Efficacy and safety of Curcuma longa either alone or in combination with metformin on glycemic status in prediabetes population: A Randomized, double-blinded, double-dummy, placebo-controlled, factorial design trial

The trial will be started after Postgraduate Research Monitoring Committee (PGRMC), the Institutional Ethics committee approval and CTRI registration. The study will be done in accordance with Indian Good Clinical Practice and ICMR ethical guidelines. After obtaining written informed consent, participants will be recruited at JIPMER through screening of high-risk populations, especially first-degree relatives of patients with type 2 diabetes mellitus as well as women with past history of gestational diabetes mellitus. The eligible participants will be randomized to receive any one of the following treatments using double dummy technique for a period of 6 months. • Group A: Tab. Curcuma longa 550 mg OD + Tab. Metformin 500 mg OD • Group B: Tab. Curcuma longa 550 mg OD + Tab. Placebo for Metformin OD • Group C: Tab. Metformin 500 mg OD + Tab. Placebo for Curcuma longa OD •   Group D: Tab. Placebo for Curcuma longa OD + Tab. Placebo for Metformin OD At baseline and at 12th weeks and 24th weeks of follow-up visits, 5 ml of blood sample will be collected using all aseptic precautions to assess HbA1c, fasting plasma glucose and postprandial blood glucose, serum insulin, liver and renal function test. Blood samples collected will be allowed to clot for 15-30 minutes and centrifuged at 2500 rpm for 10 minutes. About 1 ml of serum will be stored at -80 deg C and serum insulin level will be measured using chemiluminescence method. In all the three visits vascular function and exercise capacity will be assessed. The placebo formulations of Curcuma longa and metformin will be indistinguishable in terms of colour, size, shape with respect to the corresponding drugs. During the follow up visit those diagnosed with diabetes will be started on standard of care by the treating physicians and will not be followed up further. Periscope®, a non-invasive device (Genesis Medical Systems India) based on oscillometric principle will be used to measure arterial stiffness in supine position after 5 minutes of rest. Carotid femoral (aortic) pulse wave velocity, brachial ankle pulse wave velocity, right and left brachial arterial stiffness index, right and left arterial stiffness index, ankle brachial index, aortic systolic/diastolic pressure, aortic augmentation pressure and aortic augmentation index will be measured at baseline and at 12th weeks and 24th weeks. Exercise capacity of the patient will be assessed by Cardio Pulmonary Exercise Testing (CPET) machine (Quark CPET, Cosmed) at baseline and at 12th weeks and 24th weeks. It is a computer-controlled device whose role is to measure the levels of oxygen and carbon dioxide with the help of fast and selective breath analyzers. The detailed procedure of CPET will be explained to the patient and a demo will be shown to sensitize the patient to use the bicycle ergometer. Details like height, weight will be entered in the software and patient ID will be created. The CPET mode will be selected in the software and auto zero calibration is allowed to run for the breath analyzer. CPET is performed as symptom-limited bicycle ergometry in a sitting position. A continuously incrementing ramp protocol (increase of work rate, e.g., every 2–15 s) or minute-by-minute increments in 5–30 W/min steps to symptom-limited maximum of exercise is used as standard. CPET procedure is divided into 4 parts. Resting phase (2-3 min): Adaptation of respiration to the mask or mouthpiece including measurements of ECG (proper placement of leads is essential for a clean ECG signal) and blood pressure. Unloaded phase (“active baseline”; 2–3 min): Unloaded cycling with no added resistance (internal work rate depending on equipment: 0–15 watts) Incremental exercise phase (10 ± 2 min) Recovery phase (cool down period; 3–5 min): unloaded pedaling. The recordings are terminated and all leads and facial mask are disconnected from the patient. The primary parameters measured using flow sensor are oxygen uptake (VO2), carbon dioxide output (VCO2). Heart rate (HR). The facial mask will be disinfected before each test. The CPET will be repeated at 12th weeks and 24th weeks. HOMA-IR, QUICKI will be calculated using the formula after measuring the serum insulin levels. HOMA-IR = (FPI x FPG)/22.5 for insulin resistance QUICKI = 1/ (log FPI + log FPG) Adherence to drugs and adverse drugs reactions will be assessed from pill count, patient diary and by direct interactions during follow-up visits.