AR-301-002: Adjunctive Therapy to Antibiotics in the Treatment of S. Aureus Ventilator-Associated Pneumonia With AR-301

Sponsor

Aridis Pharmaceuticals, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03816956

Collaborator

(none)

240

Enrollment

140

Locations

Arms

37.9

Anticipated Duration (Months)

1.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

AR-301 is being evaluated as an adjunctive treatment of ventilator-associated pneumonia (VAP) due to Staphylococcus aureus (S. aureus) in combination with standard of care (SOC) antibiotic therapy in patients with confirmed S. aureus infection.

Condition or Disease	Intervention/Treatment	Phase
Lung Infection Pneumonia, Ventilator-Associated Infection, Bacterial Staphylococcus Aureus	Drug: AR-301 Other: Placebo	Phase 3

Detailed Description

This study is an international, multicenter, prospective, randomized, double blind, placebo controlled, parallel design protocol in patients with Ventilator-Associated Pneumonia (VAP) caused by S. aureus.

Patients with a documented diagnosis of pneumonia due to S. aureus, and require ICU care, who have been intubated (or have a tracheostomy tube in place) and mechanically ventilated for at least 48 hours are eligible for screening.

In total, approximately 240 subjects will be randomized 1-1 to be treated with placebo plus standard of care (SOC) or AR-301 (20 mg/kg) plus SOC in this Phase 3 study.

Study subjects will receive a single dose at Day 0 in addition to SOC antibiotic treatment, and then enter a safety, efficacy and PK study period for a total study duration of 28 days. The selection of SOC antibiotics is made in accordance with local best practices at the discretion of the investigator.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized Double-blind Placebo-controlled Multicenter Phase 3 Study of Efficacy and Safety of AR-301 as Adjunct Therapy to Antibiotics in the Treatment of Ventilator-Associated Pneumonia (VAP) Caused by S. Aureus

Actual Study Start Date :

May 3, 2019

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study treatment Investigational/ Interventional Product group: AR-301 (tosatoxumab) 20 mg/kg administered once intravenously on the day of randomization.	Drug: AR-301 AR-301 (tosatoxumab) 20 mg/kg administered once intravenously the day of enrolment. Other Names: AR-301 (tosatoxumab)
Placebo Comparator: Placebo treatment Control group: Placebo administered intravenously on the day of randomization.	Other: Placebo Placebo comparator

Arm

Intervention/Treatment

Experimental: Study treatment

Investigational/ Interventional Product group: AR-301 (tosatoxumab) 20 mg/kg administered once intravenously on the day of randomization.

Drug: AR-301

AR-301 (tosatoxumab) 20 mg/kg administered once intravenously the day of enrolment.

Other Names:

AR-301 (tosatoxumab)

Placebo Comparator: Placebo treatment

Control group: Placebo administered intravenously on the day of randomization.

Other: Placebo

Placebo comparator

Outcome Measures

Primary Outcome Measures

A comparison of Clinical Cure Rates of standard of care (SOC) alone and SOC with AR-301 [21 days]
Clinical cure rates of standard of care (SOC) alone and (SOC) with AR-301 at Day 21 as measured by all-cause mortality, need for mechanical ventilation and signs and symptoms of pneumonia.
Safety of AR-301 by treatment-emergent adverse events assessed by changes between treatment and placebo as assessed by the Principal Investigator [21 Days]
Safety of AR-301 of treatment-emergent adverse events as assessed by changes assessed by the PI between treatment and placebo
Tolerability of AR-301 measured by the number of participants with treatment-emergent adverse events classified using CTCAE v 5.0 [21 Days]
Tolerability of AR-301 will be measured and evaluated by the severity of treatment-emergent adverse events using the CTCAE v 5.0.

Secondary Outcome Measures

The difference in clinical cure rates between Standard of Care alone or with AR301 as time to clinical cure at Day 7, 14 and 28 [Day 7, 14, and 28]
Difference in Clinical Cure rates between SOC alone or with AR-301 defined by time to clinical cure (number of days) using the same criteria as for the primary efficacy objective at Day 21.
The difference in mortality between Standard of Care alone or with AR-301 at Days 7,14,28 [Day 7, 14, and 28]
Difference in mortality defined as cause of death (all-cause mortality and pneumonia-related mortality)between SOC alone or with AR-301 at Days 7,14, and 28
The difference in PaO2/FiO2 between Standard of Care alone or with AR-301 at Days 7,14,28 [Day 7, 14, and 28]
Difference in respiratory function between SOC alone or with AR-301 at Days 7,14, and 28 as changes in PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever possible OR changes in non-invasive measures of oxygenation (e.g. by pulse oximetry)
The difference in time on supplemental oxygen assessment between Standard of Care alone or with AR-301 at Days 7,14,28 [Day 7, 14, and 28]
Difference in respiratory function between SOC alone or with AR-301 at Days 7,14, and 28 as time on supplemental oxygen
Changes in baseline in SOFA score between Standard of Care alone or with AR301 at Days 7,14,28 [Day 7, 14, and 28]
Difference in Clinical Cure rates between SOC alone or with AR-301 at Days 7,14, and 28 in the following clinical outcomes: Changes from Baseline in sequential organ failure assessment (SOFA) score using the following scale: Maximum SOFA score 0-6, <10% Mortality, 7-9 15-20% mortality, 10-12 40-50% mortality, 13-14 50-60% mortality, 15 >80% mortality, 15-24 >90% mortality. Lower numbers are considered to be better outcome of mortality and higher scores worse outcome of mortality.
Duration of intubation with ventilation [28 days]
Number of days with intubation with ventilation
Duration mechanical ventilation if tracheostomy in place [28 days]
Number of days of intubation with mechanical ventilation if tracheostomy in place
Duration of stay in ICU [28 days]
Number of days of stay in ICU
Duration hospitalization [28 days]
Number of days of hospitalization
Duration antibiotic use. [28 days]
Number of days on antibiotics
Pharmacokinetic Analysis - (Cmax) [28 days]
Pharmacokinetic analysis measuring Maximum Serum Concentration (Cmax)
Pharmacokinetic Analysis - (AUC) [28 Days]
Pharmacokinetic analysis measuring Area Under the Curve (AUC)
Pharmacokinetic Analysis - (T1/2) [28 Days]
Pharmacokinetic analysis measuring time for half of the initial dose of study drug to be eliminated from the body (T1/2)
Pharmacokinetic Analysis - (Tmax) [28 Days]
Pharmacokinetic analysis measuring time at which Cmax is obtained (Tmax)
Pharmacokinetic Analysis (Blood levels of AR-301) [28 Days]
Blood levels of AR-301 in the patient over time during the study period.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written Informed Consent given by the patient or, if not possible, by a legally acceptable representative and/or an independent physician as authorized by the competent ethics committee (EC) or independent review board (IRB) and local regulations.
To be at least 18 years of age. Taiwan only: To be at least 20 years of age. South Korea only: To be at least 19 years of age.
Treated in an ICU at the time of enrollment.
Endotracheal tube in place (tracheostomy is allowed).
The patient is mechanically ventilated for at least 48 hours.
Diagnosis of pneumonia based on the following criteria (a, b, and c, all must be met):
One definitive chest X-ray diagnostic of pneumonia within 48 hours,
Hypoxemia based on PaO2/FiO2.
At least one of the following signs:

Documented fever (e.g., body temperature greater than or equal to 38º Celsius).

Hypothermia (e.g., core body temperature less than or equal to 35º Celsius).
Total peripheral white blood cell (WBC) count greater than or equal to 10,000 cells/µL (or mm3).
Leukopenia with total WBC less than or equal to 4,500 cells/µL (mm3). v. Greater than 15 percent immature neutrophils (bands) noted on peripheral blood smear.

Documented pulmonary infection with Staphylococcus aureus obtained by bronchoalveolar lavage (BAL), mini-BAL, protected endotracheal aspiration/aspirate (ETA) (collectively 'airway specimen').

Exclusion Criteria

The subject is unlikely to survive for the study duration despite delivery of adequate antibiotics and supportive care for treatment of S. aureus pneumonia.
Effective antibacterial drug therapy for the index pneumonia administered continuously for 48 hours or more prior to initiation of study treatment. Effective antibiotics would include those typically used to treat S. aureus.
Plasmapheresis (ongoing or planned), extracorporeal membrane oxygenation (ECMO) or any procedure that would remove/filter out the monoclonal antibody/study drug.
Immunocompromised patients.
Known hereditary complement deficiency.
Liver dysfunction with a Child Pugh C score > 9 (Child Pugh score of A or B are acceptable at discretion of the Principal Investigator [PI]).
Pulmonary disease that precludes evaluation of a therapeutic response (such as lung cancer resulting in bronchial obstruction or on the same side as the pneumonia, active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary infection, lung abscess, pleural empyema or post obstructive pneumonia).
Patient has received intravenous (IV) immunoglobulin therapy within 3 months prior to the Screening Visit.
Any woman of child-bearing potential (WOCBP) who does not have a negative pregnancy test result at Screening using SERUM or URINE testing based on Beta-subunit human chorionic gonadotropin (HCG) standard tests and methods from the local laboratory.
Any sexually active subject who is unwilling to use acceptable methods of contraception for 120 days after dosing.
Known lack of treatment compliance from prior studies or ongoing medical care based on medical records and PI's judgment and/or the capacity of the patient to comply with all study requirements.
Any medical, psychological, cognitive, social or legal conditions that would interfere in the ability to give an Informed Consent OR the absence of a legally valid representative of the patient or independent physician allowed and able to give consent on his/her behalf.
Participation as a subject in another interventional study within 30 days prior to the first dose of study treatment, or planned participation in such a study during the study or within 30 days of its completion by the patient.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 01	Sacramento	California	United States	95817
2	Site-15	Atlanta	Georgia	United States	30322
3	Site 02	Chicago	Illinois	United States	60611
4	Site 03	New Orleans	Louisiana	United States	70112
5	Clinical Site	Burlington	Massachusetts	United States	01805
6	Site-011	Burlington	Massachusetts	United States	01805
7	Site-13	Detroit	Michigan	United States	48202
8	Site 04	Durham	North Carolina	United States	27710
9	Site 05	Charleston	South Carolina	United States	29414
10	BLR-01	Brest		Belarus	224027
11	BLR-02	Gomel		Belarus	246029
12	BLR-03	Grodno		Belarus	230017
13	BLR-05	Minsk		Belarus	220053
14	BLR-04	Minsk		Belarus	223041
15	BLR-06	Mogilev		Belarus	212018
16	BLR-07	Vitebsk		Belarus	210009
17	BEL-04	Brussels		Belgium	1020
18	BEL-02	Brussels		Belgium	1070
19	BEL-06	Brussels		Belgium	1200
20	BEL-07	Haine-Saint-Paul		Belgium	7100
21	BEL-01	Lodelinsart		Belgium	6042
22	BEL-05	Ottignies		Belgium	1340
23	BEL-03	Yvoir		Belgium	5530
24	BRA-02	Belo Horizonte		Brazil	30110-934
25	BRA-06	Belo Horizonte		Brazil	30150-221
26	BRA-03	Campinas		Brazil	13060-904
27	BRA-08	Curitiba		Brazil	80810-050
28	BRA-04	Curitiba		Brazil	82050-350
29	BRA-01	Porto Alegre		Brazil	90610-000
30	BRA-05	São José Do Rio Preto		Brazil	15090-000
31	BRA-07	São Paulo		Brazil	17201-130
32	CHN-08	Bengbu	Bengbu City	China	233004
33	CHN-15	Changsha	Hunan	China	410011
34	CHN-07	Nanjing	Jiangsu	China	210029
35	CHN-15	Yangzhou	Jiangsu	China	225001
36	CHN-14	Shanghai	Xuhui District	China	200032
37	CHN-11	Beijing		China	100029
38	CHN-10	Changsha		China
39	CHN-04	Chongqing		China
40	CHN-09	Guangzhou		China
41	CHN-02	Guizhou		China	550004
42	CHN-12	Haikou		China
43	CHN-13	Hunan		China
44	CHN-16	Luoyang		China
45	CHN-01	Peking		China
46	CHN-05	Shanghai		China	200433
47	CHN-03	Zhanjiang		China
48	EST-01	Tallinn		Estonia	13419
49	EST-02	Tartu		Estonia	51014
50	FRA-02	Strasbourg	Cedex	France	67091
51	Hopital	Belfort		France	90000
52	FRA-02	Brive-la-Gaillarde		France	19100
53	FRA-10	Bron		France	69677
54	FRA-05	La Roche-sur-Yon		France	85925
55	CHRU de Lille-Urgence Respiratoire et Réanimation Médicale	Lille		France	59037
56	FRA-04	Limoges		France	87042
57	CHRU	Nancy		France	54035
58	FRA-01	Nantes		France	44093
59	СHRU de Nîmes -Hôpital Carémeau-Service des Réanimations	Nîmes		France	30029
60	FRA-16	Orléans		France	45067
61	FRA-11	Rennes		France	35033
62	CHRU	Strasbourg		France
63	FRA-07	Tours		France	37044
64	FRA-14	Étampes		France	91150
65	GEO-06	Gori		Georgia	0144
66	GEO-01	Kutaisi		Georgia	4600
67	GEO-03	Kutaisi		Georgia	4600
68	GEO-04	Kutaisi		Georgia	4600
69	GEO-10	Kutaisi		Georgia
70	GEO-14	Mtskheta		Georgia	3300
71	GEO-15	Tbilisi		Georgia	0114
72	GEO-02	Tbilisi		Georgia	0141
73	GEO-09	Tbilisi		Georgia	0159
74	GEO-11	Tbilisi		Georgia	0159
75	GEO-13	Tbilisi		Georgia	0159
76	GEO-07	Tbilisi		Georgia	0160
77	IND-15	Ahmedabad	Gujarat	India	380025
78	IND-06	Belagave	Karnataka	India	590010
79	IND-11	Mysuru	Karnataka	India	570004
80	IND-12	Kozhikode	Kerala	India	673008
81	IND-03	Pune	Maharastra	India	411001
82	IND-05	Ludhiāna	Punjab	India	141001
83	IND-10	Hyderabad	Telangana State	India	500096
84	IND-16	Kolkata	West Bengal	India	700020
85	Government Medical college and Hospital	Nagpur		India	440003
86	Aditya Birla Memorial Hospital	Pimpri -Chinchwad		India	411033
87	Emek Medical Center	Afula		Israel	18341
88	ISR-04	Haifa		Israel	31096
89	ISR-06	H̱olon		Israel	5822012
90	ISR-01	Ramat Gan		Israel	5262100
91	ISR-03	Tel Aviv		Israel	64239
92	LTV-05	Liepāja		Latvia	LV-3414
93	LTV-02	Riga		Latvia	LV-1006
94	Riga East Clinical University Hospital Clinic "Gailezers"	Riga		Latvia	LV1038
95	LTV-01	Valmiera		Latvia	LV-4201
96	MEX-07	Guadalajara	Jalisco	Mexico	44280
97	MEX-03	Monterrey	Nuevo Leon	Mexico	64460
98	MEX-01	Chihuahua		Mexico	31000
99	MEX-06	San Luis Potosí		Mexico	78290
100	PHL-01	Iloilo City		Philippines	5000
101	PHL-02	Manila		Philippines	1012
102	PHL-05	Quezon City		Philippines	1100
103	RUS-18	Arkhangelsk		Russian Federation	163002
104	City Clinical Hospital No.5	Barnaul		Russian Federation	656045
105	Railway Clinical Hospital on Station Chelyabinsk of JSC Russian Railways	Chelyabinsk		Russian Federation	454000
106	RUS-01	Krasnoyarsk		Russian Federation
107	RUS-04	Novosibirsk		Russian Federation	630051
108	City Clinical Hospital # 1	Novosibirsk		Russian Federation
109	RUS-08	Novosibirsk		Russian Federation
110	RUS-02	Saint Petersburg		Russian Federation	192242
111	RUS-19	Saint Petersburg		Russian Federation	195271
112	RUS-10	Smolensk		Russian Federation	214018
113	RUS-06	Tomsk		Russian Federation	634050
114	RUS-16	Zhukovskiy		Russian Federation	140180
115	Clinical Center of Serbia_Clinic for Digestive Surgery	Belgrade		Serbia
116	Clinical-Hospital Centre Bezanijska Kosa - Pulmonology Department	Belgrade		Serbia
117	linical Center Kragujevac Center for Anaesthesiology and Reanimation	Kragujevac		Serbia
118	Clinical Center Nis	Niš		Serbia	11080
119	SRB-01	Sremska Kamenica		Serbia	21204
120	Helen Joseph Hospital	Auckland Park		South Africa	2092
121	Johese Clinical Research	Centurion		South Africa	0157
122	Netcare Milpark Hospital	Johannesburg		South Africa	2193
123	Mediclinic Worcester	Worcester		South Africa	6850
124	TWN-07	Taipei City	Beitou District	Taiwan	112
125	TWN-10	Taipei City	Neihu District	Taiwan	114
126	TWN-01	Kaohsiung City	Sanmin Dist	Taiwan	807
127	TWN-11	Taipei City	Xinyi District	Taiwan	110
128	TWN-02	Taipei City	Zhongzheng District	Taiwan	10002
129	TWN-06	Kaohsiung City	Zuoying Distric	Taiwan	81362
130	TWN-04	Taichung		Taiwan	40447
131	TWN-03	Taichung		Taiwan	40705
132	TRK-05	Ankara		Turkey	06230
133	TRK-06	Istanbul		Turkey	34214
134	TRK-01	Trabzon		Turkey	61080
135	UKR-05	Chernivtsi		Ukraine	58000
136	UKR-03	Ivano-Frankivs'k		Ukraine	76008
137	Kharkiv City Clinical Hospital No 2 n.a. prof. O.O.Shalimov	Kharkiv		Ukraine	61037
138	UKR-02	Kharkiv		Ukraine	61103
139	UKR-09	Kharkiv		Ukraine	61103
140	Kyiv Regional Clinical Hospital	Kyiv		Ukraine	04107