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Metformin vs Inositol vs Diet vs Combination Therapy in PCOS (PCOS-COMBO (9))

I

Islamabad Medical and Dental College

Status

Completed

Conditions

Insulin Resistance
Polycystic Ovary Syndrome
Metabolic Syndrome

Treatments

Behavioral: Dietary Restriction
Dietary Supplement: Myo-Inositol
Combination Product: Metformin + Myo-inositol + Dietary Restriction
Drug: Metformin Hydrochloride

Study type

Interventional

Funder types

Other

Identifiers

NCT07380841
PCOS-MIDCOMBO-12W-2025
F-1/2015/ERB/SZABMU/1449) (Other Identifier)

Details and patient eligibility

About

Polycystic ovary syndrome (PCOS) is a common condition that can cause irregular periods, excess male-type hormones, weight gain, and insulin resistance. This study will compare four commonly used approaches for PCOS management: metformin, inositol, a calorie-restricted diet, and a combination of all three.

A total of 192 women aged 18-35 years with PCOS (diagnosed using Rotterdam criteria) will be randomly assigned to one of four groups for 12 weeks: (A) metformin, (B) myo-inositol plus D-chiro-inositol, (C) calorie-restricted diet, or (D) combination therapy (metformin + inositol + diet). The study will assess changes in body weight, body mass index (BMI), waist circumference, fasting glucose, fasting insulin, insulin resistance (HOMA-IR), and menstrual regularity. Hormonal measures and safety outcomes will also be evaluated. The goal is to determine which approach provides the greatest overall metabolic and reproductive benefit in women with PCOS.

Full description

This is a 12-week, prospective, randomized, parallel-group controlled clinical trial conducted at an academic tertiary-care center in Islamabad, Pakistan (July-October 2025). The trial compares the independent and combined effects of metformin, inositol, and calorie restriction on metabolic, anthropometric, hormonal, and reproductive outcomes in women with polycystic ovary syndrome (PCOS).

Participants A total of 192 reproductive-aged women (18-35 years) with PCOS diagnosed by Rotterdam criteria (≥2 of: oligo/anovulation, clinical/biochemical hyperandrogenism, polycystic ovarian morphology on ultrasound) will be enrolled. Key exclusions include thyroid dysfunction, hyperprolactinemia, congenital adrenal hyperplasia, Cushing syndrome, hepatic/renal impairment, pregnancy or lactation, and use of hormonal therapy or insulin-sensitizing agents within the preceding 3 months.

Randomization and masking Participants will be randomized in a 1:1:1:1 allocation (n=48 per group) using a computer-generated sequence, with allocation concealment using sequentially numbered, opaque, sealed envelopes. Due to the nature of interventions, participant blinding is not feasible; however, laboratory personnel and data analysts will remain blinded to group assignment.

Interventions (12 weeks) Group A (Metformin): metformin 1500-2000 mg/day orally, titrated according to gastrointestinal tolerance.

Group B (Inositol): myo-inositol 2 g plus D-chiro-inositol 50 mg, taken twice daily.

Group C (Calorie-restricted diet): individualized dietary counseling targeting 1200-1500 kcal/day with emphasis on low-glycemic carbohydrates, lean protein, and high-fiber foods.

Group D (Combination): metformin + inositol + calorie-restricted diet as above. Participants will be followed every two weeks for adherence assessment and adverse event monitoring. Medication adherence will be assessed by pill counts. Dietary adherence will be assessed using weekly dietary logs and summarized as percent compliance with prescribed caloric intake.

Outcomes

Primary outcomes assessed at baseline and 12 weeks include:

Anthropometric measures: weight, BMI, waist circumference; Metabolic measures: fasting glucose, fasting insulin, and insulin resistance (HOMA-IR; calculated as [fasting insulin × fasting glucose]/405); Menstrual regularity, defined as cycle length 21-35 days during the final four weeks of the intervention.

Secondary outcomes include serum total testosterone, LH, FSH, LH/FSH ratio, Ferriman-Gallwey score, adherence, and adverse events. Fasting blood samples will be collected and hormonal assays performed using standardized chemiluminescence immunoassay platforms.

Statistical approach Normality will be assessed using Shapiro-Wilk tests. Continuous variables will be summarized as mean ± SD. Within-group changes will be analyzed using paired t-tests. Between-group comparisons will use one-way ANOVA with Tukey HSD post-hoc testing. Effect sizes will be reported as partial eta-squared (η²). Categorical outcomes (e.g., menstrual regularity) will be compared using chi-square tests. Statistical significance will be defined as p < 0.05. Analyses will follow CONSORT reporting principle

Enrollment

192 patients

Sex

Female

Ages

18 to 40 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:Females aged 18 to 40 years. Diagnosed with polycystic ovary syndrome (PCOS) based on Rotterdam criteria (at least two of the following: oligo/anovulation, hyperandrogenism, polycystic ovaries on ultrasound).

Body mass index (BMI) ≥ 18.5 kg/m². Willing to participate and provide written informed consent. Willing to comply with study procedures and follow-up visits.

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Exclusion Criteria:

Pregnancy or lactation. Known diabetes mellitus, thyroid disease, hyperprolactinemia, Cushing's syndrome, or other endocrine disorders.

Use of metformin, inositol, hormonal therapy, or weight-loss drugs within the last 3 months.

History of renal, hepatic, or cardiovascular disease. Known hypersensitivity to metformin or inositol. Participation in another clinical trial within the last 3 months. Any serious medical or psychiatric condition that, in the investigator's opinion, would interfere with study participation.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

192 participants in 4 patient groups

Metformin Group
Experimental group
Description:
Participants will receive metformin hydrochloride tablets, 500 mg orally twice daily (total daily dose 1000 mg) after meals for 12 weeks. This arm evaluates the effect of metformin monotherapy on metabolic, hormonal, and clinical outcomes in women with polycystic ovary syndrome (PCOS).
Treatment:
Drug: Metformin Hydrochloride
Inositol Group
Experimental group
Description:
Participants will receive myo-inositol powder/sachets, 2 g orally twice daily (total daily dose 4 g) for 12 weeks. This arm evaluates the effect of inositol monotherapy on insulin resistance, hormonal profile, and clinical features of PCOS.
Treatment:
Dietary Supplement: Myo-Inositol
Dietary Restriction Group
Experimental group
Description:
Participants will follow a structured calorie-restricted diet (approximately 1200-1500 kcal/day, individualized according to baseline BMI), designed and supervised by the study team, for 12 weeks. No pharmacological treatment will be given. This arm evaluates the effect of dietary intervention alone on anthropometric, metabolic, and reproductive outcomes in PCOS.
Treatment:
Behavioral: Dietary Restriction
Combination Therapy Group
Experimental group
Description:
Participants will receive metformin hydrochloride tablets 500 mg orally twice daily plus myo-inositol 2 g orally twice daily, along with the same structured calorie-restricted diet (1200-1500 kcal/day) for 12 weeks. This arm evaluates the combined effect of pharmacological and lifestyle intervention on metabolic, hormonal, and clinical outcomes in PCOS.
Treatment:
Combination Product: Metformin + Myo-inositol + Dietary Restriction

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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