Clinical trial NCT03258723
Conditions: Diabetes
Sponsor: Yale University
Start date: 2018-07-30; Completion date: 2021-12-01
Enrollment: 114 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Specific Aim: Implement an evidence-based diabetes prevention pragmatic trial for high risk pre-diabetic individuals of Caribbean-descent to reduce the incidence of diabetes.

Hypothesis: This study seeks to test the hypothesis that implementation of a lifestyle intervention, with escalation to Metformin therapy will lower the incidence of diabetes among the highest risk pre-diabetic individuals of Caribbean-descent.

Detailed description:
The investigators propose to conduct a pragmatic trial that tests the effectiveness of lifestyle modification and Metformin use in minority populations. Our study population is Caribbean-descent individuals in Region 2, Trinidad and Barbados. The investigators will have five clinical intervention sites situated in New York - 2, Puerto Rico -1, Barbados -1, Trinidad -1 and US Virgin Islands -1. These sites were chosen because of the investigators' strong research network in these locations, and to enable us to address diabetes disparities due to geographic differences. The investigators will first modify an established lifestyle modification workshop series developed by the East Harlem Partnership for Diabetes Prevention (EHPDP) for use in the community, 10to target the population at the involved clinical sites. The investigators plan to adapt the D-CLIP protocol and escalate to Metformin therapy for the highest risk pre-diabetic patients whose hemoglobin A1c (HbA1c) has not improved or who remain morbidly obese.

The investigators will leverage our existing robust research infrastructure and network at the five sites through our Eastern Caribbean Health Outcomes Research Network (ECHORN) and now the Yale Transdisciplinary Collaborative center for Health Disparities focused on Precision Medicine (Yale-TCC). ECHORN is a research collaboration funded by the NIMHD (U2458849938) to address the burden of chronic disease in USVI, PR and the Eastern Caribbean. The Yale-TCC (U54MD010711) leverages the infrastructure and knowledge of the ECHORN, expands to include New York and New Jersey and focuses on diabetes and hypertension. The investigators' network includes community advisory boards as well as policy delegations that are well suited to inform this project and its expansion into routine healthcare practice and policy.

The control arm of this study was never activated due to COVID-19 restrictions.

Arms: arm 1: Highest risk pre-diabetic patients arm 2: Control participants in existing ECHORN sites (Puerto Rico, Barbados and Trinidad) will be recruited. ECS does not have a recruitment site in New York; therefore, the New York LIME sites will need to recruit their own control participants, through random assignment of consented participants into the intervention and control groups.
Interventions: intervention 1: Lifestyle Intervention intervention 2: Metformin
Intervention descriptions: intervention 1: The lifestyle intervention consists of a series of workshops adapted from the East Harlem Partnerships for Diabetes Prevention that discuss diabetes prevention, finding and affording healthy foods, label reading, physical activity, planning a healthy plate, making traditional foods healthy and portion control.

The newly launched East Harlem Diabetes Prevention (EHDP) project's mobile app, iHEED will be used by intervention participants to help reinforce the content they learn during the workshop series. intervention 2: At 6 months, intervention participants who have not been able to lose weight or bring their HbA1c below the high risk range of 6% (determined by point-of-care testing) will have Metformin prescribed by their provider. Metformin will be prescribed at 500mg twice a day. If no change is seen at 12 months follow up, the dose will be increased to 850mg twice a day.

Protocol documents:
ICF_002.pdf: 
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HIC#: 2000020105
COMPOUND AUTHORIZATION & CONSENT FOR PARTICIPATION IN A RESEARCH 
PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL,
UNIVERSITY OF PUERTO RICO, UNIVERSITY OF THE VIRGIN ISLANDS, UNIVERSITY OF 
THE WEST INDIES
(Baseline and Follow-up Surveys/Clinical Assessments)
Study Title: Diabetes Prevention through Lifestyle Intervention with Metformin Escalation (LIME)
Principal Investigator: 
Marcella Nunez-Smith, MD, MHS
Funding Source: National Institutes on Minority Health and Disparities
Invitation to Participate and Description of Project
You are invited to participate in a research study. This study is designed to prevent diabetes among 
individuals at high risk for developing the disease – those who have blood sugar levels that are higher 
than normal but not high enough to have diabetes (we call this pre-diabetes). We are recruiting 
participants from New York, Trinidad and Tobago, Barbados, US Virgin Islands and Puerto Rico. You 
have been asked to participate because you live in the USA or in the Eastern Caribbean and are a resident 
of one of these islands.
In order to decide whether or not you wish to be a part of this research study you should know enough 
about its risks and benefits to make an informed decision.  This consent form gives you detailed 
information about the research study, which a member of the research team will discuss with you.  This 
discussion should go over all aspects of this research: its purpose, the procedures that will be performed, 
any risks of the procedures, and possible benefits. Once you understand the study, you will be asked if 
you wish to participate; if so, you will be asked to sign this form.
Description of Procedures
If you agree to participate in this study, you will first have a finger stick blood test that will check your 
hemoglobin A1c (HbA1c). This tells us your average blood sugar over the last 3 months. If your level is 
in the high (between 6 and 6.4%) it means you are at risk for developing diabetes and can participate in 
the study. If not, your level is less than 6% or greater than 6.4%, you will be referred to your primary care 
doctor for further care. Other reasons you will not be able to take part of the study are: if you have a 
history of kidney problems or if you are pregnant (women <50years will have a urine pregnancy test 
done). If you enroll in the study, you will undergo a brief physical exam, blood collection and complete a 
survey. In the survey, we will be asking about your medical and family history, and health behaviors.  
You will take the survey on a computer in the clinic site. If you would prefer not to use a computer, a 
paper version of the survey will be provided to you. The survey is available in both English and Spanish. 
Blood samples will be collected from you at the clinic by a nurse. 15ml (or 3 teaspoons) of blood will be 
collected. Some of your blood will be tested, soon after the samples are collected. The tests will measure 
the creatinine and cholesterol levels in your blood. Creatinine is a measure of how well your kidneys are 
working (to make sure it is safe for you to take part in the study). Cholesterol is measured because high 
levels of bad cholesterol in your blood put you at risk for heart disease (we would like to see how the 
level of cholesterol changes during the study). 
After you complete the baseline survey, physical exam and blood tests, you will be asked to attend six 
workshops that inform and educate you on lifestyle practices that will help you prevent diabetes. In the 
workshops, you will learn about the causes of diabetes, and ways to prevent diabetes through healthy 
eating, stress management and physical activity. Each workshop is 2.5 hours long and will take place 
weekly, for six weeks. We will contact you 6 months after we enroll you in the study to come in for a 
follow-up visit. At this visit, you will complete a follow-up survey, brief physical exam and we will carry 
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out another test to see if your HbA1c level has come down. If your HbA1c is reduced, then we will 
encourage you to continue your lifestyle changes and bring you in for follow up again every 6 months; 
you will not be prescribed the medication Metformin.  If your HbA1c level remains unchanged or has 
increased, we will refer you to your primary care physician to prescribe you a medication called 
Metformin. You will continue this medication for the remaining period of the study (30 months total). 
Metformin pills help reduce your blood sugar and therefore your HbA1c level. Metformin is safe to use in 
people with pre-diabetes and has been shown to help prevent diabetes. 
We will contact you again at 12months from the start of the study to complete a follow up survey, 
undergo a physical exam and blood testing for HbA1c. Your cholesterol will also be measured at 12. If 
you do not come to the office to complete the follow-up survey, tests and physical exam, we will make at 
least three additional attempts to contact you to complete them. During your first visit we will ask you for 
the names and contact information of family members or friends that we can contact if we cannot reach 
you. 
Results from the blood tests that are collected and tested immediately can be made available to your 
doctor. Study staff will contact you if anything abnormal is found in your results. 
No identifying information will be included on the survey, the information from the physical exam or the 
samples we collect from you. We will collect your name and contact information so that we can contact 
you for follow-up. This contact information will be kept separate from your test results and the 
information you provide on the survey. If any identifying information is accidentally obtained, it will be 
deleted at the time of review.  All written information will be identified by a number so they will not be 
traceable to you as an individual.  Only aggregated data will be presented in any publicly disseminated 
materials. All data will be kept securely.  The Yale University Human Investigation Committee (the 
Committee that reviews, approves, and monitors human subject research) may review study records for 
auditing purposes. However, these individuals are required to keep all information confidential. Risks and 
Inconveniences
You have the choice to withdraw from participation in the study at anytime. You may be 
contacted after your withdrawal to ask if you would be interested in answering additional 
questions to help us understand the reason for your withdrawal.
You may also be contacted after completion of the study to understand reasons for completion or 
not of the study. 
As part of the LIME lifestyle workshops you will be asked to join a WhatsApp group to facilitate 
discussion between members of your group. You are free to choose to join or not join the 
WhatsApp Group. You are free to leave the group at anytime. If you decide to join the group, 
please note that the leaders of the workshop will also be part of the group to help facilitate 
discussion and answer any questions. These workshop leaders are also part of the study team. As 
part of the WhatsApp group you will be asked if you approve of the chat text to be used for 
research purposes. You will have the option to decline use of your posts or any WhatsApp data 
for research purposes. No monitoring or collection of WhatsApp data will occur before you 
provide your additional approval. This approval request will be sent to you via the WhatsApp 
group and will provide you with a secure link to accept or decline. 
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We will keep your information confidential. We ask that all group members not repeat any information 
shared during the group to others.  However, we have no control over what happens outside of the group. 
Therefore, please, be aware of what you share in the group.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
Risks and Inconveniences
Risks that we foresee include lost work time, inconvenience and potential discomfort with some of the 
questions on survey, the physical exam and sample collection.  Drawing blood may cause minor pain, 
bruising, lightheadedness and on rare occasions, infection. You may choose to withdraw from the study at 
any time prior to completion of this study. You do not have to answer any question you do not want to 
although completed surveys are more helpful than incomplete surveys.  When you are in the workshops, 
you will know the identities of other participants and they will know yours, thus your identity and those 
of your group members will not be confidential in this setting. However, participants will be told that 
participation in the trial is confidential and asked not to share the identities of other participants with 
others in their community.
Additional risks are associated with Metformin therapy if you are prescribed this drug. Metformin is a 
safe drug that is approved for and often given to patients with diabetes and pre-diabetes. However, like all 
medications, it has possible side effects. The most common side effect is diarrhea. This is reduced by 
starting with a small dose and slowly increasing the dose which we will be sure to do. Rare side effects 
that we do not anticipate you getting but you should know about include headache, dizziness, chest 
discomfort, fast heart rate and rash. Additionally, Metformin can cause low levels of a vitamin called 
vitamin B12; your doctor can test for this if he/she thinks you have signs of low levels of this vitamin 
(tingling in your feet, feeling tired). Very rare side effects that we don’t anticipate you having is an acid 
health problem in the blood called lactic acidosis. This is more common in people who have kidney 
problems which is why you are not able to be part of this study if you have kidney problems.
Benefits
It is expected that you will gain significant benefits from the lifestyle and educational sessions, both 
through joining a supportive community of other individuals working to control their pre-diabetes, and 
through information sharing, tools provided for weight loss and lowering your risks for diabetes. It is 
expected that these benefits will outweigh the inconvenience of attending educational sessions. There is 
no financial incentive to attending the lifestyle and educational sessions.
It is expected that the social benefits you will gain from participating in a supportive group that works 
toward the common goal of reducing diabetes incidence will outweigh the risk of losing anonymity 
through participation. 
Economic Considerations 
You will receive also a $20 incentive at each survey and clinical assessment visit you make.
In addition, when you complete an end of workshop survey you will be entered you into a sweepstake for 
a $400 prize.  For participants in Puerto Rico, you will receive in addition, either a $5 parking card or 
$10 to cover your commute to the study visit. 
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Confidentiality and Privacy
Any identifiable information that is obtained in connection with this study will remain confidential and 
will be disclosed only with your permission or as required by U.S. or State law. When the results of the 
research are published or discussed in conferences, no information will be included that would reveal 
your identity unless your specific consent for this activity is obtained.  
We understand that information about you obtained in connection with your health is personal, and we are 
committed to protecting the privacy of that information.  If you decide to be in this study, the researcher 
will get information that identifies you and your personal health information.  This may include information 
that might directly identify you, such as your name, address, telephone number, email address, social 
security number or country ID, and dates related to you, such as date of birth.  This information will be de-
identified at the earliest reasonable time after we receive it, meaning we will replace your identifying 
information with a code that does not directly identify you. The principal investigator (PI) will keep a link 
that identifies you to your coded information, and this link will be kept secure and available only to the PI 
or selected members of the research team. Any information that can identify you will remain confidential. 
Any research materials will be stored in locked cabinets. All data stored on the computer will be password-
protected. Any samples collected from you will be stored in locked rooms inside of locked freezers that 
only research staff can access. The link to your personal information will be kept indefinitely. 
If you decide to take part in this research study, you will be required to give us information about your 
health. In spite of our obligation to protect your identity and information, we would voluntarily report 
information about suspected or known sexual, physical, or other abuse of a child or older person, or a 
subject’s threats of violence to self or others. If any member of the research team is given such 
information, he or she will make a report to the appropriate authorities. 
 
The information about your health that will be collected in this study includes: 
Research study records, medical and laboratory records of only those services provided in connection with 
this Study, the entire research record and any medical information obtained through your participation in 
this study (including the survey and tested samples), records about phone calls made as part of this research, 
records about your study visits. Information obtained during this research regarding: your health from physical 
exams, laboratory and other test results, and survey responses. 
Information about you and your health which might identify you may be reviewed by the Study Principal 
Investigator, the National Institutes of Health (study finding source), and the Human Investigations 
Committee (Yale University) or the Institutional Review Boards at the institutions, overseeing the studies 
in your country (the committees that review, approve and monitors research on human subjects), and the  
U.S. Food and Drug Administration (FDA). This is done so that the FDA can review information about 
metformin involved in this research.  The information may also be used to meet the reporting requirements 
of drug regulatory agencies. By signing this form, you authorize the use and/or disclosure of the information 
described above for this research study.  The purpose for the uses and disclosures you are authorizing is to 
ensure that the information relating to this research is available to all parties who may need it for research 
purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability Act) are 
required to protect the privacy of your information.  The research staff at the Yale School of Medicine 
are required to comply with HIPAA and to ensure the confidentiality of your information.  Some of the 
individuals or agencies listed above may not be subject to HIPAA and therefore may not be required to 
provide the same type of confidentiality protection. They could use or disclose your information in ways 
not mentioned in this form.  However, to better protect your health information, agreements are in place 
with these individuals and/or companies that require that they keep your information confidential. 
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This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers with this Certificate may not disclose or use information, documents, or biospecimens that 
may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other action, 
suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless you have 
consented for this use. Information, documents, or biospecimens protected by this Certificate cannot be 
disclosed to anyone else who is not connected with the research except, if there is a federal, state, or local 
law that requires disclosure (such as to report child abuse or communicable diseases but not for federal, 
state, or local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research subjects. 
In Case of Injury
The Yale School of Medicine do not provide funds for the treatment of research-related injury.  If you are 
injured as a result of your participation in this study, treatment will be provided by your primary care 
provider.  You or your insurance carrier will be expected to pay the costs of treatment.  No additional 
financial compensation for injury or lost wages is available. You do not give up any of your legal rights 
by signing this form.
Voluntary Participation and Withdrawal
You are free to choose not to take part in this study.   Your health care outside the study, the payment for 
your health care, and your health care benefits will not be affected if you do not agree to participate.  
However, you will not be able to enroll in this research study and will not receive study procedures as a 
study participant if you do not allow use of your information as part of this study.
If you do become a subject, you are free to stop and withdraw from this study at any time during its 
course. 
If you sign this authorization, allowing the researchers to use your study information, and you change 
your mind, please understand that the researchers may continue to use information from your 
participation that has already been collected.  To withdraw from the study, you can call a member of the 
research team at any time and tell them that you no longer want to take part.  This will cancel any future 
appointments. If you do not want the researchers to continue to use the information they have already 
collected, you must also follow up your phone call by sending a written notice to revoke this authorization 
to the principal investigator (Marcella Nunez-Smith, ECHORN/Yale University School of Medicine; 
Ste200A, 100 Church St South, New Haven, CT. 06519). 
This authorization to use and disclose your health information will never expire unless and until you 
change your mind and revoke it.  
The researchers may withdraw you from participating in the research if necessary. Reasons for this include 
the following: you develop any of the conditions that make you ineligible for participation (e.g. pregnancy, 
kidney problems); you develop diabetes, you repeatedly exhibit inappropriate behavior towards study staff.
Questions
We have used some technical terms in this form.  Please feel free to ask about anything you don't understand 
and to consider this research and the consent form carefully – as long as you feel is necessary – before you 
make a decision.
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Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project described 
above.  Its general purposes, the particulars of my involvement and possible hazards and inconveniences 
have been explained to my satisfaction.  My signature also indicates that I have received a copy of this 
consent form.
By signing this form, I give permission to the researchers to use [and give out] information about me for 
the purposes described in this form.  By refusing to give permission, I understand that I will not be able to 
be in this research. 
Name of Subject:_____________________________
              
Signature:___________________________________
Date:______________________________________
___________________________________________
___________________
Signature of Person Obtaining Consent
Date
If you have further questions about this project or if you have a research-related problem, you may 
contact the Principal Investigator, Marcella Nunez-Smith, at 203.785.6454.    If you would like to talk 
with someone other than the researchers to discuss problems, concerns, and questions you may have 
concerning this research, or to discuss your rights as a research subject, you may contact the  Yale 
Institutional Review Boards at (203) 785-4688 or email hrpp@yale.edu.
Barbados: Dr. Joseph Herbert -- (246) 426-5051/5053
Trinidad: Dr. Kavita Dharamraj -- (868) 225-4325 Ext. 3361
USVI: Ms. Lyna Fredericks -- (340) 774-7477
Puerto Rico: Dr. Elsie Cruz – (787) 701-1121
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Prot_000.pdf: 
ClinicalTrials.gov ID: NCT03258723 
Title: Diabetes Prevention with Lifestyle Intervention and Metformin Escalation (LIME) 
Last Approved: 6/21/2021 
Document: Protocol 


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HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
Protocol Title: Diabetes Prevention with Lifestyle Intervention and Metformin 
Escalation (LIME).
Principal Investigator: Dr. Marcella Nunez-Smith
Version Date: version 7.0
(If applicable) Clinicaltrials.gov Registration #: NCT03258723
INSTRUCTIONS
This template is intended to help investigators prepare a protocol that includes all of the necessary 
information needed by the IRB to determine whether a study meets approval criteria. Read the 
following instructions before proceeding:
1. Use this protocol template for a PI initiated study that includes direct interactions with 
research subjects. Additional templates for other types of research protocols are available in 
the system Library.
2. If a section or question does not apply to your research study, type “Not Applicable” 
underneath.
3. Once completed, upload your protocol in the “Basic Information” screen in IRES IRB system. 
1. Probable Duration of Project: The expected duration of this project is 2 years 
State the expected duration of the project, including all follow-up and data analysis activities. 
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2. Does this study have a Clinical Trials Agreement (CTA)? 
Yes☐ 
No☒
a.
If so, does it require compliance with ICH GCP (E6)? 
Yes☐ 
No☐
3. Will this study have a billable service? Yes ☐  No☒
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, 
would normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the 
patient or the patient’s insurer. The service may or may not be performed by the research staff on your 
study, but may be provided by professionals within either Yale-New Haven Hospital or Yale Medical 
Group (examples include x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to 
pathology). Notes: 1. There is no distinction made whether the service is paid for by the subject or their 
insurance (Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This 
generally includes new services or orders placed in EPIC for research subjects. 
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
4. Are there any procedures involved in this protocol that will be performed at YNHH or one of its 
affiliated entities? Yes ☐  No ☒ 
If Yes, please answer questions a through c and note instructions below. 
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? Yes ☐  No ☐
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? Yes ☐  No ☐
c. Will a novel approach using existing equipment be applied? Yes ☐  No ☐
 
If you answered “no” to question 4a, or "yes" to question 4b or c, please contact the YNHH Department 
of Physician Services (688-2615) for prior approval before commencing with your research protocol.
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH 
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the 
HRU, the Principal Investigator and any co-investigators who are physicians or mid-level practitioners 
(includes PAs, APRNs, psychologists and speech pathologists) who may have direct patient contact with 
patients on YNHH premises must have medical staff appointment and appropriate clinical privileges at 
YNHH. If you are uncertain whether the study personnel meet the criteria, please telephone the 
Physician Services Department at 203-688-2615. By submitting this protocol as a PI, you attest that 
you and any co-investigator who may have patient contact has a medical staff appointment and 
appropriate clinical privileges at YNHH.
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SECTION I: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
Specific Aim: Implement an evidence-based diabetes prevention pragmatic trial for high risk pre-
diabetic individuals of Caribbean-descent to reduce the incidence of diabetes. 
Hypothesis: This study seeks to test the hypothesis that implementation of a lifestyle intervention, 
with escalation to Metformin therapy will lower the incidence of diabetes among the highest risk 
pre-diabetic individuals of Caribbean-descent. 
2. Background: Describe the background information that led to the plan for this project. Provide 
references to support the expectation of obtaining useful scientific data.
Overview
Despite over a decade of community based lifestyle only interventions, modeled on the Diabetes 
Prevention Program, the prevalence of diabetes among Blacks and Hispanic/Latinos has steadily and 
significantly increased.1,2 Diabetes prevalence in non-Hispanic Blacks and Hispanics/Latinos is now 
21.8% and 22.6% respectively, compared to 11.3% in non-Hispanic whites.3,4 Given the limitations 
of lifestyle intervention alone,5 current guidelines for the treatment of pre-diabetic patients include 
the option of pharmacotherapy with Metformin especially if there is a “history of gestational 
diabetes, age less than 60, BMI≥35kg/m2 and increasing hemoglobin A1c (HbA1c) despite lifestyle 
intervention.”6 The Diabetes Community Lifestyle Improvement Program (D-CLIP) in India was the 
first RCT to study the effect on pre-diabetic patients of step-wise escalation from lifestyle 
modification to Metformin prescribing, and showed a decreased incidence of diabetes.7 Given the 
success of D-CLIP, the addition of pharmacotherapy shows promise in curtailing the frightening 
upward trend of diabetes prevalence among minorities.8 A critical need exists for feasible and 
sustainable prevention interventions that use more than life-style intervention to reduce the incidence 
of diabetes.
We will conduct a pragmatic trial that tests the effectiveness of lifestyle modification and Metformin 
use in minority populations. Our study population is Caribbean-descent individuals in Region 2, 
Barbados, Trinidad & Tobago. We will have six clinical intervention sites situated in New York – 2 
(workshop feasibility and interviews only), Puerto Rico -1, the US Virgin Islands – 1, Barbados -1, 
and Trinidad & Tobago-1. These sites were chosen because of our strong research network in these 
locations, and to enable us to address diabetes disparities due to geographic differences.9 We will 
first modify an established lifestyle modification workshop series developed by the East Harlem 
Partnership for Diabetes Prevention (EHPDP) for use in the community, 10to target the population at 
the involved clinical sites. These workshops are based on an established Stanford Chronic Disease 
Self-Management Program that is validated and has been adapted to several different cultural 
settings. We plan to adapt the D-CLIP protocol and escalate to Metformin therapy for the highest 
risk pre-diabetic patients whose hemoglobin A1c (HbA1c) has not improved. 
We will leverage our existing robust research infrastructure and network at the six sites through our 
Eastern Caribbean Health Outcomes Research Network (ECHORN) and now the Yale 
Transdisciplinary Collaborative center for Health Disparities focused on Precision Medicine (Yale-
TCC). ECHORN is a research collaboration funded by the NIMHD (U2458849938) to address the 
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Table 1: Comparing LIME to other Diabetes Prevention Trials
burden of chronic disease in USVI, PR and the Eastern Caribbean. The Yale-TCC (U54MD010711) 
leverages the infrastructure and knowledge of the ECHORN, expands to include New York and New 
Jersey and focuses on diabetes and hypertension (please note the Yale-TCC as a center works with 
New Jersey, but this study LIME does not have a site in New Jersey). Our network includes 
community advisory boards as well as policy delegations that are well suited to inform this project 
and its expansion into routine healthcare practice and policy.
Preliminary Studies
The flagship project of ECHORN has been the ECHORN Cohort Study (ECS), a unique cross-island 
collaboration including the US Virgin Islands (USVI), PR, Barbados, and Trinidad and Tobago. ECS 
was initiated in 2011 and designed to recruit and follow a community-dwelling adult cohort to 
estimate the prevalence of known and potential risk factors associated with the development of heart 
disease, cancer, and diabetes. To date, the ECS has empaneled almost 3000 adults who are ≥ 40 
years of age, English or Spanish speaking, and who are residents on one of the islands. Preliminary 
analysis of ECS data has been important in confirming the burden of obesity and diabetes in the 
region and in framing our research questions and interventions. In ECS, preliminary results have 
shown that 72% are overweight or obese, 38% are obese (Class I, II and III). 25% of participants are 
pre-diabetic – classified by self-report or HbA1c of 5.7-6.4% or fasting glucose of 100-125 mg/dl.  
25% were diabetic – again, classified by self-report, HbA1c≥ 6.5% or fasting glucose≥126 mg/dl.  
Rationale
Our goal is to conduct a pragmatic trial that introduces a sustainable and feasible diabetes prevention 
intervention that combines lifestyle modification and Metformin prescribing to reduce the incidence 
of diabetes among the highest risk pre-diabetic patients. We utilize several rigorously done diabetes 
prevention studies to design a novel intervention that can be adopted in healthcare settings in a 
feasible and sustainable way. The first of these studies was the diabetes prevention program 
published in 2002.1 Subsequently, there have been several adaptations of the DPP into community 
settings, one of which, supported by the NIMHD, was Project-HEED (Helping Educate to Eliminate 
Diabetes) developed by EHPDP.10 HEED demonstrated the effectiveness of a community-based 
lifestyle intervention in achieving sustainable weight loss. D-CLIP was based out of an academic 
research center in India and demonstrated the effectiveness of stepwise escalation from lifestyle 
intervention to Metformin in reducing diabetes incidence.7 Our proposed LIME intervention 
combines the evidence-based lifestyle intervention of HEED and Metformin escalation of D-CLIP 
into an effective and sustainable intervention in a healthcare setting (Table 1). 
The American Diabetes Association 2017 Guidelines recommend lifestyle modification as well as 
Metformin therapy for pre-diabetic patients.6 The guidelines specify that “Metformin therapy for 
prevention of type 2 diabetes should be considered in those with pre-diabetes, especially for those 
Intervention Components
DPP
HEED
D-CLIP
LIME
Lifestyle Modification
X
X
X
X
Lifestyle + Metformin
X
X
US-based
X
X
X
Targeting Caribbean-descent individuals
X
Integrated into healthcare setting
X
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with BMI ≥35 kg/m2, those aged < 60 years, women with prior gestational diabetes mellitus, and/or 
those with rising A1C despite lifestyle intervention.” Despite this, there is little evidence of the 
effectiveness of lifestyle interventions in high risk pre-diabetics; the average HbA1c in DPP and D-
CLIP was 5.9% and 6% respectively.1,7 By focusing on the highest risk pre-diabetic patients with 
HbA1c of 6-6.4% we hope to add to the literature information on the effectiveness of lifestyle 
modification and Metformin in these individuals. 
Our LIME intervention starts with lifestyle intervention and escalates to metformin therapy 
(prescribed by the participants primary care physician) to reduce diabetes incidence in high risk pre-
diabetic individuals in Region 2 and the Eastern Caribbean. By starting with lifestyle intervention, 
our protocol is in line with the current ADA 2017 Guidelines that recommend Metformin therapy if 
HbA1c increases despite lifestyle. Additionally, guidelines recommend Metformin in all patients 
with a prior history of gestational diabetes and so this group is excluded from the study. The dose of 
Metformin to be used in diabetes prevention is not elucidated in the guidelines. DPP was done using 
a high dose of 850mg twice a day; a dose with known significant side effects. Limited data about the 
effectiveness of lower doses of Metformin for diabetes prevention among minority patients in the US 
is available.8, 12 Therefore, we recommend that the participant’s physician prescribing the Metformin 
start with a dose of 500mg of Metformin twice a day at 6 months. At the 12months follow up, 
patients whose A1c has continued to rise will get their dose gradually increased to 850mg twice a 
day or 1000mg twice a day based on availability.
The LIME study will be piloted in five sites across Region II and the Eastern Caribbean. This offers 
the opportunity to assess the replication of the study’s culturally-tailored intervention framework for 
individuals of Caribbean descent, located in different geographic locations.
3. Research Plan: Summarize the study design and research procedures using non-technical language 
that can be readily understood by someone outside the discipline. Be sure to distinguish between 
standard of care vs. research procedures when applicable, and include any flowcharts of visits 
specifying their individual times and lengths. Describe the setting in which the research will take 
place.
Intervention Sites
The sites that will be implementing the LIME intervention are as follows:
a.
Internal Medicine Clinic at the University of Puerto Rico Hospital in Carolina – Site PI: Dr. 
Elsie Cruz
b. USVI Department of Health, Community Health Services – Site PI: Lyna Fredericks
c.
University of the West Indies, Cavehill and Barbados Ministry of Health Polyclinics – Site PIs: 
Dr. Joseph Herbert, Dr. Paul-Charles, Dr. Sobers-Grannum
d. Southwest Regional Health Authority (SWRHA), La Romaine Health Center (Trinidad&Tobago) 
– Site PI: Dr. Albert Persaud, Dr. Dale Sookoo
Sites that will be implementing only the workshops to assess for feasibility and acceptability of the 
workshops in NYC (participants here may be contacted for qualitative in-depth interviews after 
completion of the workshops):
e.
Union Community Health Center (Bronx, New York) – Site PI: Dr. Vanessa Salcedo
f.
Internal Medicine Associates at Mt. Sinai (New York) – Site PI: Dr. Victoria Mayer
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Sites that are only coordinating research activities and undergoing research analysis:
Emory University School of Medicine
Patient Recruitment: 
We are targeting the highest risk pre-diabetic patients for this study. Patient recruitment will occur 
through the involved health clinics. The Research Assistant (RA) at each site will use either the 
Electronic Health Record (EHR) or paper chart to identify patients who meet the following eligibility 
criteria: 
• ≥40-60 years old 
• BMI≥23kg/m2 or WC≥80/90cm
• No history of type I or type II diabetes or gestational diabetes
• Not on blood sugar altering medication 
• Non-pregnant 
• Linkage to healthcare provider to order medication and labs
• Health insurance to cover medication and labs
• Ability to attend weekly sessions
• Normal creatinine (If prior serum creatinine present in the record)
Individuals who meet eligibility criteria will be called in to participate in one of the study site’s 
“Recruitment Days.” Entry into a sweepstake for an I-Pad Mini will provide incentive for participation 
in the “Recruitment Day.”  All participants who attend the Recruitment Day (regardless of whether or 
not they enroll in the study) will be eligible to participate in the sweepstake. 
We will also provide informational flyers to providers at each site (see attached flyers 1, 2 and 3) to 
encourage them to screen and refer patients to the study, In addition, we will post recruitment flyers in 
the waiting rooms of clinical sites aimed at garnering patient interest in the study. We will also have a 
patient tri-leaflet with pertinent study and study contact information.
Recruitment Day Procedure: here participants will hear more about the study and if interested will be 
formally consented (see consent process). Participants will then first undergo point of care (POC) 
HbA1c testing if they do not have an HbA1c result in their medical records from within 31 days of the 
Recruitment Date. If participants do have an HbA1c result from within 31 days in their medical records, 
that result will be used as their screening HbA1c value. If the measured or recorded HbA1c value is 
≥6.5%, the participants will be excluded as they are possibly diabetic and will be referred to their 
primary provider for a confirmatory serum HbA1c test. If HbA1c<5.7, these participants are neither 
diabetic nor pre-diabetic and will be excluded. If HbA1c is between 5.7 and <6, individuals are pre-
diabetic but low risk and are referred to their provider for routine care. Patients with HbA1c of 6-6.4% 
are deemed high risk pre-diabetics and can be enrolled in the study. Women of child-bearing age 
(age<50years) will undergo a urine pregnancy test to ensure eligibility for enrollment. 
Control Participants
Control participants will be individuals who were identified as being eligible for the LIME study but 
who did not come to any of the workshops (deemed non-completers). These non-completers will be 
contacted 12-24months after their initial consent to ask if they would be interested in returning to the 
assessment center for follow up survey, clinical assessment, and laboratory studies. They will be 
provided an incentive for participation in the survey as outlined in the original consent form. Control 
participants will be reconsented (see new consent form) to outline that even though they did not 
participate in the intervention they can still obtain their follow up laboratories and compensation. 
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New York Sites
The Union Community Health Center (UCHC) and the Internal Medicine Associates at Mt. Sinai (IMA) 
will not be recruiting patients for study purposes. At UCHC and IMA, providers will refer any patient 
with pre-diabetes who is interested to the LIME workshop. The patients with pre-diabetes will attend 
workshops and follow up with their provider as recommended. They will not participate in any survey, 
clinical assessment or laboratory studies.
A post-workshop evaluation that is standard as part of the curriculum is voluntary if participants would 
like to complete it at the end of the workshop series. This survey will only provide feedback on the 
workshop curriculum. 
Participants and implementers (administration and workshop facilitators) will be asked if interested in 
participating in qualitative interviews. These individuals will be contacted and consented for in-depth 
interview participation (see qualitative interviews below). 
Consent Process
Consent will be obtained by site RA trained in consenting participants. Consent forms will be available 
in English and Spanish (included with HIC protocol submission). Informed consent will be obtained at 
the prior to any data collection and participants will be asked to consent to being contacted for follow-up 
at regular intervals. Each subject will be assigned a unique ID that will follow them over the study 
period and beyond. 
The following sites will have the option of obtaining the signed consent on REDCap: Barbados, 
Trinidad, and the USVI.  These sites will have the option of obtaining signature of consent using the 
REDCap e-signature function on the REDCap data collection system. REDCap is a secure platform 
where no data is saved locally and all data is backed up automatically in a secure Yale server. 
Sample Size:
The primary outcome of the LIME pilot study is reducing the hemoglobin A1c of high-risk individuals 
with pre-diabetes. The estimated total sample size of 250 participants (125 intervention and 125 control) 
is required to provide an 80% power to detect a ≥20% difference in proportion of individuals whose A1c 
drops below the high risk cut off of 6%-6.4%. Taking into account a ~ 20% loss to follow-up We need a 
total sample size of 330. Based on prior diabetes intervention studies,1, 7 a statistically significant effect 
of the intervention on hemoglobin A1c will be seen at 12months. Control participants will be 
participants who were deemed eligible for the study but who did not attend a workshop (non-
completers). These non-completers will be contacted 12-24months after their baseline assessment to 
guague their interest in returning for a follow up assessment. 
Table 1: Sample distribution, assuming 10% attrition rate
No. 
of 
Sites
# Recruited
(10% attrition)
Overall Sample Size
330
Barbados
non-completers control
Intervention
1
40
40
Puerto Rico
1
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Intervention
40
Trinidad & Tobago
non-completers control
Intervention
1
75
65
USVI
Intervention
1
20
New York – UCHC
Control
Intervention
1
00
New York -- Sinai
Control
Intervention
1
0
0
Baseline Assessment:
Consented participants will undergo a baseline clinical assessment (height, weight, waist circumference, 
hip circumference, waist-hip ratio, neck circumference, blood pressure), baseline laboratory testing and 
complete a survey. 
Clinical assessment: 
Basic clinical assessment will be done measuring height, weight, hip circumference, waist 
circumference, neck circumference, and resting blood pressure.
Laboratory testing: 
HbA1c will already have been collected. For patients who do not have a cholesterol level or creatinine 
test in the medical record in the past 12 months, they will have blood drawn (15ml of blood) for 
cholesterol and creatinine. If creatinine is found to be elevated (contraindication to Metformin therapy), 
participants will be excluded and offered appropriate referral to a provider. 
We will provide HbA1c point-of-care machines to all sites throughout the study; this is to ensure the 
consistency of the point-of-care testing. We will cover the costs of cholesterol and creatinine tests in 
Trinidad & Tobago as the Trinidad & Tobago Ministry of Health has a shortage of reagents, therefore 
limiting their capacity to test patients despite universal health coverage.
Survey: 
A survey will be administered that covers basic socio-demographics, health history, physical activity 
level, food/beverage intake, social desirability scale and self-efficacy score. 
All participants will receive written and verbal material about pre-diabetes and results of all their 
screening tests. They will undergo a basic clinical assessment for the following measurements: weight, 
waist circumference, neck circumference, hip-to-waist ratio, and resting blood pressure. 
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Intervention
Figure 1 provides an overview of the LIME 
intervention
Lifestyle Intervention
The lifestyle intervention consists of a series 
of workshops adapted from the East Harlem 
Partnerships for Diabetes Prevention 
(EHPDP) that discuss diabetes prevention, 
finding and affording healthy foods, label 
reading, physical activity, planning a healthy 
plate, making traditional foods healthy and 
portion control. These workshops are based 
on the Stanford Chronic Disease Self-
Management Curriculum.13-16 It is a series of 
6 weekly workshops each 2.5hours long. No 
incentive will be provided for attending the 
workshop as we are assessing feasibility of 
this intervention.
Staff will call participants to remind them of 
upcoming workshop sessions (see workshop 
follow up call script)
The newly launched EHPDP project’s mobile 
app, iHEED will be used by intervention 
participants to help reinforce the content they 
learn during the workshop series. iHEED 
does NOT collect any Protected Health 
Information (PHI) and only offers lifestyle 
behavior modification resources and support. 
iHEED is designed to encourage group 
support and activities, provide updated news 
and information on diabetes prevention and tailor geographically- relevant resources to an app user’s 
select needs (http:// projectheed.com/heed-app/). 
Using mobile apps to influence healthy behavior such as healthy eating and increased physical activity 
links back to the theory of planned behavior, which posits that intended behavior (healthy eating and 
increased physical activity) is highly influenced by one’s attitude towards the behavior, subjective norms 
and perception of behavioral control. 17 App usage has been associated with adoption and maintenance 
of healthy behaviors of healthy eating and physical activity. 18 Perceived effectiveness of health 
behavior-modifying apps has also been linked to the type of app user (multiple vs. single app user), 
duration of use, adherence measured via frequency of app use in an extended time frame, and goals 
setting. 18 Some participants will not have smartphones and not be able to use this app. 
Post-workshop Survey:
At the end of the completion of the 6-week workshop series, participants will be given a short survey 
(GPAQ, NHANES DSQ, self-efficacy, choice of LSM sustainability approach). This additional survey 
will allow evaluation of sustainability of acquired healthy behaviors during the workshop series. This 
Screen for 
eligibility*
POC HbA1c** 
6-6.4%
-Baseline survey
-BMI, BP, WC, hip
-Bloodwork (chol, 
creatinine)
Intervention:
-Lifestyle intervention 
workshops***
-Metformin added at 6 
months if HbA1c remains 6-
6.4% and no significant 
weight loss 
Follow up:
@ 6, 12months
Survey, BMI, BP, WC, hip
Bloodwork (chol, HbA1c)
Control:
ECHORN Cohort Study 
participants who meet 
the same eligibility 
criteria and HbA1c 6-
6.4%
Follow up:
@12 months
BMI, BP, WC, hip 
Bloodwork (Chol, HbA1c)
*Eligibility Criteria:
• >=40-60 years old
• BMI>23 or WC>80/90cm
• No history of type II DM 
or gestational DM
• Not on blood sugar 
altering medication
• Linkage to 
provider/system to 
have blood testing and 
medication
•
Insurance to cover 
medication and testing
Figure 1: Intervention Schematic
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survey will be completed on paper and responses manually entered into REDCap by the RA or data 
coordinating center. The incentive for completion of this survey will be participation in a sweepstake for 
$400 prize. 
Metformin Escalation
At 6 months, intervention participants who continue to have an HbA1c (determined by POC testing) to 
be between 6-6.4%, and have not had at least 5% weight loss, will have Metformin prescribed by their 
provider. Participants who have an HbA1c below 6% or have lost at least 5% of their weight will not 
have Metformin prescribed at 6 months. Metformin will be prescribed at 500mg twice a day.12 There is 
data to support the effectiveness of lower doses of Metformin for diabetes prevention in Chinese and 
Indian populations, we do not have information specific to minority populations in the US.12 Therefore, 
we will start at a low dose of 500mg twice a day. With the end of the subjects participation at the 12 
month follow up visit, continued metformin doses (and whether to increase the dose or not) will be up to 
the provider’s discretion and drug/dose availability. Written and verbal information regarding 
Metformin, common side effects will be provided to the participants. Participants will be given a nurse’s 
number to call to discuss any side effects from the medication. Adherence to Metformin will be 
monitored by pill count – at scheduled visits with participant’s primary providers or at LIME follow up 
visit at12-; a self-reported adherence measure will also be used.19 It is expected that primary physicians 
who end up prescribing Metformin to the participants will routinely schedule their patients for a follow-
up appointment in less than 6 months, to assess their performance on the new medication.
Metformin will be prescribed by the providers at the LIME clinic site. These are the primary care 
physicians who routinely care for the patients who are the LIME participants. These providers are not 
listed as co-investigators; this is an evidence-based intervention that is part of appropriate and routine 
care of their patients. These providers will attend 2 in-service sessions: 1. Study Protocol and 
parameters: this will be a description of the study rationale, protocol details, inclusion/exclusion criteria, 
monitoring and evaluation. 2. Metformin Prescribing: this second session will focus on the prescribing 
of Metformin for pre-diabetes and in the context of this study. Dosing of the prescription, how to 
educate the patient on side-effects of Metformin and when to contact the provider, and bringing the 
patient back in for follow up. Monitoring of whether Metformin is being prescribed per protocol will be 
done through intermittent chart review by the research assistant at each site. 
The investigators do not have any existing clinical relationship with potential subjects. The investigators 
are affiliated with the institutions/clinics where the primary care providers deliver care to the LIME 
participants and will be prescribing Metformin. This affiliation allows them access to Clinic Provider 
Meetings and other information sessions. This will be the avenue through which, investigators and the 
research team, deliver information regarding the study and Metformin prescribing to the providers. At 
this time, there will be a discussion with providers around the evidence to support Metformin for this 
population and motivate provider adherence to the protocol and Metformin prescribing.
In Puerto Rico, the U.S. Virgin Islands, Barbados, and Trinidad patients’ insurance will cover the cost of 
Metformin. 
Follow-Up
Intervention Participants:
Follow up calls will be made with participants 3months after each visit to remind them of their 
engagement in the study and update any necessary contact information (See 3-month follow up call 
script).
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Intervention participants will be called back for follow up at 6, and 12, months. A $20 incentive will be 
offered at each follow up visit. At each follow up, the following will take place:
Clinical assessment: 
Repeat clinical assessment will be done measuring height, weight, hip circumference, waist 
circumference, resting blood pressure.
Laboratory testing: 
Laboratory testing at follow up will be done for HbA1c and Cholesterol (15ml of blood will be 
collected). HbA1c will be done by point-of-care (POC) machine every 6 months. If at any point of 
follow up the HbA1c becomes 6.5% or above; the patient will be informed that they may now be 
diabetic and need to get a serum test for HbA1c done by their provider. The result of the confirmatory 
serum HbA1c test must be subsequently reported to the LIME site to document incident cases of 
diabetes. 
Cholesterol is covered by insurance not more frequently than every year, so will be checked at 12 
months. As mentioned for baseline testing, we will cover the costs of cholesterol and creatinine tests in 
Trinidad & Tobago as the Trinidad & Tobago Ministry of Health has a shortage of reagents, thereby 
limiting their capacity to test patients despite universal health insurance.
Survey: 
A brief follow up survey will be administered that covers physical activity level, food/beverage intake, 
social desirability scale and self-efficacy score. At months 6 and 12 additional questions will be asked to 
assess the choice of sustainability approach that was used to sustain the LSM behaviors learned through 
the workshop series. 
HbA1c changes at follow up
Patients will remain in the study for the duration of the study period regardless of whether their HbA1c 
increases or decreases. Figure 2 describes what happens at different time points in the study depending 
on changes in the HbA1c.
ECS Control Participants
Control participants will be individuals who were identified as being eligible for the LIME study but 
who did not come to any of the workshops (deemed non-completers). These non-completers will be 
contacted 12-24months after their initial consent to ask if they would be interested in returning to the 
assessment center for follow up survey, clinical assessment, and laboratory studies. They will be 
provided an incentive for participation in the survey as outlined in the original consent form. Control 
participants will be reconsented (see new consent form) to outline that even though they did not 
participate in the intervention they can still obtain their follow up laboratories and compensation. 
At this follow up, they will undertake a survey, clinical assessment (weight, height, BP, WC, HC, neck 
circumference) and bloodwork (HbA1c and cholesterol) similar to the intervention participants. Of note 
here that the follow up interval for control and intervention participants is different. This is due to the 
fact that time from baseline differs depending on participant and island. A $20 incentive will be offered 
for each follow up visit.
New York Site Control Participants.
As New York’s UCHC and IMA are not recruiting patients they will not need control participants. 
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HbA1c 6-
6.4% AND 
no weight 
loss
HbA1c <6% or 
5% weight loss
Figure 2: Decision tree for intervention participants based on HbA1c changes at follow up 
intervals of 6, and 12months
Primary and Secondary Outcomes
Our primary outcome for this pilot study is reduction in HbA1c. Prior studies including DPP and D-
CLIP have shown a reduction in HbA1c in intervention arm within 6 months, so 12months should be 
sufficient to see a difference as well as any rebound increase in HbA1c. 7, 20 Our sample size has been 
powered to show a statistically significant difference in proportion of participants who have an HbA1c 
below 6-6.4% in the intervention and control study arms. 
Secondary outcomes include: cholesterol level (cholesterol is a known risk factor for cardiovascular 
disease), weight, blood pressure, diabetes risk score, 21 self-efficacy score, 22 amount of physical activity 
(self-reported using the WHO Physical Activity Questionnaire, fruit and vegetable intake, sugar-
sweetened beverage intake. 
Data Collection
Data collection will occur at all baseline and follow up visits. 
Prior to Recruitment
Prior to enrollment, staff at each clinic site will review the paper or electronic medical records of 
patients seen at each participating clinic. Clinic staff will keep a list of potentially eligible participants to 
be contacted for recruitment day. The clinic staff will contact the patient to inform them about the 
Recruitment Day and encourage them to attend so as to learn more about the LIME study and provide 
informed consent (see waiver of consent below). Staff will record the list of eligible participants, contact 
attempts, if they decline attending Recruitment Day, reason for declining, if accepting, date of 
Recruitment Day they will be attending, relevant clinic data (HbA1c, weight, height, creatinine and 
creatinine test date, last cholesterol level and cholesterol test date). This information is important in 
establishing reach of the intervention and also facilitate coordination on Recruitment Day. This form 
will be accessed through Vanderbilt University’s Research Electronic Data Capture software (REDCap) 
and provides each patient a unique patient identifier. 
Once recruitment is completed, we will de-identify all outreach REDCap data. This de-identified datea 
can then be used to evaluate characteristics of individuals who chose to participate in the study and those 
who did not.
At Baseline
The RA will complete an intake form with participants. This intake form will be administered through 
Vanderbilt University’s Research Electronic Data Capture software (REDCap) and provides each 
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participant a unique participant identifier. Participant’s name and contact information will be included in 
the intake but this information will be stored separately from other patient-related data (de-identified). 
The REDCap instrument containing the participant names and contact information will be kept separate 
from the other REDCap instruments containing PHI. Access to identifying information will be limited to 
the site PI(s) and RA(s) at each LIME site. Additionally, each LIME site will only have access to their 
site’s data, and a very limited number of individuals within each site will have access to the REDCap 
instrument containing PHI. All individuals with access to REDCap will receive extensive training in 
how to use the program and data confidentiality. The information in the LIME REDCap projects is 
temporarily stored on a tablets at each site when wi-fi/internet is not available. The information is 
backed up regularly to an online REDCap database and subsequently uploaded to a secure folder on a 
Yale Server.
Participants will have the option of completing the consent process in REDCap (they will still receive a 
paper copy). 
Participants will complete the baseline survey on a computer using REDCap. The survey will be 
available in English and Spanish. A copy of the patient survey is included in the HIC protocol 
submission. The REDCap software also has a text-to-speech (TTS) functionality that enables the 
questions to be read out loud to participant filling out the survey. RAs will orient participants to the 
program and process and will be available throughout to provide assistance as needed. The questionnaire 
will take 35-40 minutes to complete and can be interviewer- administered in pen/paper format if 
preferred by the participant. Participants will take the survey on a tablet or desktop computer. Data from 
these participants will be stored only temporarily on encrypted tablet/computer if wi-fi/internet is not 
available. All survey data stored on the tablet and computers will be backed-up on a regular basis to the 
online REDCap database at the site and will be uploaded onto a secure folder on a server at Yale. 
The clinical parameters will be collected in a private room; this will take 10 minutes. Weight will be 
obtained using an electronic scale. We will obtain blood pressure, hip to waist ratio, neck circumference, 
hip circumference and waist circumference readings twice and record the average of the results. These 
values will be entered into the REDCap database using a unique patient identifier. 
Laboratory values include the POC HbA1c, cholesterol and creatinine. 15ml of blood will be collected 
from each participant to carry out these tests. These will also be recorded in REDCap as well. 
At Follow Up
A brief follow up survey will be administered through REDCap as above. Clinical and laboratory 
parameters (POC HbA1c and Cholesterol only, 15ml of blood will be collected) will be collected and 
recorded in REDCap as at baseline.
Control Participants:
ECS participants are not able to be used as controls given COVID-19 restrictions limiting number of 
persons allowed in the assessment centers. 
We propose contacting participants who screened in as eligible but never came in for a workshop or 
subsequent visit (non-completers), we would like to ask these participants if they would be interested in 
coming in to complete a a follow up survey and clinical laboratory assessment as outlined in the original 
consent form.  We would offer this even if they did not participate in the intervention. 
Additional COVID-19 Survey
An additional survey will be distributed to all participants who have attended at least one workshop to 
understand how the COVID-19 pandemic has impacted their ability to adhere to a healthy lifestyle. 
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The LIME intervention relies heavily on the ability of participants to apply what they learned in the 
workshops regarding the maintenance of a healthy lifestyle. Unfortunately, the current COVID-19 
pandemic has made it challenging to be active outdoors and obtain fresh fruits and vegetables. This 
survey is trying to capture participant ability to maintain a healthy lifestyle. 
We will distribute the COVID-19 survey through the WhatsApp groups which most participants are 
members of. The participants will have a link. The link will take them to an informational page and 
consent addendum. We are requesting a waiver of consent for the COVID-19 Survey, so the participant 
will check the box in REDCap to provide non-signature documented consent. Once they consent they 
will be taken to the survey.
Table 2: Summary table of proposed data collection elements, frequency, and timing for LIME intervention study participants from 
baseline to 12 months  
Schedule
Baseline
Year 1
LIME non-
completers
Months
0
6
12
12-24months 
POC HbA1c




Cholesterol



Creatinine

Blood pressure




Weight




Height




Hip to waist 
ratio




Neck 
circumference




Baseline 
patient survey


Socio-
demographics

Past Medical 
History

Family History

Follow-up 
patient survey



Diabetes risk 
score



Self-efficacy 
score



Amount of 
physical 
activity




Dietary 
Screener 
Questionnaire




Medication 
Adherence



Social 
desirability 
scale



PROMIS 
Global Health




Choice of LSM 
sustainability 
approach


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Quality control
Checks of data entry will be run by the data coordinating center at Yale every 2 weeks. This will entail 
ensuring that all participants have been consented (or re-consented as appropriate), all necessary data 
fields have been entered, incentive has been given as appropriate. For clinical assessment parameters, 
quality checks will include the assessment of clinically appropriate measures. 
Data Analysis
Intention-to-treat analysis
We will adopt the intention-to-treat principle to analyze the data collected. We will compare 
participants’ self-reported demographic characteristics at baseline, using bivariate comparisons with χ2 
tests. We will also assess and compare changes in participants' HbA1c, BP, cholesterol, weight, waist 
circumference, fruit and vegetable intake, physical activity, diabetes risk prediction score, and self-
efficacy score at baseline, 6 months, and 12 months, between the control and LIME intervention groups. 
We will perform two-sample t-tests and F-tests to show any significant differences between the study 
arms and repeated measures analysis to assess the longitudinal changes of study measures over the 
duration of the study. We will note here that the follow up intervals for intervention and control 
participants are different for practical reasons. This will need to be considered in the analysis.
Feedback
Feedback from participants and providers involved in the LIME intervention will be elicited through a 
text-based or email-based survey that will be sent out every 3 months.. 
Timeline
Year 1
Year 2
Months of the Year
1-4
5-6
6-12
1-6
Intervention Months
1-6
7-12
IRB Approval by sites
Staff training to conduct 
workshops
 
Equipment purchase 
 
Staff train on POC 
machine
Patient Recruitment and 
Enrollment
 
Intervention
 
Qualitative Interviews:
To understand the contextual factors that influence implementation effectiveness we hope to conduct in-
depth interviews with participants and providers at each of our sites as outlined below.
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Interview Guide: the interview guide (see supplemental documents) is based on the Consolidated 
Framework for Implementation Research (CFIR) and seeks to understand, from the provider and 
participant perspective, the factors that influence the effectiveness of the intervention. The CFIR is an 
evidence-based, comprehensive, and practical taxonomy of constructs that influence implementation. 
The CFIR was developed by Damschroeder et al in 2009 to combine the many implementation theories 
that promote effective implementation but have different terminologies and definitions. It provides a list 
of constructs that have been shown to describe why, how, and where interventions work. Researchers 
can select constructs from CFIR that are most relevant to their study setting and use these to guide the 
design of interventions, evaluation of implementation progress, and post-implementation results.
 
Data Collection:
Research assistants (RA) at each of the 4 implementing study sites (Barbados, Trinidad, Puerto Rico, US 
Virgin Islands), already affiliated with ECHORN but not involved in the LIME study, will be trained on 
qualitative interviewing skills. This training will be a combination of online video tutorials on our 
established ECHORN training platform SchoologyTM, and online mock interviews with our team’s 
qualitative experts. Using local RAs is critical to ensuring consistency in cultural and language fluency 
at each site. Four providers at each site will be interviewed and include an administrator, a workshop 
leader, a Metformin prescriber, and a front-line staff member. Four patients at each site will be 
purposively sampled to ensure at least two men and two patients on Metformin. The trained RA will 
conduct interviews at each site 6 months after the start of recruitment (June 2019-June2020). For quality 
assurance, we will convene a team of qualitative experts to review the first set of interview recordings 
from each site. A virtual meeting with all RAs will be held to provide collective feedback. A second 
similar session will be held after the third round of interviews. Interviews will be transcribed and 
translated to English when necessary.
On each island we will interview 4 implementers and 4 participants. These individuals are chosen 
randomly based on position/role in LIME (for implementers) and gender/workshop attendance (for 
participants). 
Non-completer interviews
In addition, we will identify 2 participants who initially consented to being part of the study but 
subsequently decided not to attend the workshops. Since they did not come to the workshop these 
participants were considered non-completers of the study. These participants were contacted at least 3 
times to schedule them into a workshop; only after 3 attempts are they then labeled as non-completers. 
All noncompleters will be sent an email flyer asking them to complete a completely anonymous short 
survey via a link (survey in appendix documents). The flyer will also ask them to reply to the email with 
a phone number if they agree to be interviewed. Compensation of $25 will be offered if they are being 
interviewed. The interview will be conducted over the phone or on Zoom whichever is more convenient 
for the participant. 
Consent process for noncompleters
For the interviews, the participant will be emailed a link to a consent form on REDCap. He/She can sign 
the online consent form. The interview will also repeat the consent over the phone to ensure no 
additional questions.  [please note standard phone consent requirements cannot be followed as a result of 
the current COVID19 pandemic limiting ability to mail paper consent forms]
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NYC UCHC, Bronx Interviews
We will identify participants and implementers at the UCHC in the Bronx for in-depth interviews. We 
will use the same interview guide to address contextual factors that influence implementation 
effectiveness. The same qualitative interview consent guide will be used.
Analysis: 
Coding will start immediately and will be iterative. Content analysis using the CFIR as a framework, 
will be used for coding. Future interview guides will be amended to further explore emerging themes 
that remain unclear or under-defined. More interviews may be needed to reach saturation. Team coding 
will be multi-disciplinary and include a Yale-TCC consortium/stakeholder member who has pre-
diabetes but not involved in the study, a Caribbean-based research assistant, an expert in qualitative 
analysis, and Dr. Hassan. All team members will be trained on the use of the CFIR. We will also be 
open to new themes that arise inductively from the data. Applying previously described methodology, 
transcripts will be independently reviewed and team members will meet regularly to discuss emerging 
ideas, resolve discrepancies, and reach consensus regarding the codes. A case memo for each site will be 
generated organized by CFIR construct: where each construct has a summary statement with supporting 
quotes. Transcripts will continue to be coded, adding to the case memo. We will use ATLAS.tiTM 
(ATLAS.ti GmbH, Inc., Berlin, Germany) to facilitate data management and retrieval
Analysis of WhatsApp Data
During LIME Workshop sessions, each workshop group has spontaneously created their own WhatsApp 
group with all members of the workshop. Participants are free to post on the group, read postings, or 
remove themselves from the group as they see fit. On WhatsApp all members of the group have the 
ability to see who has read a message and who has posted a message. The research assistants who are 
also the workshop leaders for that group are all members of the WhatsApp group.
The purpose of analysing the WhatsApp data is to understand whether or not engagement in the group 
meant more engagement with the healthy lifestyle lessons that were learnt in the workshop. The 
hypothesis is that the more engaged someone was the more likely they were to adhere to lifestyle 
change. The second hypothesis is that a group that had engaged individuals was more likely to spill over 
to others in the group.
The WhatsApp group membership includes: all workshop participants and the 2 workshop leaders. We 
will be exporting the chat text from WhatsApp. WhatsApp has a chat text export function for this 
purpose. Anyone who has not consented for their data to be used will not have their information 
exported. Once exported we will de-identify all phone numbers/names and only use record ID numbers. 
The file with the chat and record ID numbers will be stored in a secure Yale Server. This will be a one 
time chat export at the 6months (2months window) and the 12months (2months window) follow up 
periods. At the 6-month mark, all data between the time the chat was initated and 6months is exported. 
At the 12months mark, all data between the 6months and 12months time point are exported. In between 
the chat export dates, there is no monitoring of participant activity so as not to contaminate the 
interaction. 
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We will count the number of times each participant reads a WhatsApp message, and posts a WhatsApp 
message. We will then see if the number of posts/reads is associated with the sustaining healthy lifestyle 
change. 
Please note that non-completer control participants do not engage in the WhatsApp Group. 
Consent process for the WhatsApp Data:
We will send a link on each of the WhatsApp groups to a consent form (see WhatsApp consent). This 
will take the participant to a secure REDCap consent where they can approve or decline. Individuals 
who do not approve or decline will be called by the RA/workshop leaders to obtain consent over the 
phone. If consent is being obtained over the phone, the participant will still be asked to sign the REDCap 
consent form. [please note standard phone consent requirements cannot be followed as a result of the 
current COVID19 pandemic limiting ability to mail paper consent forms]
If a participant declines to have their WhatsApp data used. The WhatsApp group chat can still be used 
but any posts by that participant will be deleted and cannot be used for analysis. 
4. Genetic Testing   N/A ☒
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will be 
received
iii. the types of information about the donor/individual contributors that will be entered into 
a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for future 
research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers that 
connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer identified: 
that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials 
5. Subject Population: Provide a detailed description of the types of human subjects who will be 
recruited into this study.
Patients who are recruited into this study will be patients who seek care from these six clinical sites in 
Region II and the Eastern Caribbean:
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a.
Internal Medicine Clinic at the University of Puerto Rico Hospital in Carolina 
– Site PI: Dr. Elsie Cruz
b. USVI Department of Health, Community Health Services
-- Site PI: Lyna Fredericks
c.
University of the West Indies, Cavehill and Barbados Ministry of Health Polyclinics 
– Site PIs: Dr. Joseph Herbert, Dr. Paul-Charles, Dr. Sobers-Grannum
d. Southwest Regional Health Authority (SWRHA), La Romaine Health Center 
(Trinidad&Tobago) – Site PI: Dr. Albert Persaud, Dr. Dale Sookoo
e.
Union Community Health Center (Bronx, New York)
– Site PI: Dr. Vanessa Salcedo
f.
Internal Medicine Associates at Mt. Sinai (New York) 
– Site PI: Dr. Victoria Mayer
The patients will need to be English or Spanish speaking and meet the eligibility criteria outlined below. 
The socio-demographics of the patient population at these clinics are outlined below:
University of the West Indies, Cavehill and Barbados Ministry of Health Polyclinics
Practice location: Barbados
Patient demographics (race/ethnicity and gender):
--96% African Caribbean/Black
--70% Female
Southwest Regional Health Authority (SWRHA), La Romaine Health Center
Practice location: Trinidad and Tobago
Patient demographics (race/ethnicity and gender):
--42% African Caribbean/Black
--29% East Indian
--29% Mixed
--61% Female
Union Community Health Center, Bronx, New York
Practice location: New York (Bronx)
Large proportion Hispanic
 
Mount Sinai Internal Medicine Associates
Practice location: New York (Manhattan)
Patient demographics (race/ethnicity and gender): 
--34% African American
--48% Hispanic (majority Puerto Rican)
--13% White
--5% Other
 --66% Female
USVI Department of Health, Community Health Services
Race
--Black: 73.5%       
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--White: 16.5%
--Other: 10%
Ethnicity 
--Non-Hispanic: 97.1%
--Hispanic: 2.3%
--Not Reported: 0.6%
Gender 
--Female: 65.8%
--Male 34.2%
University of Puerto Rico Hospital in Carolina Medicine Clinic
Practice location: Carolina, Puerto Rico
Demographics: all Puerto Ricans
6. Subject classification: Check off all classifications of subjects that will be specifically recruited for 
enrollment in the research project. Will subjects who may require additional safeguards or other 
considerations be enrolled in the study? If so, identify the population of subjects requiring special 
safeguards and provide a justification for their involvement.
☐Children
☐ Healthy 
☐Fetal material, placenta, or dead fetus
☒Non-English Speaking
☐ Prisoners
☒Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students 
☒ Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential 
subjects? Yes ☐  No ☒ 
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion?
Inclusion Criteria:
• ≥40-60 years old 
• BMI≥23kg/m2 or WC≥80/90cm
• No history of type I or type II diabetes or gestational diabetes
• Not on blood sugar altering medication 
• Linkage to a provider for medication prescribing and laboratory testing
• Health insurance to cover medication and laboratory testing
• Ability to attend weekly sessions
• HbA1c 6-6.4%
Exclusion Criteria:
•
Pregnant
•
Elevated creatinine with eGFR<45 mL/min/1.73 m2
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8. How will eligibility be determined, and by whom? 
Patient eligibility will be determined by the RA. The RA will use the EHR and paper health records at 
the clinical site to identify patients who meet the eligibility criteria noted above. Individuals who meet 
eligibility criteria will be called in to undergo point of care (POC) HbA1c testing. This will likely be 
done on a “Recruitment Days” for ease of scheduling. Participants will be consented and then have a 
POC HbA1c test. If the HbA1c value is ≥6.5%, the participants will be excluded as they are possibly 
diabetic and will be referred to their primary provider for a confirmatory serum HbA1c test. If 
HbA1c<5.7%, these participants are neither diabetic nor pre-diabetic and will be excluded. If HbA1c is 
between 5.7% and <6%, individuals are pre-diabetic but low risk and are referred to their provider for 
routine care. Patients with HbA1c of 6-6.4% are deemed high risk pre-diabetics and can be enrolled in 
the study. These participants will be eligible to enroll in the study. 
Women of child-bearing age (<50years) will undergo a urine pregnancy test to verify that they are not 
pregnant prior to enrolling in the study.
Of note, for our NYC site, workshops will be offered to all individuals referred by their primary care 
physician for pre-diabetes; therefore, other study eligibility criteria do not apply as long as patient has 
pre-diabetes. 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research. 
POC Testing and Venipuncture
Participants may experience a mild inconvenience during the POC HbA1c and creatinine when their 
fingers are pricked to have a drop of their blood drawn. Participants may also experience mild 
discomfort, pain or throbbing at the site of blood draw during venipuncture, when blood is drawn from 
their veins with a needle for the laboratory tests.
Time commitment
It may be time-consuming for participants to come to the clinic for testing at the beginning of the study 
and at 6 and 12 months. Attending educational sessions (6 total, each 2.5hours long) will also be time-
consuming. Additionally, participants may not have adequate transportation, so travel to the sessions 
may pose an additional burden.
Privacy/Disclosure
Care will be taken to protect subject privacy, but the possibility of a data breach is always present.
Participants in group education sessions will know the identities of other participants, thus the identities 
of the treatment group individuals with pre-diabetic glucose levels will not be confidential.
Metformin Medication
Risks associated with Metformin therapy are as follows:
-Mild possible side effects: diarrhea, gas, nausea
-Moderate (rare 1-10%) side effects: headache, dizziness, rash, decreased vitamin B12, weakness, chest 
discomfort, palpitations
-Severe (very rare <1%) side effects: lactic acidosis, megaloblastic anemia
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10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
Participant compensation: 
Participants will be compensated with a $20 gift card at each session; this should help minimize the 
inconvenience of coming in to complete survey, clinical assessment and laboratory testing. Additionally, 
participants in Puerto Rico will receive an additional $5 for parking fees or $10 for public transportation 
commute for study visits.
For in-depth interviews, participants will be given $20 for their time.
Workshop Benefits
Participants are expected to gain significant benefits from these educational sessions, both through 
joining a supportive community of other individuals working to control their weight, and through 
information sharing providing them tools for weight loss and lowering their risks for diabetes. It is 
expected that these benefits will outweigh the inconvenience of attending educational sessions. Standard 
protocol will be followed to minimize the risk of a data breach. It is expected that the social benefits 
participants will gain from participating in a supportive group that works toward the common goal of 
reducing diabetes incidence will outweigh the risk of losing anonymity through participation. Also, all 
participants will be told that participation in the trial is confidential and asked not to share the identities 
of other participants with others in their community.
Metformin therapy
To minimize risk of lactic acidosis, we will exclude patients who have renal insufficiency. Additionally, 
the Manual of Procedures (MOP) will explicitly note conditions for vitamin B12 level testing: history of 
anemia or peripheral neuropathy. This testing is indicated in the setting of Metformin therapy and should 
be covered by insurance. If not, it will be covered by the study.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the final 
determination of the risk to subjects.)
a.
What is the investigator’s assessment of the overall risk level for subjects participating in 
this study? 
We associate a greater than minimal risk level for participation in this study.
b.
If children are involved, what is the investigator’s assessment of the overall risk level for 
the children participating in this study? 
Children will not be participating in this study.
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
 available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal
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Greater Than Minimal Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency, which must be conducted at a minimum of 
every 6 months (including when re-approval of the protocol is sought).  Any and all adverse events are 
to be documented in REDCap under the notes field in the clinical assessment for the appropriate time 
interval. Furthermore, it is immediately communicated to the study PI via email and/or phone. During 
the review process, the principal investigator (monitor) will review all note fields for documented 
adverse events, evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Either the principal investigator, or the IRB have the 
authority to stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed greater than minimal for the following 
reasons: 
1. We do not view the risks associated with Metformin therapy as minimal risks.
Although we have assessed the proposed study as one of greater than minimal risk, the potential exists 
for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible 
to predict with certainty the absolute risk in any given individual or in advance of first-hand experience 
with the proposed study methods; in particular Metformin drug therapy. Therefore, we provide a plan 
for monitoring the data and safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures / design by the principal investigator Dr. Marcella Nunez-Smith according to the following 
categories:
a.) Definite: Adverse event is clearly related to the study.
b.) Probable: Adverse event is likely related to the study.
c.) Possible: Adverse event may be related to the study.
d.) Unlikely: Adverse event is likely not to be related to the study.
e.) Unrelated: Adverse event is clearly not related to the study.
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe 
5. Plan for Determining Seriousness of Adverse Events:
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Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets the 
criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it results in any of 
the following outcomes:
1. Death;
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3. A persistent or significant disability or incapacity; 
4. A congenital anomaly or birth defect; OR
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event.  
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE.  It is 
important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol 
and informed consent document and (b) the characteristics of the subject population being 
studied; AND 
2. Is related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non-
medical in nature, and include – but are not limited to – serious, unexpected, and related adverse 
events and unanticipated adverse device effects.  Please note that adverse events are reportable to the 
IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the prompt 
reporting requirements described in IRB Policy 710 should be reported to the IRB in summary form at 
the time of continuing review. If appropriate, such summary may be a simple brief statement that events 
have occurred at the expected frequency and level of severity as previously documented.  
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7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., DSMBs, study sponsors, funding and regulatory agencies, and 
regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be notified:
-All Co-Investigators listed on the protocol.
-National Institutes of Health
The principal investigator (Dr. Marcella Nunez-Smith) will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and severity of 
the adverse events and determine if modifications to the protocol or consent form are required.
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to subjects or others 
be reported, reviewed and managed?
A LIME Advisory Board (LAB) has been established that consists of regional stakeholders that are part 
of ECHORN/Yale-TCC, workshop leaders/trainers, and participants. This group meets at least twice a 
year, and quarterly if needed. The objective is to inform the LIME project and discuss and advise on any 
issues that arise. The PI, co-PIs and the RAs will be responsible for communicating adverse events and 
unanticipated problems to the data coordinating center at Yale via email reports with detailed description 
of these events and problems, as soon as they occur. These issues will be reviewed by the Yale 
coordinating center and the LAB as needed. Together a decision on the fit line of action to address the 
issues, and immediately report to the Yale IRB. All protocol amendments will be submitted as 
appropriate to reflect the actions/changes made to the study implementation, to tackle these 
events/problems. Anytime an issue is raised by the LAB, or a modification is made to the Yale IRB, 
local site PIs are informed. Subsequent to modification requests being approved at the Yale IRB, 
modifications are submitted to the local IRB in Barbados and Puerto Rico. The Yale coordinating center 
meets monthly with each of the site PIs to discuss any issues with the modification requests. Meetings 
are called more urgently if an issue is raised by the site teams or the LAB. 
Monthly meetings with site teams have several purposes: quality assurance, quality review, review of 
any implementation challenges or issues, review of adverse events and plan of action, review of progress 
and timeline. Twice a year to quarterly, all LIME sites meet together with the LAB to discuss progress, 
challenges, and opportunities.  
ii. What provisions are in place for management of interim results?
The study seeks to collect baseline demographic, clinical, and self-reported measures. We will analyze 
results at baseline, and 6months of the study period. Each study participant will receive data on local 
healthcare providers for follow-up and any lab results will be sent to his/her healthcare provider upon 
request.
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iii. What will the multi-site process be for protocol modifications?
Site PIs do have flexibility in the language regarding demographic and some self-reported measurement
data collection. The protocol for the collection of clinical data is set by the Yale-TCC at Yale and
cannot be changed by site PIs. Regarding the protocols for which there is flexibility—allowing for
language translation and cultural specificity (e.g., diet collection)—site PIs must present their
proposed protocol to the Yale-TCC Implementation Core Alliance for review and approval.
Any protocol changes are first approved by the Yale IRB. Once approved, all changes and necessary 
documentation si communicated via email and follow up email to all sites. In Puerto Rico and Barbados, 
a local IRB modification request is then submitted for approval. 
Quality assurance checks on the data are run every 2 weeks, these will incorporate checks on any 
protocol modifciations that have been made. Monthly LIME site meetings are an opportunity to discuss 
implementation of protocol changes. 
12. Statistical Considerations: Describe the statistical analyses that support the study design. 
The primary outcome of the LIME pilot study is reducing the proportion of individuals with elevated 
HbA1c. Amon  size calculation was estimated using a two-sample, paired t-test approach. 
The estimated total sample size of 330 participants at each of the four sites (n=7150 total) is required to 
provide an 80% power to detect a ≥20% difference in proportion of individuals with HbA1c below the 
high risk range of 6-6.4%.  This sample size takes into account a ≤ 10% loss to follow-up..
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the 
section.
A.  RADIOTRACERS
☒N/A
B.  DRUGS/BIOLOGICS    ☐N/A
Please note that Metformin will be prescribed by the physicians at the clinic site and dispensed at a local 
pharmacy. The Drug will not be stored or dispensed by the LIME team. The providers in the clinic who 
care for the patients are not members of the LIME study team. Follow up of the participant beyond the 
study period will therefore be undertaken by the primary provider for the patient who prescribed the 
Metformin initially. Subjects care in the clinic will be according to standard of care for that clinic
1. If an exemption from IND filing requirements is sought for a clinical investigation of a drug 
product that is lawfully marketed in the United States, review the following categories and complete 
the category that applies (and delete the inapplicable categories):
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Exempt Category 1: The clinical investigation of a drug product that is lawfully marketed in the 
United States can be exempt from IND regulations if all of the following are yes: 
1. The intention of the investigation is NOT to report to the FDA as a well-controlled study in 
support of a new indication for use or to be used to support any other significant change in 
the labeling for the drug.
☒
2. The drug that is undergoing investigation is lawfully marketed as a prescription drug 
product, and the intention of the investigation is NOT to support a significant change in the 
advertising for the product.
☒
3. The investigation does NOT involve a route of administration or dosage level or use in 
populations or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product
☒
2. The investigation will be conducted in compliance with the requirements for institutional 
(HIC) review and with the requirements for informed consent of the FDA regulations (21 
CFR Part 50 and 21 CFR Part 56).
☒
3. The investigation will be conducted in compliance with the requirements regarding 
promotion and charging for investigational drugs.
☒
2. 
Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might influence 
risks. If this is the first time this drug is being administered to humans, include relevant data on animal 
models. 
The drug Metformin and dosing at 500mg twice a day and 850mg twice a day is routinely prescribed, 
and FDA approved, for pre-diabetes. The risks associated with Metformin therapy are as follows:

Mild possible side effects: diarrhea, gas, nausea

Moderate (rare 1-10%) side effects: headache, dizziness, rash, decreased vitamin B12, weakness, 
chest discomfort, palpitations

Severe (very rare <1%) side effects: lactic acidosis, megaloblastic anemia
3. 
Source:  Identify the source of the drug or biologic to be used. 
Participants will be prescribed Metformin by their provider in compliance with FDA regulations and 
ADA guidelines. The participants will obtain their Metformin prescription from a local pharmacy at 
their clinic site or area. These pharmacies are all appropriately certified. Pharmacies can obtain 
Metformin or generic form Glucophage. 
a)
Is the drug provided free of charge to subjects? ☐YES 
☒NO 
If yes, by whom? 
Participants who are involved in LIME will have insurance that covers Metformin for pre-
diabetes.
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After completion of the study, providers will be able to discuss with the participant continuation 
(or discontinuation of the Metformin). If continuing Metformin, providers can continue the dose 
of 500mg twice a day or they can increase the dose to 850mg twice a day or to 1000mg twice a 
day.
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and pyrogenicity.
Basic storage information for Metformin is as follows: keep container tightly closed. Keep container 
in a cool, well-ventilated area.
Metformin is stable at room temperature
Preparation/dispensing of medication as per pharmacy procedures
Check applicable Investigational Drug Service utilized:
    ☐  YNHH IDS                                                        ☐  CMHC Pharmacy                                          
 ☐ West Haven VA
    ☐  PET Center                                                      ☐    None      
    ☒  Other: Metformin will be obtained from the clinic pharmacy at each of the sites. Each of the sites 
outlined above have established and appropriately certified pharmacies that comply with all 
storage/preparation regulations for all medications including Metformin.
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation. 
5. Use of Placebo: ☒Not applicable to this research project
6. Continuation of Drug Therapy After Study Closure   ☐Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
☒ Yes   If yes, describe the conditions under which continued access to study drug(s) may apply as well 
as conditions for termination of such access. 
Continuation versus termination of Metformin beyond the study period will be at the discretion of the 
physician caring for the patient. American Diabetes Association guidelines do not outline criteria for 
termination or continuation. As this drug is provided for by the participant’s insurance, funding/access to 
the drug will not be an issue.
☐ NO   If no, explain why this is acceptable. Write here
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
Targeted for enrollment at Yale for this protocol: 0.
b. If this is a multi-site study, give the total number of subjects targeted across all sites: 750.
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2. Indicate recruitment methods below. Attach copies of any recruitment materials that will be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
 
 Departmental/Center Website
 Television
 Medical Record Review*
 Departmental/Center Research Boards
 Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
  YCCI Recruitment database
 Clinicaltrials.gov Registry (do not send materials to HIC)
 Other (describe):
* Requests for medical records should be made through JDAT as described at 
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified.
We are targeting the highest risk pre-diabetic patients for this study. Patient recruitment will occur 
through the involved health clinics. The Research Assistant (RA) at each site will use either the 
Electronic Health Record (EHR) or paper chart to identify patients who meet the following eligibility 
criteria: 
• ≥40-60 years old 
• BMI≥23kg/m2 or WC≥80/90cm
• No history of type I or type II diabetes or gestational diabetes
• Not on blood sugar altering medication 
• Non-pregnant 
• Linkage to healthcare provider to order medication and labs
• Health insurance to cover medication and labs
• Ability to attend weekly sessions
• Normal creatinine (If prior serum creatinine present in the record)
Individuals who meet eligibility criteria will be called in to participate in one of the study site’s 
“Recruitment Days.” Entry into a sweepstake for an I-Pad Mini will provide incentive for participation 
in the “Recruitment Day.”  All participants who attend the Recruitment Day (regardless of whether or 
not they enroll in the study) will be eligible to participate in the study. 
Recruitment Day Procedure: here participants will hear more about the study and if interested will be 
formally consented (see consent process). Participants will then first undergo point of care (POC) 
HbA1c testing. If the HbA1c value is ≥6.5%, the participants will be excluded as they are possibly 
diabetic and will be referred to their primary provider for a confirmatory serum HbA1c test. If 
HbA1c<5.7, these participants are neither diabetic nor pre-diabetic and will be excluded. If HbA1c is 
between 5.7 and <6, individuals are pre-diabetic but low risk and are referred to their provider for 
routine care. Patients with HbA1c of 6-6.4% are deemed high risk pre-diabetics and can be enrolled in 
the study. Women of child-bearing age (age<50years) will undergo a urine pregnancy test to ensure 
eligibility for enrollment. 
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The following sites will have the option of obtaining the signed consent on REDCap: Barbados, 
Trinidad, and the USVI. 
b. Describe how potential subjects are contacted. 
Research Assistants will contact potential subjects through these avenues: 
RAs will reach potential subjects via phone calls to introduce the study to them and invite 
them to attend Recruitment Day
RAs will coordinate with care providers to meet up with potential subjects to introduce them 
to the study during a scheduled routine clinic visit 
c. Who is recruiting potential subjects? 
Research Assistants (RAs) will recruit potential subjects.
 
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical relationship 
with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only. Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☐ For inclusion of non-English speaking subject if short form is being used and there is no translated 
HIPAA research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data:
In order to identify participants who meet eligibility criteria, research assistants will need to access 
electronic health records to flag individuals who meet the eligibility criteria for the study noted above. 
These records contain the names and possibly, contact information of potential subjects that meet the 
study criteria. Without this information, we would not be able to contact potential subjects to tell them 
about the study. It is important to note that these clinical sites have existing and established treating 
relationships with these individuals, this forms the basis for the HIPAA waiver for this initial screening. 
Each clinical site will need to obtain additional IRB approval and HIPAA waiver approval through their 
affiliate institutions.
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ii. If requesting a waiver of signed authorization, describe why it would be impracticable to 
obtain the subject’s signed authorization for use/disclosure of this data:
The investigator assures that the protected health information for which a Waiver of 
Authorization has been requested will not be reused or disclosed to any person or entity other 
than those listed in this application, except as required by law, for authorized oversight of this 
research study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject name, 
purpose, date, recipients, and a description of information provided. Logs are to be forwarded to the 
Deputy HIPAA Privacy Officer.
6. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be 
obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.
Informed consent will be obtained at the Recruitment Day appointment prior to any clinical or blood 
testing or enrollment of participants. Additionally, participants will be asked to consent to being 
contacted for follow-up at regular intervals. Each subject will be assigned a unique ID that will follow 
them over the study period and beyond. Consent will be obtained by the site-specific research assistant. 
This will be done in a space/office where participants can be consented in privacy. Separate consent 
form will be used to consent participants for qualitative interviews. 
The following sites will have the option of obtaining the signed consent on REDCap: Barbados, 
Trinidad, and the USVI.
7. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
Clinical judgement will be used to determine participant ability and capacity to consent to the research 
being proposed. Given the age range of our participants – 40-60years of age – we do not anticipate any 
cases of dementia; therefore, mini-cognitive testing is not necessary. Clinical judgement will be used to 
determine participant ability and capacity to consent to the research being proposed. As all participants 
are patients within the clinic sites, research staff can consult with participant providers regarding 
participant ability and capacity to consent when needed. Any participant deemed unable to provide 
consent based on clinical judgement will have that determination confirmed by the participant’s 
provider; that participant will then be ineligible to participate in the study. 
8. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research 
involving non-English speaking subjects. If enrollment of these subjects is anticipated, translated 
copies of all consent materials must be submitted for approval prior to use. 
All consent forms will be available in both English and Spanish. Consent will be obtained from 
participants by a Research Assistant fluent in the participant’s native language. Those who are not fluent 
in English or Spanish would not be eligible to participate in the study.
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As a limited alternative to the above requirement, will you use the short form* for consenting process if 
you unexpectedly encounter a non-English speaking individual interested in study participation and the 
translation of the long form is not possible prior to intended enrollment? 
YES ☐  NO ☒
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time a 
subject speaking that language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated 
HIPAA Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the 
translation of the short form is not available on our website, then the translated short form needs to be 
submitted to the IRB office for approval via modification prior to enrolling the subject.  Please review 
the guidance and presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a 
HIPAA waiver in the section above. 
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, 
or a full waiver of consent, depending on the study. If you will request either a waiver of consent, or a 
waiver of signed consent for this study, complete the appropriate section below. 
☒Not Requesting any consent waivers 
☐Requesting a waiver of signed consent:
 
☐ Recruitment/Screening only 
☐ Entire Study (Note that an information sheet may be required.)
 For a waiver of signed consent, address the following:

Would the signed consent form be the only record linking the subject and the research?          
YES ☐  NO ☐ 

Does a breach of confidentiality constitute the principal risk to subjects? YES ☐  NO ☐
 
OR

Does the research pose greater than minimal risk? YES ☐    NO☐ 

Does the research include any activities that would require signed consent in a non-research 
context? YES ☐   NO ☐
 
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☒ Requesting a waiver of consent:
☒ Recruitment/Screening only  
☐ Entire Study 
For a waiver of consent, please address the following:

Does the research pose greater than minimal risk to subjects? 
☐ Yes  If you answered yes, stop. A waiver cannot be granted. 
☒ No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐    NO☒

Why would the research be impracticable to conduct without the waiver? 

Each clinical site will conduct chart reviews on their clinic patients to screen their patients for 
eligibility. Potentially eligible patients will be contacted by phone to inform them of the study 
and ask them if they are interested in attending a Recruitment Day event where they will get 
more information and sign an informed consent form. They will use a Recruitment Form, 
hosted on REDCap, to track outreach efforts and contact with participants. This REDCap 
database will be managed by Yale, which is an external coordinating site. The waiver of 
consent for recruitment/ screening only will allow the coordinating site to access and monitor 
the data obtained during screening and recruitment. The individuals conducting chart reviews 
and outreach to patients at these clinical sites have existing and established treating 
relationships with the patients. 

Where appropriate, how will pertinent information be returned to, or shared with subjects at a 
later date? 
No pertinent information is being collected to necessitate returning/sharing with subjects at a 
later date.
 
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
 a.    What protected health information (medical information along with the HIPAA identifiers) about 
subjects will be collected and used for the research?
Table 3. Proposed areas of LIME baseline and follow-up data collection
Self-Reported Measures
Clinical Assessment 
Sociodemographic Characteristics
Fruit and vegetable intake
Weight/Height/BMI
Gender/Sex
Sugar-sweetened beverage intake
Blood pressure
Age
Physical activity
Waist & Hip Circumference
Marital/partner status
Self-efficacy score
Neck Circumference
Self-identified race/ethnicity 
Medical history
Hemoglobin A1c
Occupation/occupational history 
Family history
Cholesterol
Education
Medication adherence
Creatinine
Wealth
Social desirability scale
Insurance status
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In addition, the following HIPAA identifiers will also be collected from participants.
HIPAA identifiers: 
 Names 
All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes 
and their equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-
available data from the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with 
the same three initial digits contains more than 20,000 people, and (2) the initial three digits of a zip code for 
all such geographic units containing 20,000 or fewer people is changed to 000. 
Telephone numbers
E-mail addresses
Social Security numbers 
Medical record numbers for recruitment and screening purposes only
All elements of dates (except year) for dates related to an individual, including: birth date, admission date, 
discharge date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, 
except that such ages and elements may be aggregated into a single category of age 90 or older 
b. How will the research data be collected, recorded and stored? 
On Recruitment Days, all clinical assessment, point-of-care and survey data will be collected online 
into REDCap. The REDCap LIME project has a separate instrument that contains patient identifying 
information. All other instruments use de-identified participant ID. Sites will only be able to view 
data that is collected at their site. Select, trained, personnel will have access to the instrument 
containing patient identifying information, including contact information. Once data is entered into 
the REDCap system, it is immediately stored on a secure Yale server. In the event of no 
internet/wifi, data is temporarily stored on the provided tablets but then uploaded via internet to the 
Yale server. No data is locally stored on laptops, tablets or desktops. 
In the event that a participant requests completing the survey on paper, that information will have to 
be manually input into the REDCap system. Only the participant ID will be on the survey, no 
identifying information. The paper survey will be scanned and securely emailed to the coordinating 
center. The paper copy will be destroyed. 
All REDCap data is exported to SAS for later statistical analysis; files containing patient identifying 
information is kept separately. All files stored on a secure Yale server. Sites will not have access to 
PHI of other site participants.
Patients who consent for laboratory tests to be sent to their provider, will have those results sent to 
their provider once completed. 
Quality assurance checks will be conducted every 2 weeks to ensure: consent has been obtained and 
documented, incentives as appropriate provided, accurate and complete data collection has been 
obtained. Quality assurance results will be communicated to site teams immediately, any issues 
addressed immediately when necessary and discussed further during monthly team meetings. 
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c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
d.    What methods and procedures will be used to safeguard the confidentiality and security of the 
identifiable study data and the storage media indicated above during and after the subject’s participation 
in the study?
We are providing wi-fi access points to all sites that have unreliable internet. This will ensure that 
data collection can always be done online directly into REDCap. In select cases, de-identified data 
may be collected offline on tablets temporarily. This data will be uploaded, once wifi is restored, to a 
secure Yale server. 
All portable devices must contain encryption software, per University Policy 5100. If there is a 
technical reason a device cannot be encrypted please submit an exception request to the Information 
Security, Policy and Compliance Office by clicking on url http://its.yale.edu/egrc or email 
it.compliance@yale.edu
e.
What will be done with the data when the research is completed? Are there plans to destroy the 
identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe 
how the data and/or identifiers will be secured.
There are no plans to destroy the identifiable data as the project may be interested in future extension 
and following participants into the future. However, the identifiable data links will all be stored at the 
TCC at Yale only on a single encrypted desktop computer that can only be accessed by the study PI 
and the Directors of the Yale-TCC.
f.   Who will have access to the protected health information (such as the research sponsor, the 
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified data) 
Only the study PIs, the Directors of the ECC and Yale-TCC, the project manager, and biostatistician 
will have direct access to PHI. Study site PIs may request PHI for participants at their site only and 
will be provided those data by the Directors of the ECC and Yale-TCC. Other research staff will not 
have access to PHI. De-identified data will be kept in separate, password protected databases from 
their code identifiers. 
g.   If appropriate, has a Certificate of Confidentiality been obtained?
N/A. A Certificate of Confidentiality is not needed.
h.   
Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents of child 
abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported. 
There are no data collection points that require mandatory reporting.
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SECTION V: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, 
either to the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this 
context of the risk benefit assessment.) 
Participants are expected to gain significant benefits from the lifestyle and educational sessions, both 
through joining a supportive community of other individuals working to control their pre-diabetes, and 
through information sharing providing them tools for weight loss and lowering their risks for diabetes. It 
is expected that these benefits will outweigh the inconvenience of attending educational sessions. 
It is expected that the social benefits participants will gain from participating in a supportive group that 
all works toward the common goal of reducing diabetes incidence will outweigh the risk of losing 
anonymity through participation. 
         SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1. Alternatives: What other alternatives are available to the study subjects outside of the research? 
The alternative available to study subjects outside of the research is simply not participating in the 
study or going to their medical centers for screening.
2. Payments for Participation (Economic Considerations): Describe any payments that will be made 
to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.
Participants will be given a $20 incentive at each follow-up. Participants in Puerto Rico will receive an 
additional $5 for parking fees or $10 for public transportation commute for study visits.
3. Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects. 
The major cost to the participants is their time. Clinical assessments, including the laboratory tests 
for cholesterol would not be of additional cost to the participant. These costs will be covered by 
insurance. Metformin for prediabetes would also be covered by insurance. If for any reason, there 
are laboratory costs that are not covered by insurance, the LIME study will cover those costs. 
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and 
for minimal risk research that presents the potential for physical harm (e.g., research involving blood 
draws).
a.
Will medical treatment be available if research-related injury occurs? 
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b. Where and from whom may treatment be obtained? 
c.
Are there any limits to the treatment being provided? 
d. Who will pay for this treatment? 
e.
How will the medical treatment be accessed by subjects? 
4a-e: We do not foresee risk of physical injury as a result of taking part in this study. However, there is a 
small risk that a patient might be injured during the clinical assessment. Research personnel will be 
trained to dial 911 should any injury occur. A first aid kit will be in each assessment center which is 
managed by a licensed RN who can provide immediate first aid. Medical costs associated with any 
injury are the responsibility of the participant.
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SAP_001.pdf: 
ClinicalTrials.gov ID: NCT03258723 
Title: Diabetes Prevention with Lifestyle Intervention and Metformin Escalation (LIME) 
Last Approved: 11/17/2022 
Document: SAP 


Page 1 of 3 
 
                    
                                    
Statistical Analysis Plan  
 
 
 
 
Protocol Title: Diabetes Prevention with Lifestyle Intervention and Metformin 
Escalation (LIME). 
 
 
 
Principal Investigator: Dr. Marcella Nunez-Smith 
 
 
Version Date: version 7.0 
 
 
Clinicaltrials.gov Registration #: NCT03258723 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 2 of 3 
 
Initial Plan:  
Study design: pre-post study design with non-equivalent control 
Sample Size: 
The primary outcome of the LIME pilot study is reducing the proportion of individuals with elevated 
HbA1c. Sample  size calculation was estimated using a two-sample, paired t-test approach.  
 
The estimated total sample size of 200 participants (control and intervention) is required to provide an 
80% power to detect a ≥20% difference in proportion of individuals with HbA1c below the high risk 
range of 6-6.4%.  This sample size takes into account a ≤ 10% loss to follow-up. 
 
Survey measures: 
Table 3. Proposed areas of LIME baseline and follow-up data collection 
 
Analysis: 
We will use the chi-squared test to compare the proportion of individuals who reduce their HbA1c 
below 6% over the 12-month period in the intervention and control groups as the primary outcome. 
Differences between the intervention and control groups in the secondary outcomes of average change in 
HbA1c, weight, BMI, systolic blood pressure, cholesterol, self-efficacy score, and quality of life will be 
compared using Student's t-tests. Within the intervention arm, we will use chi-squared and t-tests to 
identify any patient-related factors that are associated with the primary outcome of HbA1c reduction 
below 6%.  
 
Statistical analysis plan Changes resulting from COVID-19 and inability to recruit a control arm: 
 
Study Design: pre-post study design was used 
Statistical analysis: t-test was used to compare the change in primary outcome HbA1c, and secondary 
outcomes (weight, blood pressure, added sugar intake, fruit and vegetable intake, physical activity) at 
baseline with 6-months and 12-months post intervention.  
 
Physical activity was measured using the World Health Organization Global Physical Activity 
Questionnaire. Metabolic equivalents were used to classify level of physical activity as low, medium, or 
high.[1] 
 
Self-Reported Measures 
Clinical Assessment  
Sociodemographic Characteristics 
Fruit and vegetable intake 
Weight/Height/BMI 
Gender/Sex 
Sugar-sweetened beverage intake 
Blood pressure 
Age 
Physical activity 
Waist & Hip Circumference 
Marital/partner status 
Self-efficacy score 
Neck Circumference 
Self-identified race/ethnicity  
Medical history 
Hemoglobin A1c 
Occupation/occupational history  
Family history 
Cholesterol 
Education 
Medication adherence 
Creatinine 
Wealth 
Social desirability scale 
 
Insurance status 


Page 3 of 3 
 
Nutritional assessment was done using the Dietary Screening Questionnaire and established guidelines 
for the analysis of fruit and vegetable intake (servings) and added sugar intake (teaspoons). [2] 
 
REFERENCES 
1. Chu A.H., Ng S.H., Koh D., Muller-Riemenschneider F. Reliability and validity of the self- and 
interviewer-administered versions of the Global Physical Activity Questionnaire (GPAQ) PLos 
One. 2015;10(9) [PMC free article] [PubMed] [Google Scholar] 
 
2. Thompson F.E., Midthune D., Kahle L., Dodd K.W. Development and evaluation of the National 
Cancer Institute’s Dietary Screener Questionnaire Scoring Algorithms. J. 
Nutr. 2017;147(6):1226–1233. [PMC free article] [PubMed] [Google Scholar] [Ref list]