Trial Outcomes & Findings for POST-APPROVAL STUDY of TRANSCAROTID ARTERY REVASCULARIZATION in PATIENTS With SIGNIFICANT CAROTID ARTERY DISEASE (NCT NCT02536378)

Last Updated: 2020-07-29

Results Overview

Procedural success is defined as acute device success (successful insertion of the ENROUTE NPS and establishment of flow reversal), technical success (deployment of interventional tools) and the absence of a major adverse events (hierarchical stroke/death/myocardial infarction) through 30 days.

Recruitment status

COMPLETED

Target enrollment

692 participants

Primary outcome timeframe

30 Days

Results posted on

2020-07-29

Participant Flow

Participant milestones

Participant milestones
Measure	PP (Per Protocol) Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) All patients who were enrolled in the pivotal phase of the study but had major protocol deviations
Overall Study STARTED	632	60
Overall Study COMPLETED	625	53
Overall Study NOT COMPLETED	7	7

Reasons for withdrawal

Reasons for withdrawal
Measure	PP (Per Protocol) Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) All patients who were enrolled in the pivotal phase of the study but had major protocol deviations
Overall Study Physician Decision	0	2
Overall Study Withdrawal by Subject	0	1
Overall Study Death	1	2
Overall Study Patient refused further follow up	6	2

Baseline Characteristics

POST-APPROVAL STUDY of TRANSCAROTID ARTERY REVASCULARIZATION in PATIENTS With SIGNIFICANT CAROTID ARTERY DISEASE

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PP (Per Protocol) n=632 Participants Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=60 Participants Patients who were enrolled in the pivotal phase of the study but had a major protocol deviation are included	Total n=692 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	104 Participants n=5 Participants	9 Participants n=7 Participants	113 Participants n=5 Participants
Age, Categorical >=65 years	528 Participants n=5 Participants	51 Participants n=7 Participants	579 Participants n=5 Participants
Sex: Female, Male Female	204 Participants n=5 Participants	19 Participants n=7 Participants	223 Participants n=5 Participants
Sex: Female, Male Male	428 Participants n=5 Participants	41 Participants n=7 Participants	469 Participants n=5 Participants
Race/Ethnicity, Customized African American	28 Participants n=5 Participants	7 Participants n=7 Participants	35 Participants n=5 Participants
Race/Ethnicity, Customized Asian	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	560 Participants n=5 Participants	45 Participants n=7 Participants	605 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	23 Participants n=5 Participants	5 Participants n=7 Participants	28 Participants n=5 Participants
Race/Ethnicity, Customized Pacific Islander	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Unknown/Other	11 Participants n=5 Participants	1 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Mixed Race	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Symptomatic Status Asymptomatic	466 Participants n=5 Participants	46 Participants n=7 Participants	512 Participants n=5 Participants
Symptomatic Status Symptomatic	166 Participants n=5 Participants	14 Participants n=7 Participants	180 Participants n=5 Participants
Height	170.3 cm STANDARD_DEVIATION 9.91 • n=5 Participants	169.0 cm STANDARD_DEVIATION 11.8 • n=7 Participants	170.2 cm STANDARD_DEVIATION 9.93 • n=5 Participants
Weight	81.5 kg STANDARD_DEVIATION 18.23 • n=5 Participants	83.6 kg STANDARD_DEVIATION 18.72 • n=7 Participants	81.7 kg STANDARD_DEVIATION 18.48 • n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Contralateral Carotid Artery Occlusion · Yes	64 Participants n=5 Participants	3 Participants n=7 Participants	67 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Contralateral Carotid Artery Occlusion · No	568 Participants n=5 Participants	57 Participants n=7 Participants	625 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Tandem Stenoses >70% · Yes	10 Participants n=5 Participants	3 Participants n=7 Participants	13 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Tandem Stenoses >70% · No	622 Participants n=5 Participants	57 Participants n=7 Participants	679 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors High cervical carotid artery stenosis · Yes	177 Participants n=5 Participants	18 Participants n=7 Participants	195 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors High cervical carotid artery stenosis · No	455 Participants n=5 Participants	42 Participants n=7 Participants	497 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Restenosis after carotid endarterectomy · Yes	122 Participants n=5 Participants	13 Participants n=7 Participants	135 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Restenosis after carotid endarterectomy · No	510 Participants n=5 Participants	47 Participants n=7 Participants	557 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Bilateral carotid artery stenosis req. treatment · Yes	52 Participants n=5 Participants	1 Participants n=7 Participants	53 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Bilateral carotid artery stenosis req. treatment · No	580 Participants n=5 Participants	59 Participants n=7 Participants	639 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Hostile necks safe for transcarotid access · Yes	24 Participants n=5 Participants	2 Participants n=7 Participants	26 Participants n=5 Participants
High Surgical Risk Inclusion Criteria - Anatomic Risk Factors Hostile necks safe for transcarotid access · No	608 Participants n=5 Participants	58 Participants n=7 Participants	666 Participants n=5 Participants
Medical History Symptomatic	26.3 Percentage of participants n=5 Participants	23.3 Percentage of participants n=7 Participants	26 Percentage of participants n=5 Participants
Medical History Male	67.7 Percentage of participants n=5 Participants	68.3 Percentage of participants n=7 Participants	67.8 Percentage of participants n=5 Participants
Medical History Diabetes	35 Percentage of participants n=5 Participants	46.7 Percentage of participants n=7 Participants	36 Percentage of participants n=5 Participants
Medical History Hypertension	90.3 Percentage of participants n=5 Participants	95.0 Percentage of participants n=7 Participants	90.8 Percentage of participants n=5 Participants
Medical History History of Peripheral Artery Disease	24.7 Percentage of participants n=5 Participants	30.0 Percentage of participants n=7 Participants	25.1 Percentage of participants n=5 Participants
Medical History History of Coronary Artery Disease	14.6 Percentage of participants n=5 Participants	10.0 Percentage of participants n=7 Participants	14.2 Percentage of participants n=5 Participants
Medical History History of Angina	2.1 Percentage of participants n=5 Participants	0.0 Percentage of participants n=7 Participants	1.9 Percentage of participants n=5 Participants
Medical History Congestive Heart Failure	1.9 Percentage of participants n=5 Participants	0.0 Percentage of participants n=7 Participants	1.7 Percentage of participants n=5 Participants
Medical History Recent MI	0.8 Percentage of participants n=5 Participants	0.0 Percentage of participants n=7 Participants	0.7 Percentage of participants n=5 Participants
Medical History Severe Pulmonary Disease	2.8 Percentage of participants n=5 Participants	1.7 Percentage of participants n=7 Participants	2.7 Percentage of participants n=5 Participants
Medical History Dyslipidemia	85.8 Percentage of participants n=5 Participants	91.7 Percentage of participants n=7 Participants	86.3 Percentage of participants n=5 Participants
Medical History History of Stroke	15.7 Percentage of participants n=5 Participants	23.3 Percentage of participants n=7 Participants	16.4 Percentage of participants n=5 Participants
Medical History History of TIA	16.1 Percentage of participants n=5 Participants	15.0 Percentage of participants n=7 Participants	16.0 Percentage of participants n=5 Participants
Medical History History of Amaurosis Fugax	8.5 Percentage of participants n=5 Participants	8.3 Percentage of participants n=7 Participants	8.5 Percentage of participants n=5 Participants
Medical History Current Nicotine Use	21.8 Percentage of participants n=5 Participants	13.3 Percentage of participants n=7 Participants	21.1 Percentage of participants n=5 Participants
Medical History Age ≥75 Years	41.8 Percentage of participants n=5 Participants	45.0 Percentage of participants n=7 Participants	42.1 Percentage of participants n=5 Participants
Medical History Age ≥80 Years	21.2 Percentage of participants n=5 Participants	20.0 Percentage of participants n=7 Participants	21.1 Percentage of participants n=5 Participants
Medical History Contralateral Carotid Occlusion	10.1 Percentage of participants n=5 Participants	5.0 Percentage of participants n=7 Participants	9.7 Percentage of participants n=5 Participants
Medical History High Cervical Carotid Stenosis	28 Percentage of participants n=5 Participants	30.0 Percentage of participants n=7 Participants	28.2 Percentage of participants n=5 Participants
Medical History Restenosis after CEA	19.3 Percentage of participants n=5 Participants	21.7 Percentage of participants n=7 Participants	19.5 Percentage of participants n=5 Participants
Medical History Bilateral Stenosis Requiring Treatment	8.2 Percentage of participants n=5 Participants	1.7 Percentage of participants n=7 Participants	7.7 Percentage of participants n=5 Participants
Medical History Hostile Neck Safe for Transcarotid Access	3.8 Percentage of participants n=5 Participants	3.3 Percentage of participants n=7 Participants	3.8 Percentage of participants n=5 Participants
Medical History >2 Vessel Coronary Disease	14.6 Percentage of participants n=5 Participants	10.0 Percentage of participants n=7 Participants	14.2 Percentage of participants n=5 Participants

PRIMARY outcome

Timeframe: 30 Days

Outcome measures

Outcome measures
Measure	PP (Per Protocol) n=632 Participants Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=692 Participants All patients who were enrolled in the pivotal phase of the study, including patients with major protocol deviations
Number of Participants With Procedural Success	630 Participants	690 Participants

SECONDARY outcome

Timeframe: 30 days

Population: 30 day Major Adverse Events as adjudicated by CEC

Secondary endpoints include the 30-day rate of hierarchical stroke, death or myocardial infarction, the rate of hierarchical stroke, death or myocardial infarction by symptom status, the rate of cardiac death and the rate of neurological death.

Outcome measures

Outcome measures
Measure	PP (Per Protocol) n=632 Participants Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=692 Participants All patients who were enrolled in the pivotal phase of the study, including patients with major protocol deviations
Number of Participants Experiencing Major Adverse Event Myocardial Infarction	6 Major Adverse Events	6 Major Adverse Events
Number of Participants Experiencing Major Adverse Event Death	1 Major Adverse Events	3 Major Adverse Events
Number of Participants Experiencing Major Adverse Event Stroke	4 Major Adverse Events	13 Major Adverse Events

SECONDARY outcome

Timeframe: 2 hours (periprocedural)

Population: 2 enrolled patients were withdrawn by the Investigator

Acute device success is defined as the ability to insert the device, establish flow reversal, and remove the device

Outcome measures

Outcome measures
Measure	PP (Per Protocol) n=632 Participants Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=692 Participants All patients who were enrolled in the pivotal phase of the study, including patients with major protocol deviations
Number of Participants With Acute Device Success	630 Participants	690 Participants

SECONDARY outcome

Timeframe: 2 hours (periprocedural)

Technical success is defined as acute device success plus the ability to deliver interventional tools

Outcome measures

Outcome measures
Measure	PP (Per Protocol) n=632 Participants Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=692 Participants All patients who were enrolled in the pivotal phase of the study, including patients with major protocol deviations
Number of Participants With Technical Success	630 Participants	690 Participants

SECONDARY outcome

Timeframe: 90 days (extended follow-up)

Rate of cranial nerve injury suspected to be caused by surgical procedure and adjudicated by CEC.

Outcome measures

Outcome measures
Measure	PP (Per Protocol) n=632 Participants Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=692 Participants All patients who were enrolled in the pivotal phase of the study, including patients with major protocol deviations
Number of Participants in Which a Cranial Nerve Injury Occurred	8 Participants	10 Participants

Adverse Events

PP (Per Protocol)

Serious events: 27 serious events

Other events: 0 other events

Deaths: 1 deaths

ITT (Intention to Treat)

Serious events: 14 serious events

Other events: 0 other events

Deaths: 3 deaths

Serious adverse events

Serious adverse events
Measure	PP (Per Protocol) n=632 participants at risk Patients who underwent the study procedure, independent of the success of the procedure and in the absence of major protocol deviations. The analysis of the PP population excludes those subjects for whom a major protocol deviation was identified by the CEC	ITT (Intention to Treat) n=692 participants at risk All patients who were enrolled in the pivotal phase of the study in which a major protocol deviation was identified by the CEC.
Musculoskeletal and connective tissue disorders Cranial Nerve Injury	1.3% 8/632 • Number of events 8 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	1.4% 10/692 • Number of events 10 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Nervous system disorders Death - Neurological	0.00% 0/632 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	0.29% 2/692 • Number of events 2 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
General disorders Death - Other	0.16% 1/632 • Number of events 1 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	0.14% 1/692 • Number of events 1 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Cardiac disorders Myocardial Infarction	0.95% 6/632 • Number of events 6 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	1.0% 7/692 • Number of events 7 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Surgical and medical procedures NPS Device Related Event	0.32% 2/632 • Number of events 2 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	0.29% 2/692 • Number of events 2 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Nervous system disorders Stroke - Contralateral	0.16% 1/632 • Number of events 1 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	0.14% 1/692 • Number of events 1 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Nervous system disorders Stroke - Ipsilateral	0.47% 3/632 • Number of events 3 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	2.0% 14/692 • Number of events 14 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Surgical and medical procedures Possibly NPS/Stent device related event	0.79% 5/632 • Number of events 5 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	1.0% 7/692 • Number of events 7 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study
Surgical and medical procedures Stent Device Related Event	0.16% 1/632 • Number of events 1 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study	0.14% 1/692 • Number of events 1 • Adverse events were collected throughout the life of the study: 3 years, 6 months Major adverse events, cranial nerve injuries, device related, and unanticipated adverse device effect event data were collected through 30 day follow-up period and recorded on the Adverse Event CRF. The Investigator or Coordinator determined whether an adverse event occurred Major Adverse Events were defined in this study as stroke, death, or myocardial infarction as adjudicated by Clinical Events Committee. Other Adverse Events (non-serious) were not collected or assessed for this study

Other adverse events

Adverse event data not reported

Additional Information

Ric Ruedy, Executive VP, Clinical, Regulatory and Quality Affairs

Silk Road Medical, Inc.

Phone: 408-585-2112

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place