Clinical Trials Register

Summary
EudraCT Number:	2016-002808-19
Sponsor's Protocol Code Number:	030(4C)HO16241
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-07-03
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2016-002808-19

A.3

Full title of the trial

Phase III study to evaluate the efficacy of a novel antimycotic vaginal pessary combination (containing Benzydamine HCl 6 mg and Econazole nitrate 150 mg) in the Treatment of uncomplicated vulvovaginal candidosis (VVC) [BEtreat study]

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Treatment of infectious diseases and disorders affecting the female sex organs;

A.3.2

Name or abbreviated title of the trial where available

BEtreat study

A.4.1

Sponsor's protocol code number

030(4C)HO16241

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	A.C.R.A.F. S.p.A. (Aziende Chimiche Riunite Angelini Francesco)
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	A.C.R.A.F. S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	A.C.R.A.F. S.p.A. (Aziende Chimiche Riunite Angelini Francesco)
B.5.2	Functional name of contact point	Dr. Annalisa Bonelli
B.5.3	Address:
B.5.3.1	Street Address	P. Le della stazione s.n.c. S. Palomba, Pomezia
B.5.3.2	Town/ city	Rome
B.5.3.3	Post code	00071
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 06 91045364
B.5.5	Fax number	+39 06 9109729
B.5.6	E-mail	a.bonelli@angelini.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	benzydamine HCl and econazole nitrate
D.3.4	Pharmaceutical form	Pessary
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Benzydamine
D.3.9.1	CAS number	132-69-4
D.3.9.2	Current sponsor code	030(4C)
D.3.9.3	Other descriptive name	BENZYDAMINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00737MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Econazole nitrate
D.3.9.1	CAS number	24169-02-6
D.3.9.3	Other descriptive name	ECONAZOLE NITRATE
D.3.9.4	EV Substance Code	SUB01855MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Pevaryl® 150 mg vaginal pessary
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag Spa
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Pevaryl®
D.3.4	Pharmaceutical form	Pessary
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Econazole nitrate
D.3.9.1	CAS number	24169-02-6
D.3.9.3	Other descriptive name	ECONAZOLE NITRATE
D.3.9.4	EV Substance Code	SUB01855MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Uncomplicated vulvovaginal candidosis (VVC)

E.1.1.1

Medical condition in easily understood language

Diseases and disorders affecting the female sex organs;
infectious disease of female breeding organs

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10047783
E.1.2	Term	Vulvovaginal candida
E.1.2	System Organ Class	100000054373

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the microbiological and clinical efficacy, the safety and acceptability of the benzydamine HCl 6 mg and econazole nitrate 150 mg vaginal pessary, in comparison to Pevaryl® 150 mg vaginal pessary, in the treatment of uncomplicated VVC.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Females between 18 and 65 years of age (limits included), with no limitation of race.
2. Patients clinically diagnosed with uncomplicated VVC, as confirmed by a positive vaginal wet mount test.
3. Patients presenting at baseline a total score ≥ 3 in the subjective symptoms and a total score ≥ 1 in the objective signs.
4. Female of childbearing potential and women in a postmenopausal state. Females of childbearing potential and women with no menses for a period < 12 months must have a negative pregnancy test at Visit 0 and have to agree not to start a pregnancy from the signature of the informed consent up to Visit 4, using an appropriate birth control method such as combined estrogen-progestin containing hormonal contraceptives (e.g. oral, transdermal), progestin-only hormonal contraceptives (e.g. oral, injectable, implantable), intrauterine device (IUD) or intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence. The following definitions will be considered:
• Woman of childbearing potential (WOCBP): i.e., fertile, following menarche and until becoming post-menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
• A postmenopausal state is defined as no menses for 12 months without an alternative medical cause
5. Patients legally capable of giving their consent to participate in the study and available to sign and date the written informed consent.

E.4

Principal exclusion criteria

1. Known hypersensitivity or allergy to the active ingredients and/or to any component of the study medications.
2. Lactating and pregnant women.
3. Patients suffering from vaginitis of different etiology, bacterial vaginosis, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex, or human papilloma virus, according to the medical history, physical and gynecological examination
4. Treatment with systemic antifungal drugs within 4 weeks or with topical antifungal drugs within 1 week before Visit 0.
5. Use of any topical drugs on the application area and systemic drugs, including over the counter, oral anticoagulants (i.e. warfarin or acenocoumarol), anti-inflammatory and/or analgesic drugs, antibiotics or antibacterials, within 2 weeks before Visit 0. Intravaginal hormonal contraceptives and male condoms are not allowed.
6. Patients with actual menstruation at Visit 0 or expected menstruation within 11 days after Visit 0.
7. Clinically significant abnormalities at physical examination, vital signs, ECG, laboratory tests at Visit 0.
8. Patients suffering from gynecological diseases (genital tract abnormalities, lichen sclerosus, post-operative alterations of the genital tract, genital tract neoplasm) that may interfere with the study end-points and/or procedures.
9. Immunocompromised patients or patients affected by non-controlled diabetes, or patients being treated with drugs (e.g. immunosuppressants, corticosteroids, anti-infectives), which may predispose to mycological infections.
10. Signs or symptoms or clinical documentation for concurrent infections (including but not limited to sexually transmitted infections) and/or neoplasm.
11. Patients suffering from chronic/recurrent vulvovaginal mycosis, defined as four or more mycological proven symptomatic episodes during the last 12 months.
12. Inability to comply with the protocol requirements, instructions or study-related restrictions (i.e. uncooperative attitude, inability to return for study visits, unlikelihood of completing the clinical study).
13. Vulnerable patients (i.e. persons kept in detention).
14. Subjects involved in the conduct of the study (i.e. Investigator or his/her deputy, first grade relatives, pharmacist, assistant or other personnel).
15. Participation to an interventional clinical trial within 3 months prior to Visit 0.

E.5 End points

E.5.1

Primary end point(s)

Co-primary end-points: microbiological and clinical efficacy of the benzydamine HCl 6 mg and econazole nitrate 150 mg vaginal pessary vs Pevaryl® 150 mg vaginal pessary.
· First co-primary end-point: the microbiological response, defined as the absence of Candida or other yeasts at microscopy (mycological cure) at Visit 3, or at Visit 4.
· Second co-primary end-point: the clinical response, in terms of the time to first relief of symptoms, defined as the earliest time when the sum of the scores for all symptoms declines by 1 point or more with respect to the sum of the scores at baseline.

E.5.1.1

Timepoint(s) of evaluation of this end point

The first co-primary endpoint will be evaluated at Visit 3, or at Visit 4.
The second co-primary endpoint will be evaluated up to Visit 4.

E.5.2

Secondary end point(s)

Secondary end-points will be the comparison between the two treatment groups about:
· the time to total symptoms relief, defined as the time when the sum of the scores for all symptoms becomes 0;
· the clinical response, in terms of percent change of the sum of the scores for all symptoms from baseline at each time point up to Visit 1 (at 24h after the first drug administration), or at ETTV/ETV;
· the clinical efficacy, in terms of clinical cure, defined as resolution of all signs and symptoms (total score=0), assessed at Visit 3, or at ETTV/ETV;
· the clinical efficacy, in terms of clinical improvement, defined as decrease from baseline of the total score of signs and symptoms ≥50%), assessed at Visit 3, or at ETTV/ETV;
· the clinical efficacy in terms of clinical failure, defined as neither resolution nor improvement of all signs and symptoms (total score equal, or <50%, or higher than baseline), assessed at Visit 3, or at ETTV/ETV;
· the clinical efficacy, assessed as the sum of the differences of the scores at each time point and baseline for each sign and symptom, estimated as the area under the differences, up to Visit 1 (at 24h after the first drug administration), or up to
ETTV/ETV;
· the therapeutic cure, assessed as combined mycological and clinical cure at Visit 4 (TOC), or at ETTV/ETV.
· the acceptability assessment at Visit 2, or at ETTV;
- the recurrent episode of uncomplicated VVC, assessed at the Follow-Up Visit;
· the safety evaluation.

E.5.2.1

Timepoint(s) of evaluation of this end point

- the time to total symptoms relief will be evaluated up to Visit 4;
- the clinical response will be evaluated up to Visit 1 or at ETTV/ETV;
- the clinical efficacy, in terms of clinical cure, clinical improvement and clinical failure will be evaluated at Visit 3, or at ETTV/ETV;
- the clinical efficacy, assessed as the sum of the differences of the scores at each time point and baseline for each sign and symptom estimated as the area under the differences, will be evaluated up to Visit 1, or up ETTV/ETV;
-the therapeutic cure will be evaluated at Visit 4 or at ETTV/ETV;
- the acceptability will be evaluated at Visit 2, or at ETTV;
- the safety will be assessed up to Day 23
- the recurrent episode of uncomplicated VVC, assessed at the Follow-up Visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Hungary

Italy

Poland

Russian Federation

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS, including the telephonic follow-up

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2017-07-03.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

280

F.4.2.2

In the whole clinical trial

440

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not Applicable

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-02

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