Clinical Trials Register

Summary
EudraCT Number:	2016-004386-12
Sponsor's Protocol Code Number:	BHR-401-301
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-05-03
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

Germany - BfArM

A.2

EudraCT number

2016-004386-12

A.3

Full title of the trial

Double-blind trial investigating the efficacy of different doses of Progesterone compared with Placebo for treatment of vasomotor symptoms

Doppelblinde Studie zur Untersuchung der Wirksamkeit unterschiedlicher Dosierungen von Progesteron im Vergleich zu Placebo zur Behandlung von vasomotorischen Symptomen

A.3.1

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

Double-blind trial investigating the efficacy of different doses of Progesterone compared with placebo for treatment of hot flashes

Doppelblinde Studie zur Untersuchung der Wirksamkeit unterschiedlicher Dosierungen von Progesteron im Vergleich zu Placebo zur Behandlung von Hitzewallungen

A.3.2

Name or abbreviated title of the trial where available

Treatment of vasomotor symptoms with oral Progesterone

Behandlung von vasomotorischen Symptomen mit oralem Progesteron

A.4.1

Sponsor's protocol code number

BHR-401-301

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	Besins Healthcare Ireland Ltd.
B.1.3.4	Country	Ireland
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	Besins Healthcare Ireland Ltd.
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GKM Gesellschaft für Therapieforschung mbH
B.5.2	Functional name of contact point	Clinical Trials Project Management
B.5.3	Address:
B.5.3.1	Street Address	Lessingstrasse 14
B.5.3.2	Town/ city	München
B.5.3.3	Post code	80336
B.5.3.4	Country	Germany
B.5.4	Telephone number	+498920 91 200
B.5.5	Fax number	+498920 91 2030
B.5.6	E-mail	a.ulmerich@gkm-therapieforschung.de

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	Yes
D.2.1.1.1	Trade name	Utrogestan
D.2.1.1.2	Name of the Marketing Authorisation holder	Besins Healthcare (UK) Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PROGESTERONE
D.3.9.1	CAS number	57-83-0
D.3.9.4	EV Substance Code	SUB10076MIG
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	200
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	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.3.2	Product code	BHR-401
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PROGESTERONE
D.3.9.1	CAS number	57-83-0
D.3.9.4	EV Substance Code	SUB10076MIG
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	300
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Vasomotor symptoms

Vasomotorische Symptome

E.1.1.1

Medical condition in easily understood language

Hot flashes

Hitzewallungen

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

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	10020407
E.1.2	Term	Hot flashes
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the clinical trial is to demonstrate superiority of BHR401 (oral micronized progesterone) versus placebo as a monotherapy for moderate to severe VMS in postmenopausal women.

E.2.2

Secondary objectives of the trial

The key secondary objectives of the study are
• to show that BHR-401 treatment is more effective than placebo in reducing VMS severity at week 12.
• to show that BHR-401 treatment is more effective than placebo in reducing VMS frequency and severity at treatment week 4

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for inclusion in the screening period of this study must satisfy all the following criteria:
1. Willing and able to provide written informed consent
2. Adult (≥ 18 years), postmenopausal women, where postmenopause is defined as
a. at least 12 months of spontaneous amenorrhea, or
b. 6 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) levels > 40 mIU/ml, or
c. status at least 6 weeks after bilateral oophorectomy with or without hysterectomy, or
d. subject post hysterectomy without oophorectomy with documented FSH level > 40 mIU/ml and estradiol level < 20 pg/ml
3. Non-smoker
4. Mammography without pathological findings obtained within routine medical care no longer than 12 months prior to screening visit
5. Cervical smear (Papanicolaou test) without pathological findings (i.e. < III) obtained no longer than 12 months prior to screening visit
In addition subjects need to fulfil the following criterion in order to be randomized (i.e. to enter the treatment period):
6. A minimum of 50 moderate to severe VMS episodes over the last 7 consecutive days prior to the baseline visit, as documented in the patient diary

E.4

Principal exclusion criteria

1. Use of any hormone replacement therapy (including phytoestrogens and other plant-derived sex hormones) within 12 weeks prior to screening
2. Endometrial thickness ≥ 5 mm at screening visit
3. Any history or current presence or suspicion of breast cancer, including carcinoma in situ and other pre-cancerous conditions
4. Active malignant disease of any organ system (except for localized basal cell carcinoma of the skin) or history thereof in the last 5 years prior to screening visit
5. Vaginal bleeding due to unidentified reason within 6 weeks prior to screening
6. Ongoing venous thromboembolic event or history thereof within 12 months prior to screening visit
7. Known severe renal insufficiency at screening visit
8. Known lipid metabolism disturbances of genetic origin (e.g. familial hypercholesterolemia, familial hypertriglyceridemia)
9. Acute or chronic liver diseases or a history of liver disease with liver enzymes having not normalized since then
10. Severe disturbances of hepatic function (including porphyria), hepatic tumors, also in medical history
11. Rotor syndrome or Dubin-Johnson syndrome
12. History of icterus or generalized pruritus during a previous pregnancy
13. History of myocardial infarction, stroke or transient ischemic attack or severe cardiac disease, including symptomatic chronic heart failure
14. Ongoing major depression
15. Use of SSRI, SNRI for any reason within 6 weeks prior to screening or planned use during the course of the study
16. Acupuncture for VMS within 2 weeks prior to screening or planned during the course of the study
17. Diabetes mellitus
18. Hypersensitivity to progesterone or excipients (e.g. soy) of the study medication
19. Medical history of HIV infection
20. Concomitant diseases or therapies that may cause VMS or affect VMS frequency or severity, e.g. but not limited to poorly controlled thyroid dysfunction (thyroid medication should be stable for at least 12 weeks prior to screening and TSH levels should be within range), fear disorders (e.g. panic disorders)
21. Participation in a clinical trial or intake of any investigational medicinal product within three months prior to screening visit
22. Previous participation in this clinical trial
23. Known or suspected drug or alcohol abuse.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the change vs. baseline of the daily frequency of moderate or severe VMS episodes after 12 weeks of treatment with micronized progesterone or placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 12 weeks of treatment

E.5.2

Secondary end point(s)

Key secondary endpoints are
• Change vs. baseline of VMS severity after 12 weeks of treatment
• Change vs. baseline of the daily frequency of moderate or severe VMS episodes after 4 weeks of treatment
• Change vs. baseline of VMS severity after 4 weeks of treatment
Further secondary endpoints include
• Incidence of adverse events (AEs) and serious adverse events (SAEs)
• Change vs. baseline of postmenopausal symptoms as assessed by the subjects by means of the MRS after 4 weeks and 12 weeks of treatment
• Change in subjective sleep quality vs. baseline as assessed by means of the Pittsburgh Sleep Quality Index (PSQI) after 4 weeks and 12 weeks of treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

After 4 and after 12 weeks of treatment

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

Yes

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

Switzerland

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

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

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:

240

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

260

F.4.2

For a multinational trial

F.4.2.1

In the EEA

284

F.4.2.2

In the whole clinical trial

304

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)

After a subject completes the final study visit, or discontinues study participation or study medication intake prematurely she shall return to standard medical care as per discretion of the investigator

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

2017-06-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-06

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