8. adverse event reporting
8.2. eliciting and recording serious

Reporting of serious adverse events will be accomplished by collecting information on these adverse experiences during annual, semi-annual and interim follow-up visits. In order to avoid bias in eliciting serious adverse events, these adverse events will be assessed using a standardized checklist based on study outcomes and total body system assessment.  
For all participants, serious adverse events will be assessed semi-annually, as well as collected during the interim, as reported. Serious adverse events will be reported to the Coordinating Center as they occur through routine data entry (within 2-3 days), with the exception of death or other life threatening and unexpected adverse events. All deaths or other life threatening and unexpected adverse events, regardless of intervention assignment, must be reported to the Coordinating Center within 24 hours of clinic notification. The Coordinating Center will transmit the death report to the NIDDK Program Official.  
For participants assigned to the metformin treatment group, the NIH-NIDDK must provide a written report of all serious and unexpected adverse events to the Food and Drug Administration (FDA) in their annual IND report. In addition, the NIDDK must notify the FDA of all life-threatening or fatal SUSARs (Serious Unexpected Suspected Adverse Reaction) within seven calendar days; NIDDK must notify the FDA of all other SUSARs by 15 calendar days.  
All serious adverse events will be reported to local IRBs by the clinic following individual institutional guidelines.
8. adverse event reporting
9. data processing 9.1. data

DPPOS data forms are completed to document protocol performance and to collect participant data relevant to the research questions. The section that follows outlines each type of data form that is used to collect participant data and is contained in the master database maintained by the Coordinating Center (CoC). Chapter 12 is the schedule of outcomes collection. The list of DPPOS data forms appears in the study Manual of Operations, and includes administrative as well as data collection instruments.  
The CoC creates the DPPOS data form templates. At each clinic, the clinic staff, directed by the program coordinator, reviews completed data forms prior to data entry. Completed forms are edited as they are entered into the data management system, and then again via the central data management system at the CoC.
8. adverse event reporting
- follow-up visit inventories

Completed according to the schedule in Chapter 12: serious adverse event assessment, diabetes management, current concomitant prescription medications, interval medical history and interval cardiovascular history, neuropathy screening, and physical measures; and for the metformin treatment participants, pregnancy questions, and medication compliance and dispensing. In addition, outcomes outlined in Chapter 4 are completed according to the schedule in Chapter 12.  
- **Interim follow-up visit inventory:**
Reason for interim visit, serious adverse event assessment, interval history, pregnancy questions, and for metformin treatment participants, medication compliance and dispensing.  
- **Missed follow-up visit report:**
Completed anytime a participant misses a scheduled follow-up visit: reason for missed visit and inactive follow-up status.  
- **Home and phone visit report;**
Completed for outcome visits: serious adverse event assessment, interval history, current concomitant prescription medications, and physical measures (as appropriate); and for the metformin treatment participants, pregnancy questions, and medication compliance and dispensing.
8. adverse event reporting
9.1.1. other forms

The following instruments were completed during DPPOS Phases 1 & 2, or will be completed during **DPPOS Phase 3**, according to the schedule in Chapter 12:
Beck Questionnaire MOS SF-36 Health Survey Questionnaire Modifiable Activity Questionnaire Nutrition Interview Resource utilization for participants Interval History Questionnaire Quality of Well-Being Scale Urinary Incontinence Questionnaire Rockville, Maryland 53 The following event data forms are completed as needed:
Adverse event reports Diabetes confirmation report Pregnancy confirmation and outcomes reports Mortality report The following procedure worksheets collect participant status or physical information (see Chapter 12 for timing and frequency of procedures): The following report data forms are completed as needed:
CHD Risk Status Report Consent and specimen status
8. adverse event reporting
9.2. data entry and management

A secure, web-based password protected data entry and management software corresponding to the data forms completed at a clinical center is developed and maintained by the staff at the Coordinating Center (CoC). Reports are developed for use at the clinical centers to assist clinical center staff in participant management, data collection and study management. DPPOS computers are kept in a safe location in a site that is locked when not attended.  
Neuropathy Questionnaire Dietary Restraint, Exercise Self-Efficacy, Low Fat Diet Self-Efficacy Cognition questionnaires Physical functioning: Grip strength, Gait Speed, Chair Stand, Balance Cancer history and risk factor questionnaire Activities of Daily Living (ADL) and Instrumental Activities of Daily Living
(IADL)
Sexual Function Questionnaires 6-Minute Walk Test Questionnaire OGTT procedures Urine collection procedures ECG procedures Fundus photography and Optical Coherence Tomography (OCT) procedures Coronary artery calcium procedures DXA procedures Spirometry procedures
8. adverse event reporting
9.2.2. central biochemistry laboratory

The Central Biochemistry Laboratory (CBL) uses a relational database to manage analyses performed within the laboratory using a custom-developed Laboratory Information Management System (LIMS). Automated analyzers are connected to the database via communication interfaces developed and maintained by the CBL staff. Reports to the CoC are transmitted via secure FTP to the CoC with the original reports stored in the relational database as well as on a file server. All storage media containing clinical data in use at the laboratory utilize hardware fault redundancy and the data are backed up daily to a secure and remote data storage facility.
8. adverse event reporting
9.3. centralized data management system

Data entered via the web-based electronic data collection system is securely transmitted and stored on the CoC's server. Data are converted to SAS data sets after being uploaded to the CoC's server. All new data are edited for unavailable, out of range, or inconsistent values. Weekly audit programs produce more detailed edits across forms for an individual participant. Summaries are prepared for reports to the Steering Committee and Protocol Oversight Program. The CoC maintains confidentiality of patient data and emerging results per a confidentiality policy, which every staff member is required to sign.  
The CoC adheres to the Biostatistics Center's data backup and security policies to ensure the safety and confidentiality of the data. Backup procedures include: twice-weekly system backup, daily incremental back-up, and off-site disaster recovery backup. Security procedures include: logon and link password protection, and for internet access, separate Web servers which use SSL and encryption algorithms. Virus and malware protection software is used on all computers and is updated on an hourly basis. All portable computers employ full disk encryption. University computing facilities provide support in the event of a disaster. Access to the server and databases is secured by use of login user accounts and passwords. Remote access is granted only to authorized users and is accomplished using a secure virtual private network (VPN). Appropriate filtering/firewall setup is used to prevent unauthorized access.
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9.4. performance monitoring 9.4.1. training

The CoC, and Central Units, with appropriate investigator subcommittee members, have established procedures to train and certify clinical investigators in the protocol, manual of operations, and data processing procedures. Workshops are held for training personnel from the clinical centers to address the appropriate DPPOS procedures including the use of the DPPOS data forms and data processing systems. CBL personnel instruct the program coordinators on proper collection, packaging and mailing of specimens for analysis by the CBL. Central units also instruct, train and certify the program coordinators and technicians (as needed) to promote standard assessments. The CoC will maintain close contact with the program coordinators and will provide additional training or review as needed.  
Based on clinic performance monitoring, appropriate representatives from the CoC, the NIDDK, and clinic investigators will visit the clinical centers virtually or in person, as required. These site visits will review procedures with the program coordinators/technicians, assess proficiency in executing the DPPOS protocol, review deficiencies detected in monitoring the performance of the clinical centers, review the utilization of personnel relative to the amounts budgeted, and receive feedback on the adequacy of the centralized support operations.
8. adverse event reporting
9.4.1.1. periodic performance reports

During the DPPOS, the CoC will monitor the performance of the clinical centers and produce periodic reports summarizing protocol performance for the Protocol Oversight Program (POP) committee.
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9.4.1.2. retention

The CoC and the POP will monitor the performance of the clinical centers in retaining participants. The CoC will also prepare monthly reports on participant compliance with the DPPOS protocol and participants on inactive follow-up.
8. adverse event reporting
9.4.1.3. dppos data form completion

The CoC will prepare periodic reports presenting tabulations for data completion and quality. Missing data, particularly on outcome variables, will effectively reduce the power of analyses. In fact, systematic patterns of missing data could bias the study results. Therefore, many of the procedural details outlined in the Manual of Operations are designed to minimize the amount of missing data.
8. adverse event reporting
9.4.1.4. other reports

Other reports will be developed, as needed, based on requests from the Steering Committee and associated subcommittees.
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9.5. interim statistical reports

Interim reports to the Data and Safety Monitoring Board (DSMB) will include adverse events by treatment group, study progress, major issues considered and decided by the Steering Committee, protocol modifications, ancillary studies approved, protocol compliance, and data quality. Highlights of completed analyses related to study papers will be presented as they become available. During DPPOS Phase 2, there were two formal interim analyses of safety and efficacy pertaining to macrovascular events for purposes of possible "early stopping" of an intervention. The DSMB will develop a safety monitoring plan for **DPPOS Phase 3** to include a futility assessment.
8. adverse event reporting
10. study administration 10.1. organizational

Each of the participating clinical centers has agreed to implement the DPPOS Protocol.  
The clinical centers will follow participants according to protocol; assume responsibility for the completion of the protocol for each participant enrolled in the study; record participant data related to the above; review and enter information from data forms using the data entry and management system; and respond to edit queries from the Coordinating Center (CoC). Each clinical center has a Principal Investigator, a Program Coordinator, and additional staff to carry out the protocol.
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10.1.2. coordinating center

The Coordinating Center (CoC) is responsible for all aspects of biostatistical design, analysis, data processing and study communications of the DPPOS. In collaboration with the Steering Committee, the CoC is responsible for editing and document processing of the protocol and Manual of Operations and data collection forms development and testing. The CoC provides protocol performance monitoring data, and conducts the interim and final statistical analyses. The CoC collaborates with the Steering Committee members in the preparation of publications based on study results.  
Central resource units include the Central Biochemistry Laboratory (CBL), Nutrition Coding Center (NCC), ECG Grading Center (ECG), Fundus Photo Reading Center (FPRC), Quality of Well Being Coding Center (QWB), Coronary Artery Calcium Reading Center, Cognition Center, DXA Reading Center and DPPOS Central Genetics Core. Other than the Genetics Core and the Cognition Center, these units function as subcontracts to the CoC. Each is required to be in compliance with its IRB and institutional requirements for human subjects protection and HIPAA. They establish and provide baseline and/or repeated measures of study outcomes as described in Chapters 5 and 12. Quality control systems are established for these centrally performed assessments and reports will be furnished periodically to the Research Group. In addition, the units will lend expertise to help formulate the protocol and detailed procedures for participant preparation, specimen and record labeling, handling and shipping. Secure communication systems are maintained for data transfer to the Coordinating Center.
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10.2. funding mechanism/study resources

The DPPOS is supported by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, other co-funding NIH Institutes and Centers, and other DHHS co-funding Agencies. All support to the clinical centers and the Coordinating Center will be provided through the NIDDK using the mechanism of the Cooperative Agreement.  
The NIDDK program official and project scientist will provide program involvement as a participant in the scientific efforts of the DPP Research Group through development of protocols and assistance in the conduct of the DPPOS.
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10.3. working committees 10.3.1. steering

The Steering Committee (SC) is the representative body of the research group. The Committee consists of the Principal Investigator from each clinical center, CBL and the CoC, and the NIDDK Project Scientist. This committee is the policy and decision making group, and will oversee the administrative aspects of the DPPOS Research Group. It provides overall scientific direction through consideration of recommendations from the subcommittees and Executive Committee. The committee will approve the details of study design and all procedure manuals and participant management policies. The SC will monitor protocol adherence at the clinical centers including proper data generation, recording and transmittal. Members unable to attend a meeting may designate an alternate to act on their behalf. The members of the Steering Committee select the Study Chairperson and Vice-Chairperson.  
Steering Committee recommendations for changes in the Protocol require prior consideration by the appropriate subcommittee or Planning Committee, and an affirmative vote by two-thirds of the Steering Committee members present and voting.  
Although the Steering Committee is the decision and policy-making group of the DPPOS, a smaller group has been appointed to direct day-to-day activities. This Executive Committee consists of the Chair of the Steering Committee, the Vice-Chair of the Steering Committee, the Chair of the Publications and Presentations Committee, 1 or 2 Principal Investigators from the clinical centers, representatives of the Study Coordinators, the NIDDK Project Scientist and Program Official, and the Principal Investigator(s) and Project Coordinator of the CoC. The committee meets by telephone conference, as necessary, and generally on a weekly basis. Other members of the Steering Committee, such as chairs of Sub-Committees, are asked to attend the weekly conference call on a regular basis and as needed to address specific issues.  
Subcommittees comprise members of the research group. Their function is to develop detailed policies and procedures and make recommendations to the Steering Committee. During DPPOS the subcommittees will be reformed and new subcommittees and working groups formed, as necessary to address different tasks and functions.  
Standing DPPOS Subcommittees:
* Ancillary Studies * Economic Evaluation Workgroup * Outcomes Classification * Program Coordinator * Protocol Oversight Program * Publications and Presentations * Quality Control
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10.3.2. data and safety monitoring

The Data and Safety Monitoring Board (DSMB) members serve as external reviewers and advisors to the NIDDK-NIH and the Steering Committee. The DSMB consists of experts in relevant biomedical fields, Biostatistics and medical ethics. Prior to the initiation of the DPPOS and ongoing through all phases of DPPOS, the DSMB members review the protocol and study material to ensure the scientific validity of the study and safety of participants. The DSMB also assesses the performance of the CoC and clinical centers. Its principal responsibility is to monitor the emerging results to assess treatment effectiveness, or ineffectiveness, and participant safety according to the DSMB-approved interim monitoring plan. Based on these considerations, the DSMB may recommend to the NIDDK that the protocol be modified or that the study be terminated.
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10.4. policies 10.4.1. publications

The Publications and Presentations Subcommittee (PPS) coordinates, monitors, reviews, and assumes responsibility for arranging the preparation of all study-wide communications (press releases, interviews, presentations, and publications) relating to the scientific aspects of the study. There will be no publication or presentation of study plans or results which have not been reviewed and approved by a majority of the PPS, and for some types of communications, a majority of the Steering Committee.  
With respect to publications and presentations from the DPP, the goals of the PPS are to: 1. Ensure accurate, uniform, timely, and high quality reporting of the DPP activities and results; 2. Preserve the scientific integrity of the study; 3. Safeguard the rights and confidentiality of participants; 4. Assure that the timing of publications and presentations serves the right of the public to know the results of the program without jeopardizing its conduct. The PPS will organize a writing group for each publication or presentation proposed by the DPP investigators. Members of the writing group will include volunteers from the DPP investigators at large, and will not be restricted to members of the PPS. The PPS will coordinate the efforts of the writing group, establish priorities for data analysis by the Coordinating Center, and help edit the manuscripts produced by the writing groups.  
There will be several categories of publications and presentations, with different rules for authorship, ranging from publications of the main results of the study (with authorship by the entire research group) to other types of publications with named authors. The authorship rules balance the need to recognize the contributions of all investigators and staff with the need to recognize individuals for specific contributions to certain types of publications and presentations. Detailed policies are found in the Manual of Operations.
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10.4.2. ancillary studies

The Ancillary Studies Subcommittee evaluates all proposals for studies that involve DPPOS participants or stored samples and that are not a part of the protocol. These studies may be done only on a subset of participants in the DPPOS. However, studies that include all participants and studies that analyze study data in ways extracurricular to the Protocol must also be submitted to the Ancillary Studies Subcommittee. Ancillary studies have to obtain funding from outside the study.  
Major factors in consideration of ancillary studies will include:
* Clinical importance and scientific validity * Compatibility of goals with those of DPPOS * Amount of burden on study subjects and staff Ancillary studies receive a primary, secondary and statistical review. An outside reviewer may be used if there is no expertise within the study in a specific area. Reviews are returned to the applicant and appeals from the decision of the Ancillary Studies Subcommittee may be made to the Steering Committee.  
Approved ancillary studies that involve participants are reviewed by the DSMB. Detailed policies are found in the Manual of Operations.
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11. statistical considerations 11.1. data

After approximately 2.8 years of mean study time, the DPP's external Data and Safety Monitoring Board and sponsoring institute, the NIDDK, concluded that the DPP had convincingly demonstrated that the intensive lifestyle intervention and metformin therapy decreased the development of diabetes. Compared with placebo, intensive lifestyle and metformin reduced the development of diabetes by 58% and 31%, respectively. Both results were highly significant and lifestyle was significantly more effective than placebo6. The therapies were effective across all ethnic and racial groups and in men and women. The intensive lifestyle intervention cohort achieved the target goal of 7% mean weight loss and at least 150 min of activity per week at year 1. The hazard rates for development of diabetes were: placebo 11.0, metformin 7.8, and lifestyle 4.8 per 100 person-years.  
At the end of DPP, 99.6% of the study cohort was alive. The entire cohort proved to be remarkably compliant, with 94% retention of volunteers over time, and completion of > 90% of study requirements. Adherence (>80% of assigned medication) to metformin was 72%.
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11.2. study power 11.2.1. power

The duration of follow-up in the first five years of DPPOS was extended by one year from 5 to 6 years, by NIDDK. Power calculations were modified based on actual enrollment, and to correspond to the reordering of outcome measures.  
The following assumptions were used to make revised estimates of the power of the DPPOS for the Phase 1 primary outcome, development of diabetes: * The study will enroll approximately 900 participants per treatment group * The Phase 1 primary outcome is time to the confirmed development of diabetes assessed from DPP randomization through DPPOS Phase 1.  
* Type I error rate of 0.05 (two-sided) with a Bonferroni adjustment for two pair-wise comparisons of the intervention groups vs. "control".  
* Control (formerly placebo) group's time to the development of diabetes is exponentially distributed with a diabetes development hazard rate of at least 0.066 per year.  
* In the intervention groups (i.e., intensive lifestyle or metformin), the diabetes development hazard rate is reduced by at least 30%.  
* 84% participation of DPP participants in the follow-up study and a dropout rate of not more than 2%/year.  
For the comparison of lifestyle vs. control, assuming a type 1 error .025 and a 2-sided test, the study will have 84% power to detect a 35% reduction in the hazard rate for development of diabetes and 94% power to detect a 40% reduction. For the comparison of metformin vs. control (type 1 error .025, 2 sided test), the study will have 82% power to detect a 35% reduction in hazards.
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11.2.2. power for the microangiopathy

For the composite microangiopathic Phase 2 Primary outcome at year 11, assuming N=850 remaining participants per group and 1% per year dropout, and applying the resulting numbers of participants expected to develop diabetes during the follow-up study, we estimate the power of the study to be 91 percent or greater to detect 25% or greater reductions for each intervention from the control group proportion with the microangiopathic outcome, and 74% power to detect 20% reductions, using 2-sided pair-wise comparisons vs. placebo with α=0 .025.
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11.2.3. power for cancer development

For the cancer outcome for **DPPOS Phase 3**, we estimated the number of cancer cases through the first 5 years of **DPPOS Phase 3** using incidence rates based on both SEER100 and current DPPOS data. To detect 28% risk reduction in cancer for the primary comparison of metformin vs placebo with 85% power for a 2-sided significance level of 0.05, the study requires 170 events in the placebo group using a log-rank test. Assuming an increasing annual incidence rate of 1.86% by 2020 and an annual loss to follow-up of 1.04%, the projected 199 events in the placebo group will provide 89% power to detect a 28% hazard risk reduction at the end of the first 5-year period. Secondary analysis of the cancer incidence between metformin and placebo separately by men and women will be assessed in the second 5-years.
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11.2.4. power for cvd (mace)

The lower rate of CVD events in pre-diabetes than in diabetes has been documented14. It is reasonable to assume that our placebo group, all of whom started with pre-diabetes and with ~56% developing diabetes to date during the course of DPP/DPPOS, will have a CVD event rate that is a blend of pre-diabetes and diabetes. Moreover, our study population has a similar rate of treatment of traditional CVD risk factors (e.g., through use of antihypertensive agent and statins)7 to that in the general population today. This trend emphasizes the need to use contemporaneous external data to project event rates.  
In this light, the most relevant rates of MACE in non-diabetic and diabetic populations, including age-specific rates, come from a recent report on 2010 national data8. These data were collected during a period when treatment of established CVD risk factors was widespread, and therefore represent the background rates expected in our cohort. For all persons surveyed, the rate of acute myocardial infarction fell from 8.5 per 10000 person-years in 1990 to 5.7 in 2010. Among those aged 45-64 with diabetes the rate in 2010 was 51.3 per 10000 person-years (or 0.513 per 100 person-years), while those 65-74 had 66.4 and those over 75 had 143.5 events per 10000 person-years (0.664 and 1.435 per 100 person-years, respectively). These rates are within the range of rates that we observed in the Placebo group by DPPOS end (**Table 5**).  
| Table 5. MACE Event Rates and Numbers to Date in Placebo Group and Projections DPP start DPPOS start DPPOS end 5 yr projection 10yr projections 1997-1998 2002-2003 2014 2020-2021 2025   |      |      |      |      |      |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|------|------|------|------|
| Event Rate (% per yr)                                                                                                                                                                     | 0.24 | 0.50 | 0.70 | 1.17 | 1.57 |
| Total number                                                                                                                                                                              | 64   | 116  | 156  |      |      |  
We estimated the age related 2.1 fold increase in annual incidence rates in the next 10 years using Cox proportional hazards model using attained age as a time dependent covariate. This conservative increase is used to project events in the placebo participants of 116 and 156 after 5 and 10 additional years of **DPPOS Phase 3** assuming a 1.04% loss to follow-up per year.  
To detect a 30% hazard risk reduction in MACE incidence in the primary comparison of metformin and placebo with 85% power and a 2-sided significance level of 0.05 using a log-rank test, we require 145 placebo events. With the expected 156 events in the placebo group by 2025, the study will have 89% power to detect a 30% hazard risk reduction. Other important secondary comparisons will be lifestyle vs. placebo and metformin vs. lifestyle.
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11.3. analysis 11.3.1. analysis of

The primary objective for DPPOS Phase 1 was to compare the durability of the original effect during the DPP, i.e., estimation of the hazard rates for development of diabetes *going* forward among participants who had not developed diabetes during DPP among those who enrolled into DPPOS13. The analysis was based on comparing the hazard rates between the two intervention groups (the Intensive Lifestyle and Metformin groups) and the placebo group. The primary null hypothesis was that among those who had not developed diabetes by the start of DPPOS, the intervention groups did not differ from the controls in the hazard rates for development of diabetes over the interval from the beginning of DPPOS. Reasons for comparing across the interval from the start of DPPOS as the primary analysis rather than from the beginning of DPP were: 1) we had already published the comparison of the three groups over the DPP interval, and any subsequent comparison encompassing that interval would not be an independent analysis; and 2) since the interventions were indeed effective over the earlier DPP interval, the cumulative incidence curves may have had too much separation from the early DPP effects to be able come together again, even if the interventions were not effective over the longer term. The primary analysis from DPPOS baseline did not preclude secondary analyses from the beginning of DPP.  
The cohort of participants for this analysis were a subset of the original DPP study population, and as such were no longer "randomized", but rather selected by having survived DPP without developing diabetes. Beyond that selection, each participant was included in the group to which s/he was randomly assigned, regardless of compliance with study treatment. The number of participants who had not developed diabetes at DPP study end was 870 in the metformin group, 951 in the ILS, and 809 in the placebo group. The primary outcome analysis used an overall significance level of α = 0.05 (2-sided). Two pair-wise comparisons between the intervention groups and the former placebo group, set at the = 0.025 level, were performed if the overall comparison was statistically significant.  
The analysis compared the treatment groups vs. the former placebo group on DPP
baseline characteristics, and any factors on which they differed were considered for inclusion as covariates in the analysis. The primary analysis was a life-table analysis of the time to confirmed development of diabetes. Modified product-limit life-table estimated cumulative incidence curves were calculated for each treatment group and the groups compared using a log rank test3. Participants were considered "administratively censored" if they completed the full duration of follow-up without confirmed development of diabetes. Participants who prematurely discontinued their follow-up visits prior to confirmed development of diabetes were "censored" as of their last follow-up visit. A proportional hazards regression model was used to evaluate potential covariates that may modify the time to development of diabetes. Graphical procedures were used to assess the proportionality assumption. If the proportionality assumption was found to be unreasonable then other models such as the accelerated failure time model101,102,102 or the proportional odds model103 was used to evaluate the covariates.  
The analysis was also conducted within subgroups (one-way stratification) based on the following characteristics: racial/ethnic origin, sex, and age (<45, 45-<60, 60+).  
The primary analyses that focused on the intention-to-treat assignment during DPP
included all participants in the original DPP placebo, lifestyle and metformin intervention groups who enrolled in DPPOS. Since the participants originally assigned to troglitazone only had a limited exposure to that intervention, owing to the premature termination of the troglitazone arm, and were not included in the primary DPP outcome analyses, they were not included in the primary DPPOS analyses.
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11.3.2. composite outcomes of microangiopathic

The analysis of the composite primary microangiopathic outcome at year 11 for DPPOS
Phase 2, and composite secondary cardiovascular disease outcome was performed in an intentto-treat fashion on the DPP groups, as randomized, including participants who have developed diabetes.  
For this composite outcome, the objective was to determine the effect of the interventions on the proportion of participants experiencing the outcome through follow-up visit year 11. For the composite primary microangiopathic outcome, the groups were compared using the global test using general estimating equations (GEE) among DPPOS enrolled participants1.  
The year 11 data for each component was reviewed with respect to being "missing at random" before selecting the appropriate statistical methods for missing data.
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11.3.3. analysis of cancer and

The primary outcomes for DPPOS **Phase 3** are time to the development of cancer (first 5 years) and major cardiovascular disease (MACE, including non-fatal myocardial infarction and stroke, and fatal cardiovascular disease) (second 5 years). The cohort of participants for these analyses includes all participants randomized to the original DPP study. Each participant will be included in the group to which s/he was randomly assigned, regardless of compliance with study treatment. Since the participants originally assigned to troglitazone only had a limited exposure to that intervention, owing to the premature termination of the troglitazone arm, were not included in the primary DPP outcome analyses, and are no longer followed in DPPOS, they will not be included in the primary **DPPOS Phase 3** analyses.  
The primary comparison will focus on the metformin vs. the placebo group. The time to event analysis uses the date of the first occurrence of the outcomes. Participants will be considered "administratively censored" if they complete the full duration of follow-up without confirmed disease. Participants who died or prematurely discontinue their follow-up visits prior to developing the event will be "censored" as of their last follow-up visit - hence, participants who did not enroll in DPPOS will be censored as of their last contact during DPP. Separate Kaplan-Meier estimates of cumulative incidence curves are calculated for the three treatment groups and will be compared using the log rank test.  
Mortality prior to the development of cancer or MACE is a competing risk event104,105,105.  
Regression models that censor on death provide an estimate of the coefficient effect on the underlying cause-specific hazard for the outcome event. If there is a difference between groups in overall mortality, we will examine the cumulative incidence functions within groups adjusting for death as a competing risk.  
The analysis will also be conducted using subgroups (one-way stratification) to assess treatment effect modification based on the following characteristics: racial/ethnic origin, sex, and age at randomization (<45, 45-<60, 60+).  
A proportional hazards regression model will be used to evaluate potential covariates that may modify or mediate the time to development of the outcome106. To allow for model misspecification, such as non-proportional hazards, all inferences will be conducted using the robust variance estimate107 that provides a valid inference in the presence of such misspecification.
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11.3.4. secondary research questions

Secondary objectives are to evaluate the long-term effects of DPP interventions on selected individual health outcomes. These are:
* Further development of diabetes * Diabetic retinopathy * Diabetic neuropathy * Albuminuria * Renal failure * Macrovascular disease * Cardiovascular disease events * Subclinical atherosclerosis outcomes * Risk factors for cardiovascular disease * Amputation in a lower extremity not resulting from major trauma * Hospitalizations * Physical activity, nutrition, body mass and obesity * Dietary and exercise behaviors * Physical function * Quality of life indices * Health care costs * Cognitive performance * Urinary incontinence * Sexual function * DXA-derived bone density, body composition and vertebral fractures * Pulmonary function * Healthy Aging Index * All-cause and cause-specific mortality Other Analyses. Other research questions will examine the clinical course of IGT and newly diagnosed diabetes with regard to the development of microvascular, neuropathic and Rockville, Maryland 65 cardiovascular disease and their respective risk factors. These "epidemiologic" analyses will largely be descriptive. Appropriate statistical methods will be applied to analyze the interactions among putative and established risk factors and the development of different outcomes. In these analyses, treatment assignment during the DPP will be considered a covariate.  
The former troglitazone participants who continue in the DPPOS through visit year 6 will be included in the "other" outcomes exploring the relationship between incident diabetes and determinants of long-term complications of new-onset diabetes and IGT. No research data will be collected in this group beginning with protocol version 3.0.
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11.4. monitoring and timing of

An external Data and Safety Monitoring Board will review reports of study progress and safety regularly throughout the study. They will alert the NIDDK and the Steering Committee if they believe the study should be stopped for reasons of patient safety.  
Because we have already shown both interventions to be effective in delaying or preventing diabetes over 3 years, there would be no compelling reason to stop DPPOS for having demonstrated further benefit. The assessment of the composite microangiopathy occurred after the year 11 visits. Therefore, we did not implement a formal statistical monitoring plan for either of these outcomes in DPPOS. The DSMB reviewed two interim analyses of time to macrovascular event for safety during DPPOS Phase 2.  
Since the cohort size for **DPPOS Phase 3** is fixed, power is driven by the number of placebo subjects with an outcome event and the projected effect size. Projections for the placebo events assumed an exponential increase in hazard rate for cancer and MACE expressed in terms of a growth factor (i.e. ~2-fold increase over 10 years) and based on accumulated DPP/DPPOS data and results from recent studies. Given our best estimate of the accumulation of events, and using effect sizes of 25 or 30%, we expect to reach the level of required cancer events in the placebo group during the first 5-years of **DPPOS Phase 3**, and the required MACE events in the placebo group during the second 5-years of **DPPOS Phase 3**.  
| Outcomes Schedule, DPPOS Phase 1: Visit Years 1-6  Participant DPPOS visit year Year 1   | Year 2                          | Year 3          | Year 4                                          | Year 5         | Year 6         |                |     |     |     |     |     |     |
|------------------------------------------------------------------------------------------|---------------------------------|-----------------|-------------------------------------------------|----------------|----------------|----------------|-----|-----|-----|-----|-----|-----|
| Visit calendar year                                                                      | 9/1/02-10/31/03 7/1/03-10/31/04 | 7/1/04-10/31/05 | 7/1/05-10/31/06 7/1/06-10/31/07 7/1/07-10/31/08 |                |                |                |     |     |     |     |     |     |
| DPPOS funding calendar year                                                              | 2/1/03-1/31/04                  | 2/1/04-1/31/05  | 2/1/05-1/31/06                                  | 2/1/06-1/31/07 | 2/1/07-1/31/08 | 2/1/08-1/31/09 |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                 | Mid                             | Ann             | Mid                                             | Ann            | Mid            | Ann            | Mid | Ann | Mid | Ann | Mid | Ann |
| Glycemia Fasting glucose                                                                 | X                               | X               | X                                               | X              | X              | X              | X   | X   | X   | X   | X   | X   |
| 30', 120' glucose++                                                                      | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |
| HbA1c ++                                                                                 | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |
| Insulin Secretion and Sensitivity Fasting, 30' insulin++                                 | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |
| Inflammatory, clotting and fibrinolytic factors Fibrinogen                               | X                               | X               |                                                 |                |                |                |     |     |     |     |     |     |
| TPA                                                                                      | X                               | X               |                                                 |                |                |                |     |     |     |     |     |     |
| CRP                                                                                      | X                               | X               |                                                 |                |                |                |     |     |     |     |     |     |
| Lipids Lipid profile                                                                     | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |
| Particle size and sub fractions                                                          | X                               | X               |                                                 |                |                |                |     |     |     |     |     |     |
| Kidney Function Urine albumin & creatinine                                               | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |
| Serum Cystatin                                                                           | X                               | X               |                                                 |                |                |                |     |     |     |     |     |     |
| Serum Creatinine                                                                         | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |
| History Symptoms and Events                                                              | X                               | X               | X                                               | X              | X              | X              | X   | X   | X   | X   | X   | X   |
| Physical Weight                                                                          | X                               | X               | X                                               | X              | X              | X              | X   | X   | X   | X   | X   | X   |
| Height                                                                                   | X                               | X               |                                                 |                |                |                |     |     |     |     |     |     |
| Waist Circumference                                                                      | X                               | X               | X                                               | X              | X              | X              |     |     |     |     |     |     |  
| Version 4.4                                                                                             | May 22, 2019    |                 |                                                 |                |                |     |     |     |     |     |     |     |
|---------------------------------------------------------------------------------------------------------|-----------------|-----------------|-------------------------------------------------|----------------|----------------|-----|-----|-----|-----|-----|-----|-----|
| Outcomes Schedule, DPPOS Phase 1: Visit Years 1-6, Continued Participant DPPOS visit year Year 1 Year 2 | Year 3          | Year 4          | Year 5                                          | Year 6         |                |     |     |     |     |     |     |     |
| Visit calendar year 9/1/02-10/31/03                                                                     | 7/1/03-10/31/04 | 7/1/04-10/31/05 | 7/1/05-10/31/06 7/1/06-10/31/07 7/1/07-10/31/08 |                |                |     |     |     |     |     |     |     |
| DPPOS funding calendar year 2/1/03-1/31/04                                                              | 2/1/04-1/31/05  | 2/1/05-1/31/06  | 2/1/06-1/31/07                                  | 2/1/07-1/31/08 | 2/1/08-1/31/09 |     |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                                | Mid             | Ann             | Mid                                             | Ann            | Mid            | Ann | Mid | Ann | Mid | Ann | Mid | Ann |
| Blood Pressure Arm BP                                                                                   | X               | X               | X                                               | X              | X              | X   | X   | X   | X   | X   | X   | X   |
| ABI                                                                                                     | X               | X               |                                                 |                |                |     |     |     |     |     |     |     |
| Quality of Life Beck                                                                                    | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| SF-36                                                                                                   | X               | X               |                                                 |                |                |     |     |     |     |     |     |     |
| Urinary Incontinence                                                                                    | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| Physical Activity and Nutrition MAQ                                                                     | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| Nutrition Intake                                                                                        | X               | X               | X                                               |                |                |     |     |     |     |     |     |     |
| Cardiovascular ECG                                                                                      | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| Carotid Ultrasound+                                                                                     |                 |                 |                                                 |                |                |     |     |     |     |     |     |     |
| Eye Retinal photography#                                                                                | X               | X               |                                                 |                |                |     |     |     |     |     |     |     |
| Neurologic Symptom Assessment                                                                           | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| MNSI with monofilament                                                                                  | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| Heart rate variability                                                                                  | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |
| Saved Specimens Fasting EDTA Plasma                                                                     | X               | X               | X                                               | X              | X              | X   |     |     |     |     |     |     |  
| Version 4.4                                                                                                                          | May 22, 2019    |                                                 |                |                |                |     |     |     |     |     |     |     |
|--------------------------------------------------------------------------------------------------------------------------------------|-----------------|-------------------------------------------------|----------------|----------------|----------------|-----|-----|-----|-----|-----|-----|-----|
| Outcomes Schedule, DPPOS Phase 1: Visit Years 1-6, Continued Participant DPPOS visit year Year 1 Year 2                              | Year 3          | Year 4                                          | Year 5         | Year 6         |                |     |     |     |     |     |     |     |
| Visit calendar year 9/1/02-10/31/03 7/1/03-10/31/04                                                                                  | 7/1/04-10/31/05 | 7/1/05-10/31/06 7/1/06-10/31/07 7/1/07-10/31/08 |                |                |                |     |     |     |     |     |     |     |
| DPPOS funding calendar year 2/1/03-1/31/04                                                                                           | 2/1/04-1/31/05  | 2/1/05-1/31/06                                  | 2/1/06-1/31/07 | 2/1/07-1/31/08 | 2/1/08-1/31/09 |     |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                                                             | Mid             | Ann                                             | Mid            | Ann            | Mid            | Ann | Mid | Ann | Mid | Ann | Mid | Ann |
| Safety Measures Serum creatinine                                                                                                     | X               | X                                               | X              | X              | X              | X   |     |     |     |     |     |     |
| CBC*                                                                                                                                 | X               | X                                               | X              | X              | X              | X   |     |     |     |     |     |     |
| Serious Adverse event report**                                                                                                       | X               | X                                               | X              | X              | X              | X   | X   | X   | X   | X   | X   | X   |
| Pregnancy##                                                                                                                          | X               | X                                               | X              | X              | X              | X   |     |     |     |     |     |     |
| Serology IA2***, GAD*** Other Chemistries Relevant biological markers related to the  pathogenesis of diabetes and its complications | X               | X                                               |                |                |                |     |     |     |     |     |     |     |
| Economic Evaluation Resource Utilization                                                                                             | X               |                                                 |                |                |                |     |     |     |     |     |     |     |
| QWB                                                                                                                                  | X               | X                                               | X              | X              | X              | X   |     |     |     |     |     |     |  
\# Fundus photos were obtained in Year 1 or 2 on a subset of diabetic and non-diabetic participants. Year 5 photos were completed on all participants in the lifestyle, metformin and placebo arms.  
\#\# Pregnancy tests as needed for participants on metformin based on symptoms and menstrual history and measured locally. * In the Metformin treatment group on study metformin measured locally. ** Serious Adverse events will be collected at Annual, Mid-year and Interim follow-up visits. *** Specimen for IA2 and GAD antibodies will be collected at the time of confirmation and will be analyzed for those who converted.  
+ Carotid ultrasounds were collected during the DPP bridge period as a baseline for DPPOS
++ For diabetic participants: HbA1c is collected at Mid-Year visits; the 30' insulin and 30/120' glucose collections are discontinued +++ The following outcomes are not obtained for participants in the former troglitazone arm: carotid ultrasound, fundus photographs, other chemistries  
| Version 4.4                                                                             | May 22, 2019    |                 |                 |                 |                 |                 |     |     |     |     |     |     |
|-----------------------------------------------------------------------------------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----|-----|-----|-----|-----|-----|
| Outcomes Schedule, DPPOS Phase 2: Visit Years 7-12  Participant DPPOS visit year Year 7 | Year 8          | Year 9          | Year 10         | Year 11         | Year 12         |                 |     |     |     |     |     |     |
| Visit calendar year                                                                     | 9/1/08-10/31/09 | 7/1/09-10/31/10 | 7/1/10-10/31/11 | 7/1/11-10/31/12 | 7/1/12-10/31/13 | 7/1/13-10/31/14 |     |     |     |     |     |     |
| DPPOS funding calendar year                                                             | 2/1/09-1/31/10  | 2/1/10-1/31/11  | 2/1/11-1/31/12  | 2/1/12-1/31/13  | 2/1/13-1/31/14  | 2/1/14-1/31/15  |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                | Mid             | Ann             | Mid             | Ann             | Mid             | Ann             | Mid | Ann | Mid | Ann | Mid | Ann |
| Glycemia Fasting glucose                                                                | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| 30', 120' glucose+                                                                      | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| HbA1c +                                                                                 | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Insulin Secretion and Sensitivity Fasting, 30' insulin+                                 | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Inflammatory, clotting and fibrinolytic factors Fibrinogen                              | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| TPA                                                                                     | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| CRP                                                                                     | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Lipids Lipid profile                                                                    | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Particle size and subfractions                                                          | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Kidney Function Urine Albumin & Creatinine                                              | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Serum Cystatin                                                                          | X               | X               | X               | X               | X               |                 |     |     |     |     |     |     |
| Serum Creatinine                                                                        | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| History Symptoms and Events                                                             | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| Cancer History and Risk Factors                                                         | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Physical Weight                                                                         | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| Height                                                                                  | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Waist Circumference                                                                     | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| DXA (body composition measures)+++                                                      | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |  
| Version 4.4                                                                                               | May 22, 2019    |                 |                 |                 |                 |                 |     |     |     |     |     |     |
|-----------------------------------------------------------------------------------------------------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----|-----|-----|-----|-----|-----|
| Outcomes Schedule, DPPOS Phase 2: Visit Years 7-12, Continued  Participant DPPOS visit year Year 7 Year 8 | Year 9          | Year 10         | Year 11         | Year 12         |                 |                 |     |     |     |     |     |     |
| Visit calendar year                                                                                       | 9/1/08-10/31/09 | 7/1/09-10/31/10 | 7/1/10-10/31/11 | 7/1/11-10/31/12 | 7/1/12-10/31/13 | 7/1/13-10/31/14 |     |     |     |     |     |     |
| DPPOS funding calendar year                                                                               | 2/1/09-1/31/10  | 2/1/10-1/31/11  | 2/1/11-1/31/12  | 2/1/12-1/31/13  | 2/1/13-1/31/14  | 2/1/14-1/31/15  |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                                  | Mid             | Ann             | Mid             | Ann             | Mid             | Ann             | Mid | Ann | Mid | Ann | Mid | Ann |
| Blood Pressure Arm BP                                                                                     | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| ABI ++                                                                                                    | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Quality of Life Beck                                                                                      | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| SF-36                                                                                                     | X               | X               | X               | X               |                 |                 |     |     |     |     |     |     |
| Urinary Incontinence                                                                                      | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Physical Activity, Nutrition, Behavior, Functional MAQ                                                    | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Nutrition Intake                                                                                          | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Dietary Restraint, Exercise Self-Efficacy, Low Fat  Diet Self-Efficacy                                    | X               | X               | X               | X               | X               |                 |     |     |     |     |     |     |
| Physical Function tests (Grip strength, CES-D  Depression, Gait Speed, Chair Stand, Balance)              | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Cognition Cognitive Function tests                                                                        | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Cardiovascular ECG                                                                                        | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Coronary Artery Calcium ++                                                                                | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Eye Retinal Photography ++                                                                                | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Neurologic Symptom Assessment                                                                             | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Modified MNSI including monofilament                                                                      | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Heart rate variability                                                                                    | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |  
| Outcomes Schedule, DPPOS Phase 2: Visit Years 7-12, Continued  Participant DPPOS visit year Year 7 Year 8    | Year 9          | Year 10         | Year 11         | Year 12         |                 |                 |     |     |     |     |     |     |
|--------------------------------------------------------------------------------------------------------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----|-----|-----|-----|-----|-----|
| Visit calendar year                                                                                          | 9/1/08-10/31/09 | 7/1/09-10/31/10 | 7/1/10-10/31/11 | 7/1/11-10/31/12 | 7/1/12-10/31/13 | 7/1/13-10/31/14 |     |     |     |     |     |     |
| DPPOS funding calendar year                                                                                  | 2/1/09-1/31/10  | 2/1/10-1/31/11  | 2/1/11-1/31/12  | 2/1/12-1/31/13  | 2/1/13-1/31/14  | 2/1/14-1/31/15  |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                                     | Mid             | Ann             | Mid             | Ann             | Mid             | Ann             | Mid | Ann | Mid | Ann | Mid | Ann |
| Saved Specimens Fasting EDTA Plasma (no serum is stored)                                                     | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Safety Measures Serum creatinine                                                                             | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| CBC*                                                                                                         | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Serious Adverse event report**                                                                               | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| Pregnancy##                                                                                                  | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Other Chemistries Relevant biological markers related to the  pathogenesis of diabetes and its complications | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Economic Evaluation Resource Utilization                                                                     | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| QWB                                                                                                          | X               | X               | X               | X               |                 |                 |     |     |     |     |     |     |  
EOS = end of study \# Pregnancy tests as needed for participants on metformin based on symptoms and menstrual history and measured locally. * Collected from participant of the metformin treatment group on study metformin measured locally. ** Serious Adverse events will be collected at Annual, Mid-year and Interim follow-up visits. *** Specimen for IA2 and GAD antibodies will be collected at the time of confirmation and will be analyzed for those who converted. + For diabetic participants: HbA1c is collected at Mid-Year visits; the 30' insulin and 30/120' glucose collections are discontinued ++ The following will be completed at study end: ABI, retinal photography, coronary artery calcium +++ DXA scans will be completed on a sample of participants during DPPOS Year 12  
| Version 4.4                                                                               | May 22, 2019    |                 |                 |                 |                 |                 |     |     |     |     |     |     |
|-------------------------------------------------------------------------------------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----|-----|-----|-----|-----|-----|
| Outcomes Schedule, DPPOS Phase 3: Visit Years 13-18  Participant DPPOS visit year Year 13 | Year 14         | Year 15         | Year 16         | Year 17         | Year 18         |                 |     |     |     |     |     |     |
| Visit calendar year                                                                       | 7/1/14-10/31/15 | 7/1/15-10/31/16 | 7/1/16-10/31/17 | 7/1/17-10/31/18 | 7/1/18-10/31/19 | 7/1/19-10/31/20 |     |     |     |     |     |     |
| DPPOS funding calendar year                                                               | 2/1/15-1/31/16  | 2/1/16-1/31/17  | 2/1/17-1/31/18  | 2/1/18-1/31/19  | 2/1/19-1/31/20  | 2/1/20-1/31/21  |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                  | Mid             | Ann             | Mid             | Ann             | Mid             | Ann             | Mid | Ann | Mid | Ann | Mid | Ann |
| Glycemia Fasting glucose                                                                  | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| 120' glucose+                                                                             | X               | X               | X               |                 |                 |                 |     |     |     |     |     |     |
| HbA1c                                                                                     | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Insulin Secretion and Sensitivity Fasting insulin                                         | X               | X               | X               | X               |                 |                 |     |     |     |     |     |     |
| Lipids Lipid profile                                                                      | X               | X               | X               |                 |                 |                 |     |     |     |     |     |     |
| Kidney Function Urine Albumin & Creatinine                                                | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Serum Creatinine                                                                          | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| History Symptoms and Events (including CVD and Cancer)                                    | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| Cancer Risk Factors                                                                       | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Physical Weight                                                                           | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Height                                                                                    | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Waist Circumference                                                                       | X               | X               | X               |                 |                 |                 |     |     |     |     |     |     |
| DXA (bone and body composition measures)++                                                | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Blood Pressure Arm BP                                                                     | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Quality of Life Beck                                                                      | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| SF-36                                                                                     | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Urinary Incontinence                                                                      | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |  
| Version 4.4                                                                                                 | May 22, 2019    |                 |                 |                 |                 |                 |     |     |     |     |     |     |
|-------------------------------------------------------------------------------------------------------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----------------|-----|-----|-----|-----|-----|-----|
| Outcomes Schedule, DPPOS Phase 3: Visit Years 13-18, Continued Participant DPPOS visit year Year 13 Year 14 | Year 15         | Year 16         | Year 17         | Year 18         |                 |                 |     |     |     |     |     |     |
| Visit calendar year                                                                                         | 7/1/14-10/31/15 | 7/1/15-10/31/16 | 7/1/16-10/31/17 | 7/1/17-10/31/18 | 7/1/18-10/31/19 | 7/1/19-10/31/20 |     |     |     |     |     |     |
| DPPOS funding calendar year                                                                                 | 2/1/15-1/31/16  | 2/1/16-1/31/17  | 2/1/17-1/31/18  | 2/1/18-1/31/19  | 2/1/19-1/31/20  | 2/1/20-1/31/21  |     |     |     |     |     |     |
| Mid-year or Annual visit                                                                                    | Mid             | Ann             | Mid             | Ann             | Mid             | Ann             | Mid | Ann | Mid | Ann | Mid | Ann |
| Physical Activity, Nutrition, Behavior, Functional ADL/IADL                                                 | X               | X               | X               |                 |                 |                 |     |     |     |     |     |     |
| Sexual Function                                                                                             | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Physical Function including the 6-minute walk test                                                          | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Spirometry                                                                                                  | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| MAQ                                                                                                         | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Cognition Cognitive Function                                                                                | X               | X               | X               |                 |                 |                 |     |     |     |     |     |     |
| Cardiovascular ECG                                                                                          | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Eye Retinal Photography and OCT                                                                             | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Neurologic Monofilament                                                                                     | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| MNSI                                                                                                        | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| MNSI questionnaire only                                                                                     | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Sensory exam (vibration and pinprick)                                                                       | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Heart rate variability                                                                                      | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Saved Specimens Fasting Serum and EDTA Plasma                                                               | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Spot Urine                                                                                                  | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| Additional Safety Measures Serum Creatinine                                                                 | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| CBC*                                                                                                        | X               |                 |                 |                 |                 |                 |     |     |     |     |     |     |
| Vitamin B12*                                                                                                | X               | X               |                 |                 |                 |                 |     |     |     |     |     |     |
| Serious Adverse Event report**                                                                              | X               | X               | X               | X               | X               | X               | X   | X   | X   | X   | X   | X   |
| Pregnancy#                                                                                                  | X               | X               | X               | X               | X               | X               |     |     |     |     |     |     |
| The Biostatistics Center, George Washington University                                                      | 74              |                 |                 |                 |                 |                 |     |     |     |     |     |     |  
Rockville, Maryland  
74  
| Version 4.4                                                                        | May 22, 2019   |    |
|------------------------------------------------------------------------------------|----------------|----|
| Economic Evaluation Resource Utilization                                           | X              | X  |
| QWB                                                                                | X              |    |
| + For diabetic participants: The OGTT with 120' glucose collection is discontinued |                |    |  
QWB X
+ For diabetic participants: The OGTT with 120' glucose collection is discontinued \# Pregnancy tests as needed for participants on metformin based on symptoms and menstrual history and measured locally.  
* CBC and/or B12 for participants actively taking study metformin
** Serious Adverse events will be collected at Annual, Mid-year and Interim follow-up visits.  
++ DXA scans will be completed on a sample of participants during DPPOS Year 17
8. adverse event reporting
12.1. visit schedule

Annual visits will be targeted for the anniversary of the participant's original DPP
randomization date. Mid-year visits will take place 6 months before and after annual visits.
8. adverse event reporting
13. study timetable

| Diabetes Prevention Program                |                                      |                                            |
|--------------------------------------------|--------------------------------------|--------------------------------------------|
| Phase I                                    | July 1994 - June 1996                | Protocol Development and Implementation    |
| July 1994 - December 1995                  | Protocol Development                 |                                            |
| January 1996 - June 1996                   | Protocol Implementation              |                                            |
| Phase II                                   | July 1996 - June 2002                | Participant Randomization and Follow-up    |
| July 1996 - June 1999                      | Recruitment and Follow-up            |                                            |
| July 1999 - December 2001                  | Participant Follow-up                |                                            |
| Phase III                                  | June 2001                            | Initiate Study Close-out and Data Analysis |
| Phase IV                                   | January 1, 2002                      | Bridge Period Starts                       |
| August 31, 2002                            | Bridge Period Ends                   |                                            |
| Diabetes Prevention Program Outcomes Study |                                      |                                            |
| Planning                                   | January 2002 - August 31, 2002       | Protocol development                       |
| Phase 1                                    | September 1, 2002 - January 31, 2009 | Participant follow-up                      |
| July 2006 - October, 2007                  | Year 5 major visit                   |                                            |
| February 1, 2008 - January 31, 2009        | Phase 1 Analysis                     |                                            |
| June 2008                                  | Submit funding renewal               |                                            |
| Phase 2                                    | February 1, 2009 - October 2015      | Participant follow-up                      |
| July 2012 - October 2013                   | Year 11 major visit                  |                                            |
| October 2013                               | Begin Phase 2 Analysis               |                                            |
| May 2014                                   | Submit funding renewal               |                                            |
| March 2015                                 | Re-submit funding renewal            |                                            |  
Rockville, Maryland 77 Phase 3 February 1, 2015 - October 2020 Participant follow-up  
February 1, 2015 - January 2016 Bridge period funding awarded July 2017 - October 2018 Year 16 major visit May 2020 Submit funding renewal February 1, 2019 - January 31, 2021 DPPOS Phase 3 (first 5 years) analysis
8. adverse event reporting
14. bibliography

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