TABLE OF CONTENTS

Example 2 - ACCORD ............................................................................................................................ 2

Challenges ........................................................................................................................................ 2

Applying Feasibility Checklist ............................................................................................................ 3

Feasibility questionnaire ................................................................................................................... 4

Parameters Input for ACCORD Protocol ............................................................................................ 5

ACCORD Results ................................................................................................................................ 7

Part 1: Lipid trial ........................................................................................................................... 7

Part 2: Systolic blood pressure trial ............................................................................................... 9

FIGURES

Figure 2-1. EVPI results for ACCORD - Lipid trial ......................................................................................... 7

Figure 2-2. EVSI results for ACCORD - Lipid trial ......................................................................................... 8

Figure 2-3. EVPI results for ACCORD - Systolic blood pressure trial ........................................................... 9

Figure 2-4. EVSI results for ACCORD - Systolic blood pressure trial ......................................................... 10

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OTHER EXAMPLES FOR VICTOR PLATFORM

In addition to the SHEP trial, we also use the VICTOR platform for another three trials:

(1) ALLHAT – Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (2) ACCORD – Action to Control Cardiovascular Risk in Diabetes Trial (3) AIMHIGH – Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglyceride

and Impact on Global Health Outcomes

For each trial, we first use feasibility checklist and questionnaire to determine whether the VICTOR platform can be used to estimate the expected value of perfect information (EVPI) and the expected value of sample information (EVSI). If so, we will list the parameters input and results, and also describe challenges and potential solutions to obtain these parameters.

Example 2 - ACCORD

The ACCORD was a randomized trial using double 2 X 2 factorial design for patients with type 2 diabetes mellitus, which included three components (glycemia trial, lipid trial, and systolic blood pressure (SBP) trial). In this example, we used the VICTOR platform to estimate the value of information for lipid trial and systolic blood pressure trial, but not for the glycemia trial. The glycemia trial was designed to randomly assign all 10,000 participants to receive either intensive-therapy and standard-therapy group to lower the level of glycated hemoglobin for the glycemia trial. Among these 10,000 participants, 5,800 patients were included in the lipid trial (first 2 X 2 trial), and 4,200 patients were assigned to the SBP trial (second 2 X 2 trial). The participants in the lipid trial were randomized to use either fenofibrate or placebo, and those in the SBP trial were received either intensive or standard blood pressure control.

Challenges

The primary endpoint of the lipid trial and the SBP trial were composite of cardiovascular causes death (CVD death), non-fatal myocardial infarction (MI), and non-fatal stroke (MACE). However, the protocol only reported overall event rate of the control group and estimated treatment effect which was 20% for both lipid trial and SBP trial. To use the VICTOR platform, we first got the annual event rate of intervention group by applying 20% treatment effect to the annual event rate of the control group. Then, we obtained the percentage of CVD death, non-fatal MI and non-fatal from the published trial results in each group and multiplied annual event rate by these percentage to obtain the parameters input for intervention and control group respectively. 1,2

3

Applying Feasibility Checklist

FEASIBILITY FACTOR FEASIBILITY QUESTION ACCORD STUDY POPULATION: Is the condition of interest for your study

population listed? Patients with type 2 diabetes mellitus Y/N

STUDY TYPE: Is your proposed study design listed? Double 2 X2 factorial design Y/N

ENDPOINTS: Is your proposed primary study endpoint listed? Non-fatal MI, stroke, & CVD death Y/N

INTERVENTION EFFECTS: Can the effect of the intervention in your proposal be expressed using one of the options listed?

• Lipid trial à fenofibrate or placebo à 20% treatment effect

• Blood pressure trial à intense vs standard à 20% treatment effect

Y/N

BACKGROUND CLINICAL DATA FOR CONTROL GROUP, BY ENDPOINT

Do you have listed data on the control group for the primary endpoint?

Only overall event rate was reported1 Y/N BACKGROUND CLINICAL DATA ON INTERVENTION EFFECTS, BY ENDPOINT

Do you have listed data on selected intervention effects?

1 An event was defined as the occurrence of fatal CHD or fatal/non-fatal stroke or myocardial infarction.

4

Feasibility questionnaire

5

Parameters Input for ACCORD Protocol

• Note that study parameters are the same for both lipid trial and systolic blood pressure trial because of same primary endpoint. However, the clinical parameters input was different for each trial.

Study Parameters

• Target population o Mean Age : 63.5 o Female(%) : 40 o MI history composition (%) : 35

• Study design features

o Number of comparators (Fixed at 2) o Expression of intervention effects : Absolute

level o Primary endpoint : MACE o Treatment effectiveness duration : 6

• Other model input

o Target population size : 100,000 o Discount rate(%) : 3 o Horizon duration (years) : 20

• EVSI parameters

o Total length of proposed study : 10.5 o Sample size for each arm : 1,000-10,000 o Number of sample size to be evaluated : 10

• Advanced VOI parameters

o Decision-making criterion : 95% CI o Current use rate of treatment : Decision-

making criterion

6

Lipid trial Systolic blood pressure trial

Clinical Parameters (Mean ±SE)

• Intervention group o annual rate (%) for non-fatal MI :

0.36± 0.15 o annual rate (%) for non-fatal stroke :

0.05± 0.11 o annual rate (%) for fatal CVD :

0.67 ± 0.27 • Control group

o annual rate (%) for non-fatal MI : 0.5 ± 0.18

o annual rate (%) for non-fatal stroke : 0.06 ± 0.13

o annual rate (%) for fatal CVD : 0.91 ± 0.3

Clinical Parameters (Mean ±SE)

• Intervention group o annual rate (%) for non-fatal MI :

0.56 ± 0.21 o annual rate (%) for non-fatal

stroke : 0.09 ± 0.16

o annual rate (%) for fatal CVD : 0.97 ± 0.41

• Control group o annual rate (%) for non-fatal MI :

0.7 ± 0.24 o annual rate (%) for non-fatal

stroke : 0.11 ± 0.18

o annual rate (%) for fatal CVD : 1.21 ± 0.46

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ACCORD Results Part 1: Lipid trial Figure 2-1. EVPI results for ACCORD - Lipid trial

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Figure 2-2. EVSI results for ACCORD - Lipid trial

9

Part 2: Systolic blood pressure trial Figure 2-3. EVPI results for ACCORD - Systolic blood pressure trial

10

Figure 2-4. EVSI results for ACCORD - Systolic blood pressure trial

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Reference 1. Group TAS. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. New England

Journal of Medicine. 2010;362(17):1563-1574. 2. Group TAS. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. New England

Journal of Medicine. 2010;362(17):1575-1585.