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Spontaneous Reproductive Outcomes After Oral Inositol Supplementation in Infertile Polycystic Ovarian Syndrome Women. (IROP-1)

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ClinicalTrials.gov Identifier: NCT03598374
Recruitment Status : Not yet recruiting
First Posted : July 25, 2018
Last Update Posted : July 25, 2018
Sponsor:
Collaborator:
Universita di Verona
Information provided by (Responsible Party):
Antonio Simone Laganà, Università degli Studi dell'Insubria

Brief Summary:

Polycystic ovarian syndrome (PCOS) is a heterogeneous, multifaceted and complex disorder characterized by insulin resistance (IR), hyperinsulinemia, and hyperandrogenism leading ovarian disfunction and infertility. Given the central pathogenic role of IR in the endocrine, reproductive, and metabolic disturbances of PCOS, several pharmacological and non-pharmacological approaches have been proposed to counteract the hyper insulinemic IR typical of the syndrome. Two Inositol stereoisomers, Myo-Inositol (MI) and D-chiro-inositol (DCI), captured the attention of researchers for their insulin-sensitizing actions, which configure them as proper candidates for the treatment of PCOS.

Very few studies reported on spontaneous clinical pregnancy rates, none were powered for this outcome, and none reported on the clinically relevant outcome of live birth. Therefore, data about clinical pregnancy rate, live birth rate, and miscarriage rate comparing inositols with placebo are limited.

Conversely, about infertility and assisted reproduction techniques (ART), improvements have been reported in PCOS women who underwent fertility treatment using inositol in different forms, combinations or doses. This data, considering the different tissue-specific ratios (i.e., 100:1 in the ovary) and the different physiological roles of inositol stereoisomers, suggest that DCI supplementation alone might not be the optimal or appropriate approach for improving IVF outcomes in PCOS patients, and drawn attention to the importance of MI and DCI supplementation in a physiological ratio in order to restore normal ovary functionality. Indeed, the combination of MI and DCI, at a more physiological ratio of 40:1, was able to more quickly restore to normal the hormonal and metabolic parameters in PCOS women than MI treatment alone or DCI treatment alone, improving the endocrine profile and IR of women with PCOS.

Nevertheless, regarding infertility the primary outcomes that should be considered are clinical pregnancy rate, miscarriage rate and live birth rate. Although many studies showed improved hormonal and metabolic profile and improved ovulation rate and higher quality and number of oocyte retrieved in ART in PCOS women after inositols administration, data about clinical pregnancy rate, live birth rate, and miscarriage rate are limited with several concerns regarding interpretation of the studies.


Condition or disease Intervention/treatment Phase
Polycystic Ovarian Syndrome Infertility, Female Dietary Supplement: Inositol + Folic acid Dietary Supplement: Folic acid Behavioral: Regular intercourses Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized multi centre double-blind controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The patients, care provides, investigators and outcome assessors are blinded for the treatment: Inositol + Folic acid versus Folic acid alone. The treatment allocation is identified by code number before the study start, and will be revealed only after data analysis.
Primary Purpose: Treatment
Official Title: Effects of Oral Inositol Supplementation on Spontaneous Reproductive Outcomes in Infertile Polycystic Ovarian Syndrome Women.
Estimated Study Start Date : January 1, 2019
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: Inositol + Folic acid

Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Inositol (Myo-inositol and D-chiro-inositol at 40:1 ratio) plus Folic acid for 6 months.

Couples are required to have regular intercourse with the aim to achieve a spontaneous conception.

Dietary Supplement: Inositol + Folic acid

Daily oral supplementation of for 6 months or until pregnancy conception:

Myo-Inositol: 1100 mg D-chiro-inositol: 27.6 mg Folic acid: 400 mcg


Behavioral: Regular intercourses
Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.

Placebo Comparator: Folic acid

Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Folic acid for 6 months.

Couples are required to have regular intercourse with the aim to achieve a spontaneous conception.

Dietary Supplement: Folic acid

Daily oral supplementation of for 6 months:

Folic acid: 400 mcg


Behavioral: Regular intercourses
Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.




Primary Outcome Measures :
  1. Clinical pregnancy rate [ Time Frame: Within 6 months from the enrollment ]
    Number of spontaneous pregnancies conceived per women diagnosed by transvaginal ultrasound. Diagnosis is based on the identification of intrauterine gestational sac with embryo and/or yolk sac.

  2. Miscarriage rate [ Time Frame: Within 6 months from the enrollment ]
    Number of spontaneous abortion per women diagnosed by positive pregnancy test with subsequent spontaneous interruption of the pregnancy.

  3. Live birth rate [ Time Frame: Within 18 months from the enrollment ]
    Number of spontaneous pregnancies per women resulted in a delivered viable fetus.

  4. Spontaneous ovulation rate [ Time Frame: Change in spontaneous ovulation rate, through study completion (an average of 18 months) ]
    Spontaneous ovulation activity evaluated by menstrual cycle regularization. Menstrual cycles evaluated by intervals between menstruations (days), day of menstrual blood flow. Rate evaluate considering the number of women with restored regular menstrual cycles per women with irregular menstrual cycles.


Secondary Outcome Measures :
  1. Glucose metabolism [ Time Frame: Change in glucose metabolism, through study completion (an average of 18 months) ]
    OGTT: values of oral glucose tolerance test. Impaired glucose metabolism is diagnosed if fasting glucose values were abnormal (100-125 mg/dl) or glucose tolerance is impaired (2 h plasma glucose within OGTT range of 140-199 mg/dl), and when glucose values exceed threshold values for gestational diabetes (fasting glu- cose value ≥92mg/dl, 1‐hour glucose value ≥180mg/dl or 2- hour glucose value ≥153mg/dl)

  2. BMI [ Time Frame: Change in BMI, through study completion (an average of 18 months) ]
    Body mass index

  3. Lipid metabolism [ Time Frame: Change in Lipid metabolism, through study completion (an average of 18 months) ]
    Lipid profile assessed by evaluation the high density lipoprotein level and triglycerides level.

  4. Blood pressure [ Time Frame: Change in Blood pressure, through study completion (an average of 18 months) ]
    systolic and diastolic blood pressure

  5. Androgens profile [ Time Frame: Change in Androgens profile, through study completion (an average of 18 months) ]
    Serum free testosterone, dehydroepiandrosterone sulfate, and serum SHBG serum concentrations.



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Women with PCOS diagnosed by Rotterdam criteria in couple that desire to conceive.

Exclusion Criteria:

  • Male infertility factor that require in vitro fertilization technique.
  • Women with infertility factors that require in vitro fertilization technique.
  • Couple with infertility factors that require in vitro fertilization technique.
  • Diabetes mellitus that require insulin or oral drugs treatment.
  • Any other pre-pregnancy or pregnancy-induced/related disease.
  • Any other pharmacological, non-pharmacological or nutraceutical treatment (beside oral folic acid supplementation) more than 3 months before the enrollment (wash-out period) or during the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03598374


Contacts
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Contact: Antonio Simone Laganà, M.D. ‭+39 329 6279579‬ antoniosimone.lagana@asst-settelaghi.it
Contact: Simone Garzon, M.D. ‭+39 347 0782287‬ simone.garzon@univr.it

Sponsors and Collaborators
Università degli Studi dell'Insubria
Universita di Verona
Investigators
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Principal Investigator: Antonio Simone Laganà, M.D. Università degli Studi dell'Insubria
Principal Investigator: Simone Garzon, M.D. Universita di Verona
Study Chair: Fabio Ghezzi, M.D. Università degli Studi dell'Insubria
Study Chair: Massimo Franchi, M.D. Universita di Verona

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Responsible Party: Antonio Simone Laganà, Principal Investigator, Università degli Studi dell'Insubria
ClinicalTrials.gov Identifier: NCT03598374     History of Changes
Other Study ID Numbers: IROP-1
First Posted: July 25, 2018    Key Record Dates
Last Update Posted: July 25, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Keywords provided by Antonio Simone Laganà, Università degli Studi dell'Insubria:
Inositol
Polycystic ovarian syndrome
Fertility
Clinical pregnancy rate
Miscarriage rate
Live birth rate

Additional relevant MeSH terms:
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Inositol
Syndrome
Infertility
Polycystic Ovary Syndrome
Infertility, Female
Disease
Pathologic Processes
Genital Diseases, Male
Genital Diseases, Female
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Folic Acid
Vitamin B Complex
Hematinics
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs