<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03306745</url>
  </required_header>
  <id_info>
    <org_study_id>1232/2016</org_study_id>
    <nct_id>NCT03306745</nct_id>
  </id_info>
  <brief_title>Micronutrient Supplementation in PCO-syndrome</brief_title>
  <official_title>Micronutrient Supplementation for Women With PCO-syndrome - Influence of Nutrition and Physiology on the Development of PCOS-typical Parameters</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Vienna</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The role of micronutrients in fertility has recently gained increased attention. In women who&#xD;
      suffer from polycystic ovary syndrome (PCOS) and infertility, we aim to test the impact of a&#xD;
      standardized, multinutrient supplementation on the course of PCOS-specific parameters namely&#xD;
      anti-Mullerian hormone (AMH), testosterone, and androstenedione. A total of 60 infertile&#xD;
      women with PCOS, previously untreated, will be randomized to receive either a combined&#xD;
      standardized multinutrient supplementation (containing folic acid, selenium, vitamin E,&#xD;
      catechins, glycyrrhizin, coenzyme Q10 and omega-3-fatty acids; study group) or folic acid&#xD;
      alone (control group) in a double-blinded, randomized manner. These study medications will be&#xD;
      provided for 3 months and pre- to posttreatment levels of AMH, testosterone, and AMH will be&#xD;
      analysed. The study will be performed at the Clinical Division of Gynecologic Endocrinology&#xD;
      and Reproductive Medicine of the Medical University of Vienna.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction and scientific background:&#xD;
&#xD;
      In the Western world, malnutrition and subfertility have become increasingly common problems&#xD;
      affecting both men and women. A recent study showed that conforming to nutritional&#xD;
      recommendations significantly increased the probability of a clinical pregnancy following&#xD;
      vitro fertilisation (IVF)/ intracytoplasmatic sperm injection (ICSI). They included fruit,&#xD;
      vegetables, certain types of meat, fish, whole-grain products and specific fats (according to&#xD;
      the Netherlands Nutrition Centre Foundation). Another study specifically analysed&#xD;
      preconceptional consumption of unsaturated fatty acids by women before IVF/ICSI. It&#xD;
      discovered a positive effect on the embryo's morphology.&#xD;
&#xD;
      The effect of micronutrients on female fertility is currently under investigation. A 2012&#xD;
      review on the subject included 13 studies with more than 90,000 female participants and&#xD;
      provided no generalised recommendations, but allowed the authors to deduce a certain positive&#xD;
      effect of supplementation with certain micronutrients on female fertility.&#xD;
&#xD;
      This current study will test the effect of a currently available micronutrient&#xD;
      supplementation in women suffering from polycystic ovary (PCO)-syndrome and sterility. The&#xD;
      product (PROfertil ® female, Lenus Pharma, Seeböckgasse 59, 1160 Vienna, Austria) is based on&#xD;
      several studies that showed (i) an increased need for these micronutrients of women with a&#xD;
      desire to have a child or currently pregnant and/or (ii) a positive effect on female&#xD;
      fertility. PROfertil ® female is a micronutrient supplement containing selenium, vitamin E,&#xD;
      catechins, glycyrrhizin, co-enzyme Q10, folic acid and omega-3 fatty acids.&#xD;
&#xD;
      This study seems of impact from a scientific perspective. Clinical experience with PROfertil&#xD;
      ® female suggests that patients suffering from PCO-syndrome experience an increase of&#xD;
      anti-müllerian hormone and androgen levels. The reductive effect of PCO-typical serum&#xD;
      parameters can be explained pathophysiologically: A chronic low-level pro-inflammatory state&#xD;
      - both locally in the ovary and systemically - appears to be among the central&#xD;
      pathophysiological correlates of PCO-syndrome. PROfertil ® female contains a mix of several&#xD;
      antioxidative agents. A favourable effect on PCO-syndrome is expected. Metformin is an&#xD;
      anti-inflammatory substance commonly used to treat PCO-syndrome. The anti-inflammatory effect&#xD;
      is seen as positive. This explains why women suffering from PCO-syndrome without&#xD;
      insulin-glucose balance problems react positively to treatment with metformin.&#xD;
&#xD;
      The aim of this study is to perform a prospective randomized test comparing PROfertil ®&#xD;
      female to supplementation with folic acid alone for female patients suffering from&#xD;
      PCO-syndrome and infertility. Supplementation with folic acid is the current state of the art&#xD;
      in micronutrient supplementation of infertile women.&#xD;
&#xD;
      Study aims The primary aim of this study is to analyse the effects of three months of&#xD;
      treatment with PROfertil ® female compared to a supplementation with 400µg of folic acid for&#xD;
      women suffering from PCO-syndrome, sterility, anovulation. The study will examine the&#xD;
      parameters typical for PCO-syndrome (anti-müllerian hormone, total testosterone,&#xD;
      androstenedione).&#xD;
&#xD;
      The secondary goal is to document the individual course of further fertility treatment.&#xD;
&#xD;
      The products being administered to the patients for four weeks are:&#xD;
&#xD;
        -  PROfertil ® female (Lenus Pharma Gesellschaft mit beschränkter Haftung [GesmbH],&#xD;
           Seeböckgasse 59, 1160 Vienna; treatment group) - one soft capsule (500mg Omega-3-fatty&#xD;
           acids) and one pill (folic acid: 800µg, selenium 70µg, vitamin E 30mg, catechine: 4mg,&#xD;
           glycyrrhizin 12mg, and coenzyme Q10: 30mg) per day.&#xD;
&#xD;
        -  200µg folic acid (folic acid capsules 400µg ®, OTC Produktion und Forschung GesmbH,&#xD;
           Fischergasse 17, 5020 Salzburg; control group) - two capsules per day.&#xD;
&#xD;
      The study will be performed in a double-blinded manner. The medications are unlabeled for&#xD;
      both groups and will be dispensed in unlabeled blisters. However, patients could search for&#xD;
      the actual look of the PROfertil ® female soft capsules and the pills (for example on the&#xD;
      internet). Since they differ from the folic acid capsules, patients could identify the&#xD;
      control medications. The study team is aware of the fact that this kind of blinding is not&#xD;
      according to standards and could introduce some kind of bias.&#xD;
&#xD;
      Study hypotheses:&#xD;
&#xD;
      First hypothesis: A three-month treatment with PROfertil ® female causes a drop of&#xD;
      anti-müllerian hormone, total testosterone and androstenedione levels. This does not happen&#xD;
      if treated with 400µg folic acid.&#xD;
&#xD;
      Outcome parameters:&#xD;
&#xD;
      Primary outcome parameters: anti-müllerian hormone (AMH), total testosterone and&#xD;
      androstenedione levels&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      Monocentric, prospective randomized double-blinded trial&#xD;
&#xD;
      Recruitment:&#xD;
&#xD;
      The participants are recruited by medical professionals at the Department of Obstetrics and&#xD;
      Gynecology of the Medical University of Vienna using the above mentioned criteria during&#xD;
      routine examinations before any treatment for PCO-syndrome and/or sterility is initiated.&#xD;
      Potential participants are informed about the procedure, clinical relevance and possible&#xD;
      additional effort caused by study participation. The patients willing to participate then&#xD;
      have to sign the written informed consent.&#xD;
&#xD;
      Sample size calculation:&#xD;
&#xD;
      Assuming a reduction of the mean AMH levels by 2 ng/ml at a standard deviation of 3 ng/ml and&#xD;
      an alpha value of 0.05 and a power of 0.90, the paired t-test requires 26 patients per group.&#xD;
      Due to the fact that the participants wish to conceive a child and have been diagnosed with&#xD;
      sterility, a low drop-out rate can be expected. There is no reliable data on this or similar&#xD;
      treatments that allow prediction of the chance to conceive. Due to the favourable&#xD;
      benefit-to-risk profile, a 15% drop-out rate is assumed. This corresponds to 4 patients per&#xD;
      group. Thus, the final sample size is calculated as 30 patients per group, which leads to a&#xD;
      total study population of 60.&#xD;
&#xD;
      Statistical analysis:&#xD;
&#xD;
      The bio-statistician will randomise the data using nQuery advisorTM Version 7.0. The&#xD;
      information will then be packaged in an envelope by a person independent of the participating&#xD;
      medical professionals and other scientific personnel. This will only be opened after the&#xD;
      inclusion of the patient. Categorical variables will be presented as absolute numbers and&#xD;
      percentages, numerical variables as median and interquartile range.&#xD;
&#xD;
      The following statistical analyses are planned: The result parameters and the patient&#xD;
      characteristics of the two groups will be compared using the Welch test (for numerical&#xD;
      variables) and the Chi-square-test or Fisher's exact test (for categorical variables). A&#xD;
      p-value of &lt;0.05 is considered to be statistically significant. The statistical analyses will&#xD;
      be performed using SPSS 24.0 for Windows (SPSS Inc, 1989-2017).&#xD;
&#xD;
      Further details on study design:&#xD;
&#xD;
      After recruiting the participants at the outpatient clinics for Gynecologic Endocrinology and&#xD;
      Infertility Treatment, they are randomly assigned to one of the groups.&#xD;
&#xD;
      Participants will receive either 2 unlabelled soft capsules containing 200µg folic acid each&#xD;
      or 1 unlabelled soft capsule containing omega-3 fatty acids and 1 tablet containing folic&#xD;
      acid, selenium, vitamin E, catechins, glycyrrhizin, and co-enzyme Q10 (see Table above for&#xD;
      details on doses).&#xD;
&#xD;
      The planned examination of AMH, total testosterone and androstenedione levels will take place&#xD;
      after a minimum of 90 days (and a maximum of 100 days) after beginning supplementation with&#xD;
      PROfertil ® female or folic acid. The maximum duration of participation is thus 100 days.&#xD;
      After taking the micronutrient supplementation (PROfertil ® female or folic acid) beyond the&#xD;
      planned minimum treatment duration, an individualised fertility treatment can be performed.&#xD;
&#xD;
      There are two study-specific consultations: After including the patient (consultation 1:&#xD;
      randomisation, distribution of drugs and start of study) and after 90 to 100 days&#xD;
      (consultation 2). During consultation 2, unused study blisters are collected and patients are&#xD;
      questioned on peculiarities and possible side effects of the micronutrient supplementation&#xD;
      used.&#xD;
&#xD;
      It is expected that 30 minutes for consultation 1 and 15 minutes for consultation 2 will have&#xD;
      to be spent by the patient. The consultations will be held during regular outpatient&#xD;
      treatments and will be part of the planned routine examinations. They include discussions of&#xD;
      examination results and recommendations for further treatment.&#xD;
&#xD;
      Benefits-to-risk assessment and preventive measures:&#xD;
&#xD;
      Risks or complications due to the use of PROfertil ® female and additional venepuncture are&#xD;
      not expected. A recent study using the same product showed no substance-related side effects&#xD;
      (number of the ethics committee of the Medical University of: 1659/2013; accepted on&#xD;
      2013-09-24) (9). A direct benefit for the treatment group is possible. A positive effect on&#xD;
      PCO syndrome can be assumed, which might result in a higher chance of pregnancy. The&#xD;
      substance administered to the control group is state of the art for female fertility&#xD;
      treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2, 2017</start_date>
  <completion_date type="Actual">June 25, 2018</completion_date>
  <primary_completion_date type="Actual">June 25, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The medications are unlabeled for both groups and will be dispensed in unlabeled blisteres. However, patients could search for the actual look of the PROfertil ® female soft capsules and the pills (for example on the internet). Since they differ from the folic acid capsules, patients could identify the control medications. We are aware of the fact that this kind of blinding is not according to standards and could introduce some kind of bias.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Anti-Mullerian Hormone (AMH)</measure>
    <time_frame>Change from pre-treatment, baseline serum level to serum level at 3 months of treatment.</time_frame>
    <description>Change in serum AMH level</description>
  </primary_outcome>
  <primary_outcome>
    <measure>testosterone</measure>
    <time_frame>Change from pre-treatment, baseline serum level to serum level at 3 months of treatment.</time_frame>
    <description>Change in serum testosterone level</description>
  </primary_outcome>
  <primary_outcome>
    <measure>androstenedione</measure>
    <time_frame>Change from pre-treatment, baseline serum level to serum level at 3 months of treatment.</time_frame>
    <description>Change in serum androstenedione level</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Polycystic Ovary Syndrome</condition>
  <condition>Infertility, Female</condition>
  <condition>Micronutrient Deficiency</condition>
  <arm_group>
    <arm_group_label>Study group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 soft capsule/day containing 500mg omega-3 fatty acids&#xD;
one tablet/day containing 800mg folic acid, 70mg selenium, 30 mg Vitamin E, 4 mg catechin, 12 mg glycyrrhizin, and 30 mg coenzyme Q10</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>200µg folic acid - two capsules per day</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Profertil female</intervention_name>
    <description>For micronutrient ingredients please see details above. PROfertil ® female is approved in Austria by the Austrian Ministry of Health and has a &quot;Free Sales Certificate&quot;.</description>
    <arm_group_label>Study group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Folic acid 400 mg</intervention_name>
    <description>Folic acid 400 mg</description>
    <arm_group_label>Control group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The patient has been diagnosed with PCO-syndrome using revised 2004 Rotterdam-criteria&#xD;
             (7).&#xD;
&#xD;
          2. The patient is sterile, defined as being unable to become pregnant within a year&#xD;
             despite unprotected sexual intercourse.&#xD;
&#xD;
          3. The patient suffers either from oligomenorrhoea (defined as an interval of ≥60 days&#xD;
             between the last three menstruations) or complete amenorrhoea for at least 90 days.&#xD;
&#xD;
          4. The patient has given her written informed consent after detailed information on the&#xD;
             study by medical professionals at the Department of Obstetrics and Gynecology of the&#xD;
             Medical University of Vienna.&#xD;
&#xD;
          5. Both partners are at least 19 years old and are younger than 35. The age limit was&#xD;
             chosen to take physiologically reduced fertility beyond this age (8). This measure&#xD;
             allowed the women to avoid a 100-day delay of fertility treatments due to this study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. No informed consent.&#xD;
&#xD;
          2. At least one partner is younger than 19 years or older than 35 years.&#xD;
&#xD;
          3. The patient has been subject to one of the following PCO-syndrome-related treatments&#xD;
             within three months before inclusion: metformin, combined oral contraceptives,&#xD;
             cortisol therapy, inositol, ovarian drilling, any kind of ovarian stimulation,&#xD;
             in-vitro fertilisation. Promoting menstruation using gestagen products is acceptable.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Medical University of Vienna, Clinical Division of Gynecologic Endocrinology and Reproductive Medicine</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>July 16, 2017</study_first_submitted>
  <study_first_submitted_qc>October 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 11, 2017</study_first_posted>
  <last_update_submitted>September 5, 2018</last_update_submitted>
  <last_update_submitted_qc>September 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Johannes Ott</investigator_full_name>
    <investigator_title>Assoc.-Prof. Priv.-Doz. Dr.</investigator_title>
  </responsible_party>
  <keyword>Polycystic Ovary Syndrome</keyword>
  <keyword>Anti-Mullerian Hormone</keyword>
  <keyword>Androgens</keyword>
  <keyword>Micronutrient Supplementation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Polycystic Ovary Syndrome</mesh_term>
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Infertility, Female</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Folic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 16, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/45/NCT03306745/Prot_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 16, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/45/NCT03306745/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03306745
org study id: 1232/2016
nct id: NCT03306745
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The role of micronutrients in fertility has recently gained increased attention. In women who
      suffer from polycystic ovary syndrome (PCOS) and infertility, we aim to test the impact of a
      standardized, multinutrient supplementation on the course of PCOS-specific parameters namely
      anti-Mullerian hormone (AMH), testosterone, and androstenedione. A total of 60 infertile
      women with PCOS, previously untreated, will be randomized to receive either a combined
      standardized multinutrient supplementation (containing folic acid, selenium, vitamin E,
      catechins, glycyrrhizin, coenzyme Q10 and omega-3-fatty acids; study group) or folic acid
      alone (control group) in a double-blinded, randomized manner. These study medications will be
      provided for 3 months and pre- to posttreatment levels of AMH, testosterone, and AMH will be
      analysed. The study will be performed at the Clinical Division of Gynecologic Endocrinology
      and Reproductive Medicine of the Medical University of Vienna.
Introduction and scientific background:

      In the Western world, malnutrition and subfertility have become increasingly common problems
      affecting both men and women. A recent study showed that conforming to nutritional
      recommendations significantly increased the probability of a clinical pregnancy following
      vitro fertilisation (IVF)/ intracytoplasmatic sperm injection (ICSI). They included fruit,
      vegetables, certain types of meat, fish, whole-grain products and specific fats (according to
      the Netherlands Nutrition Centre Foundation). Another study specifically analysed
      preconceptional consumption of unsaturated fatty acids by women before IVF/ICSI. It
      discovered a positive effect on the embryo's morphology.

      The effect of micronutrients on female fertility is currently under investigation. A 2012
      review on the subject included 13 studies with more than 90,000 female participants and
      provided no generalised recommendations, but allowed the authors to deduce a certain positive
      effect of supplementation with certain micronutrients on female fertility.

      This current study will test the effect of a currently available micronutrient
      supplementation in women suffering from polycystic ovary (PCO)-syndrome and sterility. The
      product (PROfertil ® female, Lenus Pharma, Seeböckgasse 59, 1160 Vienna, Austria) is based on
      several studies that showed (i) an increased need for these micronutrients of women with a
      desire to have a child or currently pregnant and/or (ii) a positive effect on female
      fertility. PROfertil ® female is a micronutrient supplement containing selenium, vitamin E,
      catechins, glycyrrhizin, co-enzyme Q10, folic acid and omega-3 fatty acids.

      This study seems of impact from a scientific perspective. Clinical experience with PROfertil
      ® female suggests that patients suffering from PCO-syndrome experience an increase of
      anti-müllerian hormone and androgen levels. The reductive effect of PCO-typical serum
      parameters can be explained pathophysiologically: A chronic low-level pro-inflammatory state
      - both locally in the ovary and systemically - appears to be among the central
      pathophysiological correlates of PCO-syndrome. PROfertil ® female contains a mix of several
      antioxidative agents. A favourable effect on PCO-syndrome is expected. Metformin is an
      anti-inflammatory substance commonly used to treat PCO-syndrome. The anti-inflammatory effect
      is seen as positive. This explains why women suffering from PCO-syndrome without
      insulin-glucose balance problems react positively to treatment with metformin.

      The aim of this study is to perform a prospective randomized test comparing PROfertil ®
      female to supplementation with folic acid alone for female patients suffering from
      PCO-syndrome and infertility. Supplementation with folic acid is the current state of the art
      in micronutrient supplementation of infertile women.

      Study aims The primary aim of this study is to analyse the effects of three months of
      treatment with PROfertil ® female compared to a supplementation with 400µg of folic acid for
      women suffering from PCO-syndrome, sterility, anovulation. The study will examine the
      parameters typical for PCO-syndrome (anti-müllerian hormone, total testosterone,
      androstenedione).

      The secondary goal is to document the individual course of further fertility treatment.

      The products being administered to the patients for four weeks are:

        -  PROfertil ® female (Lenus Pharma Gesellschaft mit beschränkter Haftung [GesmbH],
           Seeböckgasse 59, 1160 Vienna; treatment group) - one soft capsule (500mg Omega-3-fatty
           acids) and one pill (folic acid: 800µg, selenium 70µg, vitamin E 30mg, catechine: 4mg,
           glycyrrhizin 12mg, and coenzyme Q10: 30mg) per day.

        -  200µg folic acid (folic acid capsules 400µg ®, OTC Produktion und Forschung GesmbH,
           Fischergasse 17, 5020 Salzburg; control group) - two capsules per day.

      The study will be performed in a double-blinded manner. The medications are unlabeled for
      both groups and will be dispensed in unlabeled blisters. However, patients could search for
      the actual look of the PROfertil ® female soft capsules and the pills (for example on the
      internet). Since they differ from the folic acid capsules, patients could identify the
      control medications. The study team is aware of the fact that this kind of blinding is not
      according to standards and could introduce some kind of bias.

      Study hypotheses:

      First hypothesis: A three-month treatment with PROfertil ® female causes a drop of
      anti-müllerian hormone, total testosterone and androstenedione levels. This does not happen
      if treated with 400µg folic acid.

      Outcome parameters:

      Primary outcome parameters: anti-müllerian hormone (AMH), total testosterone and
      androstenedione levels

      Study design:

      Monocentric, prospective randomized double-blinded trial

      Recruitment:

      The participants are recruited by medical professionals at the Department of Obstetrics and
      Gynecology of the Medical University of Vienna using the above mentioned criteria during
      routine examinations before any treatment for PCO-syndrome and/or sterility is initiated.
      Potential participants are informed about the procedure, clinical relevance and possible
      additional effort caused by study participation. The patients willing to participate then
      have to sign the written informed consent.

      Sample size calculation:

      Assuming a reduction of the mean AMH levels by 2 ng/ml at a standard deviation of 3 ng/ml and
      an alpha value of 0.05 and a power of 0.90, the paired t-test requires 26 patients per group.
      Due to the fact that the participants wish to conceive a child and have been diagnosed with
      sterility, a low drop-out rate can be expected. There is no reliable data on this or similar
      treatments that allow prediction of the chance to conceive. Due to the favourable
      benefit-to-risk profile, a 15% drop-out rate is assumed. This corresponds to 4 patients per
      group. Thus, the final sample size is calculated as 30 patients per group, which leads to a
      total study population of 60.

      Statistical analysis:

      The bio-statistician will randomise the data using nQuery advisorTM Version 7.0. The
      information will then be packaged in an envelope by a person independent of the participating
      medical professionals and other scientific personnel. This will only be opened after the
      inclusion of the patient. Categorical variables will be presented as absolute numbers and
      percentages, numerical variables as median and interquartile range.

      The following statistical analyses are planned: The result parameters and the patient
      characteristics of the two groups will be compared using the Welch test (for numerical
      variables) and the Chi-square-test or Fisher's exact test (for categorical variables). A
      p-value of <0.05 is considered to be statistically significant. The statistical analyses will
      be performed using SPSS 24.0 for Windows (SPSS Inc, 1989-2017).

      Further details on study design:

      After recruiting the participants at the outpatient clinics for Gynecologic Endocrinology and
      Infertility Treatment, they are randomly assigned to one of the groups.

      Participants will receive either 2 unlabelled soft capsules containing 200µg folic acid each
      or 1 unlabelled soft capsule containing omega-3 fatty acids and 1 tablet containing folic
      acid, selenium, vitamin E, catechins, glycyrrhizin, and co-enzyme Q10 (see Table above for
      details on doses).

      The planned examination of AMH, total testosterone and androstenedione levels will take place
      after a minimum of 90 days (and a maximum of 100 days) after beginning supplementation with
      PROfertil ® female or folic acid. The maximum duration of participation is thus 100 days.
      After taking the micronutrient supplementation (PROfertil ® female or folic acid) beyond the
      planned minimum treatment duration, an individualised fertility treatment can be performed.

      There are two study-specific consultations: After including the patient (consultation 1:
      randomisation, distribution of drugs and start of study) and after 90 to 100 days
      (consultation 2). During consultation 2, unused study blisters are collected and patients are
      questioned on peculiarities and possible side effects of the micronutrient supplementation
      used.

      It is expected that 30 minutes for consultation 1 and 15 minutes for consultation 2 will have
      to be spent by the patient. The consultations will be held during regular outpatient
      treatments and will be part of the planned routine examinations. They include discussions of
      examination results and recommendations for further treatment.

      Benefits-to-risk assessment and preventive measures:

      Risks or complications due to the use of PROfertil ® female and additional venepuncture are
      not expected. A recent study using the same product showed no substance-related side effects
      (number of the ethics committee of the Medical University of: 1659/2013; accepted on
      2013-09-24) (9). A direct benefit for the treatment group is possible. A positive effect on
      PCO syndrome can be assumed, which might result in a higher chance of pregnancy. The
      substance administered to the control group is state of the art for female fertility
      treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: The medications are unlabeled for both groups and will be dispensed in unlabeled blisteres. However, patients could search for the actual look of the PROfertil ® female soft capsules and the pills (for example on the internet). Since they differ from the folic acid capsules, patients could identify the control medications. We are aware of the fact that this kind of blinding is not according to standards and could introduce some kind of bias.
measure: Anti-Mullerian Hormone (AMH)
time frame: Change from pre-treatment, baseline serum level to serum level at 3 months of treatment.
description: Change in serum AMH level
measure: testosterone
time frame: Change from pre-treatment, baseline serum level to serum level at 3 months of treatment.
description: Change in serum testosterone level
measure: androstenedione
time frame: Change from pre-treatment, baseline serum level to serum level at 3 months of treatment.
description: Change in serum androstenedione level
arm group label: Study group
arm group type: Experimental
description: 1 soft capsule/day containing 500mg omega-3 fatty acids
one tablet/day containing 800mg folic acid, 70mg selenium, 30 mg Vitamin E, 4 mg catechin, 12 mg glycyrrhizin, and 30 mg coenzyme Q10
arm group label: Control group
arm group type: Placebo Comparator
description: 200µg folic acid - two capsules per day
intervention type: Dietary Supplement
intervention name: Profertil female
description: For micronutrient ingredients please see details above. PROfertil ® female is approved in Austria by the Austrian Ministry of Health and has a "Free Sales Certificate".
arm group label: Study group
intervention type: Dietary Supplement
intervention name: Folic acid 400 mg
description: Folic acid 400 mg
arm group label: Control group
criteria: 
gender: Female
minimum age: 19 Years
maximum age: 35 Years
healthy volunteers: No
facility: 
country: Austria
responsible party type: Principal Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Johannes Ott
investigator title: Assoc.-Prof. Priv.-Doz. Dr.
mesh term: Polycystic Ovary Syndrome
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Syndrome
mesh term: Folic Acid
sharing ipd: No
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