Condition category
Not Applicable
Date applied
27/03/2019
Date assigned
18/04/2019
Last edited
18/04/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
NG 8706/1 is a novel fixed dose combination containing ramipril and bisoprolol, developed by Neopharmed Gentili S.r.l., Italy. Ramipril and bisoprolol are frequently prescribed in association for the treatment of essential hypertension.

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat hypertension and congestive heart failure. Ramipril works by relaxing the smooth muscles of small blood vessels; this, in turn, reduces blood pressure (BP).
Bisoprolol is a competitive adrenergic antagonist which inhibits catecholamine stimulation of β1-adrenergic receptors in the heart and vascular smooth muscles. Bisoprolol effects include a reduction of heart rate, cardiac output, BP and possibly reflex orthostatic hypotension.
Bisoprolol is indicated in the secondary prevention of myocardial infarction, heart failure, angina pectoris and mild to moderate hypertension.

Neopharmed Gentili S.r.l., Italy, has developed 6 strength combinations as immediate release capsules. The proposed 6 strength combinations cover the majority of the needs of patients in terms of combined therapy. The present randomised cross-over, two-stage bioequivalence study aimed at assessing the bioequivalence of the novel fixed combination at the highest dose (10 mg of ramipril/5 mg of bisoprolol) vs. the extemporaneous combination of 2 marketed reference products.

Who can participate?
Healthy male and female aged 18-55 years

What does the study involve?
A single dose of the test product and of the reference products, both corresponding to ramipril 10 mg and bisoprolol fumarate 5 mg, was administered to healthy male and female volunteers under fasting conditions in two study periods according to a randomised 2-way cross-over design, with a wash-out interval of at least 14 days between consecutive administrations. Vitals signs were checkedand blood sample collection for PK analysis were collected at specific time points

What are the possible benefits and risks of participating?
Both ramipril and bisoprolol are well known drugs which have been used for decades. No specific benefits for the participants in the current study were foreseen, except for the physical examination as part of the study procedures and a possible, although not certain, positive wellbeing effect.

Where is the study run from?
CROSS Research SA (Switzerland)

When is the study starting and how long is it expected to run for?
May 2018 - August 2018

Who is funding the study?
Neopharmed Gentili S.r.l. (Italy)

Who is the main contact?
Dr. Francesco Gianese, MD, g.ferrari@mediolanum-farma.com

Trial website

Contact information

Type

Scientific

Primary contact

Mr Francesco Gianese

ORCID ID

Contact details

Via San Giuseppe Cottolengo
Milan
20143
Italy
+39 (0)289132357
g.ferrari@mediolanum-farma.com

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

Study CRO-PK-18-328 - Sponsor code NG8706/1-C02

Study information

Scientific title

Bioequivalence study of a novel ramipril 10 mg/bisoprolol fumarate 5 mg hard capsule fixed dose combination (Neopharmed Gentili S.r.l.) versus a free combination of ramipril 10 mg tablets
(Triatec®, Sanofi-Aventis) and bisoprolol fumarate 5 mg filmcoated tablets (Congescor®, Daiichi Sankyo) in healthy male and female volunteers under fasting conditions

Acronym

Ramipril/bisoprolol fixed dose combination bioequivalence-NG8706/1

Study hypothesis

The objective of the study was to assess the bioequivalence of ramipril and bisoprolol (NG8706/1), when administered in single dose in 2 consecutive study periods as a new fixed combination (ramipril 10 mg/bisoprolol fumarate 5 mg hard gel capsule) versus a free combination of ramipril 10 mg tablet ( Triatec®) and bisoprolol fumarate 5 mg film-coated tablet (Congescor®) to healthy male and female volunteers under fasting conditions.

Ethics approval

Approved 29/03/2018, Cantonal Ethics Commitee Ticino (c / o Health Office, Via Orico 5, 6501 Bellinzona, Switzerland; +41 91 814 30 57; dss-ce@ti.ch), ref: 2018-00399 / CE 3339

Study design

Single-dose open-label randomised two-period cross-over two-stage bioequivalence study

Primary study design

Interventional

Secondary study design

Randomised cross over trial

Trial setting

Other

Trial type

Other

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Not applicable, this is s Bioequivalence study

Intervention

The following visits were performed:
Screening phase
-Screening – visit 1: between Day -14 and Day -2
-Period 1 – visit 2: Day -1
Interventional phase
-Period 1 – visit 3: Days 1-3
-Wash-out interval of at least 14 days
-Period 2 – visit 4: Day -1
-Period 2 – visit 5: Days 1-3
Final phase
-Final visit/early termination visit (ETV). In case of early discontinuation, discontinued subjects underwent an early termination visit (ETV)

Subjects were randomised in both arms according to the cross-over design

A single dose of the test fixed dose combination or of the reference extemporaneous combination, both corresponding to ramipril 10 mg and bisoprolol fumarate 5 mg, was administered to healthy male and female volunteers under fasting conditions in two study periods according to a randomised 2-way cross-over design, with a wash-out interval of at least 14 days between consecutive administrations.

Both test and reference treatments were orally administered in the morning of study Day 1, at 08:00±1h.

One hard capsule of fixed dose combination of ramipril 10 mg / bisoprolol fumarate 5 mg (test treatment) or one tablet of Triatec®, 10 mg + one tablet of Congescor®, 5 mg (reference treatment) were swallowed with 150 mL of still mineral water by the subjects.
Vital signs were checked and blood samples for PK analysis were collected at specific time points.

TEST (T): IMP Ramipril 10 mg / Bisoprolol fumarate 5 mg hard capsules (NG8706/1), Neopharmed Gentili S.r.l., Italy
REFERENCE (R) IMP: Triatec®, 10 mg ramipril tablets + Congescor®, 5 mg bisoprolol fumarate film-coated tablets

Intervention type

Drug

Phase

Phase I

Drug names

Test treatment: Ramipril 10 mg / Bisoprolol fumarate 5 mg hard capsules
(NG8706/1), Neopharmed Gentili S.p.A., Italy
Reference treatment: Triatec®, 10 mg ramipril tablets, Sanofi-Aventis S.p.A., Italy +
Congescor®, 5 mg bisoprolol fumarate film-coated tablets, Daiichi
Sankyo Italia S.p.A., Italy

Primary outcome measure

The bioequivalent rate (Cmax) and extent (AUC0-48h) of absorption of ramipril and bisoprolol after single dose administration of test and reference products. Plasma concentrations were evaluated using an LC/MS-MS assay.

Secondary outcome measures

1. The plasma PK profile (0-48h) of ramipril and bisoprolol after single dose administration of test and reference products. Plasma concentrations were evaluated using an LC/MS-MS assay.
2. Safety and tolerability of test and reference products after single dose administration were evaluated in both study periods using patient notes.

Overall trial start date

29/03/2018

Overall trial end date

07/07/2018

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Informed consent: signed written informed consent before inclusion in the study
2. Sex and Age: males/females, 18-55 year old inclusive
3. Body Mass Index (BMI): 18.5-28 kg/m2 inclusive
4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 60-89 mmHg, heart rate (HR) 50-90 bpm, measured after 5 min at rest in the sitting position
5. Body temperature: 35.7-37.5° C at screening
6. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study
7. Contraception and fertility (females): females of child-bearing potential had to be using at least one of the following reliable methods of contraception:
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit
c. A male sexual partner who agrees to use a male condom with spermicide
d. A sterile sexual partner
Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects, pregnancy test result had to be negative at screening.
8. Contraception (males): males with partners of childbearing potential had to either be sterile or agree to use one of the following approved methods of contraception from the first study drug administration until at least 45 days after the last administration:
a. A male condom with spermicide
b. A sterile sexual partner or a partner in post-menopausal status for at least 1 year
c. Use by the female sexual partner of an IUD, a female condom with spermicide, a contraceptive sponge with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, or hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit
9. Male subjects had to accept to inform their partners of the participation in the clinical study

Participant type

Healthy volunteer

Age group

Adult

Gender

Both

Target number of participants

36

Participant exclusion criteria

1. Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities
2. Physical findings: clinically significant abnormal physical findings indicative of physical illness
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness
4. Virology: positive result of serum virology assays
5. Allergy: ascertained or presumptive hypersensitivity to the active principles and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considered could affect the outcome of the study
6. Hypotension and heart rate: during the screening procedures or history of orthostatic hypotension or syncope/fainting or HR<50 bpm
7. Diseases: significant history of renal, hepatic, cardiovascular, respiratory, skin, haematological, endocrine, neurological, psychiatric and in particular gastrointestinal diseases that could interfere with the aim of the study. History of heart failure. Raynaud's syndrome. Events of haemorrhage (e.g. epistaxis) for 90 days before the day of screening
8. Medications: any medications, including over the counter (OTC) medications and herbal remedies, and vitamins for 2 weeks before the start of the study. Organ-toxic drugs (e.g. any drug with a well-defined potential for toxicity to a major organ or system such as chloramphenicol, which may cause bone marrow suppression) and systemic drugs known to alter hepatic metabolism within 3 months before first dosing. Any prescription systemic treatment within 28 days before first dosing. Hormonal contraceptives for females were allowed
9. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval was calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
10. Blood donation: blood donations for 3 months before this study
11. Drug, alcohol, caffeine, tobacco: history of drug, alcohol (>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015-2020), caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day)
12. Drug test: positive result at the drug test at screening
13. Alcohol test: positive alcohol breath test at day -1
14. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians
15. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women
16. Previous study: participation in previous trials of ramipril/bisoprolol alone or in a fixed dose combination

Recruitment start date

30/05/2018

Recruitment end date

07/07/2018

Locations

Countries of recruitment

Switzerland

Trial participating centre

CROSS Research SA Phase I Unit
Via F.A. Giorgioli 14
Arzo
6864
Switzerland

Sponsor information

Organisation

Neopharmed Gentili S.r.l.

Sponsor details

Via San Giuseppe Cottolengo 15
Milan
20143
Italy
+39 (0)289132357
g.ferrari@mediolanum-farma.com

Sponsor type

Industry

Website

Funders

Funder type

Industry

Funder name

Neopharmed Gentili S.r.l.

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement:
The datasets generated and analysed during the current study will be available upon request at Neopharmed Gentili S.p.A. contacting Dr Francesco Gianese at the following email address: f.gianese@mediolanum-farma.com or alternatively, g.ferrari@mediolanum-farma.com. The results are not available since the sponsor is performing additional analysis.

Intention to publish date

31/12/2020

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

29/03/2019: Trial’s existence confirmed by IRB