Investigate the Efficacy and Safety of Low-Glu in Patients Newly Diagnosed With Type II Diabetes Mellitus

Study Overview
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Brief Summary
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Ficus deltoidea leaves, Cinnamomum cassia and Black seed powdered extract have long been used for the treatment of type 2 diabetes mellitus.

Detailed Description
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Diabetes Mellitus (DM), commonly referred to as Diabetes is defined by World Health Organization (WHO) as a group of metabolic disorders characterized by chronic Hyperglycemia resulting from defects in insulin secretion, insulin action or both. Long-term organ damage, organ dysfunction and organ failure are associated with the chronic Hyperglycemia of Diabetes. Possible Diabetes complications can be classified into two major categories; macrovascular and microvascular including Ischemic Heart Disease (IHD), Peripheral Vascular Disease (PVD), and Cerebrovascular Disease (CVD) macrovascular, and Nephropathy, Retinopathy, and Neuropathy microvascular resulting in organ and tissue damage in almost one third to one half of population with diabetes. According to the International Diabetes Federation (IDF), the three main types of Diabetes are Type 1 Diabetes, Type 2 Diabetes and Gestational Diabetes. Type 1 DM, formerly described as Insulin Dependent Diabetes Mellitus (IDDM) results from β-cells destruction, usually leading to absolute deficiency of insulin. Type 2 DM formerly described as Non-Insulin-Dependent Diabetes Mellitus (NIDDM) results from a progressive insulin secretory defect on the background of insulin resistance. Gestational Diabetes, which appears during pregnancy, is associated with increasing the risk of developing type 2 Diabetes in both mother and child later in life. Diabetes is a rapidly growing health concern in both developed and developing nations and its prevalence is continuously increasing worldwide. Globally, in 2014, approximately 422 million adults were having diabetes, with type 2 making up about 91%of the cases. In 2015, according to IDF, an estimated 415 million adults were having diabetes along with an estimated 318 million adults with impaired glucose tolerance. Both WHO and IDF predict that by 2030, this number will be doubled. In 2016 the WHO global report on Diabetes stated that the prevalence of Diabetes has increased faster in low- and middle-income countries than in high-income countries. Type 2 Diabetes is characterized by insulin resistance and/or abnormal insulin secretion, either of which may predominate. It is associated with several metabolic defects such as obesity, hypertension, and dyslipidemia, which contribute to the very high rate of cardiovascular morbidity and mortality. Medicinal herbs were used to treat a wide range of diseases long time before the birth of conventional medicine systems. The World Health Organization (WHO) has listed 21,000 plant names, which are used for medicinal purposes around the world, so despite the fact that medicinal herbs are at times misconceived as being unscientific, their continual existence proves they are able to be alternatives or complementary to conventional drugs at some point. Specifically, Ficus deltoidea leaves, Cinnamomum cassia L. powdered Extract and Black seed powdered extract have been used for the treatment of Diabetes Mellitus and other medical conditions for over 2000 years. Ficus deltoidea is an evergreen shrub reaching to 2 meters of height, with whitish grey bark, broadly spoon-shaped to obovate leaves and spherical or round figs. Over the years, it has been used to treat many diseases such as; Diabetes Mellitus, Hypertension, Hyperlipidemia and Gout. Numerous studies were conducted over the past years to assess the safety of Ficus deltoidea, Cinnamomum cassia L. powdered extract and Black seed powdered extract and their efficacy in treating type 2 Diabetes Mellitus. As the available data on NW Low-Glu efficacy, safety and dosing regimen is not enough, this study will be conducted to compare the hypoglycemic effect of two doses of a herbal medicinal product of ficus and Cinnamomum cassia L. powdered Extract + Black seed powdered extract (NW Low-Glu) to that of Metformin as measured by the mean change in HbA1c levels in patients newly diagnosed with type II diabetes mellitus.

Official Title
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A Phase II, Randomized, Double Blind, Double Dummy, Active-Controlled Clinical Trial to Investigate the Efficacy and Safety of Low-Glu in Patients Newly Diagnosed With Type II Diabetes Mellitus

Conditions
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Type2 Diabetes Mellitus

Intervention / Treatment
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* Dietary Supplement: Natural Wellness Low-Glu low dose
* Dietary Supplement: Natural Wellness Low-Glu high dose
* Other: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent. Males and females aged between 18 and 65 years of age. Newly diagnosed with type II diabetes mellitus patients as per the following criteria (FBG ≥ 126 mg/dl) or, 2h- post prandial ≥ 200 mg/dl during OGTT or, HbA1c ≥ 6.5% Anti-diabetic treatment naïve patients. Able and willing to perform SMBG and to complete subject diaries. Exclusion Criteria: Pregnant or lactating women; women of childbearing potential must agree to use an accepted method of contraception during the course of the study and for 1 month after their last dose of study drug. Patients with BMI > 40 Kg/m2 or BMI < 18.5 Kg/m2. eGFR <60 mL/min/1.73 m2 (measured by the CKD-EPI equation) 3. History of Positive human immunodeficiency virus, hepatitis B surface antigen (HBsAG), or hepatitis C antibody test. History of type I diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes such as Cushing's syndrome or acromegaly. History of diabetic complications such as diabetic ketoacidosis, lactic acidosis or state of hyperosmolar hyperglycemia, diabetic proliferative retinopathy, or severe diabetic neuropathy (requiring treatment with antidepressants or opioids) and history of decompensated diabetes (polyuria, polydipsia, nocturia, fatigue). History of chronic gastrointestinal (GI) conditions that could impede gastric emptying or potentially affect the interpretation of the study data. History of weight loss surgery or weight loss procedure involving the GI tract, such as gastric bypass, gastric stapling, or gastric banding. History of an eating disorder (e.g., bulimia, anorexia). History of malignancy (except treated basal or squamous cell skin cancer) within 5 years prior to screening. History of significant cardiovascular disease (such as congestive heart failure, myocardial infarction, coronary disease) or uncontrolled hypertension. History of clinically significant renal or liver disease. Receipt of an investigational drug within 30 days prior to screening, or active enrollment in another investigational medication or device trial. Known or suspected allergy to the trial products. Any condition, in the judgment of the investigator, that would interfere with the patient's ability to comply with all study requirements or that would place the patient at unacceptable risk by his/her participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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
Interventional Model Description: This was a double-blind, double dummy, randomized, active-controlled, three-arm, parallel-group, interventional phase II clinical trial to investigate efficacy and safety of a herbal medicinal product of (NW Low-Glu) in patients newly diagnosed with type II diabetes mellitus. Study duration: 3 months of recruitment and 3 months of treatment. Sample Size: It was planned to enroll 68 patients per arm, 204 in total. Participants were patients between 18 and 65 years of age, newly diagnosed with type II diabetes mellitus and consenting to participate in this study. Eligible patients were randomized in a 1:1:1 allocation ratio, into one of the three treatment groups, to receive either Metformin or one of the two doses of NW Low-Glu.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm 1 Metformin ( 64 patients)<br>Metformin 1000 mg tablets were used. First Dose: One Metformin 1000 mg tablet + Two Placebo Capsules administered PO on empty stomach with plenty of water 2 hours after meals. Second Dose: Two Placebo Capsules administered PO on empty stomach with plenty of water 2 hours after meals. Third Dose: One Metformin 1000 mg tablet + Two Placebo Capsules administered PO on empty stomach with plenty of water 2 hours after meals. A total dose of 2000 mg was administered per day. | Other: Metformin<br>* A total dose of 2000 mg was administered per day.<br>|
| Experimental: Experimental Arm 2: Low Dose NW Low-Glu ( 65 patients)<br>The contents of 4 capsules of NW Low-Glu were equally distributed and inserted into 6 capsules size 0, and administered in 3 daily doses as follows: First Dose: One Placebo tablet + Two size 0 NW Low-Glu Capsules administered PO on empty stomach with plenty of water 2 hours after meals. Second Dose: Two size 0 NW Low-Glu Capsules administered PO on empty stomach with plenty of water 2 hours after meals. Third Dose: One Placebo tablet + Two size 0 NW Low-Glu Capsules administered PO on empty stomach with plenty of water 2 hours after meals. | Dietary Supplement: Natural Wellness Low-Glu low dose<br>* The contents of 4 capsules of NW Low-Glu were equally distributed and inserted into 6 capsules size 0, and administered in 3 daily doses<br>* Other names: Mas Cotek powdered Extract 300 mg + Cinnamomum cassia L. powdered Extract 100 mg + Black seed powdered extract 250 mg;|
| Experimental: Experimental Arm 3: High Dose NW Low-Glu ( 69 patients)<br>The contents of 5 capsules of NW Low-Glu were equally distributed and inserted into 6 capsules size 0, and administered in 3 daily doses as follows: First Dose: One Placebo tablet + Two size 0 NW Low-Glu Capsules administered PO on empty stomach with plenty of water 2 hours after meals. Second Dose: Two size 0 NW Low-Glu Capsules administered PO on empty stomach with plenty of water 2 hours after meals. Third Dose: One Placebo tablet + Two size 0 NW Low-Glu Capsules administered PO on empty stomach with plenty of water 2 hours after meals. | Dietary Supplement: Natural Wellness Low-Glu high dose<br>* The contents of 5 capsules of NW Low-Glu were equally distributed and inserted into 6 capsules size 0, and administered in 3 daily doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the hypoglycemic effect of two doses of a herbal medicinal product (NW Low-Glu) to that of Metformin as measured by the mean change in HbA1c levels in patients newly diagnosed with type II diabetes mellitus. | Comparing the mean change in HbA1c levels between each experimental arm and active-control arm | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure the incidence of hypoglycemia events and other adverse events in patients newly diagnosed with type II diabetes mellitus (Safety) | Comparing the mean change in fasting plasma glucose levels between each experimental arm and active-control arm | 12 weeks | 
| To compare the mean change in the 2h-post prandial glucose levels between each experimental arm and active-control arm (efficacy) | To compare the mean change in the 2h-post prandial glucose levels between each experimental arm and active-control arm. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ficus deltoidea, HbA1c, weight, metabolic syndrome, medicinal plants