Clinical trial NCT03610412: Cinnamomum Cassia Effect on IGF1 and Metabolic Control in Patients With DM2 Without Glycemic Control Metformin Treated
Official title: Effect of Cinnamomum Cassia as an Enhancer of the Insulin Response of the Insulin-Like Growth Factor-1 and Metabolic Control in Patients With Type 2 Diabetes Mellitus Treated With Metformin Without Glycemic Control
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes Mellitus Type 2
IGF1
Cinnamomum cassia
Metabolic control
Metformin
Lead sponsor: Coordinación de Investigación en Salud, Mexico
Sponsor class: OTHER_GOV
First posted: 2018-08-01
Enrollment: 28
Sex: ALL
Minimum age (years): 40
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Controlled clinical trial, of two parallel groups, double blind, with random assignment and control group.

Process:

Visit 1 / Day -7: Period of scrutiny, study information, consent signature, clinical history, anthropometry, baseline laboratory tests.

Visit 2 / Day 0: Start the intervention period, simple random assignment for study groups, delivery of medication, general recommendations of diet and exercise.

Visit 3 / Day 30 - Visit 4 / Day 60: Adherence to treatment, taking laboratory tests, evaluation of adverse events, general recommendations of diet and exercise, general recommendations of diet and exercise will be evaluated.

Final Visit / Day 90 ± 7: Anthropometric measurements will be taken, laboratory tests will be taken, treatment adherence and adverse events will be evaluated, end of the intervention period.
Primary purpose: TREATMENT

Brief summary: Among the multiple treatment options for Diabetes Mellitus Type 2 (DM2), the influence on Insuline like growth factor 1 (IGF1) plays a causal role in diabetes but has shown similarities with insulin, both in its structure and in its function, including a rapid reduction in glucose levels in blood, could improve glycemic control in patients.

Oral administration of 3 g of cinnamomum cassia for 90 days acts as an enhancer of the IGF1 insulin response and on metabolic control (fasting glucose, glycosylated hemoglobin (HbA1c), triglycerides, total cholesterol, high density cholesterol, low density cholesterol, very low density cholesterol, systolic and diastolic blood pressure (TAS and TAD), body weight) in patients with DM2 without glycemic control treated with metformin at doses ≤ 850 mg daily.

Detailed description: Introduction:

DM2 is a chronic disease, considered a public health problem, scenario in which each year increases the number of people affected, has a high prevalence in the investigator's country, 9.4% (ENSANUT 2016), which causes a high morbidity and mortality. Conceptually it is defined as a heterogeneous syndrome originated by the genetic-environmental interaction and characterized by a chronic hyperglycemia, as a consequence of a deficiency in the secretion or action of insulin, which triggers acute complications (ketoacidosis and hyperosmolar coma), microvascular chronicles (retinopathies) and neuropathies) and macrovascular (coronary heart disease, cerebrovascular and peripheral vascular diseases).

Growth hormones such as IGF1 with important biological effects on metabolism have been shown to promote the absorption of glucose in certain peripheral tissues. It has been shown that IGF1 binds to insulin receptors to stimulate the transport of glucose in fat and muscle, inhibiting the production of hepatic glucose by lowering blood glucose while at the same time suppressing insulin secretion, increasing sensitivity to insulin and improves the lipid profile.

For the treatment of DM2 the use of botanical products can improve glucose metabolism by hypoglycemic effect, as well as that of lipids and antioxidant, aqueous extracts of cinnamomum cassia have been shown to enhance glucose uptake and glycogen synthesis in vitro and increase phosphorylation of the insulin receptor with possible effect on IGF1 receptor.

The emergence of other therapies can generate new treatments for patients with DM2, which in turn reduce costs and help improve the quality of life.

Justification:

The prevalence of diabetes and metabolic decontrol is high both in Mexico and in the world and conditions the development of long-term complications. The concentrations of IGF1 in blood are diminished in the patients with diabetes mellitus and by its effects similar to the insulin in the metabolism of the glucose when normalizing this can produce control of the diabetes.

In vitro studies have shown that cinnamomum cassia increases glucose uptake, glycogen synthesis and insulin receptor phosphorylation. In humans it has been confirmed that it increases the levels of glucagon-like peptide 1 (GLP-1), favors the activation of peroxisome proliferator-activated receptor (PPAR-γ and PPAR-α) promoting insulin sensitivity, as well as inhibits hepatic 3-hydroxy 3-methylglutaryl coenzyme A reductase to reduce the synthesis of cholesterol and has a vasodilator effect by activity on the enzyme nitric oxide synthase.

Cinnamomum cassia also has a proposal on the signaling of IGF1 receptors (GRB2), which activated by phosphatidylinositol 3-kinase (PI3K) control the proliferation of IGF1, this IGF1 having reduced levels in patients with diabetes becomes a therapeutic target for improved control metabolic. However, the direct application of IGF1 has as main limitation important collateral effects which has inhibited its use, so it is intended to evaluate the stimulatory effect on IGF1 with cinnamomum cassia considering phytopharmaceutical of good quality and low side effects.

General hypothesis:

Cinnamomum cassia acts as an enhancer of the insulin response of IGF1 and metabolic control in patients with DM2 without glycemic control treated with metformin at low doses.

Goals:

GENERAL To evaluate the effect of cinnamomum cassia as an enhancer of the insulin response of IGF1 on metabolic control in patients with DM2 without glycemic control treated with metformin.

SPECIFIC

To analyze the effect before and after daily oral administration of 850mg of metformin plus 3g of cinnamomum cassia compared to placebo for 90 days on:

* Levels of IGF1.
* Fasting glucose value, HbA1c, triglycerides, total cholesterol, high density cholesterol, low density cholesterol, very low density cholesterol, systolic and diastolic blood pressure, body weight.

SECONDARY

To analyze the effect before and after daily oral administration of 850mg of metformin plus 3g of cinnamomum cassia compared to placebo for 90 days on:

* Insulin sensitivity, body mass index (BMI), waist circumference, % body fat.
* Determine the pharmacological attachment and tolerability of CC and placebo.

Working universe:

Patients with DM2, (men and women with a recent diagnosis, treated with 850 mg of metformin daily, without glycemic control). Residents of Guadalajara and metropolitan area and that for the development of the protocol they will go to the facilities of the National Medical Center of the West, Specialty Hospital.

Sample size:

It was calculated according to the following formula for clinical trials: n= 2 \[ (Zα - Z1-β) (δ) / d\] 2 Two working groups will be formed at random, which will be integrated as follows: 1) a group of 14 patients (7 women and 7 men) with DM2 without adequate control, treated with metformin 850 mg daily, who will receive 1 g of cinnamomum cassia orally every 8 hours, for 90 days, and 2) a group of 14 patients (7 women and 7 men) with DM2 without adequate control, treated with metformin 850 mg daily, who will receive 1 g of placebo (calcined magnesia ) orally every 8 hours, for 90 days. In this way, the total number of participants required for the study will be, at least, 28 volunteers.

Variables:

Independent variable:

Pharmacological intervention:

* Intervention group: Administration of metformin 850mg daily and cinnamomum cassia 1g orally before each meal, for 90 days.
* Control group: Administration of metformin 850mg daily and of placebo approved 1g (calcined magnesia) orally before each meal, for 90 days.

Dependent variables:

Primary outcome dependent variables:

* Laboratory determinations: IGF1, fasting glucose, HbA1c, lipid profile.
* Clinical determinations: systolic and diastolic blood pressure, body weight.

Dependent secondary outcome variables:

* Laboratory determinations: serum creatinine, liver profile.
* Clinical determinations: Insulin sensitivity, body mass index, waist circumference and percentage of adiposity.

Intervening variables:

* Diet.
* Exercise and physical activity.
* Phase of the menstrual cycle.
* Age.
* Gender.

Clinical procedures:

All the anthropometric and vital signs determinations, as well as the procedures for the interrogation, physical examination and integration of the corresponding clinical history will be carried out by means of universally accepted methods and in accordance with the General Health Law, in its Regulation on the Provision of Medical Care Services.

The history and clinical exploration will be performed at the first visit of the participant in order to establish eligibility to continue in the study. All positive and clinically interesting data will be recorded in the data collection notebook (CRD).

Paraclinical procedures:

During each of the scheduled visits to the research unit it will be necessary to determine a clinical chemistry study, for this purpose it will be essential to collect blood samples and their subsequent processing. For the collection of all blood samples in each of the visits to the research center all participants will be cited at 8:00 am and will be an indispensable requirement in each of the collections of samples that come in a fasting state of 12 hours.

Once the blood sample has been taken, the patient will be given general guidance and recommendations on diet and exercise for a healthy lifestyle. From the 3rd visit the attachment to the treatment will be evaluated, this determination will be made with the following formula, considering as acceptable a value ≥ 80%:

Compliance rate (%) = Total number of capsules you ingested / Total number of capsules you should have ingested = Result multiplied by 100.

Quality control in procedures:

The quality and information management procedures will have the following quality control strategies:

* Review of the database in duplicate.
* Electronic comparison of duplicate database.
* Statistical review of the quality of the information.
* Statistical adjustment of the information.
* Calculation in duplicate of the statistical parameters of quality control.

Data management and analysis:

Database All participants will have a complete clinical record during the development of the study. All the clinical and biochemical data that are submitted to statistical analysis must be registered in the corresponding CRD of each participant. The database will be developed from the CRDs, according to the coding included in said document, in \* .xls format of the Microsoft Excel program. Updating and verification of the initial database will be done every time new data is obtained throughout the development of the field work. Once all the participants complete all the visits of the field work phase of the study, a review, verification and final validation of the initial database will be carried out. When the absence of errors in the initial database is verified, it will be converted to the format for analysis under the statistical package SPSS version 21 or higher for Windows.

Statistic analysis:

The most appropriate and reliable statistical procedures for the analysis of the data will be decided based on the result of the normality test. Overall the descriptive statistics used in the presentation of the data will include qualitative measures in frequency and percentage and quantitative measures of central tendency and dispersion (arithmetic mean and standard deviation), when considered appropriate it will also include median, minimum and maximum values or dispersion ranges.

For all cases, the significance will be p ≤ 0.05. All patients receiving at least one dose of intervention treatment will be taken into account in the statistical analysis as part of the intention-to-treat analysis of the eliminated subjects.

Ethical and legal framework:

All the procedures and activities carried out during the development of this clinical trial will be carried out in full compliance with the legal provisions of the General Health Law of the United Mexican States, and in accordance with the ethical principles for pharmacological research on human beings detailed in the latest revision of the Helsinki Declaration and the International Harmonization Conference.

The research protocol will be submitted for approval by the local Research Committee of the Specialties Hospital of the National Medical Center of the West. The study is classified within the General Health Law and its regulations on research in humans as of risk greater than the minimum, since it is a pharmacological study with potential risk; for which it is required to obtain a consent under written information signed at the beginning of the study. The document will be signed in duplicate by the participant, two witnesses from outside the research team and preferably relatives or friends of the participant, and by the principal investigator of the center. One of the duplicates of informed consent will remain with the principal investigator, while the other will be delivered to the study participant.

According to the guidelines of good clinical practice all participants in the study will be identified only by initials and number in the database. The records and laboratory results will be available only to the principal investigators, and with the restrictions of law for the participant.

Conflicts of interest:

There are no conflicts of interest for the conduct of the study. The information obtained from this study will be made available to privileged researchers involved in the development of it.

Eligibility criteria: Inclusion Criteria:

* Signature of consent under written information prior to the completion of any procedure in the study.
* Men and women aged 40 to 59 years old, residents of Guadalajara, Jalisco and the metropolitan area.
* Ability to communicate and meet all the requirements of the study.
* BMI less than or equal to 34.9 kg / m2.
* Diagnosis of DM2 according to the ADA:

  * Plasmatic glucose ≥126mg / dl (7.0 mmol / L) in an 8-hour fast.
  * Plasmatic glucose ≥200mg / dl (11.1 mmol / L) at 2 hours after an oral glucose tolerance test.

or HbA1C ≥6.5% (48 mmol / mol).

o Plasmatic glucose ≥200mg / dl (11.1 mmol / L) in a random sample to the patient with classic symptoms of hyperglycemia.

* Evolution of DM2 less than 1 year.
* Be receiving pharmacological treatment with metformin in doses less than or equal to 850mg.
* Stable body weight within 3 months prior to the start of the study, defined as a variability in body weight of less than 10%.
* Eumenorrheic women with mechanical or definitive contraceptive method without hormonal treatment.

Exclusion Criteria:

* Determination of HbA1c less than 6.5%, greater than 10% or fasting glucose greater than 250 mg / dL.
* Serum total cholesterol concentration greater than or equal to 240mg / dl.
* Serum triglyceride concentration greater than or equal to 400mg / dl.
* History of hypersensitivity to study drugs.
* Intake of drugs with known effects on glucose metabolism, lipids, and weight.
* Uncontrolled arterial hypertension, defined as systolic blood pressure values greater than or equal to 140mm / Hg and a diastolic blood pressure greater than or equal to 90mm / Hg.
* History of cardiovascular disease, blood disorders, kidney, pancreatic or thyroid disease.
* Women with suspicion or confirmation of pregnancy
* Women in breastfeeding period.
* History of smoking at any intensity within 12 months prior to the start of the study.
* History of drug abuse or alcoholism.
* Inability to attend or answer the evaluations made in each of the visits.
* Pacemaker bearing, or any other permanent bioelectronic element that can modify the electric bioimpedance reading or be affected by it.

Primary outcomes:
measure: The effect of cinnamomum cassia on IGF1 levels.
timeFrame: 90 days
measure: The effect of cinnamomum cassia potentiates the insulin response of IGF1 on metabolic control in patients with DM2 without glycemic control treated with metformin.
timeFrame: 90 days
measure: The effect of cinnamomum cassia on metabolic control in patients with DM2 without glycemic control treated with metformin
timeFrame: 90 days
measure: The effect of cinnamomum cassia on metabolic control
timeFrame: 90 days
measure: The effect of cinnamomum cassia on blood pressure
timeFrame: 90 days
measure: The effect of cinnamomum cassia on body weight
timeFrame: 90 days
Secondary outcomes:
measure: The effect of cinnamomum cassia potentiates the IGF1 insulin response on insulin sensitivity.
timeFrame: 90 days
measure: The effect of cinnamomum cassia potentiates the IGF1 insulin response on BMI.
timeFrame: 90 days
measure: The effect of cinnamomum cassia potentiates the IGF1 insulin response on waist circumference.
timeFrame: 90 days
measure: The effect of cinnamomum cassia potentiates the IGF1 insulin response on body fat%.
timeFrame: 90 days
Other outcomes:
Locations:
city: Guadalajara
country: Mexico
facility: Biomedical Unit Research 02, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Social Security Institute.
state: Jalisco
Study officials:
affiliation: Instituto Mexicano del Seguro Social, Unidad de Investigación Biomédica 02
name: Sandra O Hernández González, Doctorado
role: PRINCIPAL_INVESTIGATOR
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