Prevention of S. Aureus Pneumonia Study in Mechanically Ventilated Subjects Who Are Heavily Colonized With S. Aureus.

• Sponsor: Arsanis, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02940626
• Collaborator: (none)
• Enrollment: 155
• Locations: 93
• Arms: 2
• Actual Duration (Months): 22.9
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is the prevention of Staphylococcus aureus pneumonia in mechanically ventilated subjects heavily colonized with S. aureus. Staphylococcus aureus is a human pathogenic bacterium that causes severe infections, including pneumonia and sepsis. Hospital-acquired bacterial pneumonia (HABP) caused by S. aureus, including ventilator-associated bacterial pneumonia (VABP) in mechanically ventilated subjects, is a significant public health threat despite efforts to optimize antibiotic treatment. ASN100 is an investigational monoclonal antibody product that targets the toxins produced by S. aureus to protect subjects from developing S. aureus pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia, Ventilator-associated; Pneumonia, Staphylococcal	Drug: ASN100; Drug: Placebo	Phase 2

Detailed Description

This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for the prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized with S. aureus. This will be a global study conducted at approximately 65 sites to assess the safety, tolerability, and efficacy of ASN100.

Eligible subjects who meet all of the inclusion criteria and none of the exclusion criteria will be screened by semi-quantitative culture of an endotracheal aspirate (ETA) to identify those who are heavily colonized with S. aureus (3+ to 4+). Upon determination of eligibility, subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups, ASN100 or placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 155 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Safety and Efficacy of a Single Dose of ASN100 for the Prevention of Staphylococcus Aureus Pneumonia in Heavily Colonized, Mechanically Ventilated Subjects
• Actual Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jul 19, 2018
• Actual Study Completion Date: Sep 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo administered as 2 separate intravenous (IV) infusions	Drug: Placebo; Placebo
Experimental: ASN100 ASN100 administered as 2 separate intravenous (IV) infusions	Drug: ASN100; monoclonal antibody combination of ASN-1 and ASN-2; Other Names: ASN-1 and ASN-2

Outcome Measures

Primary Outcome Measures

1. Efficacy of a Single Intravenous (IV) Dose of ASN100 [Incidence of S. aureus pneumonia up to but not including Day 22]

   Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis.

Secondary Outcome Measures

1. Duration of Mechanical Ventilation [21 days]

   Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the Modified Intent-to-Treat (MITT) Population

2. Length of ICU Stay [21 days]

   Total length of ICU stay during the first 21 days post-randomization for subjects in the MITT Population

3. 28-day All-cause Mortality [28 days]

   28-day all-cause mortality in the MITT Population

4. ASN-1 and ASN-2 Maximum Serum Concentration (Cmax) [through day 90]

   The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling.

5. ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum [through day 90]

   The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion

6. ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum [through day 90]

   The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion

7. ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum [through day 90]

   The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject is currently hospitalized and is mechanically ventilated endotracheally (i.e., orotracheal or nasotracheal) and, in the Investigator's opinion, will require ongoing ventilator support for at least 48 hours;

Exclusion Criteria:

• Subject has a chest X-ray or thoracic computed tomography (CT) scan that is definitive for a diagnosis of pneumonia

• Subject has a known and documented ETA culture showing heavy colonization with a -Gram-negative organism at enrollment or at any time during the Screening period;

• Significant Neutropenia

• Severe non-pulmonary source of infection.

• Subjects with a known history or current (suspected) diagnosis of cytokine release syndrome associated with the administration of peptides, proteins, and/or antibodies.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Phoenix	Arizona	United States	85006
2	Research Site	Sacramento	California	United States	95817
3	Research Site	San Francisco	California	United States	94110
4	Research Site	Aurora	Colorado	United States	80045
5	Research Site	Chicago	Illinois	United States	60611
6	Research Site	Chicago	Illinois	United States	60612
7	Research Site	Georgetown	Kentucky	United States	40324
8	Research Site	Hazard	Kentucky	United States	41701
9	Research Site	Burlington	Massachusetts	United States	01805
10	Research Site	Saint Louis	Missouri	United States	63110
11	Research Site	Buffalo	New York	United States	14215
12	Research Site	Charlotte	North Carolina	United States	28207
13	Research Site	Cleveland	Ohio	United States	44106
14	Research Site	Pittsburgh	Pennsylvania	United States	15240
15	Research Site	Chattanooga	Tennessee	United States	37408
16	Research Site	Memphis	Tennessee	United States	38163
17	Research Site	Dallas	Texas	United States	75390
18	Research Site 040-001	Wien		Austria	1090
19	Research Site 040-002	Wien		Austria	1090
20	Research Site	Praha 10		Czechia	100 34
21	Research Site	Praha 6		Czechia	169 02
22	Research Site	Argenteuil		France	95107
23	Research Site	Lille Cedex		France	59037
24	Research Site	Limoges		France	87042
25	Research Site 268-007	Rustavi		Georgia	3700
26	Research Site 268-005	Tbilisi		Georgia	114
27	Research Site 268-009	Tbilisi		Georgia	141
28	Research Site 268-004	Tbilisi		Georgia	144
29	Research Site 268-006	Tbilisi		Georgia	144
30	Research Site 268-002	Tbilisi		Georgia	159
31	Research Site 268-008	Tbilisi		Georgia	159
32	Research Site 268-011	Tbilisi		Georgia	159
33	Research Site 268-003	Tbilisi		Georgia	160
34	Research Site 268-010	Tbilisi		Georgia	163
35	Research Site 268-001	Tbilisi		Georgia	191
36	Research Site	Budapest		Hungary	H-1134
37	Research Site	Budapest		Hungary	H-1135
38	Research Site	Debrecen		Hungary	H-4032
39	Research Site	Ózd		Hungary	3600
40	Research Site	Bangalore		India	560002
41	Research Site	Hyderabad		India	500096
42	Research Site	Jaipur		India	302016
43	Research Site	Mahara		India	440003
44	Research Site	Mumbai		India	400008
45	Research Site	Pune		India	411001
46	Research Site	Hadera		Israel	38100
47	Research Site	H̱olon		Israel	5822012
48	Research Site	Ramat Gan		Israel	5265601
49	Research Site	Tel Aviv		Israel	6423906
50	Research Site	Białystok		Poland	15-027
51	Research Site	Białystok		Poland	15-950
52	Research Site	Opole		Poland	45-418
53	Research Site	Abrantes		Portugal	2200
54	Research Site	Amadora		Portugal	2720-276
55	Research Site	Lisboa		Portugal	1500-461
56	Research Site	Lisboa		Portugal	1649-035
57	Research Site	Loures		Portugal	2674-514
58	Research Site	Viana do Castelo		Portugal	4901-858
59	Research Site	Bucharest		Romania	21661
60	Research Site	Bucharest		Romania	22328
61	Research Site	Craiova		Romania	200642
62	Research Site	Timişoara		Romania	300723
63	Research Site	Arkhangel'sk		Russian Federation	163001
64	Research Site	Barnaul		Russian Federation	656045
65	Research Site	Moscow		Russian Federation	117997
66	Research Site	Novosibirsk		Russian Federation	630008
67	Research Site	Novosibirsk		Russian Federation	630047
68	Research Site	Novosibirsk		Russian Federation	630075
69	Research Site	Saint Petersburg		Russian Federation	192242
70	Research Site	Saint Petersburg		Russian Federation	194104
71	Research Site	Saint Petersburg		Russian Federation	196247
72	Research Site	Sestroretsk		Russian Federation	197706
73	Research Site 688-001	Belgrad		Serbia	11000
74	Research Site 688-002	Belgrad		Serbia	11000
75	Research Site 688-005	Belgrad		Serbia	11000
76	Research Site 688-004	Kragujevac		Serbia	34000
77	Research Site 688-003	Niš		Serbia	18000
78	Research Site	Pretoria		South Africa	84
79	Research Site	Soweto		South Africa	1860
80	Research Site	Badalona		Spain	8916
81	Research Site	Barcelona		Spain	28025
82	Research Site	Barcelona		Spain	8035
83	Research Site	Barcelona		Spain	8036
84	Research Site	Barcelona		Spain	8221
85	Research Site	Barcelona		Spain	8907
86	Research Site	Madrid		Spain	28040
87	Research Site	Sevilla		Spain	41013
88	Research Site	Tarragona		Spain	43005
89	Research Site	Valencia		Spain	46026
90	Research Site	Dnipro		Ukraine	49005
91	Research Site	Ivano-Frankivs'k		Ukraine	76008
92	Research Site	Kharkiv		Ukraine	61176
93	Research Site	Lviv		Ukraine	79010

Sponsors and Collaborators

• Arsanis, Inc.

Investigators

• Study Director: Arsanis, Inc, Arsanis, Inc.

Study Documents (Full-Text)

• Study Protocol: Primary VAP Prevention Study - May 2, 2017
• Study Protocol: Site-specific VAP Treatment Sub-study - Apr 23, 2018
• Statistical Analysis Plan: SAP Addendum - Oct 25, 2018
• Statistical Analysis Plan: Primary Plan - Jun 25, 2018

More Information

Publications

None provided.

• Responsible Party: Arsanis, Inc.
• ClinicalTrials.gov Identifier: NCT02940626
• Other Study ID Numbers: ASN100-201; 2016-002146-23
• First Posted: Oct 21, 2016
• Last Update Posted: Jul 31, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Arsanis, Inc.: Pneumonia; S. aureus; Mechanically ventilated
• Additional relevant MeSH terms: Pneumonia; Pneumonia, Ventilator-Associated; Pneumonia, Staphylococcal

Study Results

Participant Flow

Recruitment Details	Subjects were randomized at 35 centers in the United States, Austria, Czechia, France, India, Israel, Poland, Portugal, Romania, Serbia, Spain, Rep. of Georgia, and Russian Federation
Pre-assignment Detail	Eligible subjects underwent daily screening of endotracheal aspirates to determine if they met randomization criteria. Only subjects who were randomized are included in the study analysis and summarized in the Participant Flow. A single subject was randomized/treated in a site-specific pneumonia treatment sub-study.

Arm/Group Title	ASN100	Placebo
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) [administered once]	Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo [administered once]
Period Title: Overall Study
STARTED	77	78
Randomized Into Primary Prevention Study	77	77
Randomized Into Treatment Sub-study	0	1
Received Study Treatment	77	77
Completed Through Study Day 22	42	49
COMPLETED	30	43
NOT COMPLETED	47	35

Baseline Characteristics

Arm/Group Title	ASN100	Placebo	Total
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) [administered once]	Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo [administered once]	Total of all reporting groups
Overall Participants	76	76	152
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	40 52.6%	43 56.6%	83 54.6%
>=65 years	36 47.4%	33 43.4%	69 45.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.5	62	62.5
Sex: Female, Male (Count of Participants)
Female	26 34.2%	26 34.2%	52 34.2%
Male	50 65.8%	50 65.8%	100 65.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.6%	3 3.9%	5 3.3%
Not Hispanic or Latino	70 92.1%	71 93.4%	141 92.8%
Unknown or Not Reported	4 5.3%	2 2.6%	6 3.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.3%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	2 2.6%	2 1.3%
White	71 93.4%	74 97.4%	145 95.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 5.3%	0 0%	4 2.6%
Region of Enrollment (participants) [Number]
Romania	1 1.3%	2 2.6%	3 2%
United States	10 13.2%	11 14.5%	21 13.8%
Czechia	1 1.3%	0 0%	1 0.7%
Portugal	0 0%	1 1.3%	1 0.7%
India	1 1.3%	0 0%	1 0.7%
Russia	19 25%	23 30.3%	42 27.6%
Spain	1 1.3%	1 1.3%	2 1.3%
Austria	1 1.3%	0 0%	1 0.7%
Poland	4 5.3%	5 6.6%	9 5.9%
Georgia	34 44.7%	29 38.2%	63 41.4%
Israel	1 1.3%	3 3.9%	4 2.6%
France	1 1.3%	0 0%	1 0.7%
Serbia	2 2.6%	1 1.3%	3 2%
Body Mass Index Category (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.98 (5.985)	27.17 (4.335)	27.07 (5.209)

Outcome Measures

1. Primary Outcome

Title	Efficacy of a Single Intravenous (IV) Dose of ASN100
Description	Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis.
Time Frame	Incidence of S. aureus pneumonia up to but not including Day 22

Outcome Measure Data

Analysis Population Description

MITT: There are 2 SDO definitions. SDO1 meets either respiratory OR signs/symptoms requirements while SDO2 must meet BOTH. Individual assessments for each randomized subject were collapsed to assign a SDO1/SDO2 of Yes, No, Indeterminate (insufficient data to assign a SDO of Yes or No), or Censored (subject died prior to the Day 22 assessment).

Arm/Group Title	ASN100	Placebo
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Measure Participants	76	76
Developed S. aureus Pneumonia	5 6.6%	7 9.2%
Did Not Develop S. aureus Pneumonia	42 55.3%	48 63.2%
Censored	20 26.3%	17 22.4%
Indeterminate	9 11.8%	4 5.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ASN100, Placebo
	Comments	Subjects were analyzed for efficacy in the group to which they randomized. Sponsor defined outcomes were based on review of microbiology results from samples tested at the central lab. If sample was not sent to the central lab., determination was based on results from the local microbiology lab. In cases where both local & central lab results were available, concordance was confirmed for S. aureus. Therefore, the analysis used local microbiology data in order to utilize a more complete dataset.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.5470
	Comments
	Method	Wald Test on equality of proportions
	Comments

2. Secondary Outcome

Title	Duration of Mechanical Ventilation
Description	Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the Modified Intent-to-Treat (MITT) Population
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat (MITT): Includes All subjects in ITT Population (randomized) who received study drug and were heavily colonized with S. aureus determined by quantitative or semi-quant. culture of an ETA specimen. Exclusion from the MITT was determined programmatically. Subjects on MV < 2 days post treatment were excluded from analysis.

Arm/Group Title	ASN100	Placebo
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Measure Participants	73	71
Mean (Standard Deviation) [Days]	11.6 (7.47)	10.1 (6.93)

3. Secondary Outcome

Title	Length of ICU Stay
Description	Total length of ICU stay during the first 21 days post-randomization for subjects in the MITT Population
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat (MITT): Includes all subjects in ITT Population (randomized) who received study drug and were heavily colonized with S. aureus determined by quantitative/semi-quant. culture of an ETA specimen. Exclusion from the MITT determined programmatically. Subjects not listed as being in ICU post treatment were excluded from analysis

Arm/Group Title	ASN100	Placebo
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Measure Participants	74	75
Mean (Standard Deviation) [Days]	13.7 (6.69)	13.6 (7.21)

4. Secondary Outcome

Title	28-day All-cause Mortality
Description	28-day all-cause mortality in the MITT Population
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Modified Intent to treat (MITT): includes all subjects in the ITT Population (randomized subjects) who receive study drug and who are heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an ETA specimen. Exclusion from the MITT Population was determined programmatically for each ITT subject.

Arm/Group Title	ASN100	Placebo
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2	Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
Measure Participants	76	76
Count of Participants [Participants]	30 39.5%	25 32.9%

5. Secondary Outcome

Title	ASN-1 and ASN-2 Maximum Serum Concentration (Cmax)
Description	The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling.
Time Frame	through day 90

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.

Arm/Group Title	ASN-1	ASN-2
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)
Measure Participants	71	73
Mean (Standard Deviation) [μg/mL]	414.43 (125.55)	460.88 (149.76)

6. Secondary Outcome

Title	ASN-1 and ASN-2 Time to Maximum Concentration (Tmax) in Serum
Description	The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
Time Frame	through day 90

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.

Arm/Group Title	ASN-1	ASN-2
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)
Measure Participants	71	73
Mean (Standard Deviation) [Hours (from end of infusion)]	6.34 (10.25)	4.52 (5.77)

7. Secondary Outcome

Title	ASN-1 and ASN-2 Area Under the Concentration-time Curve in Serum
Description	The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
Time Frame	through day 90

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.

Arm/Group Title	ASN-1	ASN-2
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)
Measure Participants	71	73
Mean (Standard Deviation) [μg*h/mL]	44192.3 (25080.9)	49366.7 (29337.9)

8. Secondary Outcome

Title	ASN-1 and ASN-2 Terminal Elimination Half-life (t1/2) in Serum
Description	The levels of ASN-1 and ASN-2 measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
Time Frame	through day 90

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: All subjects in the MITT population with at least 1 serum PK sample collected post-dose. Of the 76 subjects who received ASN100, 74 were included in the PK analysis as a result of 2 not having sufficient data. Additional reductions in the number of participants analyzed is due to missing or out of window samples.

Arm/Group Title	ASN-1	ASN-2
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2. Pharmacokinetic analysis was performed and reported based on the separate antibodies (i.e. ASN-1 or ASN-2)
Measure Participants	54	58
Mean (Standard Deviation) [Hours]	178.9 (101.13)	185.1 (136.09)

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit). Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
Arm/Group Title	ASN100		Placebo
Arm/Group Description	ASN100 administered as 2 separate intravenous (IV) infusions ASN100: monoclonal antibody combination of ASN-1 and ASN-2		Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo
All Cause Mortality
	ASN100		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/77 (53.2%)		32/77 (41.6%)
Serious Adverse Events
	ASN100		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/77 (63.6%)		38/77 (49.4%)
Blood and lymphatic system disorders
Thrombocytopenia	1/77 (1.3%)	1	0/77 (0%)	0
Cardiac disorders
Cardiac Arrest	5/77 (6.5%)	5	1/77 (1.3%)	1
Cardiac Failture Acute	2/77 (2.6%)	2	2/77 (2.6%)	2
Ventricular Fibrillation	1/77 (1.3%)	1	2/77 (2.6%)	2
Cardiovascular Insufficiency	2/77 (2.6%)	2	0/77 (0%)	0
Ventricular Asytole	2/77 (2.6%)	2	0/77 (0%)	0
Bradycardia	0/77 (0%)	0	1/77 (1.3%)	1
Cardiac Disorder	1/77 (1.3%)	1	0/77 (0%)	0
Cardiac Failure Congestive	0/77 (0%)	0	1/77 (1.3%)	2
Cardiopulmonary Failure	0/77 (0%)	0	1/77 (1.3%)	1
Coronary Artery Disease	0/77 (0%)	0	1/77 (1.3%)	1
Left ventricular Failure	1/77 (1.3%)	1	0/77 (0%)	0
Myocardial Infarction	0/77 (0%)	0	1/77 (1.3%)	1
Pericardial Haemorrhage	0/77 (0%)	0	1/77 (1.3%)	1
Ventricular Rupture	0/77 (0%)	0	1/77 (1.3%)	1
Gastrointestinal disorders
Haematemesis	0/77 (0%)	0	1/77 (1.3%)	1
Ileus	1/77 (1.3%)	1	0/77 (0%)	0
Intestinal Obstruction	1/77 (1.3%)	1	0/77 (0%)	0
General disorders
Multiple Organ Dysfunction Syndrome	1/77 (1.3%)	1	3/77 (3.9%)	3
Death	0/77 (0%)	0	1/77 (1.3%)	1
Hepatobiliary disorders
Hepatic Cirrhosis	1/77 (1.3%)	1	0/77 (0%)	0
Immune system disorders
Drug Hypersensitivity	0/77 (0%)	0	1/77 (1.3%)	1
Infections and infestations
Septic Shock	3/77 (3.9%)	3	3/77 (3.9%)	3
Pneumonia	3/77 (3.9%)	3	1/77 (1.3%)	1
Sepsis	2/77 (2.6%)	2	0/77 (0%)	0
Meningitis	1/77 (1.3%)	1	0/77 (0%)	0
Meningitis Bacterial	1/77 (1.3%)	1	0/77 (0%)	0
Splenic Abscess	1/77 (1.3%)	1	0/77 (0%)	0
Injury, poisoning and procedural complications
Brain Herniation	4/77 (5.2%)	4	2/77 (2.6%)	2
Craniocerebral Injury	2/77 (2.6%)	2	0/77 (0%)	0
Spinal Shock	0/77 (0%)	0	1/77 (1.3%)	1
Metabolism and nutrition disorders
Hyperkalemia	1/77 (1.3%)	1	0/77 (0%)	0
Metabolic Acidosis	0/77 (0%)	0	1/77 (1.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm Progression	0/77 (0%)	0	1/77 (1.3%)	1
Nervous system disorders
Cerebral Congestion	6/77 (7.8%)	6	3/77 (3.9%)	3
Brain Oedema	3/77 (3.9%)	3	4/77 (5.2%)	4
Coma	3/77 (3.9%)	3	3/77 (3.9%)	3
Ischemia Stroke	3/77 (3.9%)	3	2/77 (2.6%)	2
Haemorrhagic Transformation Stroke	2/77 (2.6%)	2	0/77 (0%)	0
Nervous System Disorder	0/77 (0%)	0	2/77 (2.6%)	2
Cerebrospinal Fluid Circulation Disorder	1/77 (1.3%)	1	0/77 (0%)	0
Guillain-Barre Syndrome	1/77 (1.3%)	1	0/77 (0%)	0
Polyneuropathy	1/77 (1.3%)	1	0/77 (0%)	0
Toxic Encephalopathy	1/77 (1.3%)	1	0/77 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	3/77 (3.9%)	3	6/77 (7.8%)	6
Acute Respiratory Distress Syndrome	1/77 (1.3%)	1	1/77 (1.3%)	1
Chronic Obstructive Pulmonary Disease	1/77 (1.3%)	1	1/77 (1.3%)	1
Tracheal Stenosis	0/77 (0%)	0	2/77 (2.6%)	2
Acute Respiratory Failure	1/77 (1.3%)	1	0/77 (0%)	0
Atelectasis	1/77 (1.3%)	1	0/77 (0%)	0
Pneumonia Aspiration	1/77 (1.3%)	1	0/77 (0%)	0
Pulmonary Oedema	1/77 (1.3%)	1	0/77 (0%)	0
Vascular disorders
Hypotension	2/77 (2.6%)	2	1/77 (1.3%)	1
Shock	1/77 (1.3%)	1	1/77 (1.3%)	1
Deep vein Thrombosis	0/77 (0%)	0	1/77 (1.3%)	1
Neurogenic Shock	1/77 (1.3%)	1	0/77 (0%)	0
Peripheral Artery Thrombosis	1/77 (1.3%)	2	0/77 (0%)	0
Peripheral Ischaemia	1/77 (1.3%)	1	0/77 (0%)	0
Other (Not Including Serious) Adverse Events
	ASN100		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/77 (96.1%)		69/77 (89.6%)
Blood and lymphatic system disorders
Anaemia	15/77 (19.5%)	17	11/77 (14.3%)	11
Thrombocytopenia	5/77 (6.5%)	5	2/77 (2.6%)	2
Cardiac disorders
Atrial Fibrillation	6/77 (7.8%)	6	4/77 (5.2%)	4
Tachycardia	5/77 (6.5%)	5	5/77 (6.5%)	6
Congenital, familial and genetic disorders
Tracheo-oesophageal Fistula	1/77 (1.3%)	1	4/77 (5.2%)	4
Gastrointestinal disorders
Constipation	3/77 (3.9%)	3	4/77 (5.2%)	4
Diarrhoea	8/77 (10.4%)	8	5/77 (6.5%)	7
General disorders
Pyrexia	17/77 (22.1%)	25	8/77 (10.4%)	12
Infections and infestations
Bronchitis	8/77 (10.4%)	8	5/77 (6.5%)	5
Bronchitis Bacterial	16/77 (20.8%)	16	7/77 (9.1%)	7
Sinusitis	4/77 (5.2%)	4	2/77 (2.6%)	2
Tracheobronchitis	5/77 (6.5%)	7	7/77 (9.1%)	8
Urinary Tract Infection	16/77 (20.8%)	16	14/77 (18.2%)	14
Metabolism and nutrition disorders
Hyperglycemia	5/77 (6.5%)	5	4/77 (5.2%)	4
Hyperkalemia	7/77 (9.1%)	9	6/77 (7.8%)	7
Hypernatremia	5/77 (6.5%)	5	3/77 (3.9%)	4
Hypoalbuminaemia	8/77 (10.4%)	8	2/77 (2.6%)	2
Hypocalcemia	4/77 (5.2%)	4	1/77 (1.3%)	1
Hypokalemia	9/77 (11.7%)	10	6/77 (7.8%)	13
Metabolic Acidosis	8/77 (10.4%)	9	3/77 (3.9%)	4
Renal and urinary disorders
Acute Kidney injury	8/77 (10.4%)	8	5/77 (6.5%)	5
Renal Failure	2/77 (2.6%)	2	4/77 (5.2%)	4
Respiratory, thoracic and mediastinal disorders
Hydrothorax	6/77 (7.8%)	9	3/77 (3.9%)	3
Skin and subcutaneous tissue disorders
Decubitus Ulcer	3/77 (3.9%)	4	8/77 (10.4%)	9
Vascular disorders
Hypotension	18/77 (23.4%)	18	17/77 (22.1%)	19

Limitations/Caveats

An interim analysis of 118 subjects was performed by a DRC to assess S. aureus pneumonia rates and the conditional power to detect a statistically significant treatment effect at study completion (354 subjects). The study was terminated for futility.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.