Back to resultsProbiotic Intervention in PCOS (ProPCO-RCT)
Primary Purpose
Polycystic Ovary Syndrome
Status
Recruiting
Phase
Phase 4
Locations
Austria
Study Type
Interventional
Intervention
Probiotic
Metformin Hydrochloride
Probiotic Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Polycystic Ovary Syndrome focused on measuring PCOS, Probiotic, Metformin, RCT
Eligibility Criteria
Inclusion Criteria:
- Polycystic Ovary Syndrome diagnosed based on at least two out of three rotterdam criteria: hyperandrogenism, polycystic ovarian morphology, oligo-/anovulation
- signed informed consent
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- Missing or withdrawn consent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, dipeptidyl peptidase 4 (DPP-4) inhibitors, Glucagon-like peptide 1 (GLP-1) analogs, sodium-glucose-cotransporter 2 (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 within the last six months prior to study procedures
- Oral or intravenous therapy with antibiotics less than three months before the onset of study procedures
- Alcohol and/or drug abuse
Sites / Locations
- Medical University of Graz, Division of Endocrinology and DiabetologyRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Placebo Comparator
Active Comparator
Arm Label
Probiotic
Placebo
Metformin
Arm Description
Probiotic product consisting of these 7 bacterial strains: Lactobacillus salivarius W57 Lactobacillus casei W56 Lactobacillus rhamnosus W71 Lactococcus lactis W58 Enterococcus faecium W54 Lactobacillus plantarum W62 Lactobacillus acidophilus W22 Additional ingredients: Corn starch, maltodextrin, fructo-oligosaccharides, galacto-oligosaccharides, polydextrose, plant proteins, potassium chloride, magnesium sulfate, bacterial strains, manganese sulfate, lactose, 2000 IU vitamin D Participants ingest one sachet of powder (5 grams) in 200 ml of water per day for 6 months
Similar to probiotic product in optics and smell, less ingredients and no bacterial strains or vitamin D Ingredients: Corn starch, maltodextrin, potassium chloride, magnesium sulphate, manganese sulphate
Metformin is an established drug for treating PCOS-related symptoms. The investigators are comparing the probiotic not only to a placebo group, but also to the benchmark treatment. Participants in the metformin arm will start treatment with 500 mg daily for the first week, then increasing the dose to 2x500 mg daily for the duration of the intervention.
Outcomes
Primary Outcome Measures
Free testosterone
Changes in free testosterone levels [pg/ml] in serum after intervention
Secondary Outcome Measures
Anti-Müllerian hormone (AMH)
Changes in AMH levels in serum after intervention [ng/ml]
Androstenedione
Changes in androstenedione levels in serum after intervention [ng/ml]
Dehydroepiandrosterone-sulphate (DHEA-S)
Changes in DHEA-S levels in serum after intervention [µg/ml]
17-Hydroxyprogesterone (17-OH-progesterone)
Changes in 17-OH-progesterone levels in serum after intervention [ng/ml]
17-OH-estradiol
Changes in 17-OH-estradiol levels in serum after intervention [ng/ml]
Total testosterone
Changes in total testosterone levels in serum after intervention [ng/ml]
25-OH-cholecalciferol
Changes in 25-OH-cholecalciferol levels in serum after intervention [ng/ml]
Luteinizing hormone (LH), Follicle-stimulating hormone (FSH)
Changes in LH and FSH levels in serum after intervention [mU/ml]
LH to FSH ratio
Changes in LH to FSH ratio after intervention [1]
Insulin
Changes in insulin levels in serum as measured with a two-hour oral glucose tolerance test (75 mg glucose in 300 ml water, blood draws at 0 minutes, 30 min, 60 min and 120 min) [mU/l]
Glucose
Changes in glucose levels in sodium-fluoride plasma as measured with a two-hour oral glucose tolerance test (75 mg glucose in 300 ml water, blood draws at 0 minutes, 30 min, 60 min and 120 min) [mg/dl]
Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index
Changes in HOMA-IR index (fasting insulin [mU/l] * fasting glucose [mg/dl]/405) after intervention
Glucose mean
Changes in mean glucose levels (measured with oral glucose tolerance test with the formula g=(glucose0 + 2*glucose30 + 3*glucose60 + 2*glucose120)/8 [mg/dl]
Insulin mean
Changes in mean insulin levels (measured with oral glucose tolerance test with the formula i=(insulin0 + 2*insulin30 + 3*insulin0 + 2*insulin120)/8 [mU/l]
Matsuda index
Changes in matsuda index after intervention measured with the formula M=10000/squareroot(glucose0 * insulin0 * glucose mean (see outcome 14) * insulin mean (see outcome 15))
Hirsutism
measured by modified Ferriman-Gallwey-score (mFG-score), ranging from 0 to 36, with 0 being the best possible value and 36 the worst
Body-mass-index (BMI)
BMI measured with the formula BMI=weight [kg]/height² [m]
waist-to-hip ratio
Calculated with the formula: waist circumference/hip circumference [1]
Sucrose-lactulose-mannitol test
Functional gut permeability test consisting of ingesting 20 g sucrose, 5 g mannitol and 10 g lactulose in 100 ml water solution. Measurement of those three component concentrations in urine collected for 5 hours after solution ingestion by the participants. Lactulose to mannitol ratio may be calculated.
Diaminooxidase
Changes in serum diaminooxidase levels after intervention
Stool and serum zonulin
Changes in stool and serum zonulin levels after intervention [ng/ml]
Lipopolysaccharide
Changes in lipopolysaccharide levels after intervention
Soluble cluster of differentiation (sCD14)
Changes in sCD14 levels in serum after intervention
Calprotectin
Changes in stool calprotectin levels after intervention
Bacterial DNA
Changes in bacterial DNA amounts in serum after intervention
Gut lumen and mucosa microbiome composition and metagenomic profile
Measured from stool samples via 16S-RNA gene sequencing
Phytoestrogen production
Changes in daidzein and equol concentrations after intervention [ng/ml] measured in urine samples of participants after ingestion of soy milk
Equol producer status
Equol producer status as determined by the decadic logarithm of the equol/daidzein ratio [1]: A value above -0.5 is defined as an equol producer
Quality of life (QOL)
QOL assessed by General Depression Scale (German: Allgemeine Depressionsskala), German equivalent of the Depression Scale by the Center for Epidemiological Studies (CES-D). The scale ranges from 0 to 60, with 0 being the best possible score and 60 the worst.
QOL
QOL assessed by Beck´s Depression Inventory (BDI), a scale ranging from 0 to 63, with 0 being the best possible score and 63 the worst.
QOL
Quality of Life measured by a PCOS questionnaire ranging from 0 to 156, with 0 being the best possible score and 156 the worst
Full Information
NCT ID
NCT04593459
First Posted
October 12, 2020
Last Updated
April 5, 2022
Sponsor
Medical University of Graz
Collaborators
Institut AllergoSan, Winclove Probiotics B.V.
1. Study Identification
Unique Protocol Identification Number
NCT04593459
Brief Title
Probiotic Intervention in PCOS
Acronym
ProPCO-RCT
Official Title
Probiotic Dietary Intervention in Polycystic Ovary Syndrome (PCOS) - A Randomized Controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 3, 2020 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of Graz
Collaborators
Institut AllergoSan, Winclove Probiotics B.V.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The investigators are conducting a double-blinded randomized controlled trial to determine whether a probiotic mixture is effective in reducing PCOS-related symptoms. For this purpose, 180 participants will be recruited in three intervention arms (Probiotic, Placebo and Metformin), with 60 participants per arm. The intervention period will last 6 months, with extensive medical history, blood work, urine and stool analysis at the beginning and the conclusion of the trial.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycystic Ovary Syndrome
Keywords
PCOS, Probiotic, Metformin, RCT
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Probiotic vs placebo (double-blinded) vs metformin (open-label)
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Only the probiotic and placebo are blinded, metformin is an open intervention arm
Allocation
Randomized
Enrollment
180 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Probiotic
Arm Type
Experimental
Arm Description
Probiotic product consisting of these 7 bacterial strains:
Lactobacillus salivarius W57
Lactobacillus casei W56
Lactobacillus rhamnosus W71
Lactococcus lactis W58
Enterococcus faecium W54
Lactobacillus plantarum W62
Lactobacillus acidophilus W22
Additional ingredients: Corn starch, maltodextrin, fructo-oligosaccharides, galacto-oligosaccharides, polydextrose, plant proteins, potassium chloride, magnesium sulfate, bacterial strains, manganese sulfate, lactose, 2000 IU vitamin D
Participants ingest one sachet of powder (5 grams) in 200 ml of water per day for 6 months
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Similar to probiotic product in optics and smell, less ingredients and no bacterial strains or vitamin D
Ingredients: Corn starch, maltodextrin, potassium chloride, magnesium sulphate, manganese sulphate
Arm Title
Metformin
Arm Type
Active Comparator
Arm Description
Metformin is an established drug for treating PCOS-related symptoms. The investigators are comparing the probiotic not only to a placebo group, but also to the benchmark treatment.
Participants in the metformin arm will start treatment with 500 mg daily for the first week, then increasing the dose to 2x500 mg daily for the duration of the intervention.
Intervention Type
Dietary Supplement
Intervention Name(s)
Probiotic
Intervention Description
See Arm description
Intervention Type
Drug
Intervention Name(s)
Metformin Hydrochloride
Intervention Description
See Arm description
Intervention Type
Dietary Supplement
Intervention Name(s)
Probiotic Placebo
Intervention Description
See Arm description
Primary Outcome Measure Information:
Title
Free testosterone
Description
Changes in free testosterone levels [pg/ml] in serum after intervention
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Anti-Müllerian hormone (AMH)
Description
Changes in AMH levels in serum after intervention [ng/ml]
Time Frame
6 months
Title
Androstenedione
Description
Changes in androstenedione levels in serum after intervention [ng/ml]
Time Frame
6 months
Title
Dehydroepiandrosterone-sulphate (DHEA-S)
Description
Changes in DHEA-S levels in serum after intervention [µg/ml]
Time Frame
6 months
Title
17-Hydroxyprogesterone (17-OH-progesterone)
Description
Changes in 17-OH-progesterone levels in serum after intervention [ng/ml]
Time Frame
6 months
Title
17-OH-estradiol
Description
Changes in 17-OH-estradiol levels in serum after intervention [ng/ml]
Time Frame
6 months
Title
Total testosterone
Description
Changes in total testosterone levels in serum after intervention [ng/ml]
Time Frame
6 months
Title
25-OH-cholecalciferol
Description
Changes in 25-OH-cholecalciferol levels in serum after intervention [ng/ml]
Time Frame
6 months
Title
Luteinizing hormone (LH), Follicle-stimulating hormone (FSH)
Description
Changes in LH and FSH levels in serum after intervention [mU/ml]
Time Frame
6 months
Title
LH to FSH ratio
Description
Changes in LH to FSH ratio after intervention [1]
Time Frame
6 months
Title
Insulin
Description
Changes in insulin levels in serum as measured with a two-hour oral glucose tolerance test (75 mg glucose in 300 ml water, blood draws at 0 minutes, 30 min, 60 min and 120 min) [mU/l]
Time Frame
6 months
Title
Glucose
Description
Changes in glucose levels in sodium-fluoride plasma as measured with a two-hour oral glucose tolerance test (75 mg glucose in 300 ml water, blood draws at 0 minutes, 30 min, 60 min and 120 min) [mg/dl]
Time Frame
6 months
Title
Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index
Description
Changes in HOMA-IR index (fasting insulin [mU/l] * fasting glucose [mg/dl]/405) after intervention
Time Frame
6 months
Title
Glucose mean
Description
Changes in mean glucose levels (measured with oral glucose tolerance test with the formula g=(glucose0 + 2*glucose30 + 3*glucose60 + 2*glucose120)/8 [mg/dl]
Time Frame
6 months
Title
Insulin mean
Description
Changes in mean insulin levels (measured with oral glucose tolerance test with the formula i=(insulin0 + 2*insulin30 + 3*insulin0 + 2*insulin120)/8 [mU/l]
Time Frame
6 months
Title
Matsuda index
Description
Changes in matsuda index after intervention measured with the formula M=10000/squareroot(glucose0 * insulin0 * glucose mean (see outcome 14) * insulin mean (see outcome 15))
Time Frame
6 months
Title
Hirsutism
Description
measured by modified Ferriman-Gallwey-score (mFG-score), ranging from 0 to 36, with 0 being the best possible value and 36 the worst
Time Frame
6 months
Title
Body-mass-index (BMI)
Description
BMI measured with the formula BMI=weight [kg]/height² [m]
Time Frame
6 months
Title
waist-to-hip ratio
Description
Calculated with the formula: waist circumference/hip circumference [1]
Time Frame
6 months
Title
Sucrose-lactulose-mannitol test
Description
Functional gut permeability test consisting of ingesting 20 g sucrose, 5 g mannitol and 10 g lactulose in 100 ml water solution. Measurement of those three component concentrations in urine collected for 5 hours after solution ingestion by the participants. Lactulose to mannitol ratio may be calculated.
Time Frame
6 months
Title
Diaminooxidase
Description
Changes in serum diaminooxidase levels after intervention
Time Frame
6 months
Title
Stool and serum zonulin
Description
Changes in stool and serum zonulin levels after intervention [ng/ml]
Time Frame
6 months
Title
Lipopolysaccharide
Description
Changes in lipopolysaccharide levels after intervention
Time Frame
6 months
Title
Soluble cluster of differentiation (sCD14)
Description
Changes in sCD14 levels in serum after intervention
Time Frame
6 months
Title
Calprotectin
Description
Changes in stool calprotectin levels after intervention
Time Frame
6 months
Title
Bacterial DNA
Description
Changes in bacterial DNA amounts in serum after intervention
Time Frame
6 months
Title
Gut lumen and mucosa microbiome composition and metagenomic profile
Description
Measured from stool samples via 16S-RNA gene sequencing
Time Frame
6 months
Title
Phytoestrogen production
Description
Changes in daidzein and equol concentrations after intervention [ng/ml] measured in urine samples of participants after ingestion of soy milk
Time Frame
6 months
Title
Equol producer status
Description
Equol producer status as determined by the decadic logarithm of the equol/daidzein ratio [1]: A value above -0.5 is defined as an equol producer
Time Frame
6 months
Title
Quality of life (QOL)
Description
QOL assessed by General Depression Scale (German: Allgemeine Depressionsskala), German equivalent of the Depression Scale by the Center for Epidemiological Studies (CES-D). The scale ranges from 0 to 60, with 0 being the best possible score and 60 the worst.
Time Frame
6 months
Title
QOL
Description
QOL assessed by Beck´s Depression Inventory (BDI), a scale ranging from 0 to 63, with 0 being the best possible score and 63 the worst.
Time Frame
6 months
Title
QOL
Description
Quality of Life measured by a PCOS questionnaire ranging from 0 to 156, with 0 being the best possible score and 156 the worst
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Lipid metabolism
Description
Low-density lipoproteins (LDL), high-density lipoproteins (HDL), lipoprotein a (LP(a)), triacylglycerols
Time Frame
6 months
Title
Fluorescence-activated cell sorting (FACS) analysis
Description
B cell subtypes measured via FACS from whole blood
Time Frame
6 months
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Polycystic Ovary Syndrome diagnosed based on at least two out of three rotterdam criteria: hyperandrogenism, polycystic ovarian morphology, oligo-/anovulation
signed informed consent
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, dipeptidyl peptidase 4 (DPP-4) inhibitors, Glucagon-like peptide 1 (GLP-1) analogs, sodium-glucose-cotransporter 2 (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 within the last six months prior to study procedures
Oral or intravenous therapy with antibiotics less than three months before the onset of study procedures
Alcohol and/or drug abuse
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Valentin Borzan, MD
Phone
0043-316-385
Ext
14290
Email
valentin.borzan@medunigraz.at
First Name & Middle Initial & Last Name or Official Title & Degree
Barbara Obermayer-Pietsch, Prof. MD
Phone
0043-316-385
Ext
12383
Email
barbara.obermayer@medunigraz.at
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barbara Obermayer-Pietsch, Prof. MD
Organizational Affiliation
Medical University of Graz, Division of Endocrinology and Diabetology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University of Graz, Division of Endocrinology and Diabetology
City
Graz
State/Province
Styria
ZIP/Postal Code
8036
Country
Austria
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barbara Obermayer-Pietsch, Prof. MD
Phone
+43316-385-80253
Email
barbara.obermayer@medunigraz.at
First Name & Middle Initial & Last Name & Degree
Valentin Borzan, MD
Phone
+43316-385-14290
Email
valentin.borzan@medunigraz.at
First Name & Middle Initial & Last Name & Degree
Barbara Obermayer-Pietsch, Prof. MD
First Name & Middle Initial & Last Name & Degree
Valentin Borzan, MD
First Name & Middle Initial & Last Name & Degree
Christian Trummer, PhD, MD
First Name & Middle Initial & Last Name & Degree
Stefan Pilz, Assoc.Prof., MD, PhD
First Name & Middle Initial & Last Name & Degree
Verena Theiler-Schwetz, MD, PhD
First Name & Middle Initial & Last Name & Degree
Claudia Stiegler, MD
First Name & Middle Initial & Last Name & Degree
Marlene Pandis, MD
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
For research and cooperation purposes, pseudonymized individual participant data may be shared with other researchers, the decision to do so lies with the principal investigator. In case of publication of our results in a peer-reviewed journal, all relevant data will be made publicly accessible without any personal information
IPD Sharing Time Frame
to be determined
IPD Sharing Access Criteria
to be determined
Citations:
PubMed Identifier
28045919
Citation
Lindheim L, Bashir M, Munzker J, Trummer C, Zachhuber V, Leber B, Horvath A, Pieber TR, Gorkiewicz G, Stadlbauer V, Obermayer-Pietsch B. Alterations in Gut Microbiome Composition and Barrier Function Are Associated with Reproductive and Metabolic Defects in Women with Polycystic Ovary Syndrome (PCOS): A Pilot Study. PLoS One. 2017 Jan 3;12(1):e0168390. doi: 10.1371/journal.pone.0168390. eCollection 2017.
Results Reference
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PubMed Identifier
32492805
Citation
Haudum C, Lindheim L, Ascani A, Trummer C, Horvath A, Munzker J, Obermayer-Pietsch B. Impact of Short-Term Isoflavone Intervention in Polycystic Ovary Syndrome (PCOS) Patients on Microbiota Composition and Metagenomics. Nutrients. 2020 Jun 1;12(6):1622. doi: 10.3390/nu12061622.
Results Reference
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Probiotic Intervention in PCOS
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