healthmarketinnovations.org · Web viewA1C will be measured using the Bio-rad in2it point of care analyzer, which uses affinity chromatography (boronic acid) to separate glycated

TITLE

Management of Type 1 Diabetes in a Limited Resource Context: A Study of the DREAM Trust Model in Nagpur, Central India

INVESTIGATORS

Principal InvestigatorDr. Caroline Zuijdwijk (MD, FRCPC)Pediatric Endocrinology Fellow, CHEO

Co-Investigators - CHEODr. Alexandra Ahmet (MD, FRCPC)Pediatric Endocrinologist, CHEOAssistant Professor, Pediatrics, University of Ottawa

Dr. Alex MacKenzie (MD, PhD, FRCPC)Pediatrician with special interest in diabetes, CHEOProfessor, Pediatrics, University of OttawaPast Chief Executive Officer and Scientific Director of CHEO’s Research Institute

Co-Investigators – Outside of CHEO

Dr. James Ron (PhD Sociology)Harold Stassen Chair in International Affairs (as of August 29, 2011)Humphrey School of Public Affairs and Department of Political ScienceUniversity of Minnesota (Minneapolis, USA)

Dr. Sharad Pendsey (MD) Diabetologist and Chief Physician Dream Trust (Nagpur, India)

Dr. Rutuja Sharma (MD) Diabetologist and Assistant PhysicianDream Trust (Nagpur, India)

Seema Chalkhore Dietician and Diabetes EducatorDream Trust (Nagpur, India)

ABSTRACT

Type 1 diabetes (T1D) is one of the most common chronic childhood diseases, with an increasing incidence of approximately 3% annually worldwide. When managed effectively with a careful balance of insulin, food and activity, children with T1D can live healthy and productive lives. Unfortunately, optimal management of this disease is resource and


technology intensive; as a result, there are many barriers to optimal T1D care in developing countries. Without effective insulin therapy, children with T1D die or succumb to multiple diabetes-related complications.

DREAM Trust (DT) is a non-governmental organization and registered charity in the city of Nagpur, located in India’s Maharashtra State. It offers complete healthcare, including free insulin and syringes, to underprivileged children with T1D. During a scoping visit to the Nagpur clinic in summer 2010, we found that DT has established a less resource intensive method for treating children with T1D that appears to function well and provide good health outcomes. Given these preliminary findings, it is vitally important that researchers document, evaluate, and disseminate the results of DT’s efforts. The scholarly literature does not currently describe, document or evaluate apparently successful models of low-cost TID care in resource-poor settings. As a result, there is an urgent need for such models throughout the developing world. After all, it is unlikely that developing-world T1D health practitioners and patients will have access to the abundant resources available to developed-world patients anytime soon.

Our primary goal is thus to systematically describe and evaluate the DT model in terms of its approach to T1D management, its cost and its outcomes, and to assess the model’s applicability to other resource-poor contexts.

In the future, we plan to expand our research to identify other developing-world models for managing T1D, compare them to one another, and then build a series of contextually appropriate “best practices” for developing-world care settings.

INTRODUCTION

Over a decade ago, a World Health Organization (WHO) study estimated India’s diabetes prevalence at a staggering 31.7 million, 135,700 of which were aged 0 to 19. China and the United States followed with 20.8 and 17.7 million diagnosed patients, respectively, meaning that India’s patient population was far and away the world’s largest. Estimates of Years of Life Lost (YLLs) and Disability Adjusted Life Years (DALYs) due to diabetes by WHO India for the year 2004 were 1.2 and 2.3 million years, respectively . The WHO has also predicted an over twofold increase in the total number of Indians suffering from diabetes by the year 2030, but could not distinguish between different diabetes subtypes due to poor availability of T1D incidence data. However, most diagnosed patients under the age of 19 are likely to be suffering from T1D, and the latter is estimated at 5-10% of all diabetes cases worldwide.

T1D is a metabolic disorder characterized by hyperglycemia due to the autoimmune destruction of the pancreatic beta cells that produce insulin . It is one of the most common chronic childhood diseases, with an increasing incidence of approximately 3% annually worldwide . T1D appears to be most common in individuals of Northern European decent, with the highest recorded incidence rates in Finland . In Canada, the incidence of T1D in children aged 0-14 is 21.7 per 100,000 , or approximately 1,187 children per year.

Protocol Version: Amendment #1, June 13, 2011CHEO Protocol Number: #11/14E

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Although many developing countries report low rates of T1D incidence, accurate diagnosis is often difficult, suggesting that the true developing world incidence figures may be far higher . Yet even assuming that the published incidences are accurate, the number of affected children is large, given the size of the developing world’s overall population. Thus while India’s reported T1D incidence in children under 14 is only 4.2 per 100,000 annually , this represents approximately 15,742 new cases of T1D per year, or 13 times as many cases as in Canada. Thus, despite low reported incidence rates, India’s T1D burden is clinically important.

TID Management

T1D is caused by a lack of insulin; appropriate management requires insulin replacement through subcutaneous injection. Studies such as the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) have demonstrated a close relationship between glycemic control and the development of micro- and macrovascular diabetes complications . Microvascular complications include retinopathy, nephropathy and neuropathy, while macrovascular complications include cardiovascular, cerebrovascular and peripheral vascular disease .

Without any insulin therapy whatsoever, most children with T1D will die of diabetic ketoacidosis (DKA) within a short time. With suboptimal therapy, moreover, children are likely to experience growth retardation, osteopenia, features of Mauriac syndrome including moon face, protuberant abdomen, proximal muscle wasting, and enlarged liver due to fat and glycogen infiltration, or develop features of the syndrome of limited joint mobility including tight, waxy skin, growth impairment, and maturational delay. Over the long term, poorly treated patients develop microvascular and macrovascular complications associated with premature death.

Overtreatment with insulin, conversely, can result in hypoglycemia, severe cases of which can cause seizures, loss of consciousness, and death. Proper T1D management, therefore, involves a fine balance of constant insulin administration, carefully monitored food intake and calibrated physical activity.

In resource-intensive countries, multi-disciplinary health teams typically manage children with T1D with the help of physicians, nurses, dieticians and social workers. Patients receive insulin injections two to four times a day, or are treated with a pump that administers insulin on a continuous basis. Health workers provide education on the balance of insulin, food and exercise at diagnosis and on an ongoing basis. Patients or caregivers monitor blood glucose at least four times daily to titrate insulin dose to optimal effect. In addition, A1C levels - a marker of average blood glucose – are measured 3 to 4 times a year, typically in conjunction with clinic visits. When thus managed, children and youth with T1D can lead healthy and productive lives.

Without adequate access to insulin, supplies, and expert advice, however, T1D is associated with significant morbidity and mortality, imposing severe emotional, economic, and social costs on patients, families, and entire communities.


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The Challenges of T1D Management in Developing Countries

In his article, “State of the world’s children with diabetes,” Daneman hypothesized that “the outcome of youth with type 1 diabetes is very much dependent on the macro- (societal and community) and micro- (institutional, interpersonal and intrapersonal) environments in which they ‘find’ themselves”. He goes on to outline five fundamental requirements for diabetes care :

1. Availability of food and clean water2. Availability of insulin3. Availability of urine and/or blood testing equipment4. Prevention of both hyperglycemia-induced DKA and hypoglycemia5. Protection against harm

The literature describes many of the challenges involved in delivering appropriate T1D care, including :

Barriers to Access: factors preventing patients from accessing the services they needo Lack of available insulin and syringeso High cost of insulin, syringes and blood glucose monitoring stripso Insulin storage (discussed below)o Access to care: cost and distance, with many patients living in rural areas far

from hospitals and physicianso Lack of patient understanding of their disease: low educational provision,

coupled with illiteracyo Social barriers to insulin injections

Barriers to Provision: factors preventing health care providers within health systems from providing the services that patients need

o Diagnostic challenges: lack of knowledge of health care workers and lack of diagnostic reagents

o Lack of trained personnel/teams for T1D management

Access to insulin is particularly vital, but poor availability and high costs often prevent patients from accessing this crucial treatment. As a result, life expectancy for newly diagnosed T1D patients in some parts of Africa may be as short as 1 year ; life expectancy in other developing regions remains unknown.

Yet insulin alone is not sufficient. Proper care also requires accessible, decentralized, and trained personnel, along with suitable diagnostic and monitoring facilities . The International Insulin Foundation argues that it is the responsibility of national and international governmental and non-governmental agencies, private organizations and individuals to ensure proper diabetes management worldwide . We accept this argument, and believe that CHEO’s pediatric endocrinology team, in collaboration with other researchers and practitioners, should contribute to these efforts.

One tool that has been developed and trialed in Africa is the “Rapid Assessment Protocol for Insulin Access,” the aim of which is to provide situational analyses of T1D in specific locations. This data, in turn, should help health advocates make recommendations to national ministries of health and diabetes associations about access to insulin, syringes, monitoring, and care. This tool has served as a catalyst for bringing T1D to the attention of


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national health authorities. By identifying areas of success and concern, the Rapid Assessment Protocol is a first step in changing developing country T1D management.

In 1993, the International Society for Pediatric and Adolescent Diabetes (ISPAD) set targets for achievement by the year 2000, known at the Declaration of Kos:

1. To make insulin available to all children and adolescents with diabetes2. To reduce diabetes-related morbidity and mortality due to acute metabolic

complications or missed diagnosis 3. To make age-appropriate care and education available to ALL children and

adolescents with diabetes, as well as to their families4. To increase the availability of appropriate urine and blood self-monitoring

equipment to ALL children and adolescents with diabetes5. To develop and encourage research on diabetes in children and adolescents around

the world6. To prepare and disseminate written guidelines and standards for practice, realistic

care and education for young people with diabetes and their families. These should emphasize the crucial role of healh care professionals –not just physicians –around the world

These laudable goals, however, have not been met, and while the literature makes many recommendations for general management principles and infrastructure , few scholars or practitioners have proposed, elaborated or documented practical and appropriate models of T1D care in resource-poor settings.

Moreover, lessons learned from the management of other resource-intensive diseases - such as HIV - have yet to be applied to diabetes or other chronic diseases. In the developing world, HIV was a death sentence until long after the discovery of anti-retrovirals (ARVs). Barriers to health care provision included insufficient numbers of trained health professionals; the costs and technology required for diagnostic tests to determine viral loads; and weak and poorly regulated anti-retroviral distribution mechanisms. Barriers to accessing services included the financial costs of consultation by health professionals as well as ARVs; the stigma faced by those living with HIV; and geographic distance to care facilities. Health care professionals needed to develop appropriate methods for providing care under difficult circumstances. They eventually did develop these methods, chiefly by advocating community-based models. From these models, WHO developed low-tech guidelines for AIDS treatment in 2002. While expanding access to treatment has not been easy, the WHO guidelines have helped to change the debate. As a result, efforts have moved from defining the barriers to treatment to finding ways of expanding access to treatment for people living with HIV.

For people living with diabetes, there is one basic question: how can patients realistically secure appropriate T1D care in developing countries and under-served communities?

India is a good environment for engaging with this question. As noted above, it has the world’s largest population of persons living with diabetes, and its T1D population is vast and growing. And while the country is an economic powerhouse overall, it is also deeply unequal, heavily populated, and often desperately poor. Although India high economic growth rates have lifted many out of poverty, much of the country’s vast population still has insufficient access to appropriate healthcare, food, clean water, and housing.


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Insulin Storage

One of the biggest challenges for patients with T1D in resource-poor settings is proper insulin storage. This problem is particularly acute in India, where temperatures often soar to 45 degrees Celsius and above.

Insulin is a peptide hormone, and like all proteins, its biological activity is affected by temperature extremes. Manufacturers recommend storing insulin between 2oC and 8oC (in a refrigerator) and to keep it protected from light. Vials or cartridges of insulin in use may be stored at room temperature (up to 25-300C) for up to 4 weeks .

Insulin storage is typically not a problem in countries with high rates of electrification and refrigeration. Many patients in India and other developing countries, however, have access to neither. As a result, health workers have adapted existing low-tech storage and cooling systems for insulin storage. In Saudi Arabia, for example, health practitioners have adapted the ‘zeer’, a semi-porous clay pot widely used throughout the Middle East for storing water. Water slowly evaporates through the zeer’s walls, using up heat trapped inside and cooling the remaining water. Shaibi et al. measured the mean fall in blood glucose following administration of insulin that had been stored in a zeer vs. ambient temperature vs. refrigerator for up to six weeks. They found that the mean zeer temperature was 26.6oC, the ambient temperature 38.3oC, and the refrigerator temperate 4oC. When administered, however, there was no statistically significant difference between the declines in blood glucose observed for insulin stored in the zeer, and insulin stored in refrigerators. They concluded that storage of insulin in a zeer for up to six weeks does not significantly affect its bioactivity or safety.

Vimalavathini and Gitanjali offer similarly promising findings in a study that determined in vitro and in vivo insulin potency from three different manufacturers at five different temperatures every seven days for a period of 28 days. Although insulin stored at 32oC (room temperature) and 37oC (summer room temperature) showed a significant decline in efficacy, there was no significant difference in insulin potency stored at 5oC (refrigerator) vs. 25oC (air conditioned room) vs. 26oC (clay pot) for the duration of the study.

The DREAM Trust in Nagpur, India (described below), has developed a similar low-cost system for cooling insulin. It uses a container made of furnace-baked clay that is, in essence, a pot-within-a-pot. The insulin is stored in the innermost pot, and the gap between the pots is filled with water on a regular basis. In addition, the pot’s lid has a cup-like store for water with a slit in the corner that allows water to run along the lid’s corrugated pathways. As with the zeer, this system works by allowing the water-evaporation process to act as a cooling system. The average ambient temperature in India is 42-48oC, and the temperature of the innermost pot has been measured at between 21oC and 25oC. Each pot costs only $3 USD, and is thus a far cheaper option than even the smallest electrical fridge.

DREAM Trust & Scoping visit

DREAM Trust (DT) is a non-government organization and registered charity in the city of Nagpur, located in the Indian State of Maharashtra. It was established by Dr. Sharad


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Pendsey in 1995, and its primary objective is to offer healthcare to underprivileged children with T1D, with a particular focus on girls . The DT currently supports over 500 children with free insulin, syringes, and regular medical follow-up. Funding comes through private Indian and international donors, as well as through the International Diabetes Federation’s “Life for a Child” program. Life for a Child supports close to 8000 children with T1D in 27 countries worldwide, and supports 45 patients at DT specifically . CHEO’s Division of Endocrinology has established a partnership with the DT, and raised $5,000 CAD to date in support of the charity’s medical activities.

We undertook a scoping project of DT in July 2010 to better understand how it functions. It quickly became apparent to us that our North American model of care could not be applied to T1D management in this context. The blood glucose test strips and frequent A1C measurements that are commonplace in Canada and other wealthy countries are not feasible for most patients in India, where a single test strip can cost an entire day’s wages. We were encouraged, however to learn that Dr. Pendsey and his Nagpur team have adapted their treatment strategies to their context, providing life-saving treatment to hundreds of children.

DT follows over 500 children and youth with T1D every 3 to 4 months in its clinic. At these visits, patients receive a three-month supply of insulin and syringes, which they store either in a refrigerator, if available, or in a clay pot provided by DT. They are also assessed by one of the DT team members who monitor growth (height and weight), and review reported symptoms of hyper- and hypoglycemia. Based on these parameters, the DT team recommends insulin adjustments. Most children take a combination of short and intermediate acting insulin 3 to 4 times daily.

The key component of this low-cost treatment model is the lack of regular blood glucose testing. Since test strips cost a comparative fortune, many patients reportedly monitor their blood glucose only 1 to 4 times a month based on symptoms and may make adjustments to their insulin doses based on these readings. The same is true for the A1C tests that are, in wealthy countries, measured several times a year; because of the high comparative cost, DT patients do not regularly receive an A1C test. DT personnel monitor thyroid function yearly and complication screening begins five years after diagnosis. Overall, the DT’s treatment model costs an average of $350 USD/year per child. Although this sum is still extraordinarily high for a country where per capita GDP (in current international dollars, PPP-adjusted) is only $3,300, according to a 2009 World Bank estimate, it is still far lower than the average cost for care in developed countries such as Canada, where the per capita GDP (PPP-adjusted) is 10 times higher. Nagpur District’s per capita income, moreover, was estimated in 2008-09 at $1,540 USD.

During our DT scoping visit, DT staff introduced us to 80 patients who appeared healthy and had been growing well since coming under the DT’s care. Although we did not do a systematic study and not all patients had A1C results to report, the A1C levels that we did see did not differ markedly from those seen in our own Canadian context. All patients reported that they were pleased with the level of care they were receiving.

With India’s current level of public healthcare funding, the alternatives to DT for T1D management are not feasible for most patients. Private pharmacies are costly, with insulin and supplies often adding up to 50% or more of a poor household’s income. In theory,


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insulin is available at central government hospitals free of charge to those holding Below the Poverty Line certificates, and at a reduced rate to everyone else. In reality, however, the DT patients and healthcare professionals we spoke with reported that insulin is distributed only once per week at the government hospitals, and that even this restricted supply is often unavailable. Even when available, moreover, government hospitals provide only a 15 day insulin supply, making it difficult and costly for patients living far away to maintain a constant insulin supply. Travel in central India, we learned, is both slow and prohibitively expensive for poor patients.

We also learned that physicians in both public and private institutions have only limited experience with T1D, especially among young children. As a result, the T1D management available to most patients – especially those with reduced incomes - is either suboptimal or entirely absent.

STUDY RATIONALE

DT has established a low-cost method of treating children with T1D in a resource-poor setting. Based on our preliminary, limited and unsystematic scoping visit, this model appears to function reasonably well, and to provide good outcomes. Since the extant literature does not describe successful models of low-cost TID care delivery in resource-poor contexts, there is an urgent need for careful, systematic, and scientifically valid documentation and evaluation of existing developing-world programs.

Our primary goal is thus to systematically describe and evaluate the DT model. Later, we will assess its utility as a model for T1D management in other resource-poor contexts.

In the future, we plan to expand our study to other developing-world clinics receiving Life for a Child support. We will describe, document, and evaluate other developing country TID care models, and then develop a series of best practices for T1D management in resource poor settings. We will then disseminate our discussion of the scientifically evaluated and successful T1D care models to practitioners and scholars across Africa, Asia, the Middle East, and Latin America with the help of the International Diabetes Federation and ISPAD, using workshops, papers, journal publications, a dedicated website, and other electronic means.

In so doing, we will emulate similar efforts for other major diseases in the developing world. In years past, for example, studies have established effective delivery-of-care models for HIV and cancer in the developing world . T1D management in poor countries requires similar attention; children must not die from a chronic disease that is eminently treatable.

OBJECTIVES

Primary Objective

1. To describe diabetes management at DT including: a. Insulin regimenb. Insulin dose (units/kg)


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c. Insulin storaged. Glucose monitoringe. Average A1Cf. Diabetes-related complications

Secondary Objectives

1. To describe the patient population at DT, thus allowing for assessment of the generalizability (external validity) of our findings.

2. To determine if there is a significant improvement in diabetes control in patients previously followed in other diabetes clinics/public hospitals since being followed at DT, as measured by A1C, growth parameters, annual number of DKA episodes, and annual number of events of severe hypoglycemia.

3. To determine if sociodemographic factors influence diabetes outcome among DT patients, as measured by A1C, growth parameters, annual number of DKA episodes, and annual number of events of severe hypoglycemia.

4. To determine if there is a significant difference in diabetes control between patients whose insulin is refrigerated vs. stored in a clay pot, as measured by A1C, growth parameters, annual number of DKA episodes, and annual number of events of severe hypoglycemia.

5. To comment on insulin dose (units/kg): a. Before and after diabetes management at DT b. In individuals using a refrigerator vs. those using a clay pot

STUDY DESIGN & METHODS

DesignCohort study including prospective interview and retrospective chart review.

Study population All patients followed by DT for T1D management for one year or more Inclusion criteria

o Followed at DT for management of T1Do Followed at DT for ≥ 1 yearo Age <16 years at time of DT presentation

Exclusion criteriao Diagnosis other than T1D: type 2 diabetes, monogenic diabetes

Sample sizeWe will include all patients followed by DT who meet our study criteria and who consent to participate. We anticipate enrolment of approximately 500 subjects.

Subject Enrolment, Data Collection & Management


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Data will be collected by a combination of interview and chart review.

Patients will be invited to participate in the study at the time of their next visit to the DT. They will be approached by an individual separate from the investigative team who will request their consent. Either written or verbal consent will be obtained, depending on the patient’s (or patient’s parent/guardian’s) level of literacy (Appendix 1). Verbal consent will be indicated by a thumbprint and the signature of a witness (of the patient’s or patient’s parent/guardian’s choosing). The written or verbal consent of a parent/guardian will be required for all patients under the age of 18 years. If they are old enough to understand the study, children will be asked to indicate their assent by signature or thumbprint. All study material and consent forms will be available in English and Hindi.

The project research assistant will then complete the questionnaire (Appendix 2) with the patient (and/or parent/guardian) in person. A visual aid will be provided to help individuals to answer Likert scale questions (Appendix 3). Certain items will be entered based on information contained in the patient’s chart (e.g. A1C levels, insulin dose and growth parameters at presentation to DT). We piloted the questionnaire and chart review in January 2011 on four patients, and estimate that the entire process will take 20 minutes per patient.

Each patient will have four A1C levels in a 12-month period performed by a local pharmaceutical company through a charitable, in-kind donation to the DT. A1C will be measured using the Bio-rad in2it point of care analyzer, which uses affinity chromatography (boronic acid) to separate glycated and nonglycated hemoglobin. This method has been found to have satisfactory performance.

This study will not require the patient to make any additional visits to DT or have additional testing outside of routine care. As a result of the pharmaceutical company’s charitable donation, the four annual A1C tests have become part of the DT’s care routine, and are being done outside of the context of this study.

We will assign a unique study number to each patient, which will be linked to the patient’s name in a password-protected file. Data from each interview, with patients identified only by their study number, will be kept in a separate, password-protected file on study laptops. Only individuals who are part of the study group will have access to patient data.

Duration Data collection: 12 months, beginning in summer 2011. Data analysis: 6 months

ANALYSIS OF THE STUDY

The following data will be collected at the time of the study visit by interview or chart review (see Appendix 2), and will then be analyzed by the research team with the help of a CHEO Research Institute statistician. Patient characteristics

Age (years) Sex (male or female)


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Diabetes History & Management o Duration of diabetes (years)o T1D presentation:

DKA or other Management in a public or private hospital or clinic

o Duration of management at DT (years)o Total daily insulin dose (units/kg/day)

Current dose Dose at presentation to DT

o Number of insulin injections per dayo Type(s) of insulin used: regular or/and intermediate or/and basal and/or

premixedo Insulin storage: refrigerator, clay pot, or no storage unito Number of blood sugar tests in last 30 dayso Number of urine sugar tests in last 30 dayso Number of DT visits in last 12 monthso DT sponsor: Life for a Child, private individual Indian, or private individual

internationalo Personal cost of diabetes care (rupees per week)

Total cost Cost of: blood glucose test strips, urine test strips, syringes and A1C

(per year). Medical history

o Other chronic medical condition(s). o Other medication(s)

Sociodemographic datao Casteo Religiono Number of persons in the householdo Average weekly household incomeo Population of hometown, city or village?o Level of parental educationo Is the patient in school, working or both?o Patient marital status & number of childreno Sibling data: number living sibling, sex, diagnosed with T1D or other chronic

medical condition(s)o Travel to clinic: distance (km), duration (hours), cost (rupees per person),

number of people who accompany patient, and DT subsidy per visit (if any, in rupees)

Outcome measures

These measures will be collected retrospectively by chart review at baseline (first presentation to DT) and at the study visit with corresponding dates.

Glycemic control (A1C)o A1C is widely accepted as the gold standard for assessment of glycemic

control.o Samples will be measured on the Biorad in2it by affinity chromatography


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Growth Parameterso Height: will be used to obtain the height standard deviation score (SDS) –

based on the calculations used by the National Health and Nutrition Examination Survey (NHANES) and CDC growth chart information (2000)

o Weight: will be used to obtain the weight SDS - based on the calculations used by the NHANES and CDC growth chart information (2000)

Number of reported episodes of DKA per yearo Number of DKA episodes since diagnosiso Number of DKA episodes since presentation to DT

Number of reported severe hypoglycemic events per yearo Severe hypoglycemia is defined as an episode of hypoglycemia associated

with seizure, coma or requiring assistance with treatment beyond that expected for the child’s given age.

o Number of severe hypoglycemic events since diagnosiso Number of severe hypoglycemic events since presentation to DT

HYPOTHESES

The study’s first and third objectives are descriptive and carry no associated hypotheses:1. To describe diabetes management at DT2. To describe the patient population at DT, thus allowing for assessment of

generalizability (external validity) The other objectives are outlined below with their associated hypothesis:

3. To determine if there is a significant improvement in diabetes control in patients previously followed in other diabetes clinics/public hospitals since being followed at DT, as measured by A1C, growth parameters, annual number of DKA episodes, and annual number of events of severe hypoglycemia.

Hypothesis 2:There is a difference in the baseline (presentation to DT) and follow-up measurements of:

A1C level Height and weight SDS Mean number of episodes of DKA per year Mean number of events of severe hypoglycemia per year

4. To determine if sociodemographic factors influence the diabetes outcomes of DT

patients, as measured by A1C, growth parameters, annual number of DKA episodes, and annual number of events of severe hypoglycemia.

Hypothesis 3:Sociodemographic factors (gender, religion, distance from clinic, mean family income etc.) will not be associated with the following diabetes outcomes of DT


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patients: A1C levels Growth parameters Mean number of episodes of DKA per year Mean number of events of severe hypoglycemia per year

5. To determine if there is a significant difference in diabetes control in patients whose insulin is refrigerated vs. stored in a clay pot, as measured by A1C, growth parameters, annual number of DKA episodes, and annual number of events of severe hypoglycemia. Hypothesis 4:The diabetes control for those patients whose insulin is stored in a clay pot vs. refrigerated will be equivalent at follow-up for:

A1C levels Growth parameters Mean number of episodes of DKA per year Mean number of events of severe hypoglycemia per year

6. To comment on insulin dose (units/kg):

a. Before and after diabetes management at DT b. In individuals using a refrigerator vs. those using a clay pot

Hypothesis 5There is a difference in the doses of insulin at baseline and follow-up. This association may account for improved diabetes control when managed at DT.

Hypothesis 6There is a difference in the insulin doses observed in individuals at follow-up who store their insulin in clay pots vs. a refrigerator. This association may be due to the fact that insulin stored at higher temperature can experience denaturation, thus necessitating higher doses to attain the same treatment effect.

STATISTICAL ANALYSIS

Descriptive statistics will be used to summarize the study sample using mean +/- standard deviation (SD) for continuous variables and number of patients (%) for categorical variables. Univariate comparisons of differences between groups will be analyzed using the wilcoxon rank sum test for continuous variables and the fisher’s exact test for categorical variables. For analysis for equivalence of groups, this will be tested based on pre-specified equivalence limits. Adjusted analyses based on linear regression will be used to address the effects of time and other covariates on the outcomes.

ETHICAL CONSIDERATIONS

Given that this research will take place in a developing country, certain considerations need


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to be taken into account. Here we outline the eight ethical principles and benchmarks for multinational clinical research as proposed by Emanuel et al. :

1. Collaborative partnershipThe idea for this study was born out of our scoping visits to DT. Dr. Pendsey is a local expert and is collaborating on this study as a co-investigator. He is an experienced researcher, having collaborated on many local and international projects. He and his team of experienced health practitioners (including a second local physician, Dr. Rutuja Sharma and a diabetes educator/dietician, Seema Chalkhore), have been intimately involved in developing this research protocol and are delighted to provide local support for the study at no additional cost. Their clinic staff will collect the DT data. Dr. Pendsey has deep ties to his community as well as to local policy makers. He is a strong advocate of pediatric T1D care, and is energetically involved in charitable medical services for T1D patients. Moreover, he is active in raising funds locally and abroad on behalf of his charitable T1D management efforts. The Australian medical team managing the International Diabetes Federation’s Life for a Child program recommended Dr. Pendsey and DT to us.

2. Social valueThe potential beneficiaries of this research are hundreds of thousands of current and future pediatric patients with T1D in resource-poor settings, including the participants in this study. T1D affects as many as 170,000 children in India, and many more in resource-poor settings worldwide. Establishing an effective, practical and sustainable model for T1D care through this research, as well as through future study of other T1D care models, could save lives and prevent long-term health complications. If our findings are positive, we plan to disseminate this indigenous T1D care model to practitioners and scholars in India, as well as across Africa, Asia, the Middle East, and Latin America, using workshops, papers, journal publications, a dedicated website, and other electronic means.

3. Scientific validityThis study was designed by a multidisciplinary team to ensure validity: Dr. Alexandra Ahmet (pediatric endocrinologist), Dr. Caroline Zuijdwijk (pediatic endocrine fellow), Dr. Sharad Pendsey (diabetologist), Dr. James Ron (Ph.D. sociology), and Kathryn Williams (statistician). It has been subsequently reviewed by Dr. Alex MacKenzie (MD, PhD, and past scientific director of the CHEO Research Institute); Dr. Graham Ogle (Pediatric Endocrinologist and Program Manager, International Diabetes Federation’s Life for a Child); Dr. Valerie Percival (DPh, Public Health); and Dr. Rutuja Sharma (diabetolotist). The study questionnaire and chart review were piloted at DT in January 2011 by Dr. James Ron and Seema Chalkhore, DT program manager, for feasibility.

4. Fair selection of study populationAll pediatric patients followed at DT will have the opportunity to participate. We are seeking to describe and evaluate the models of care, and to describe the patient population to determine generalizability.

5. Favourable risk-benefit ratioGiven the nature of this chart review and interview, we anticipate no harmful effects for the patients. Patients will be invited to participate in the study. Participation is voluntary; there will be no adverse effect on their care if they decline participation. They may choose not to answer any question(s) with which they are uncomfortable. Participation will not require


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additional testing or visits to DT. Information will be kept anonymously, with only a study number as identification. Results will be collated so that individual information cannot be identified.

The CHEO Research Ethics Board (REB) has raised concerns over the collection of demographic data on caste and religion, suggesting possible group harms should our research find a statistically significant association between poor health outcomes and membership in a particular caste or religion.

Before responding to this concern in depth, we note Nagpur’s demographic structure:

Nagpur is a major urban centre in eastern Maharashtra State. According to the 2001 Indian census, over four million people live in Nagpur District, some two million of which live in Nagpur City . Scheduled Castes and Tribes comprise some 17% and 11% of Nagpur District’s population, respectively. About 75% of Nagpur District’s populace is Hindu; Buddhists comprise approximately 14%, and Muslims 7.5%.

To ensure that this project is comprehensive, ethical and scientifically valid, we plan to gather information on a wide variety of standard socio-demographic variables, including sex, education, household income, education, family size, size of patient’s home community, and patient distance from a major city. As is common to most studies of Indian social, economic, political and health phenomena, moreover, we will also gather data on patients’ caste and religious identity. We do this for a range of reasons.

1. Scholarly convention: First, as noted in the Oxford Companion to Politics in India, caste is treated by most everyone in India from the “lay public to ... serious academic analysts” as “an important variable.” Few analysts, moreover, “would contest that [in India] religious sensibilities dominate individual collective lives to some extent.” Both caste and religion, in other words, are constitutive sociological factors in India, akin in their importance to other standard demographic factors such as sex, income, occupation, family size, education, and geo-location. As evidence, we note that caste - like race in the United States – forms the basis for a series of affirmative action programs in the Indian educational establishment and its public service, while religious communities may enjoy some separate legal protections.

As a result, any study that examined Indian health outcomes without controlling for caste or religion would suffer, in theory, from omitted variable bias. As such, it would rightfully be regarded by both scholars and health practitioners as scientifically invalid. The non-inclusion of caste and religion in our study, in other words, would be a violation of our ethical obligation to engage in scientifically valid research. 2. Effects on Health Outcomes: The case for including caste, moreover, goes beyond scholarly convention, since previous research has demonstrated an empirical link between caste and health outcomes. One study of 4,196 non-elderly women in rural Kerala , for example, found that women from Scheduled Castes, Tribes, and Other Backward Castes reported higher rates of ill-health than higher-caste women, while another of 4000 rural children found that Scheduled Tribe life expectancy was five years lower than that of higher caste Hindus. The life expectancy of Dalits, moreover, was seven years lower . Another study of anaemia, diarrhoea, and infant mortality found that Scheduled Castes, Tribes, and Other


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Backward Castes scored lower on a range of relevant health outcomes, and benefited less from maternal health and child vaccination initiatives .

Taken together, these and other studies offer strong empirical support for the scientific relevance of caste to any serious study. Any research effort that failed to control for the potential impact of caste would rightly be viewed as scientifically suspect.

3. Discrimination: It would also be ethically remiss to avoid investigating potential discrimination on the part of DT personnel. Although we have absolutely no reason to suspect that any such discrimination is present, prior research demonstrates that health practitioners may subject lower castes to discriminatory practices.

One study in the Punjab region, for example, found that lower-caste girls received less and poorer-quality medical care than higher-caste children of both sexes , while another study found that grassroots health workers discriminated against Dalits in both the private and the public sectors, although public health practitioners were more equitable .

Again, while we have absolutely no reason to fear that the DT engages in discrimination of any kind, it would be ethically remiss to ignore the possibility. It would be both scientifically and ethically remiss to evaluate the DT’s treatment model without controlling for all potentially influential factors, especially those regarded by Indian experts as central to that country’s socio-economic, health and political outcomes. We intend to use caste and religion as control variables only. To avoid any potential “stigmatization” of caste or religious groups, we will be extremely careful in our methods and style of data presentation. We will take all necessary steps to avoid portraying any group in such a way so as to attract negative commentary, and will ensure that all drafts of our articles, papers, and oral presentations are vetted by Indian experts with that concern in mind.

It is important to note, moreover, that we are not doing a population-based study of the Nagpur area, and thus are not making any attempt to estimate overall prevalence of the disease amongst various castes or religions in Nagpur or, indeed, of any region in India. This study focuses only on the DT’s patient population. There should, therefore, be no reason to fear that consumers of our research would infer anything at all from our findings about general disease prevalence or management.

We are collecting information on caste and religion, like any other demographic factor, because it is important to ensure that we have an accurate picture of how different sub-sections of the patient population are faring under the DT’s model. For example, if we discover that Scheduled Caste patients appear to have worse outcomes than upper caste individuals (after controlling for other confounding factors), this is crucial information for the DT, its donors, and our research team. If belonging to a certain caste or religion is associated with poorer diabetes outcomes, both the DT and our research group will have to engage in further qualitative research to ascertain these outcomes’ causes. To design a study that would NOT detect this possible problem would be ethically remiss; we could be missing a possible problem that might pose a risk to the health of specific, vulnerable sectors of the patient population.


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We further note that most DT resources come from overseas donors, and are of a charitable nature; there are no Indian public funds involved. As a result, it is highly unlikely that anyone will argue that public resources are somehow being “wasted” on groups who fail to control their diabetes well. Overseas donors (including large charitable organizations such as Life for a Child, or pharmaceutical companies such as Eli Lilly) are not likely to use poor diabetes control as an argument against awarding resources to specific groups of any kind.

Finally, it should be noted that the DT itself has no concerns about collection of this demographic data.

Given all this, we firmly maintain that it is vital to collect all relevant demographic data, including data on caste and religion. Otherwise, we will not be in a position to conduct a valid and ethical study in India.

6. Independent reviewThis review by the CHEO REB will serve as an independent review. Dr. Graham Ogle of the International Diabetes Federation’s Life for a Child program has also reviewed this proposal, as has Dr. Valerie Percival of Carleton University.

Dr. Pendsey will also forward this protocol and the CHEO REB review to a local REB: “Institutional Ethical Committee of Diabetes Clinic and Research Centre” (see Appendix 4 – address and member information). We will advise the CHEO REB of the deliberations and decisions made by the local REB.

7. Informed consentWe will obtain informed written or verbal consent as described above (Appendix 1). Our team will make it very clear to all patients that their participation is voluntary and that they can refuse participation or withdraw from the study at any time. Their care at the clinic will not be affected in any way by their decision to participate or not in the study. No incentives will be offered for participation.

8. Respect for recruited participants and study communitiesAs described above, participation is voluntary and confidentiality will be respected. Patient information will only be available to the study group and the CHEO REB upon request. Glenmark Pharmaceutical, the company funding A1C testing, will not have access to any patient data.

Once the study is complete, participants and the study community will have access to the results.

BUDGET

Total amount requested: $ 0

Budget justification: At A1C tests: Testing donated by Glenmark Pharmaceuticals

o Glenmark Pharmaceutical, a local pharmaceutical company, has agreed to provide all patients with four A1Cs during a period of 12 months, using the


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Bio-rad in2it point of care analyzer. o A1C testing already being done outside of the study context, but we will use

this information in our study. Laptop

o Donated by Dr. Alexandra Ahmet Data collection & entry

o Labour donated in kind by DT Data collection supervision

o Labour donated in kind by DT Data analysis (statistician)

o Donated in kind by the CHEO Research Institute, given that this project is unfunded


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REFERENCES


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Documents

healthmarketinnovations.org · Web viewA1C will be measured using the Bio-rad in2it point of care analyzer, which uses affinity chromatography (boronic acid) to separate glycated