SPIRIT III Clinical Trial of the XIENCE V® Everolimus Eluting Coronary Stent System (EECSS)

SPIRIT III: A Clinical Evaluation of the Investigational Device XIENCE V® Everolimus Eluting Coronary Stent System (EECSS) in the Treatment of Subjects With de Novo Native Coronary Artery Lesions

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00180479

Enrollment

1002

Registered

2005-09-16

Start date

2005-06-30

Completion date

2011-11-30

Last updated

2011-11-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Coronary Artery Disease, Coronary Artery Restenosis, Coronary Artery Stenosis, Myocardial Ischemia, Stents, Stent Thrombosis, Total Coronary Occlusion, Vascular Disease

Keywords

Everolimus

Brief summary

This study is divided into 5 arms: 1. Randomized Clinical Trial (RCT): Prospective, randomized, active-controlled, single blind, parallel two-arm multi-center clinical trial in the United States (US) comparing XIENCE V® Everolimus Eluting Coronary Stent System (CSS) (2.5, 3.0, 3.5 mm diameter stents) to the Food and Drug Administration (FDA) approved commercially available active control TAXUS® EXPRESS2™ Paclitaxel Eluting Coronary Stent (TAXUS® EXPRESS2™ PECS) System 2. US 2.25 mm non-randomized arm using 2.25 mm diameter XIENCE V® Everolimus Eluting CSS 3. US 4.0 mm non-randomized arm using 4.0 mm diameter XIENCE V® Everolimus Eluting CSS 4. US 38 mm non-randomized arm using 38 mm in length XIENCE V® Everolimus Eluting CSS 5. Japanese non-randomized arm using XIENCE V® Everolimus Eluting CSS (2.5, 3.0, 3.5, 4.0 mm diameter stents) in Japan The TAXUS® EXPRESS2™ Paclitaxel Eluting Coronary Stent System is Manufactured by Boston Scientific.

Detailed description

The purpose of the SPIRIT III clinical trial is to evaluate the safety and efficacy of the XIENCE V® Everolimus Eluting Coronary Stent System (XIENCE V® EECSS). The XIENCE V® EECS (XIENCE V® arm) will be compared to an active control group represented by the FDA approved commercially available Boston Scientific TAXUS® EXPRESS2™ Paclitaxel-Eluting Coronary Stent (TAXUS® EXPRESS2™ PECS) System (TAXUS® arm). The SPIRIT III clinical trial consists of a randomized clinical trial (RCT) in the US which will enroll approximately 1,002 subjects (2:1 randomization XIENCE V® EECS : TAXUS® EXPRESS2™ PECS) with a maximum of two de novo native coronary artery lesion treatment within vessel sizes \>= 2.5 mm and \<= 3.75 mm. The SPIRIT III clinical trial also consists of three concurrent US non-randomized arms (2.25 mm diameter stent, 4.0 mm diameter stent and 38 mm length stent arms) and one Japanese non-randomized arm as follows: 1. 105 subjects with a maximum of two de novo native coronary artery lesion within vessel sizes \> 2.25 mm and \< 2.5 mm and lesion length \<= 22 mm will be enrolled concurrently in the US 2.25 mm non-randomized treatment arm 2. 80 subjects with a maximum of two de novo native coronary artery lesion within vessel sizes \> 3.75 mm and \>= 4.25 mm and lesion length \<= 28 mm will be enrolled concurrently in the US 4.0 mm non-randomized treatment arm 3. 105 subjects with a maximum of two de novo native coronary artery lesion within vessel sizes \> 3.0 mm and \< 4.25 mm and lesion length \> 24 mm and \< 32 mm will be enrolled concurrently in the US 38 mm non-randomized treatment arm. 4. 88 Japanese subjects with a maximum of two de novo native coronary artery lesions within vessel sizes \>= 2.5 mm and \<= 4.25 mm and lesion length \<= 28 mm will be enrolled concurrently in the non-randomized Japanese arm. All subjects in the RCT and the four non-randomized arms will be screened per the protocol required inclusion/exclusion criteria. The data collected will be compared to data from the subjects enrolled into the TAXUS® arm of US RCT. Subjects enrolled in the US RCT will be sub-grouped based on whether they will have an angiographic and/or an intravascular ultrasound (IVUS) follow-up at 240 days as follows: Group A: Angiographic and IVUS follow-up at 240 days (N=240) Group B: Angiographic follow-up at 240 days (N=324) Group C: No angiographic or IVUS follow-up (N=438) All subjects will have clinical follow-up at 30, 180, 240 and 270 days (Data collected through 270 days will be submitted as the primary data set for US and Japanese market approval), and 1, 2, 3, 4, and 5 years (for annual reports). All subjects enrolled into three US non-randomized arms (N=105 for 2.25 mm arm, N=80 for 4.0 mm arm and N=105 for 38 mm stent arm) will have clinical follow-up at 30, 180, 240, and 270 days, and angiographic follow-up at 240 days. No IVUS follow-up is required for subjects enrolled in these arms. All subjects enrolled into the Japanese non-randomized arm (N=88) will have clinical follow-up at 30, 180, 240, and 270 days, and angiographic and IVUS follow-up at 240 days. All subjects who receive a bailout stent will be assigned to Group A follow-up subgroup (angiographic and IVUS follow-up at 240 days after the index procedure), regardless of their primary assignment at randomization. At sites without IVUS capability, subjects receiving bailout stent will be assigned to Group B follow-up subgroup (angiographic follow-up at 240 days after the index procedure). Angiographic follow-up is required for all bailout subjects at 240 days. Data from the US RCT will be submitted to the FDA as the primary data set for product approval for RVD \>= 2.5 mm and \<= 3.75 mm (2.5 mm, 3.0 mm and 3.5 mm stents). Combined data of the US trial/Japanese non-randomized arm will be submitted to the Japanese Ministry of Health, Labor and Welfare (MHLW) for Japanese approval for RVD\>=2.5 mm and \<= 4.25 mm (2.5 mm, 3.0 mm 3.5 mm and 4.0 mm stents). Data from the Japanese non-randomized arm will be submitted to the FDA as additional safety data. Data from the US non-randomized arms of the trial will be the primary data sets for approval for 2.25 mm diameter stent (RVD \> 2.25 mm and \< 2.5 mm), 4.0 mm diameter stent (RVD \> 3.75 mm and \<= 4.25 mm) and 38 mm length stent (RVD \> 3.0 mm and \<= 4.25 mm and lesion length \> 24 mm and \<= 32 mm), respectively in the US. A pharmacokinetic substudy will be carried out in a minimum of 5 pre-determined sites in the US and a minimum of 5 pre-determined sites in Japan. In the US, the pharmacokinetics (PK) of everolimus, as delivered by the XIENCE V® EECS will be analyzed in a subset of 15 subjects (minimum) with single vessel/lesion treatment, and up to 20 subjects with dual vessel/lesion treatment, respectively. In Japan, a minimum of 10 subjects with single vessel/lesion treatment and up to 20 subjects with dual vessel/lesion treatment will have a PK measurements performed. These subsets will include subjects receiving overlapping stents.

Interventions

DEVICEXIENCE V® Everolimus Eluting Coronary Stent

Drug eluting stent implantation stent in the treatment of coronary artery disease.

DEVICETAXUS® EXPRESS2™ Paclitaxel Eluting Coronary Stent

Drug eluting stent implantation stent in the treatment of coronary artery disease.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Target lesion(s) must be located in a native epicardial vessel with visually estimated diameter between \>= 2.25 mm and \<= 4.25 mm and a lesion length \<= 32 mm * The target lesion(s) must be in a major artery or branch with a visually estimated stenosis of \>= 50% and \< 100% with a thrombolysis in myocardial infarction (TIMI) flow of \>= 1 * Non-study, percutaneous intervention for lesions in a non-target vessel is allowed if done \>= 90 days prior to the index procedure (subjects who received brachytherapy will be excluded from the trial)

Exclusion criteria

* Located within an arterial or saphenous vein graft or distal to a diseased (vessel irregularity per angiogram and \> 20% stenosed lesion by visual estimation) arterial or saphenous vein graft * Lesion involving a bifurcation \>= 2 mm in diameter or ostial lesion \> 50% stenosed by visual estimation or side branch requiring predilatation * Located in a major epicardial vessel that has been previously treated with brachytherapy * Located in a major epicardial vessel that has been previously treated with percutaneous intervention \< 9 months prior to index procedure * Total occlusion (TIMI flow 0), prior to wire passing * The target vessel contains thrombus * Another significant lesion (\> 40% diameter stenosis \[DS\]) is located in the same epicardial vessel as the target lesion

Design outcomes

Primary

Measure	Time frame	Description
Primary Endpoint: In-segment Late Loss (LL)	240 days	In-segment minimal lumen diameter (MLD) post-procedure minus (-) in segment MLD at 240 day follow-up and 5 mm proximal and 5mm distal to the stent equals Late Loss. MLD defined: The average of two orthogonal views (when possible) of the narrowest point within the area of assessment.

Secondary

Measure	Time frame	Description
Target Vessel Failure (TVF)	30 days	The composite endpoint comprised of: * Cardiac death (death in which a cardiac cause cannot be excluded) * Myocardial infarction (MI, classified as Q-wave and non-Q wave) * Ischemia-driven target lesion revascularization (TLR) by CABG or PCI * Ischemia-driven target vessel revascularization (TVR) by CABG or PCI
Ischemia Driven Target Lesion Revascularization (ID-TLR)	30 days	Revascularization @ target lesion associated w/ any of following: (+) functional ischemia study Ischemic symptoms & angiographic diameter stenosis ≥50% by core lab quantitative coronary angiography (QCA) Revascularization of a target lesion w/ angiographic diameter stenosis ≥70% by core laboratory QCA without angina or (+) functional study
Ischemia Driven Target Vessel Revascularization (ID-TVR)	30 days	Revascularization at the target vessel associated with any of the following * Positive functional ischemia study * Ischemic symptoms and angiographic diameter stenosis ≥ 50% by core laboratory QCA * Revascularization of a target vessel with angiographic diameter stenosis ≥ 70% by core laboratory QCA without angina or positive functional study Derived from Non-Hierarchical Subject Counts of Adverse Events
Ischemia Driven Major Adverse Cardiac Event (MACE)	30 days	The composite endpoint comprised of: * Cardiac death * Myocardial infarction (MI, classified as Q-wave and non-Q wave) * Ischemia-driven target lesion revascularization (TLR) by CABG or PCI
Ischemia Driven Major Adverse Cardiac Event(MACE)	2 years	The composite endpoint comprised of: * Cardiac death * Myocardial infarction (MI, classified as Q-wave and non-Q wave) * Ischemia-driven target lesion revascularization (TLR) by CABG or PCI
In-stent % Angiographic Binary Restenosis (% ABR) Rate	at 240 days	Percent of subjects with a follow-up in-stent percent diameter stenosis of ≥ 50% per quantitative coronary angiography (QCA)
In-segment % Angiographic Binary Restenosis (% ABR) Rate	240 days	Percent of subjects with a follow-up in-segment percent diameter stenosis of ≥ 50% per QCA
Persisting Incomplete Stent Apposition, Late-acquired Incomplete Stent Apposition, Aneurysm, Thrombosis, and Persisting Dissection	at 240 days	Incomplete Apposition (Persisting & Late acquired): Failure to completely appose vessel wall w/ ≥1 strut separated from vessel wall w/ blood behind strut per ultrasound. Aneurysm: Abnormal vessel expansion ≥ 1.5 of reference vessel diameter. Thrombus: Protocol & ARC definition. Persisting dissection @ follow-up, present post-procedure.
Major Secondary Endpoint: Ischemia Driven Target Vessel Failure (ID-TVF)	270 days	The composite endpoint comprised of: * Cardiac death (death in which a cardiac cause cannot be excluded) * Myocardial infarction (MI, classified as Q-wave and non-Q wave) * Ischemia-driven target lesion revascularization (TLR) by CABG or PCI * Ischemia-driven target vessel revascularization (TVR) by CABG or PCI
Acute Success: Clinical Procedure	In-hospital	Successful delivery and deployment of study stent/s @ the intended target lesion and successful withdrawal of the stent delivery system with final residual stenosis \< 50%.
Proximal Late Loss	at 240 days	Proximal Minimum Lumen Diameter (MLD) post-procedure minus proximal MLD at follow-up (proximal defined as within 5 mm of healthy tissue proximal to stent placement)
Distal Late Loss	240 days	Distal MLD post-procedure minus distal MLD at follow-up (distal defined as within 5 mm of healthy tissue distal to stent placement)
In-stent Late Loss	at 240 days	In-stent MLD post-procedure minus in-stent MLD at follow-up (in-stent defined as within the margins of the stent)
% Volume Obstruction (% VO)	at 240 days	Defined as stent intimal hyperplasia and calculated as 100\*(Stent Volume - Lumen Volume)/Stent Volume by IVUS.
In-stent % Diameter Stenosis (% DS)	at 240 days	In-stent: Within the margins of the stent, the value calculated as 100 \* (1 - in-stent MLD/RVD) using the mean values from two orthogonal views (when possible) by QCA.
In-segment % Diameter Stenosis (% DS)	240 days	Within the margins of the stent, 5 mm proximal and 5 mm distal to the stent, the value calculated as 100 \* (1 - in-segment MLD/RVD) using the mean values from two orthogonal views (when possible) by QCA.
Acute Success: Clinical Device	In-hospital	Successful delivery and deployment of 1st implanted study stent/s @ the intended target lesion and successful withdrawal of the stent delivery system with final residual stenosis \< 50%.

Countries

United States

Participant flow

Recruitment details

1002 subjects were recruited at 65 sites. Eligible subjects invited to participate either in-hospital or in-clinic prior to first procedure and required to provide signed informed consent prior to enrollment. Final eligibility based on angiogram before the intended procedure. Dates of recruitment: 6/22/05 through 3/15/06.

Pre-assignment details

Subjects were randomized via telephone randomization and stratified by single and dual lesion/vessel treatment, diabetes mellitus status, and study sites. Randomization only occurred after verification of the inclusion/exclusion criteria and successful pre-dilatation. See the Eligibility Criteria (inclusion/exclusion criteria) for details.

Participants by arm

Arm	Count
XIENCE V® EECSS XIENCE V® Everolimus Eluting Coronary Stent System	669
TAXUS® EXPRESS2™ ECSS TAXUS® EXPRESS2™ Paclitaxel Eluting Coronary Stent System. 1 patient randomized never signed consent, therefore no data collected. Taxus analysis group = 332.	333
Total	1,002

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	4	2
Overall Study	Informed consent not signed	0	1
Overall Study	Lost to Follow-up	9	7
Overall Study	Withdrawal by Subject	3	3

Baseline characteristics

Characteristic	TAXUS® EXPRESS2™ ECSS	XIENCE V® EECSS	Total
Age Categorical <=18 years	0 participants	0 participants	0 participants
Age Categorical >=65 years	141 participants	293 participants	434 participants
Age Categorical Between 18 and 65 years	191 participants	376 participants	567 participants
Age Continuous	62.80 years STANDARD_DEVIATION 10.24	63.23 years STANDARD_DEVIATION 10.53	63.08 years STANDARD_DEVIATION 10.43
Gender Female	114 participants	200 participants	314 participants
Gender Male	218 participants	469 participants	687 participants
Region of Enrollment United States	333 participants	669 participants	1002 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	71 / —	55 / —
serious Total, serious adverse events	219 / —	126 / —

Outcome results

Primary

Primary Endpoint: In-segment Late Loss (LL)

In-segment minimal lumen diameter (MLD) post-procedure minus (-) in segment MLD at 240 day follow-up and 5 mm proximal and 5mm distal to the stent equals Late Loss. MLD defined: The average of two orthogonal views (when possible) of the narrowest point within the area of assessment.

Time frame: 240 days

Population: Only a certain number of patients were required to have angiographic follow-up to provide this endpoint information.

Arm	Measure	Value (MEAN)	Dispersion
XIENCE V® EECSS	Primary Endpoint: In-segment Late Loss (LL)	0.14 millimeters	Standard Deviation 0.41
TAXUS® EXPRESS2™ ECSS	Primary Endpoint: In-segment Late Loss (LL)	0.28 millimeters	Standard Deviation 0.48

Comparison: Primary endpoint analyzed for intent-to-treat \& per-treatment evaluable pop. Hypothesis test based on per-subject analysis of intent-to-treat pop. using analysis lesion. The null hypothesis evaluated using non-inferiority test with asymptotic test statistic.p-value: <0.0001t-test, 1 sided

Secondary

Acute Success: Clinical Device

Successful delivery and deployment of 1st implanted study stent/s @ the intended target lesion and successful withdrawal of the stent delivery system with final residual stenosis \< 50%.

Time frame: In-hospital

Arm	Measure	Value (NUMBER)
XIENCE V® EECSS	Acute Success: Clinical Device	98.3 percentage of participants
TAXUS® EXPRESS2™ ECSS	Acute Success: Clinical Device	98.7 percentage of participants

Secondary

Acute Success: Clinical Procedure

Successful delivery and deployment of study stent/s @ the intended target lesion and successful withdrawal of the stent delivery system with final residual stenosis \< 50%.

Time frame: In-hospital

Arm	Measure	Value (NUMBER)
XIENCE V® EECSS	Acute Success: Clinical Procedure	98.5 percentage of participants
TAXUS® EXPRESS2™ ECSS	Acute Success: Clinical Procedure	97.3 percentage of participants

Secondary

Distal Late Loss

Distal MLD post-procedure minus distal MLD at follow-up (distal defined as within 5 mm of healthy tissue distal to stent placement)

Time frame: 240 days

Population: Only a certain number of patients were required to have angiographic or IVUS follow-up. The analysis population for these follow-ups may have changed due to patient's not completing an angiographic or IVUS follow-up procedure. Patients may also have missed the follow-up visits due to early termination from the study.

Arm	Measure	Value (MEAN)	Dispersion
XIENCE V® EECSS	Distal Late Loss	0.09 millimeters	Standard Deviation 0.36
TAXUS® EXPRESS2™ ECSS	Distal Late Loss	0.10 millimeters	Standard Deviation 0.37

Secondary

In-segment % Angiographic Binary Restenosis (% ABR) Rate

Percent of subjects with a follow-up in-segment percent diameter stenosis of ≥ 50% per QCA

Time frame: 240 days

Arm	Measure	Value (NUMBER)
XIENCE V® EECSS	In-segment % Angiographic Binary Restenosis (% ABR) Rate	4.7 percentage of participants
TAXUS® EXPRESS2™ ECSS	In-segment % Angiographic Binary Restenosis (% ABR) Rate	8.9 percentage of participants

Secondary

In-segment % Diameter Stenosis (% DS)

Within the margins of the stent, 5 mm proximal and 5 mm distal to the stent, the value calculated as 100 \* (1 - in-segment MLD/RVD) using the mean values from two orthogonal views (when possible) by QCA.

Time frame: 240 days

Arm	Measure	Value (MEAN)	Dispersion
XIENCE V® EECSS	In-segment % Diameter Stenosis (% DS)	18.77 percent of in-segment diameter stenosis	Standard Deviation 14.43
TAXUS® EXPRESS2™ ECSS	In-segment % Diameter Stenosis (% DS)	22.82 percent of in-segment diameter stenosis	Standard Deviation 16.35

Secondary

In-stent % Angiographic Binary Restenosis (% ABR) Rate

Percent of subjects with a follow-up in-stent percent diameter stenosis of ≥ 50% per quantitative coronary angiography (QCA)

Time frame: at 240 days

Arm	Measure	Value (NUMBER)
XIENCE V® EECSS	In-stent % Angiographic Binary Restenosis (% ABR) Rate	2.3 percentage of participants
TAXUS® EXPRESS2™ ECSS	In-stent % Angiographic Binary Restenosis (% ABR) Rate	5.7 percentage of participants

Secondary

In-stent % Diameter Stenosis (% DS)

In-stent: Within the margins of the stent, the value calculated as 100 \* (1 - in-stent MLD/RVD) using the mean values from two orthogonal views (when possible) by QCA.

Time frame: at 240 days

Arm	Measure	Value (MEAN)	Dispersion
XIENCE V® EECSS	In-stent % Diameter Stenosis (% DS)	5.92 percent diameter stenosis	Standard Deviation 16.4
TAXUS® EXPRESS2™ ECSS	In-stent % Diameter Stenosis (% DS)	10.30 percent diameter stenosis	Standard Deviation 21.43

Secondary

In-stent Late Loss

In-stent MLD post-procedure minus in-stent MLD at follow-up (in-stent defined as within the margins of the stent)

Time frame: at 240 days

Arm	Measure	Value (MEAN)	Dispersion
XIENCE V® EECSS	In-stent Late Loss	0.16 millimeters	Standard Deviation 0.41
TAXUS® EXPRESS2™ ECSS	In-stent Late Loss	0.30 millimeters	Standard Deviation 0.53

Secondary