Clinical Trials Register

Summary
EudraCT Number:	2020-000228-20
Sponsor's Protocol Code Number:	16012020001
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-07-31
Trial 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

Austria - BASG

A.2

EudraCT number

2020-000228-20

A.3

Full title of the trial

Probiotic dietary Intervention in Polycystic Ovary Syndrome – A Randomized Controlled Trial

Probiotische Interventionsstudie bei Polyzystischem Ovarsyndrom (PCOS) - eine randomisiert kontrollierte Studie

A.3.1

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

The effect of ingesting gut bacteria in women with Polycystic Ovary Syndrome, a condition with elevated male sex hormones - a comparison between the supplement and a placebo and metformin, the standard therapy for the condition

Der Effekt von zugeführten Darmbakterien in Frauen mit dem Polyzystischen Ovarsyndrom (PCOS), einer hormonellen Störung mit erhöhten männlichen Geschlechtshormonen - ein Vergleich zwischen dem Nahrungsergänzungsmittel, einem Placebo und Metformin, der Standardtherapie für PCOS

A.3.2

Name or abbreviated title of the trial where available

ProPCO-RCT

A.4.1

Sponsor's protocol code number

16012020001

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	Medical University of Graz
B.1.3.4	Country	Austria
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medical University of Graz
B.4.2	Country	Austria
B.4.1	Name of organisation providing support	Center for Biomarker Research
B.4.2	Country	Austria
B.4.1	Name of organisation providing support	Institute Allergosan
B.4.2	Country	Austria
B.4.1	Name of organisation providing support	Winclove Probiotics
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medical University of Graz
B.5.2	Functional name of contact point	Endokrinologieambulanz
B.5.3	Address:
B.5.3.1	Street Address	Auenbruggerplatz 15
B.5.3.2	Town/ city	Graz
B.5.3.3	Post code	8036
B.5.3.4	Country	Austria
B.5.4	Telephone number	0043316385-12303
B.5.6	E-mail	endo.ambulanz@klinikum-graz.at

D. IMP Identification
D.IMP: 1
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	Glucophage
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Metformin
D.3.2	Product code	A10BA02
D.3.4	Pharmaceutical form	Film-coated tablet
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	METFORMIN HYDROCHLORIDE
D.3.9.1	CAS number	1115-70-4
D.3.9.4	EV Substance Code	SUB03200MIG
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	500
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.3.1	Product name	Winclove 843
D.3.2	Product code	60077
D.3.4	Pharmaceutical form	Powder and solvent for oral suspension
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	Enterococcus faecium W54
D.3.9.3	Other descriptive name	ENTEROCOCCUS FAECIUM
D.3.9.4	EV Substance Code	SUB13676MIG
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lactibacillus acidophilus W22
D.3.9.1	CAS number	68333-16-4
D.3.9.3	Other descriptive name	LACTOBACILLUS ACIDOPHILUS
D.3.9.4	EV Substance Code	SUB14308MIG
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lactobacillus casei W56
D.3.9.3	Other descriptive name	LACTOBACILLUS CASEI
D.3.9.4	EV Substance Code	SUB33691
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lactobacillus rhamnosus W71
D.3.9.1	CAS number	L04001-00-0
D.3.9.3	Other descriptive name	LACTOBACILLUS RHAMNOSUS
D.3.9.4	EV Substance Code	SUB30311
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lactobacillus plantarum W21
D.3.9.3	Other descriptive name	LACTOBACILLUS PLANTARUM
D.3.9.4	EV Substance Code	SUB35051
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	lactobacillus salivarius W57
D.3.9.3	Other descriptive name	LACTOBACILLUS SALIVARIUS
D.3.9.4	EV Substance Code	SUB26481
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lactococcus lactis W58
D.3.9.1	CAS number	8001002-33-3
D.3.9.3	Other descriptive name	LACTOCOCCUS LACTIS
D.3.9.4	EV Substance Code	SUB15396MIG
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/g colony forming unit(s)/gram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vitamin D3
D.3.9.3	Other descriptive name	CHOLECALCIFEROL CONCENTRATE (POWDER FORM)
D.3.9.4	EV Substance Code	SUB37745
D.3.10	Strength
D.3.10.1	Concentration unit	µg/kg microgram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
D.3.11.13.1	Other medicinal product type	Probiotic dietary supplement

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	Powder and solvent for oral suspension
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

Polycystic Ovary Syndrome (PCOS) is a hormonal and metabolic disorder
affecting up to 20 percent of women worldwide, depending on diagnostic
criteria. A very common definition of PCOS based on the revised
Rotterdam criteria includes at least two out of three symptoms:
• Oligo-/Amenorrhea
• Polycystic ovarian morphology (PCOM)
• Clinical or biochemical hyperandrogenism

Das Polyzystische Ovarsyndrom ist eine hormonelle und
Stoffwechselerkrankung, die bis zu 20% aller Frauen weltweit betrifft.
Die Diagnose von PCOS basiert auf mindestens zwei von drei möglichen
Rotterdam Kriterien:
• Oligo-/Amenorrhoe
• Polyzystische Ovarien Morphologie (PCOM)
• Klinischer oder biochemischer Hyperandrogenismus

E.1.1.1

Medical condition in easily understood language

Polycystic Ovary Syndrome (PCOS) is a hormonal and metabolic
disorder. Due to elevated male sex hormone levels, it can cause
menstrual irregularities as well as excess hair growth

Das Polyzystische Ovarsyndrom ist eine hormonelle und
Stoffwechselerkrankung, bei der erhöhte männliche Geschlechtshormone
einen unregelmäßigen Zyklus, mehr Haarwuchs verursachen

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Our primary aim is to establish probiotics as a possible PCOS treatment
option by showing a significant improvement of free testosterone levels
in comparison to placebo after a 6-month intervention period.

Unser primäres Ziel ist es, Probiotika als eine mögliche Therapie bei
PCOS zu etablieren, indem wir zeigen, dass eine 6-monatige Intervention
mit Probiotika statistisch signifikant besser ist als ein Placebo in der
Reduktion von freiem Testosteron im Blut.

E.2.2

Secondary objectives of the trial

Our secondary objectives are:
to compare the secondary outcome parameters to placebo and show a
significant improvement in the probiotic group
to compare the ourcome parameters of the probiotic treatment to
metformin

Als sekundäre Ziele wollen wir:
die Probiotikagruppe mit dem placebo vergleichen in Hinsicht auf die
sekundären Endpunkte
Die Probiotikagruppe mti der Metformingruppe vergleichen

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 Premenopausal women with PCOS aged 18 to 45 years meeting two
out of three Rotterdam criteria: polycystic ovarian morphology,
biochemical and/or clinical hyperandrogenism and oligo-/anovulation
 Signed informed consent form

E.4

Principal exclusion criteria

 Missing or withdrawn consent
 Hyperandrogenism of a cause other than PCOS (Cushing´s syndrome,
hyperprolactinemia, adrenal tumours, congenital adrenal hyperplasia,
rare genetic disorders)
 Pregnancy or nursing period (first 6 months after giving birth)
 Soy or other allergies with respect to study procedures
 Diabetes mellitus type 1
 Chronic inflammatory bowel disease, history of cancer in the
gastrointestinal tract or acute gastrointestinal infection
 Any malignancies that required treatment within the last 3 years
prior to study procedures
 Any other chronic disease requiring medical check-ups or hospital
treatments at least once every three months (exception: diabetes
mellitus type 2)
 Major surgery in the gastrointestinal tract (e.g. colectomy, gut
segment excision with stoma surgery, Whipple´s surgery.) Surgical
removal of the appendix and/or the gall bladder is NOT considered major
surgery.
 Therapy with antidiabetic drugs (metformin, sulfonylureas, DPP-4
inhibitors, GLP-1 analogs, SGLT-2 inhibitors, insulin variants) within the
last six months prior to study procedures
 Therapy with proton pump inhibitors within the last six months prior
to study procedures
 Therapy with hormonal contraceptives or systemic (oral) intake of
steroids
 Oral or intravenous therapy with antibiotics less than three months
before the onset of study procedures
 Alcohol and/or drug abuse

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is a change in serum free testosterone
concentration in women with PCOS after a 6-month intervention with
probiotics compared to placebo treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline, after 6 months intervention, and an additional 6 months (voluntary) follow-up

E.5.2

Secondary end point(s)

 Glucose metabolism (Oral glucose tolerance test)
 Other hormonal parameters of PCOS (AMH; androstenedione; FSH; LH; DHEAS; 17-OH-progesterone; 17-OH-estradiole;
dihydrotestosterone, total testosterone)
 Hirsutism (modified Ferriman-Galway-score)
 Body weight (BMI; waist-to-hip-ratio)
 Gut permeability and inflammation (Functional sugar test; surrogate
parameters: serum diaminooxydase; stool zonulin; calprotectin;
lipopolysaccharide; soluble CD14; bacterial DNA)
 Gut lumen and mucosa microbiome composition and metagenomic
profile (16S-RNA gene sequencing)
 Phytoestrogen production (soy challenge test; urine daidzein and
equol concentrations)
 Quality of life (PCOS questionnaire; depression questionnaires; diet
questionnaires)

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline, after 6 months intervention, and an additional 6 months (voluntary) follow-up

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

E.6.5

Efficacy

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Probiotics vs. placebo is double-blinded, metformin is open-labelled

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

metformin is our comparator; Our investogational product is a dietary supplement (probiotics)

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

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

last visit of the last subject undergoing the trial
E.

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

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:

180

F.1.3

Elderly (>=65 years)

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 2020-07-31.

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

180

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)

Participants taking either probiotics or the probiotics placebo during
the trial my receive another 6 months´ worth of probiotics and may
additionally return after those 6 months for a follow-up visit.

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

2020-08-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-12-10

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