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Study Protocol
Revised

Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol

[version 3; peer review: 2 approved with reservations, 3 not approved]
PUBLISHED 04 Mar 2024
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This article is included in the Datta Meghe Institute of Higher Education and Research collection.

Abstract

Background

Poor synthesis of insulin by beta cells present in the pancreas combined with resistance of insulin in peripheral organs is referred to as type 2 diabetes mellitus. Insulin resistance leads to an increase in plasma fatty acids, which reduces transfer of glucose within the cells of muscles and increases breakage of lipids, resulting in an increase in hepatic glucose production. Nishamalaki (a formulation of turmeric and Indian gooseberry) is suggested in the therapy of all kinds of Madhumeha (diabetes mellitus) in Ayurveda classics. Turmeric and Indian gooseberry are the two main ingredients. Both are considered as effective medicines in the management of Madhumeha individually as well as in combined form.

Aim

To compare the efficacy of Nishaamalaki and metformin in obese patients of type2 diabetes mellitus.

Methods

The study will include 60 obese type 2 diabetes mellitus patients who will be distributed into two distinct categories, each with 30 patients. Nishamalaki Churna 3gm two times a day before food with warm water for 60 days in Group N (Experimental Group) and 500 mg metformin tablets twice daily before meals for 60 days in Group M (Control Group). Every 15th day, an assessment will be made (15th, 30th, 45th and 60th day).

Results

Objective outcomes will be assessed.

Conclusion

Conclusion will be based on the data received after the completion of the study.

Keywords

Nishaamalaki Churna, Metformin, Obese Type2 Diabetes Mellitus

Revised Amendments from Version 2

The tense used in the randomisation section is corrected now
Study tool is used to denote Body mass Index instead of Investigations
Durable efficacy is explained properly.

See the authors' detailed response to the review by Srihari Sheshagiri
See the authors' detailed response to the review by Naushira Pandya
See the authors' detailed response to the review by Supriya Bhalerao

Introduction

Poor pancreatic beta-cell insulin production accompanied by peripheral insulin resistance is referred to as type 2 diabetes mellitus.1 Insulin resistance causes an increase in fatty acids in the plasma, resulting in reduced glucose transport into muscle cells and increased fat breakdown, which leads to an increase in hepatic glucose production. For type 2 diabetes mellitus to develop, insulin resistance and pancreatic-cell failure must both occur at the same time. Insulin resistance affects everyone who is overweight or obese, but diabetes only develops in those who don’t have enough insulin production to meet their level of insulin resistance.

The prevalence of obesity has increased recently, highlighting the issue’s importance on a global scale. In the United States, almost two thirds of adults are thought to be overweight or obese. In many parts of the world, identical trends may be found.2 Numerous physical, psychological, and social problems have been linked to obesity, the most significant of which is type 2 diabetes. 171 million individuals were predicted to have type 2 diabetes mellitus after the completion of this era, and by 2030, this figure is projected to reach 360 million.3

The basic metabolism defect in type II Diabetes mellitus is either delayed insulin secretion relative to glucose load (impaired insulin secretion) or the peripheral tissue are unable to respond to insulin (insulin resistance) Type II Diabetes mellitus is a heterogeneous disorder with a more complex etiology and is far more common than type I, but much less is known about its pathogenesis.

The drug metformin is now routinely used to treat diabetes mellitus. With lifestyle changes, it is now regarded as the first line of treatment for type 2 diabetes mellitus because of its outstanding safety standards, effectiveness, tolerability, and high hypoglycaemia.4 Excitingly, epidemiological, and preclinical studies have recently shown that metformin has positive effects in addition to its effects on Glycaemic indices. It has been demonstrated to lower body weight, reduce cancer incidence and death, and extend longevity.4 Metformin has been a popular study topic for disorders related to obesity and ageing as a result of these effects.

Nishaamalaki is suggested in the management of obese patients suffering from diabetes mellitus in Ayurveda classics.5 Turmeric and Indian gooseberry are the two main ingredients. Both are individually as well as in combined form are considered as effective medicines in the management of Madhumeha (diabetes mellitus). In experimental animal models, its rhizomes were shown to exhibit anti-diabetic characteristics. Curcumin, the key component, was shown to have anti-diabetic properties, according to researchers.6 In one animal study, it is also found to be a weight reducing agent.7

Indian gooseberry contains Ellagic acid which exhibits blood sugar lowering effects by stimulating insulin production and decreasing glucose intolerance in diabetic rats. Immunohistochemistry of the pancreas revealed that in diabetic rats, Indian gooseberry increased Beta cell size as well as its count. Additionally, it decreased the glucose intolerance of diabetic rats and raised the generation of insulin stimulated by blood glucose from isolated islets.8 Some of the main compounds in the fruits of Emblica officinalis (such as gallotanin, corilagin, and ellagic acid) have blood glucose lowering qualities due to their characteristics of free radical scavenging, according to studies. Hyperglycaemia, heart problems, diabetic nephropathy, neuropathy, cataractogenesis, and other conditions have all been linked to it.9

Amalaki is rich in vitamin C. It has been shown that taking extra vitamin C helps diabetics with sorbitol build-up in their red blood cells. Vitamin C also lessens capillary fragility, which increases the risk of complications from diabetes.10 Additionally, previous research indicates that prolonged vitamin C treatment has advantageous effects on lipid and glucose metabolism in T2DM patients.11

Type 2 diabetes mellitus and obesity are progressive and rapidly spreading metabolic diseases. Both have strong correlation. In modern medicine, it is studied that metformin has antidiabetic as well as anti-obesity effect. There are numerous studies on Nisha-amalaki showing its antidiabetic effect, but it is not studied in obese type 2 diabetic patients hence this study is planned.

Methods

Study design

This single-blind, randomised, standard-controlled experiment includes a parallel group. A 60-day treatment term and a 15-day follow-up period are both included in the trial.

A total of 60 patients are chosen for the trial, and they will be distributed into 2 equal groups according to the allocation ratio. Group M is a conventional standard group while Group N is a trial group.

Study setting

Recruitment of patients will take place at MGACH&RC, Wardha, from the OPD and IPD of the Department of Kayachikitsa. Patients will also be chosen from a variety of peripheral camps with diverse specialties.

Trial registration number: This trial has the CTRI registration number CTRI/2021/10/037263.

Diagnostic criteria: The patients will be assessed based on blood sugar level (Fasting and Postprandial) and Body Mass Index.

Eligibility criteria: Age between 30 to 60 years of either sex. Patients having Fasting Blood Sugar Level >126 mg/dL and/or Postprandial Blood Sugar Level >200 mg/dL. B.M.I. in between 25-30 kg/m2.

Interventions

Group N – Nishamalaki Churna 3 gm two times a day before meals.

Group M – 500 mg metformin tablets two times a day before meals.

Randomization

Participants will meet the criteria for randomization, and they will be assigned to the experimental and control groups in a 1:1 ratio. A lottery-based randomization system that operates remotely provided researchers with access to the treatment allocation for each eligible participant. A total of 60 patients will be chosen for the trial, and they will be distributed into 2 equal groups. The experimental group is Group N, while the usual controlled group is Group M.

Folded slips of both metformin as well as Nishaamalaki will be kept in a bowl and patients will be asked to choose any one of the slips. After which the patient will be allocated to that particular group which he/she will choose.

Blinding treatment

The assignments will be kept a secret until the trial is finished. The will all be blinded. Throughout the trial, doctors evaluate all of the participants. Using the lottery-based method of randomization of patients, the practitioner applied for a randomised assignment for each eligible patient, and a prescription for “Nishamalaki Churna with honey before meal two times a day” was written. The patients will then be escorted to the Dattatraya Rasa Shala’s designated drug managers, accompanied by a study assistant. All of the medications are packed in the same way. The actual names of both the groups, i.e., standard as well as trial groups will be kept blinded unless any adverse event or side effect of any of the group is observed.

Screening investigations (base line): Fasting Blood Sugar, Postprandial Blood Sugar.

Study tools used: Body Mass Index.

Investigation (end line): Fasting Blood Sugar, Postprandial Blood Sugar.

Withdrawal criteria

  • Subjects will be withdrawn from the trial if any unintended occurrence, signs of reaction of medication, adverse or side effect emerged, and the therapy will be supplied to such a patient totally free of cost until the difficulty subsided. We will measure the amount of Churna consumed to assess and monitor drug adherence, and the subject will be monitored during therapy.

Follow-up

Follow up of patients will be done in every 15 days during treatment.

Results

  • Primary: Clinicians will examine the impact of therapeutic drugs on blood sugar levels (Fasting and Post meal).

  • Secondary: To study the reduction of B.M.I. Score.

  • Durable efficacy: Respondents will be categorised as durable efficacy responders if they get desirable improvement for a minimum of one month during treatment. If the patients got decreased level of Fasting blood sugar level, Postprandial blood sugar level and/or Body Mass Index, then the results will be considered as durable efficacious.

Analytical statistics

A level of significance of 5% (two-sided) will be regarded statistically significant. Intention-to-treat and in accordance with protocol populations will be used in the analysis. For each group, baseline characteristics will be offered, as well as predicting factors. We shall express discrete variables with percentages and frequencies from baseline to each time point, whereas for data with a distribution that is normal, variables that are continuous can be characterised by the mean or standard deviation, or by the median and interquartile range, for data with an irregular distribution. Paired and unpaired t tests will be performed to assess the Results for each time point’s comparisons between the trial and standard groups.

Predictive factor analysis will be performed with the following two steps:

The univariate analysis is the initial phase. The sufficient alleviation follow-up responder rates (day 15 and 30) will be employed as dependent variables, with predictor variables such as demographic and clinical features, as well as important elements of Nishamalaki Churna, serving as independent variables. An analysis of logistic regression will be carried out. The independent variable’s selection criteria are defined as = 0.1. Multivariate analysis is the next phase. The predicted factors chosen in initial phase will be incorporated into 2 different models of regression with the desirable improvement pattern of the patient as the variable which is dependent on the other one (day 45). It was decided to do a sensitivity analysis. The main and safety outcomes will be compared across all randomised respondents.

Recruitment: The patients will be enrolled and assigned by the principal investigator.

Methods: Data collection, analysis, and management.

Objectives: BS-PP, FBS (at the start and end of the treatment). The assessment will be done using the values at the start of the study, and on the 60th day (after treatment). The therapeutic strategy will be overseen by the main examiner, who contacted the respondents and kept track of their progress in paperwork.

Plan to ensure that participants are retained, and that all follow-up is completed: By getting the patient’s phone number, we may stay in touch while giving them timely medication and advice for the follow-up, with the information from the follow-up being justifiably stored in the paperwork.

Management of data

Patients’ data will be gathered through clinical examination. The main examiner will enter the data into the master sheet, assess it using the appropriate statistical method, and code the data.

Consent

Before the trial begins, patients will be asked for their written informed permission.

Ethical approval

The study was approved by the Institutional Ethics Committee, letterno. MGACHRC/IEC/July/2021/331.

Results

The methods may work to lower blood sugar levels (fasting and post-meal) in the trial and control group. Implementing suitable dietary regimen and proper exercise during treatment may decrease the likelihood of return of symptoms compared to taking regular metformin tablets for the patient.

Discussion

This study will compare the therapeutic efficacy of Nishamalaki Churna with honey and metformin tablets in individuals with type 2 diabetes mellitus who are obese. Nishamalaki is mentioned as the effective management of Madhumeha (Type-2 DM) in Ayurveda classics, according to ayurvedic literature. Haridra (Curcuma longa L) is a preferred medicine for type 2 diabetes mellitus. Both Nishamalaki Churna with honey and metformin tablets were found to effectively lower FBS and BS-PP levels. Turmeric and Indian gooseberry are found in Nishamalaki Churna. Haridra (turmeric) in Veerya (potency) is Ushna (hot), and Tikta Rasa (bitter) is useful in Kaphaja Vikaras (disorders related to kapha biohumour). These substances contain qualities such as Ruksha (dry), Ushna (hot), Tishna (bitter), and Katu Vipaka (pungent), which aid in Samprapti Vighatana (pathogenesis) and hence aid in managing the obese patients suffering from Type-2 DM. However, in this work, we will look at the differences in both formulations and their influence on objective metrics. In obese type 2 diabetes mellitus, the total effects will reveal which formulation is effective.

Conclusions

Conclusion will be based on the data received after the completion of the study.

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Version 3
VERSION 3 PUBLISHED 25 Sep 2023
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Chhabra DA, Kuchewar V and Joshi T. Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.12688/f1000research.139045.3)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 3
VERSION 3
PUBLISHED 04 Mar 2024
Revised
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Reviewer Report 07 Jan 2025
Raymond Tjandrawinata, Atma Jaya Catholic University of Indonesia, South Jakarta, Indonesia 
Not Approved
VIEWS 0
The protocol compares Nishaamalaki Churna with metformin for treating obese patients with type 2 diabetes mellitus (T2DM). The rationale is partly clear, as the study objective shifts focus between glycemic control and obesity without clearly differentiating the primary aim. The randomized design ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Tjandrawinata R. Reviewer Report For: Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.5256/f1000research.163086.r353713)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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8
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Reviewer Report 10 Jun 2024
Yoshitaka Hashimoto, Matsushita Memorial Hospital, Moriguchi, Japan 
Not Approved
VIEWS 8
This protocol study will examine the effect of Nishaamalaki in obese patients with type 2 diabetes mellitus. Several problems should be resolved.

1. Sample size. How to calculate the sample size was unclear.
2. Inclusion criteria were ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Hashimoto Y. Reviewer Report For: Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.5256/f1000research.163086.r286660)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 2
VERSION 2
PUBLISHED 24 Nov 2023
Revised
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Reviewer Report 08 Feb 2024
Srihari Sheshagiri, Department of PG Studies in Kaumarabhritya, JSS Ayurvedic Medical College, Mysore, Karnataka, India 
Approved with Reservations
VIEWS 12
1. Blinding may not be appropriate as two different forms of medicines are being administered. 

2. Words used in the Randomisation paragraph (in methods section) are in past tense implying that the study is already concluded. The ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Sheshagiri S. Reviewer Report For: Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.5256/f1000research.159185.r225291)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 13 Apr 2024
    Dr. Aman Chhabra, Kayachikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    13 Apr 2024
    Author Response
    Respected Sir
    Thanks for the comments given by you on my protocol. I would like to respond you with the rectifications in the comments.
    1. The medicines in both the ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 13 Apr 2024
    Dr. Aman Chhabra, Kayachikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    13 Apr 2024
    Author Response
    Respected Sir
    Thanks for the comments given by you on my protocol. I would like to respond you with the rectifications in the comments.
    1. The medicines in both the ... Continue reading
Version 1
VERSION 1
PUBLISHED 25 Sep 2023
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Reviewer Report 21 Nov 2023
Srihari Sheshagiri, Department of PG Studies in Kaumarabhritya, JSS Ayurvedic Medical College, Mysore, Karnataka, India 
Approved with Reservations
VIEWS 19
  1. Grammatical errors needs corrections, in few area present tense and in few area past tense has been utilised by the authors. 
     
  2. In methods (abstract), inclusion of obese type 2 patients have been
... Continue reading
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CITE
HOW TO CITE THIS REPORT
Sheshagiri S. Reviewer Report For: Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.5256/f1000research.152287.r210017)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 30 Nov 2023
    Dr. Aman Chhabra, Kayavhikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    30 Nov 2023
    Author Response
    Respected Sir, Thanks for your valuable review and comments on my manuscript. I would like to respond and clarify the comments given one by one.

    1. Grammatical errors are ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 30 Nov 2023
    Dr. Aman Chhabra, Kayavhikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    30 Nov 2023
    Author Response
    Respected Sir, Thanks for your valuable review and comments on my manuscript. I would like to respond and clarify the comments given one by one.

    1. Grammatical errors are ... Continue reading
Views
16
Cite
Reviewer Report 21 Nov 2023
Supriya Bhalerao, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, India 
Not Approved
VIEWS 16
  1. The protocol is for assessing the efficacy of Nishamalaki in obesity, then why the introduction refers more to diabetes?
     
  2. ‘Type of trial’ is wrong term. It should be ‘study design’.
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Bhalerao S. Reviewer Report For: Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.5256/f1000research.152287.r213873)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 30 Nov 2023
    Dr. Aman Chhabra, Kayavhikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    30 Nov 2023
    Author Response
    Respected Mam, Thanks for your valuable review and comments on my manuscript. I would like to respond and clarify the comments one by one.

    1. As mentioned in the ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 30 Nov 2023
    Dr. Aman Chhabra, Kayavhikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    30 Nov 2023
    Author Response
    Respected Mam, Thanks for your valuable review and comments on my manuscript. I would like to respond and clarify the comments one by one.

    1. As mentioned in the ... Continue reading
Views
23
Cite
Reviewer Report 16 Nov 2023
Naushira Pandya, Kiran Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, USA 
Approved with Reservations
VIEWS 23
Comments:

1.The mechanisms for T2 diabetes could be expanded (eg; hepatic glucose production, renal reabsorption etc). What is meant by completion of this era in paragraph 2 of the Introduction?

2. How was the ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Pandya N. Reviewer Report For: Comparative study of Nishaamalaki and metformin in obese patients of type 2 diabetes mellitus (Madhumeha): A study protocol [version 3; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2024, 12:1199 (https://doi.org/10.5256/f1000research.152287.r213867)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 30 Nov 2023
    Dr. Aman Chhabra, Kayavhikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    30 Nov 2023
    Author Response
    Respected Mam,
    Thanks for your valuable review and comments on my manuscript. I would like to respond on each comments given by you and do the necessary corrections in the ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 30 Nov 2023
    Dr. Aman Chhabra, Kayavhikitsa, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India
    30 Nov 2023
    Author Response
    Respected Mam,
    Thanks for your valuable review and comments on my manuscript. I would like to respond on each comments given by you and do the necessary corrections in the ... Continue reading

Comments on this article Comments (0)

Version 3
VERSION 3 PUBLISHED 25 Sep 2023
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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