Effects of Triple Drug Cocktail Therapy on Metabolic, Endocrine Alterations and Perceived Stress in Patients With Poly Cystic Ovary Syndrome

Study Overview
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Brief Summary
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The investigators aim is to conduct a double blind randomized clinical trial, to study the effects of triple drug cocktail (metformin, pioglitazone and acetyl L-Carnitine) therapy on metabolic, endocrine alterations and perceived stress response in patients with Polycystic Ovary Syndrome (PCOS). Women diagnosed with PCOS, using criteria proposed in November 2015, by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), and Androgen Excess and PCOS Society (AES) for PCOS should include two of the following three criteria: chronic an ovulation, hyperandrogenism (clinical/biologic), and polycystic ovaries. The investigators propose that PCOS women may have altered metabolic, endocrine levels and increased perceived stress response and combination therapy may have beneficial influences on these parameters in women diagnosed with PCOS.

Detailed Description
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Polycystic Ovarian Syndrome (PCOS) is an endocrinopathy which affects 5-10% of reproductive age women (1). The three main features of the syndrome are polycystic ovaries, high levels of androgen in blood and chronic an-ovulation/oligo-an ovulation (2). Women with PCOS have a greater risk of developing hyperinsulinemia and insulin resistance (3). PCOS may lead to insulin resistance and dyslipidemia (3). Recent long-term follow up studies of the syndrome have shown that women suffering from the syndrome have hyperlipidemia and enhanced risk of cardiovascular diseases (3). Recent evidence has demonstrated that anti-inflammatory drug treatments ameliorate insulin resistance. Metformin belongs to a family of drugs called the biguanides, currently used as an antihyperglycemic drug for treatment of type II diabetes mellitus (4). Around 15 years ago it was reported for the first time that use of metformin in PCOS effectively reduced insulin resistance (4). Increasing evidence has shown the importance of metformin not only in hyperinsulinemic patients but also in PCOS resolving several other issues like menstrual cycles, fertility, hormonal imbalance and metabolic syndromes (4). Pioglitazone is a drug from class thiazolidinedione (TZD) with hypoglycemic (anti-hyperglycemic, anti-diabetic) action in the management of type 2 diabetes (5). Recent studies have shown that pioglitazone may be considered a new treatment option for patients with PCOS, since it is able to restore normal menstrual cycle and have improved ovulation (6). Recent randomized placebo controlled clinical trials have also shown that it is associated with good serum lipid profile levels (7). Acetyl L-Carnitine is an isomer synthesized by two amino acids lysine and methionin mainly distributed among skeletal and cardiac muscles in mammals (8, 9). Acetyl L-Carnitine is involved in fatty acid oxidation by transporting long chain fatty acids into mitochondria for oxidation to produce metabolic energy and have effects on oxidative metabolism of glucose in tissues (9). Acetyl L-Carnitine is known to regulate energy production (10). Studies have shown that patients treated with acetyl L-Carnitine have improved ovulation and pregnancy rates and is well tolerated by the patients (8). PCOS patients have shown reduced adiponectin levels associated with insulin resistance states and type 2 diabetes mellitus and treatment with L-Carnitine has shown reduced blood glucose levels, increased insulin sensitivity and also improved adiponectin levels, which can be attributed to L-carnitine-induced increase in beta-oxidation of fatty acids and basal metabolic rates (11). PCOS is a systemic condition, an endocrinopathy whose etiology is still not understood. Correct treatment regimens of PCOS will not only improve menstrual cycles of the patients but will also improve the metabolic or endocrine parameters (2). PCOS sufferers are also known to have increased perceived stress response which will be considered in the study. Little evidences are available on combination therapy for treatment of PCOS patients. The aim of this study is to come up with a better treatment option to ameliorate the signs and symptoms associated with the disease. Study objectives: To find the effects of triple drug cocktail therapy (metformin, pioglitazone and acetyl L-Carnitine) on metabolic, endocrine alterations and perceived stress response in patients with PCOS.

Official Title
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Effects of Triple Drug Cocktail Therapy on Metabolic, Endocrine Alterations and Perceived Stress Response in Patients With PCOS: A Double Blind Randomized Clinical Trial

Conditions
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PCOS

Intervention / Treatment
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* Drug: Metformin (1000 mg daily), Pioglitazone (30 mg daily), Acetyl-L-carnitine (3 gm daily)
* Drug: Metformin, pioglitazone and placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment naive PCOS women having age from 14-45 years with scanty or no menstruation, hirsutism and elevated serum androgen levels, will be diagnosed on the basis of AES (Androgen access society) guidelines 2006 according to which when two of the following criteria are present patient will be said to have the syndrome Hirsutism or hyperandrogenism Oligo or an-ovulation and or polycystic ovaries - Exclusion Criteria: Women with previous history of Cushing syndrome Thyroid disorders Hyperprolactinemia Ovarian tumors Congenital adrenal hyperplasia androgen-producing tumors, History of seizures Patients on warfarin, Coumadin and Sintrom because of drug interaction with acetyl-L-Carnitine, Pregnancy or using contraceptive medications, Patients on hormonal therapy that alters the biochemical or hormonal profile

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination therapy group<br>Arm 1: Metformin (1000 mg daily), Pioglitazone (30 mg daily), Acetyl-L-carnitine (3 gm daily) | Drug: Metformin (1000 mg daily), Pioglitazone (30 mg daily), Acetyl-L-carnitine (3 gm daily)<br>* 72 patients with PCOS receiving metformin, pioglitazone and Acetyl L-Carnitine 500 mg, 15 mg and 1.5 gm BD daily respectively.<br>* Other names: Zolid plus and Acetyl-L-carnitine;|
| Placebo Comparator: Standard therapy group<br>Arm 2: Metformin (1000 mg daily), Pioglitazone (30 mg daily), Placebo | Drug: Metformin, pioglitazone and placebo<br>* 72 patients with PCOS receiving metformin, pioglitazone and placebo 500 mg, 15 mg and placebo BD daily respectively.<br>* Other names: Zolid plus and placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin resistance | PCOS associated insulin resistance and hyperinsulinemia through HOMA-IR | 3 months | 
| Hypoadiponectinemia | PCOS associated Hypoadiponectinemia. Measurement of adiponectin level through ELISA | 3 months | 
| Ovary volume | Polycystic ovaries volume measurement by abdominal ultrasound | 3 months | 
| Stress response | Perceived stress response and profile of mood stress by structured questionnaire | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body fat analysis | Body fats measurement through measurement scale | 3 months | 
| Hirsutism | Hirsutism score | 3 months | 
| Menstrual irregularities | Oligo/anovulation | 3 months | 
| Androgenic Alopecia | Hair on head area | 3 months | 
| Pregnancy | Fertility/infertility | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCOS, Acetyl-L-Carnitine