1

RAPID Phase II Protocol Working GroupSPEED Popliteal Example

October 4, 2017

2

Indication Expansion with RWE

Current Indication

Indicated to improve luminal diameter in the treatment of symptomatic de-novo or restenotic lesions in the native superficial femoral artery (SFA) and/or proximal popliteal artery (PPA).

Proposed Indication

Indicated to improve luminal diameter in the treatment of symptomatic de-novo or restenotic lesions in the native superficial femoral artery (SFA) and/or full popliteal artery (P1-P3).

3

Study Design

DesignRetrospective, non-randomized, propensity score 1:1 matchPre-specified analysis of existing VQI registry data.

Primary ObjectiveTo expand the labeled indications of the SFA/PPA device to include distal popliteal based on Real World Evidence (RWE) from the VQI PCI registry.

Discussion Points: Is there an adequate quantity of data available in VQI database for

propensity score 1:1 match? Possibility of 2:1 match? (as all prospective test subjects should

be included in the analysis)

4

Primary Endpoints

Safety EndpointThe safety endpoint assesses a composite MAE rate defined as: • All Cause Death through 30 days • Target limb major amputation through 12 months • Target Lesion Revascularization through 12 months

Effectiveness EndpointVessel Primary Patency rate at 12 months as determined by Duplex Ultrasound. Vessel primary patency is defined as freedom from more than 50% stenosis based on DUS peak systolic velocity ratio comparing data within the target segment to the proximal normal arterial segment in the absence of Target Lesion Revascularization or bypass.

Discussion Points:Outcome access control: how to establish a protection mechanism

in the early phase to prevent the observed outcomes from leaking?

5

Key Inclusion/Exclusion CriteriaInclusion Criteria1. Enrollment in VQI all comers registry 2. Patients 18 years and older3. Patients treated with subject stent in the Distal

PPA (P2/P3)4. Chronic symptomatic lower limb ischemia

defined as Rutherford categories 2, 3 or 45. Patent popliteal artery, i.e., single vessel

runoff or better with at least one of three vessels patent (<50% stenosis) to the ankle or foot

Discussion Points: Does this criteria make sense for a

retrospective study? Is this information available in the VQI

database? Would this criteria have any impact to

outcomes (especially retrospectively)? Is this criteria too restrictive for a

registry?

Exclusion Criteria1. Previous stent placement in the target vessel2. Subjects who have undergone prior surgery in

the target limb to treat atherosclerotic disease3. Subjects who have undergone prior

percutaneous transluminal angioplasty (PTA) in the target lesion (within 3 months of index procedure)

4. Use of atherectomy devices or other adjunctive treatment during the index procedure

5. History of major amputation in the same limb as the target lesion

6. Life expectancy less than 12 months due to other medical co-morbid condition(s)

7. Known hypersensitivity or contraindication to contrast dye that, in the opinion of the investigator, cannot be adequately pre-medicated.

8. Intolerance to antiplatelet, anticoagulant, or thrombolytic medications

9. Platelet count <150,000 mm3 or >600,000 mm3

10. Concomitant renal failure with a serum creatinine >2.0 mg/dL

11. Receiving dialysis or immunosuppressant therapy

12. Pregnancy

6

Statistical Plan

Primary Effectiveness Statistical HypothesisThe primary effectiveness hypothesis to be tested is that 12-month primary patency in subjects treated with Test Device is superior to subjects treated with Control Device (from VQI database) at an one-sided significance level of 2.5%.

Primary Effectiveness Statistical Test MethodA normal approximation test will be used to assess the hypothesis of superiority in proportions:

H0: Pt - Pc 0H1: Pt - Pc > 0

where Pt and Pc are the 12-month primary patency for the Test Device and Control Device group, respectively.

7

Sample Size

Sample Size Parameters• Power ≥ 85%• One-sided significance level (alpha) = 2.5%• Expected Control Device 12-month primary patency = 45%• Expected Test Device 12-month primary patency = 70% • Test Device to demonstrate 25% treatment effect• Propensity score to match 1:1• N = 138 (total) evaluable subjects are required at 12 months

– 69 Test Device (prospective and/or retrospective)– 69 Control Device (retrospective only)

Sample Size• xx subjects to be enrolled (depending on yy subjects available in VQI database)• up to 69 prospective patients in the U.S. or Canada treated with the device

Discussion Points:Only enroll prospective test patients if not enough retrospective data

in VQI. Need understanding of amount of data in VQI database.

8

FDA Submission Path

180 Day PMA Supplement = User Fee $46,615 (FY 2018)

Panel Track PMA Supplement = User Fee $233,073 (FY 2018)

Discussion Points:Which submission type would FDA require?Estimated costs to access VQI data?Determine timelines for data collection and submission reviewCompany needs costs and timelines defined prior to project

approval