search
Back to results

The Effects of Acetyl L--Carnitine and Myo/Chiro-Inositol on Improving Ovulation, Pregnancy Rate, Ovarian Function and Perceived Stress Response in Patients With PCOS (PCOS)

Primary Purpose

Infertility, Female, PCOS (Polycystic Ovary Syndrome) of Bilateral Ovaries

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
metformin
Sponsored by
Khyber Medical University Peshawar
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Infertility, Female focused on measuring PCOS, INFERTILTY

Eligibility Criteria

18 Years - 35 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:Married women with PCOS aged ≥18 years to ≤35 years who is infertile (primary and secondary) and have a wish to conceive will be included in the study. The diagnosis of PCOS will be made according to the NIH 2012 extension of ESHRE/ASRM 2003 criteria (21). Identification of specific phenotypes will be included: A. Hyperandrogenism plus Ovulatory dysfunction plus Polycystic Ovarian Morphology (HA +OD+PCOM) B. Hyperandrogenism plus Ovulatory dysfunction (HA+OD) C. Hyperandrogenism plus Poly Cystic Ovarian Morphology (HA+PCOM). D. Ovulatory dysfunction plus Polycystic Ovarian Morphology (OD+PCO) Couple inclusion criteria; Being a sterility trial couples ensuing to do their semen analysis regularly or provide record showing their sperm concentration to be at least 15 million /ml in at least one ejaculation during the past one year with some motile sperm. Similarly, couples having ability and readiness to perform sexual intercourse as and when directed by the investigator will be included. Female subjects should have at least one open fallopian tube and normal uterus from inside on hysterosalpingography /hysteroscopy/laparoscopy or have normal course of conception, delivery during the past 03 years. Patients should have no history of tubal ligation or vasectomy procedure that has been reversed Exclusion Criteria: Females having history of having an infertile male partner in the past, Cushing syndrome, diabetes, thyroid disorders, hyperprolactinemia, ovarian tumors, congenital adrenal hyperplasia, androgen-producing tumors, history of seizures, pregnancy undiagnosed vaginal bleeding History of suspected cervical or endometrial carcinoma breast carcinoma using contraceptive anti-coagulants, antiplatelet, isoproterenol and potassium sparing diuretics, anti-depressants and medications that alters the biochemical or hormonal profile will be excluded. Participants who have been prescribed hormones during the past at least 3 months before the study will not be included in the study. Patient who is willing to participate in the study is using any medicine that can be discontinued (e.g., oral contraceptive or ovulation induction agents (GnRH agonist and antagonist; gonadotropins, HCG) will be allowed wash out period of 02 months before being included in the study. -

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Active Comparator

    Experimental

    Experimental

    Experimental

    Arm Label

    Metformin Group

    Inositol isomers Group

    Acetyl-L- Carnitine Group

    Combine Group

    Arm Description

    Metformin will be used in dose of 500mg BD daily for 30 infertile female PCOS patients

    Inositols isomers (Myo inositol and D- Chiro Inositol in its physiological ratio) will be used 2000mg BD Daily for 30 infertile female PCOS patients

    Acetyl-L-Carnitine will be given in dose of 1000mgBD Daily for 30 infertile female PCOS patients

    Inositol isomers and Acetyl-L-Carnitine will be given in dose of 2000mg and 1000mg respectively BD daily for 30 infertile female PCOS patients

    Outcomes

    Primary Outcome Measures

    CLINICAL PREGNANCY
    intrauterine pregnancy with positive fetal heart motion as determined on transvaginal ultrasound or HCG level is more than 1500IU/L

    Secondary Outcome Measures

    OVULATION
    will be defined as serum Progesterone ( ≥3ng/ml or 9.54nmol/l) r on u/s examination
    Conception
    positive serum level of HCG
    Biochemical Pregnancy
    Falling B-HCG concentration on serial determination
    tetosterone levels
    clinically on mFG , Biochemically on FAI

    Full Information

    First Posted
    March 2, 2023
    Last Updated
    March 2, 2023
    Sponsor
    Khyber Medical University Peshawar
    Collaborators
    University of Cagliari
    search

    1. Study Identification

    Unique Protocol Identification Number
    NCT05767515
    Brief Title
    The Effects of Acetyl L--Carnitine and Myo/Chiro-Inositol on Improving Ovulation, Pregnancy Rate, Ovarian Function and Perceived Stress Response in Patients With PCOS
    Acronym
    PCOS
    Official Title
    The Effects of Acetyl L--Carnitine and Myo/Chiro-Inositol on Improving Ovulation, Pregnancy Rate, Ovarian Function and Perceived Stress Response in Patients With PCOS
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    April 15, 2023 (Anticipated)
    Primary Completion Date
    October 25, 2023 (Anticipated)
    Study Completion Date
    October 30, 2023 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Khyber Medical University Peshawar
    Collaborators
    University of Cagliari

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The large number of women in their child bearing age is affected by Polycystic ovarian syndrome (PCOS) leading to infertility. However it is considered as a multisystem disorder with comorbidities rather than a gynecological and a dermatological problem. Patient mostly have anovulation presented as oligomennorhea or amenorrhea and hyperandrogenism presented as hirsutism along with hyperinsulinemia and insulin resistance. The presence of multiple cysts in the ovaries is not essential for diagnosis. Many etiological factors are reported but those actually responsible for PCOS in females still need to be explored. However hyperandrogenism and insulin resistance being the key triggering condition apart from cardiovascular disease, type 2 diabetes, hypertension and obesity. Nearly 100 million women are effected with this disease worldwide. World Health Organization (WHO) has considered Infertilty as public health problem. it was the objective of UN conference 2015 to provide access and quality reproductive health services to all individuals. About 50 to 80% women having PCOS are obese. Researchers reported the obesity role in occurrence of PCOS and its Infertilty relation . Poly cystic ovary syndrome is not a simple pathophysiologic process for which one treatment address all manifestation. Treatment should target specific manifestations and individualized patient goals. When choosing a treatment regimen, physicians must take into account comorbidities and the patient's desire for pregnancy. First-line agents for ovulation induction and treatment of infertility in patients with PCOS include metformin and clomiphene alone or in combination. It has been approved as category "A "to regulate ovulation and improves pregnancy rates in women with PCOS . Mostly it result in complication like multiple follicle recruitment rate, multiple pregnancy and thining of endometrial wall leading to early abortion and endometrial cancers.The use of naturally occurring compounds like myoinositol, D-chiro- inositol and L- carnitine which are already part of human body are expected to produce significant results without any side effects . The proposed study will provide an alternative to current treatments available for infertility due to PCOS. The expected project execution time is 1 years. Thus, the present project will discover new insights about treatment of infertilty and thus generate new knowledge which will help Academia, scientists and health care professionals. Moreover, the proposed project involves, "the formulation of new drugs" which can be patent and may benefit Pharmaceutical industry of Pakistan as well. Results of the study will be disseminated on different forums including to policy makers , Pharmaceutical, national and international agencies. The result will be published in journal both national and international with good impact factors. The outcome of the project will be used as publication in high impact international journals, filling of patents and will also be presented in national and international forums.
    Detailed Description
    Introduction A tremendously high number of women in their child bearing age is affected by Polycystic ovarian syndrome (PCOS) leading to infertility (1). PCOS is not a simple gynecological or dermatological problem but a multisystem disorder with comorbidities. Patients mostly have anovulation presented as oligomennorhea or amenorrhea and hyperandrogenism presented with symptoms of hirsutism along with hyperinsulinemia and insulin resistance. The presence of multiple cysts in the ovaries however, is not essential for diagnosis (2). Hyperandrogenism and insulin resistance being the key triggering condition apart from cardiovascular disease, type 2 diabetes, hypertension and obesity. PCOS and infertility involves genetic and environmental factors, however, in Pakistani the cultural background of intermarriages is contributing noticeably towards the multiplicity of disease (3). World Health Organization (WHO) has considered infertility as public health problem. It was the objective of UN conference 2015 to provide access and quality reproductive health services to all individuals. Management of PCOS require prolong use of pharmaceuticals which has serious effects sometimes even fatal, therefore the natural, easily available, cost effective nutraceuticals has tremendous effects and have now used safely in many clinical trials(4) The current study aims to provide evidence to support the use of neutraceuticals in the management of PCOS in infertile patients and their comparison with standard drug used in treatment of infertility caused by PCOS.. This study can help run a long way in achieving the millennium goals MDG(3) SGD(3) to which Pakistan is a signatory and to reduce maternal mortality and improve reproductive health of its female population The following agent is used as standard drug in an infertile women with PCOS in a clinical set-up Metformin a biguanide, used as first line drug for the treatment of diabetes and PCOS. It works by preventing hepatic gluconeogenesis and intestinal glucose absorption thus improving insulin sensitivity (5). In addition to its systemic effects on insulin signaling it effect autocrine/paracrine signaling in ovarian tissue thus improving ovarian steriodogensis and endometrial receptivity (6). In a recent study its role in infertile PCOS women was established resulting in significant number of ovulation and live birth than controls (7). Complementary and alternative medicine approach for the treatment of PCOS is becoming popular in recent years. It is claimed that dietary supplements and herbal remedies are safer than conventional drugs. Acetyl L-Carnitine : Carnitine a quaternary ammonium compound made in the body from lysine and methionine and is available in an active ( L) and an inactive (D ) form. L-carnitine is available in supplemental form and has significant role in enhancing metabolism, producing energy and protecting against oxidative stress. Role of carnitine in treating insulin resistance is being frequently discussed with reference to accrual of acyl-CoA derivatives (8). Hence as suggested if the normal levels of carnitine in the diabetics and obese patients is ensured the insulin insensitivity can be drastically improved. Further the level of L-carnitine in PCOS patients was found to be considerably less. Follicogensis is a highly energy dependent process on mitochondria. In PCOS the functioning of mitochondria is effected due to inflammation and other deregulations because of accumulation of testosterone and insulin in ovary. It help in transport of lipids from cytosol to mitochondria in breakdown of lipids for production of energy (9) Inositol; Inositols present in plants and animal a member of sugar alcohol comprising nine cyclohexane-1, 2, 3, 4, 5, 6-hexol stereoisomers. Being vitamin like it is made in human body as well as synthetically. It is a component of cell membrane and acts as a second messenger, has important role in release of different autacoids, hormones, and neurotransmitters (10).The promising role of two of its isomers namely Myo-inositol (MI) and D-chiro-inositol (DCI) in the treatment of PCOS has been documented. Studies have demonstrated that performance of MI to induce ovulation in patients with infertility due to PCOS can be improved if DCI is combined to it. Best results are achieved when the two isomers are used in 40:1 ratio which is the normal amount in which they exist in the body (11). Both MI and DCI can influence oxidative and non-oxidative metabolism. Apart from being involved in activation of multiple enzymes MI is involved in glucose transport and DCI in insulin production from B- cells and ATP production (12) DCI contributes in mediating insulin activity mainly on non-ovarian tissues, MI displays specific effects on ovary, chiefly by modulating glucose metabolism and FSH-signaling. Moreover, MI may also improve ovarian functions by modulating steroid metabolism through non-insulin-dependent pathways In PCOS patient due IR there is dysregulation in MI/DCI ratio in non- ovarian tissue related to reduced epimarse activity. However ovaries being insulin sensitive have lower level of MI than DCI due to increase epimerase activity (13). Rationale The incidence of PCOS is increasing throughout the world. It is much higher in Pakistani women (52%) than Caucasian women (20-25%) and is contributing towards both primary (50%) and secondary (25%) infertility (14). Infertilty has its sociocultural connotations resulting in emotional and mental stress. Infertilty due to PCOS should be treated with nutraceuticals for being natural, cost effective, easily available and with minimum side effects. The inositol isomers in its physiological ratio (40:1) and carnitine as an antioxidant has shown significant effects in regularization of metabolic and endocrine parameters of the body Rationale of the present study is that Inositol and Carnitine alone and in combination may be a better alternate for treatment of infertility in patients with PCOS, compared to Metformin. To the best of our knowledge no study till date is documented for synergistic effects of Acetyl-L Carnitine and inositol isomers when used, in physiological balanced ratio, for infertilty Objectives 1. To compare the effects of Inositol isomers and Acetyl-LCarnitine ( alone and in combination) with Metformin on improving ovulation, pregnancy rate, restoring ovarian function, metabolic balance and perceived stress response in patient with PCOS Hypothesis It is hypothesized that Inositol and Acetyl L-Carnitine alone may produce better or at least comparable results to Metformin in improving Pregnancy rate, ovulation, restoring ovarian function, metabolic balance and perceived stress response in infertile patients with PCOS. It is also hypothesized that the synergistic action of Inositol isomers and Acetyl L-Carnitine in combination may produce better or at least comparable results to Metformin in improving pregnancy rate, ovulation, restoring ovarian function, metabolic balance and perceived stress response in infertile patients with PCOS STUDY DESIGN: This will be a noncommercial randomized double blind clinical trial (RCT) in which subject and treatment provider will blinded to treatment intervention. In this study we will compare the treatment of naturally occurring nutraceuticals with Metformin (control group) which is used as first line drug in treatment of PCOS for infertile women. The nature of study will be explained in both Pashto and Urdu and informed consent will be taken SETTINHS: OPD patients in Gynecology and Obstetrics Department, Pakistan Institute of Medical Sciences, Islamabad (PIMS) and Bacha Khan Medical Complex, Swabi, (BKMC) KP DURATION: The study is expected to be completed in 1.year with duration for 6 months. SAMPLE SIZE: The study will include 120 patients with PCOS according to our inclusion of the NIH 2012 extension of ESHRE/ASRM 2003 criteria. .

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Infertility, Female, PCOS (Polycystic Ovary Syndrome) of Bilateral Ovaries
    Keywords
    PCOS, INFERTILTY

    7. Study Design

    Primary Purpose
    Supportive Care
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Model Description
    Treatment of PCOS with Myo/D-chiro Inositol and comparison with metformin
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    120 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Metformin Group
    Arm Type
    Active Comparator
    Arm Description
    Metformin will be used in dose of 500mg BD daily for 30 infertile female PCOS patients
    Arm Title
    Inositol isomers Group
    Arm Type
    Experimental
    Arm Description
    Inositols isomers (Myo inositol and D- Chiro Inositol in its physiological ratio) will be used 2000mg BD Daily for 30 infertile female PCOS patients
    Arm Title
    Acetyl-L- Carnitine Group
    Arm Type
    Experimental
    Arm Description
    Acetyl-L-Carnitine will be given in dose of 1000mgBD Daily for 30 infertile female PCOS patients
    Arm Title
    Combine Group
    Arm Type
    Experimental
    Arm Description
    Inositol isomers and Acetyl-L-Carnitine will be given in dose of 2000mg and 1000mg respectively BD daily for 30 infertile female PCOS patients
    Intervention Type
    Drug
    Intervention Name(s)
    metformin
    Other Intervention Name(s)
    myo inositol, D- chiro Inositol, Acetyl-L-Carnitine
    Intervention Description
    Treatment of infertile female with PCOS with inositol isomers and Acetyl-L-Carnitine
    Primary Outcome Measure Information:
    Title
    CLINICAL PREGNANCY
    Description
    intrauterine pregnancy with positive fetal heart motion as determined on transvaginal ultrasound or HCG level is more than 1500IU/L
    Time Frame
    6 MONTHS
    Secondary Outcome Measure Information:
    Title
    OVULATION
    Description
    will be defined as serum Progesterone ( ≥3ng/ml or 9.54nmol/l) r on u/s examination
    Time Frame
    6 MONTHS
    Title
    Conception
    Description
    positive serum level of HCG
    Time Frame
    6 Months
    Title
    Biochemical Pregnancy
    Description
    Falling B-HCG concentration on serial determination
    Time Frame
    6 months
    Title
    tetosterone levels
    Description
    clinically on mFG , Biochemically on FAI
    Time Frame
    6 MONTHS

    10. Eligibility

    Sex
    Female
    Gender Based
    Yes
    Gender Eligibility Description
    Infertilty
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    35 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria:Married women with PCOS aged ≥18 years to ≤35 years who is infertile (primary and secondary) and have a wish to conceive will be included in the study. The diagnosis of PCOS will be made according to the NIH 2012 extension of ESHRE/ASRM 2003 criteria (21). Identification of specific phenotypes will be included: A. Hyperandrogenism plus Ovulatory dysfunction plus Polycystic Ovarian Morphology (HA +OD+PCOM) B. Hyperandrogenism plus Ovulatory dysfunction (HA+OD) C. Hyperandrogenism plus Poly Cystic Ovarian Morphology (HA+PCOM). D. Ovulatory dysfunction plus Polycystic Ovarian Morphology (OD+PCO) Couple inclusion criteria; Being a sterility trial couples ensuing to do their semen analysis regularly or provide record showing their sperm concentration to be at least 15 million /ml in at least one ejaculation during the past one year with some motile sperm. Similarly, couples having ability and readiness to perform sexual intercourse as and when directed by the investigator will be included. Female subjects should have at least one open fallopian tube and normal uterus from inside on hysterosalpingography /hysteroscopy/laparoscopy or have normal course of conception, delivery during the past 03 years. Patients should have no history of tubal ligation or vasectomy procedure that has been reversed Exclusion Criteria: Females having history of having an infertile male partner in the past, Cushing syndrome, diabetes, thyroid disorders, hyperprolactinemia, ovarian tumors, congenital adrenal hyperplasia, androgen-producing tumors, history of seizures, pregnancy undiagnosed vaginal bleeding History of suspected cervical or endometrial carcinoma breast carcinoma using contraceptive anti-coagulants, antiplatelet, isoproterenol and potassium sparing diuretics, anti-depressants and medications that alters the biochemical or hormonal profile will be excluded. Participants who have been prescribed hormones during the past at least 3 months before the study will not be included in the study. Patient who is willing to participate in the study is using any medicine that can be discontinued (e.g., oral contraceptive or ovulation induction agents (GnRH agonist and antagonist; gonadotropins, HCG) will be allowed wash out period of 02 months before being included in the study. -
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Mohsin Shah, PhD
    Phone
    +9203429620074
    Email
    mohsin.ibms@kmu.edu.pk
    First Name & Middle Initial & Last Name or Official Title & Degree
    Meena Gul, M.PHIL
    Phone
    +9203145198024
    Email
    drmeenagul@hotmail.com

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    28938447
    Citation
    Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and Risk Factors of Type 2 Diabetes in a Nationwide Population of Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017 Oct 1;102(10):3848-3857. doi: 10.1210/jc.2017-01354.
    Results Reference
    background
    PubMed Identifier
    24322653
    Citation
    Orio F, Palomba S. Reproductive endocrinology: New guidelines for the diagnosis and treatment of PCOS. Nat Rev Endocrinol. 2014 Mar;10(3):130-2. doi: 10.1038/nrendo.2013.248. Epub 2013 Dec 10.
    Results Reference
    background
    PubMed Identifier
    25604364
    Citation
    Akram M, Roohi N. Endocrine correlates of polycystic ovary syndrome in Pakistani women. J Coll Physicians Surg Pak. 2015 Jan;25(1):22-6.
    Results Reference
    background
    PubMed Identifier
    23662276
    Citation
    Chauhan B, Kumar G, Kalam N, Ansari SH. Current concepts and prospects of herbal nutraceutical: A review. J Adv Pharm Technol Res. 2013 Jan;4(1):4-8. doi: 10.4103/2231-4040.107494.
    Results Reference
    background
    PubMed Identifier
    26743209
    Citation
    An H, He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol. 2016 Mar;228(3):R97-106. doi: 10.1530/JOE-15-0447. Epub 2016 Jan 7.
    Results Reference
    background
    PubMed Identifier
    12749437
    Citation
    Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. 2003 Apr;79(4):956-62. doi: 10.1016/s0015-0282(02)04925-7.
    Results Reference
    background
    PubMed Identifier
    29183107
    Citation
    Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017 Nov 29;11(11):CD003053. doi: 10.1002/14651858.CD003053.pub6.
    Results Reference
    background
    PubMed Identifier
    34047916
    Citation
    Tauqir S, Israr M, Rauf B, Malik MO, Habib SH, Shah FA, Usman M, Raza MA, Shah I, Badshah H, Ehtesham E, Shah M. Acetyl-L-Carnitine Ameliorates Metabolic and Endocrine Alterations in Women with PCOS: A Double-Blind Randomized Clinical Trial. Adv Ther. 2021 Jul;38(7):3842-3856. doi: 10.1007/s12325-021-01789-5. Epub 2021 May 28.
    Results Reference
    background
    PubMed Identifier
    31294953
    Citation
    Salehpour S, Nazari L, Hoseini S, Moghaddam PB, Gachkar L. Effects of L-carnitine on Polycystic Ovary Syndrome. JBRA Assist Reprod. 2019 Oct 14;23(4):392-395. doi: 10.5935/1518-0557.20190033.
    Results Reference
    background
    Citation
    10. Porcaro G, Bizzarri M, Monastra G, et al Strategies for the treatment of polycystic ovary syndrome (PCOS) women: the role of myoinositol (MI) and d-chiro-inositol (DCI) between diet and therapy. Nova science publishers. 2016 1-18
    Results Reference
    background
    Citation
    11. Facchinetti F, Dante G, Neri I. The ratio of MI to DCI and its impact in the treatment of polycystic ovary syndrome: experimental and literature evidences. Front Gynecol Endocrinol 2015;3:103-9.
    Results Reference
    background
    PubMed Identifier
    24189751
    Citation
    Heimark D, McAllister J, Larner J. Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocr J. 2014;61(2):111-7. doi: 10.1507/endocrj.ej13-0423. Epub 2013 Nov 2.
    Results Reference
    background
    PubMed Identifier
    30595691
    Citation
    Bevilacqua A, Bizzarri M. Inositols in Insulin Signaling and Glucose Metabolism. Int J Endocrinol. 2018 Nov 25;2018:1968450. doi: 10.1155/2018/1968450. eCollection 2018.
    Results Reference
    background

    Learn more about this trial

    The Effects of Acetyl L--Carnitine and Myo/Chiro-Inositol on Improving Ovulation, Pregnancy Rate, Ovarian Function and Perceived Stress Response in Patients With PCOS

    We'll reach out to this number within 24 hrs