Protocol - The New England Journal of Medicine

Protocol

This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-30. DOI: 10.1056/NEJMoa1704154

Angiotensin II for the Treatment of Vasodilatory Shock

Ashish Khanna, et al.

Protocol and Statistical Analysis Plan

Changes to Listing for the ATHOS-3 Protocol (NCT02338843) ........................... 2 Clinical Study Protocol: LJ501-CRH01 ............................................................................................ 5 Statistical Analysis Plan: LJ501-CRH01.......................................................................................... 62

La Jolla Pharmaceutical Company, Inc. Protocol: LJ501-CRH01

The following are the administrative changes to the trial registration as recorded in ; there were no changes to the ATHOS-3 protocol from inception to completion of the trial. There was a single amendment to the statistical analysis plan (SAP) which occurred prior to study completion and data unblinding. The amendment clarified and aligned the SAP with the protocol and did not involve any changes to the primary or secondary efficacy analyses.

Changes to Listing for the ATHOS-3 Protocol (NCT02338843)

Updated 2015_01_13 2015_01_14 2015_05_04

2015_06_22 2015_07_27 2015_07_30 2015_08_17 2015_08_24 2015_08_31 2015_09_08 2015_09_28 2015_10_13 2015_10_21

Type of Info Changed Nothing (earliest version on record) Protocol, Administrative

Recruitment status, Recruitment, Location/Contact, Misc. Recruitment, Location/Contact, Misc. Recruitment, Location/Contact, Misc. Location/Contact, Misc.

Recruitment, Location/Contact, Misc. Location/Contact, Misc.

Location/Contact, Misc.

Recruitment, Location/Contact, Misc. Recruitment, Location/Contact, Misc. Recruitment, Location/Contact, Misc. Location/Contact, Misc.

Before N/A

After N/A

Blank fields for NCT, blank field for description of placebo

NCT02338843 entered, placebo entered and named 0.9% Sodium Chloride Solution USP

Not yet recruiting, date field set to 2015-01, last release Recruiting, date field set to 2015-05, last release date 2015-

date 2015-01-13

05-01

Recruiting date field set to 2015-05, last release date 2015-05-01

Recruiting date field set to 2015-06, last release date 2015-06-21

Last release date 2015-07-25

Recruiting date field set to 2015-06, last release date 2015-0621

Recruiting date field set to 2015-07, last release date 2015-0725

Last release date 2015-07-29

Recruiting date field set to 2015-07, last release date 2015-07-29

Last release date 2015-08-16

Recruiting date field set to 2015-08, last release date 2015-0816

Last release date 2015-08-21

Last release date 2015-08-21

Last release date 2015-08-29

Recruiting date field set to 2015-08, last release date 2015-08-29

Maximum age field blank, last release date 2015-09-05

Recruiting date field set to 2015-09, last release date 2015-0905

Maximum age field deleted, last release date 2015-09-27

Recruiting date field set to 2015-09, last release date 2015-09-27

Last release date 2015-10-11

Recruiting date field set to 2015-10, last release date 2015-1011

Last release date 2015-10-21

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La Jolla Pharmaceutical Company, Inc. Protocol: LJ501-CRH01

Updated Type of Info Changed

Before

2015_10_29 Location/Contact, Misc. Last release date 2015-10-21

After Last release date 2015-10-29

2016_01_11 2016_03_02 2016_05_02

Recruitment, Location/Contact, Misc.

Recruitment, Location/Contact, Misc.

Protocol, Recruitment, Location/Contact, Misc.

2016_09_04 Recruitment, Location/Contact, Misc.

2016_12_22

Protocol, Recruitment status, Recruitment, Location/Contact, Misc.

Recruiting date field set to 2015-10, last release date 2015-10-29

Recruiting date field set to 2016-01, last release date 2016-0109

Recruiting date field set to 2016-01, last release date 2016-01-09

Recruiting date field set to 2016-03, last release date 2016-0301

Brief Summary: Catecholamine-resistant hypotension Brief Summary: Catecholamine-resistant hypotension (CRH) is

(CRH) is an often fatal condition resulting from an

an often fatal condition resulting from an underlying cause

underlying cause such as septic shock, blood loss due such as septic shock, inflammation due to trauma, or

to trauma, or severe drug reactions.

severe drug reactions.

Condition: Catecholamine-resistant Hypotension (CRH)

Recruiting date field set to 2016-03, last release date 2016-03-01

Condition: Catecholamine-resistant Hypotension (CRH), distributive shock, high output shock, sepsis

Recruiting date field set to 2016-04, last release date 2016-0430

Recruiting date 2016-04 Last follow-up date (anticipated) 2016-09 Primary completion date (anticipated) 2016-06 Last release date 2016-04-30

Recruiting date 2016-09 Last follow-up date (anticipated) 2017-03 Primary completion date (anticipated) 2016-12 Last release date 2016-09-02

Brief Summary: This is a Phase 3, double-blind,

Brief Summary: This is a Phase 3, double-blind, randomized

randomized study of LJPC-501 (angiotensin II) in adult study of LJPC-501 (angiotensin II) in adult patients diagnosed

patients diagnosed with catecholamine-resistant

with catecholamine-resistant hypotension (CRH) conducted in

hypotension (CRH) conducted in multiple

multiple centers globally.

centers in the United States.

Detailed Description: Catecholamine-resistant hypotension

Detailed Description: Catecholamine-resistant

(CRH) is an often fatal condition resulting from an underlying

hypotension (CRH) is an often fatal condition resulting cause such as septic shock, inflammation due to trauma, or

from an underlying cause such as septic shock,

severe drug reactions. When these conditions occur, most

inflammation due to trauma, or severe drug reactions. patients will respond to either volume expansion or

When these conditions occur, most patients will respond vasopressor treatment. However, some patients will require

to either volume expansion or vasopressor treatment. excessive doses of vasopressors and will be deemed to be

However, 6-7% of patients will require excessive resistant.

doses of vasopressors and will be deemed to be Status: Active, not recruiting

resistant.

Date: 2016-12

Status: Recruiting

Primary outcome measure: An increased MAP, defined as achievement of a Day 1 MAP at 3 hours following the initiation

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La Jolla Pharmaceutical Company, Inc. Protocol: LJ501-CRH01

Updated Type of Info Changed Date: 2016-09

Before

Primary outcome measure: Increased mean arterial pressure (MAP)

Safety Issue: Yes Secondary Outcome Measure: SOFA Score Safety Issue: Yes Enrollment (anticipated): 315 Last release date 2016-09-02

2017_04_06

Changes submitted and are Overall status: Active, not recruiting

pending

Estimated Study Completion Date: March 2017

Estimated Primary Completion Date: December 2016

Enrollment (actual): 345

Last release date 2016-12-22

After of study drug, of 75 mmHg OR a 10 mmHg increase in baseline MAP

Safety Issue: No

Secondary outcome measure: Change in cardiovascular (CV) and total SOFA score at hour 48 Safety Issue: No

Other outcome measure: Mortality at 7 days and 28 days; timeframe Day 7 and Day 28 Safety Issue: No

Other outcome measure: Achievement of MAP 75 mmHg obtained at Hour 1 and Hour 2; timeframe Hour 1 and Hour 2 Safety Issue: No

Other outcome measure: Change in average heart rate between the intervals of Hours 0 to 3, and Hours 3 to 48; timeframe Hours 0 to 3, and Hours 3 to 48 Safety Issue: No

Other outcome measure: Change in vasopressor dosing between Hours 3 and 48; timeframe Between Hours 3 and 48 Safety Issue: No

Enrollment (actual): 345

Last release date 2016-12-22

Overall status: Completed

Study Completion Date: February 18, 2017 [actual]

Primary Completion Date: December 1, 2016 [actual]

Enrollment (actual): 344

Last release date 2017-04-06;

Details are not provided for non-essential changes, ie contact info, locations, etc.

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