal ACTH stimulation test.
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).
Time frame: Day 8 and 9 of each Period
HPA axis - 24-hour cortisol profile
24-hour cortisol profile: time-point-by-time-point differences Day 7 vs. baseline
Time frame: Baseline and Day 7 of each Period

Other outcomes

Safety - Adverse Events
Adverse events reporting
Time frame: From screening to follow up (approximately 59 days)
Safety - Laboratory values
Incidence of abnormal laboratory test results (Urinalysis, biochemical and haematological tests performed)
Time frame: At screening, before each period and at follow-up (+21 days after the end of Period 2)

Study locations

1 site

Centro Ricerche Cliniche AOU Integrata di Verona - Policlinico Universitario G.B. Rossi
Verona, 37134, Italy

References and documents

Individual participant data

Plan to share: Yes

Supporting information: Study protocol, Icf, Csr

No publications or documents are linked to this record.

Registry details

Key details

Study ID: NCT04873063
Lead sponsor: SOFAR S.p.A.
Responsible party: Sponsor
First posted: May 5, 2021
Start date: Oct 22, 2021
Primary completion: Apr 28, 2022
Completion: Apr 28, 2022
Last update: May 4, 2022

Oversight

FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in May 2022. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies from this sponsor

SOFAR S.p.A.

Start the discussion