Cinnamomum Cassia Effect on IGF1 and Metabolic Control in Patients With DM2 Without Glycemic Control Metformin Treated
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Cinnamomum Cassia; Placebo (calcined magnesia)
Intervention type(s): Other; Other
Intervention description(s): The intervention period will be 90 days, unlike other trials with Cinnamomum cassia and the main effect sought is on IGF1 levels, in addition to metabolic control.; The intervention period will be 90 days, unlike other trials with Cinnamomum cassia and comparison with placebo. The main effect sought is on IGF1 levels, in addition to metabolic control.
Intervention MeSH terms: Magnesium Oxide
Allocation: Randomized
Intervention model: Parallel Assignment
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.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Diabetes Mellitus Type 2; IGF1; Cinnamomum cassia; Metabolic control; Metformin