Trial of Andexanet Alfa in ICH Patients Receiving an Oral FXa Inhibitor

Sponsor

Alexion Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03661528

Collaborator

(none)

1,200

Enrollment

213

Locations

Arms

61.8

Anticipated Duration (Months)

5.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Randomized, controlled clinical trial evaluating the efficacy and safety of andexanet alfa versus usual care in patients with intracranial hemorrhage anticoagulated with a direct oral or indirect subcutaneous/intravenous anticoagulant

Condition or Disease	Intervention/Treatment	Phase
Acute Intracranial Hemorrhage	Drug: andexanet alfa Drug: Usual Care	Phase 4

Detailed Description

This is a randomized, multicenter clinical trial designed to determine the efficacy and safety of andexanet alfa compared to usual care in patients presenting with acute intracranial hemorrhage within 6 hours of symptom onset to baseline scan and within 15 hours of taking an oral factor Xa inhibitor. The study will use a prospective, randomized, open label (PROBE) design. The primary efficacy outcome will be adjudicated by a blinded Endpoint Adjudication Committee. To support the adjudication of hemostatic efficacy, a blinded Imaging Core Laboratory will review all available scans. Between 900 and 1200 patients are planned to be enrolled in the study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

ANNEXA-I is a randomized, open-label study with blinded adjudication on primary efficacy and safety outcomes, including death and thrombotic events.

Primary Purpose:

Treatment

Official Title:

A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor

Actual Study Start Date :

Jun 6, 2019

Anticipated Primary Completion Date :

May 31, 2024

Anticipated Study Completion Date :

Jul 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: andexanet alfa Patients will receive one of two dosing regimens of andexanet alfa based on which FXa inhibitor they received and the amount and timing of the most recent dose.	Drug: andexanet alfa Andexanet alfa is a recombinant version of human FXa
Other: Usual Care Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.	Drug: Usual Care Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.

Arm

Intervention/Treatment

Experimental: andexanet alfa

Patients will receive one of two dosing regimens of andexanet alfa based on which FXa inhibitor they received and the amount and timing of the most recent dose.

Drug: andexanet alfa

Andexanet alfa is a recombinant version of human FXa

Other: Usual Care

Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.

Drug: Usual Care

Outcome Measures

Primary Outcome Measures

To evaluate the effect of andexanet alfa (andexanet) versus usual care on the rate of effective hemostasis. [12 hours]
Effective haemostasis is defined as change from baseline NIHSS of +6 or less at the 12 hour timepoint AND ≤35% increase in haematoma volume compared to baseline on a repeat CT or MRI scan at 12hrs AND no rescue therapies administered between 3 hours and 12 hours after randomization.

Secondary Outcome Measures

To evaluate the effect of andexanet versus usual care on anti-fXa activity. [1-2 hours]
Percent change from baseline to nadir in anti-fXa activity during the first 2 hours post-randomization

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent. Either the patient or his or her medical proxy (or legally authorized representative if permissible by local or regional laws and regulations) has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening.

Deferred consent procedure is allowed where approved by local ethics committees. In cases of deferred consent, the time of the study physician's documented decision to include the patient into the study will serve as "time of consent" with respect to protocol-specific procedures.
In all cases where the patient does not sign informed consent prior to study entry, informed consent from the patient will be obtained as soon as realistically possible after inclusion in the trial and in accordance with the Declaration of Helsinki, International Conference on Harmonization-Good Clinical Practice (GCP), the Data Protection Directive (Directive 95/46/EC) and national and local regulations.

Age ≥ 18 years old at the time of consent.
An acute intracerebral bleeding episode, defined as an estimated blood volume ≥ 0.5 to ≤ 60 mL acutely observed radiographically within the cerebrum. Patients may have extracerebral (e.g., subdural, subarachnoid, epidural) or extracranial (e.g., gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage must be considered the most clinically significant bleed at the time of enrollment.
Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 2 hours prior to randomization (the baseline scan may be repeated only once to meet this criterion).
Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban [last dose 10 mg or greater], edoxaban [last dose 30 mg or greater], or enoxaparin [last dose 1 mg or greater]):

≤ 15 hours prior to randomization.
15 hours prior to randomization or unknown time of last dose, if documented anti fXa activity is > 100 ng/mL for direct fXa inhibitors (apixaban, rivaroxaban or edoxaban) or > 0.5 IU/mL for enoxaparin may be enrolled, irrespective of the time of the last dose, and the patient is within 2 hours prior to consent. Note: Patients enrolled in this manner should receive a high andexanet dosing regimen.

Time from bleeding symptom onset < 6 hours prior to the baseline imaging scan. Time of trauma (if applicable) or time last seen normal may be used as surrogates for time of symptom onset. (If the baseline scan is repeated to meet Inclusion Criterion #4, the time from bleeding symptom onset must be < 6 hours prior to the repeat baseline imaging scan.)
Female patients of childbearing potential and male patients with female partners of childbearing potential must follow protocol-specified guidance for avoiding pregnancy for 30 days after the last dose of study drug.
Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
NIHSS score ≤ 35 at the time of consent. Exclusion Criteria

If a patient meets any of the following criteria, he or she is not eligible to participate in this trial:

Planned surgery, including Burr holes for hematoma drainage, within 12 hours after randomization. Minimally invasive surgery/procedures not directly related to the treatment of intracranial bleeding and that are not expected to significantly affect hematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines.
GCS score < 7 at the time of consent. If a patient is intubated and/or sedated at the time of consent, they may be enrolled if it can be documented that they were intubated/sedated for non-neurologic reasons within 2 hours prior to consent.
Purposefully left blank.
Anticipation that the baseline and follow up brain scans will not be able to use the same imaging modalities (i.e., patients with a baseline CT scan should have a CT scan in follow up; similarly, for MRI).
Expected survival of less than 1 month (not related to the intracranial bleed).
Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of the following:

○ Venous Thromboembolism (VTE: e.g., deep venous thrombosis, PE, cerebral venous thrombosis), myocardial infarction (MI), Disseminated Intravascular Coagulation (DIC), cerebral vascular accident, transient ischemic attack (TIA), acute coronary syndrome, or arterial systemic embolism.

Acute decompensated heart failure or cardiogenic shock at the time of randomization.
Severe sepsis or septic shock at the time of randomization.
The patient is a pregnant or lactating female.
Receipt of any of the following drugs or blood products within 7 days prior to consent:
VKA (e.g., warfarin).
Dabigatran.
PCC (e.g., KCentra®) or rfVIIa (e.g., NovoSeven®), or anti-inhibitor coagulant complex (e.g., FEIBA®), FFP, and whole blood.
Past use of andexanet (or planned use of commercial andexanet).
Treatment with an investigational drug < 30 days prior to consent.
Any tumor-related bleeding.
Known hypersensitivity to any component of andexanet.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Phoenix	Arizona	United States	85013
2	Clinical Trial Site	Tucson	Arizona	United States	85724
3	Clinical Trial Site	Orange	California	United States	92868
4	Clinical Trial Site	Fort Lauderdale	Florida	United States	33308
5	Clinical Trial Site	Jacksonville	Florida	United States	32207
6	Clinical Trial Site	Pensacola	Florida	United States	32504
7	Clinical Trial Site	Tampa	Florida	United States	33606
8	Clinical Trial Site	Augusta	Georgia	United States	30912
9	Clinical Trial Site	Maywood	Illinois	United States	60153
10	Clinical Trial Site	Springfield	Illinois	United States	62702
11	Clinical Trial Site	Iowa City	Iowa	United States	52242
12	Clinical Trial Site	Lexington	Kentucky	United States	40536
13	Clinical Trial Site	Annapolis	Maryland	United States	21401
14	Clinical Trial Site	Boston	Massachusetts	United States	02111
15	Clinical Trial Site	Detroit	Michigan	United States	48201
16	Clinical Trial Site	Detroit	Michigan	United States	48236
17	Clinical Trial Site	Royal Oak	Michigan	United States	48073
18	Clinical Trial Site	Troy	Michigan	United States	48085
19	Clinical Trial Site	Columbia	Missouri	United States	65212
20	Clinical Trial Site	Saint Louis	Missouri	United States	63110
21	Clinical Trial Site	Albany	New York	United States	12208
22	Clinical Trial Site	Brooklyn	New York	United States	11220
23	Clinical Trial Site	Syracuse	New York	United States	13210
24	Clinical Trial Site	Cleveland	Ohio	United States	44106
25	Clinical Trial Site	Cleveland	Ohio	United States	44195
26	Clinical Trial Site	Columbus	Ohio	United States	43210
27	Clinical Trial Site	Tulsa	Oklahoma	United States	74104
28	Clinical Trial Site	Allentown	Pennsylvania	United States	18103
29	Clinical Trial Site	Hershey	Pennsylvania	United States	17033
30	Clinical Trial Site	Pittsburgh	Pennsylvania	United States	15224
31	Clinical Trial Site	Nashville	Tennessee	United States	37232
32	Clinical Trial Site	Austin	Texas	United States	78701
33	Clinical Trial Site	Austin	Texas	United States	78712
34	Clinical Trial Site	Huntington	West Virginia	United States	25701
35	Clinical Trial Site	Innsbruck		Austria	6020
36	Clinical Trial Site	Klagenfurt		Austria	9020
37	Clinical Trial Site	Linz		Austria	4020
38	Clinical Trial Site	Linz		Austria	4021
39	Clinical Trial Site	Salzburg		Austria	5020
40	Clinical Trial Site	St. Polten		Austria	3100
41	Clinical Trial Site	Wien		Austria	1020
42	Clinical Trial Site	Wien		Austria	1090
43	Clinical Trial Site	Brugge		Belgium	9000
44	Clinical Trial Site	Brussels		Belgium	1200
45	Clinical Trial Site	Genk		Belgium	3600
46	Clinical Trial Site	Kortrijk		Belgium	8500
47	Clinical Trial Site	Leuven		Belgium	3000
48	Clinical Trial Site	Ostend		Belgium	8400
49	Clinical Trial Site	Ottignies		Belgium	1340
50	Clinical Trial Site	Calgary	Alberta	Canada	T2N 2T9
51	Clinical Trial Site	Edmonton	Alberta	Canada	T6G 2G3
52	Clinical Trial Site	New Westminster	British Columbia	Canada	V3L 3W7
53	Clinical Trial Site	Vancouver	British Columbia	Canada	V5Z 1M9
54	Clinical Trial Site	Hamilton	Ontario	Canada	L8L 2X2
55	Clinical Trial Site	London	Ontario	Canada	N6A 5A5
56	Clinical Trial Site	Montreal	Quebec	Canada	H3A2B4
57	Clinical Trial Site	Montreal	Quebec	Canada	H3T 1E2
58	Clinical Trial Site	QC	Quebec	Canada	G1J 1Z4
59	Clinical Trial Site	Brno		Czechia	656 91
60	Clinical Trial Site	Jihlava		Czechia	586 33
61	Clinical Trial Site	Olomouc		Czechia	77520
62	Clinical Trial Site	Ostrava		Czechia	703 84
63	Clinical Trial Site	Prague		Czechia	150 06
64	Clinical Trial Site	Prague		Czechia	169 02
65	Clinical Trial Site	Aalborg		Denmark	DK-9000
66	Clinical Trial Site	Aarhus		Denmark	8200
67	Clinical Trial Site	Copenhagen		Denmark	DK-2600
68	Clinical Trial Site	Glostrup Municipality		Denmark	2400 NV
69	Clinical Trial Site	Tallinn		Estonia	10617
70	Clinical Trial Site	Tartu		Estonia	51014
71	Clinical Trial Site	Helsinki		Finland	00029
72	Clinical Trial Site	Turku		Finland	FI-20521
73	Clinical Trial Site	Angers		France	49933
74	Clinical Trial Site	Bordeaux		France	33076
75	Clinical Trial Site	Bourg-en-Bresse		France	01012
76	Clinical Trial Site	Clermont-Ferrand		France	63003
77	Clinical Trial Site	Lyon		France	69437
78	Clinical Trial Site	Montpellier		France	34295
79	Clinical Trial Site	Nancy		France	54035
80	Clinical Trial Site	Paris		France	75010
81	Clinical Trial Site	Paris		France	75014
82	Clinical Trial Site	Paris		France	75018
83	Clinical Trial Site	Paris		France	75019
84	Clinical Trial Site	Suresnes		France	92150
85	Clinical Trial Site	Toulon		France	83800
86	Clinical Trial Site	Toulouse		France	31300
87	Clinical Trial Site	Altenburg		Germany	04600
88	Clinical Trial Site	Augsburg		Germany	86156
89	Clinical Trial Site	Bad Neustadt An Der Saale		Germany	97616
90	Clinical Trial Site	Berlin		Germany	12003
91	Clinical Trial Site	Bochum		Germany	44892
92	Clinical Trial Site	Bonn		Germany	53127
93	Clinical Trial Site	Bremen		Germany	28755
94	Clinical Trial Site	Celle		Germany	29223
95	Clinical Trial Site	Chemnitz		Germany	09166
96	Clinical Trial Site	Dortmund		Germany	44137
97	Clinical Trial Site	Dresden		Germany	01067
98	Clinical Trial Site	Dresden		Germany	01307
99	Clinical Trial Site	Erlangen		Germany	91054
100	Clinical Trial Site	Essen		Germany	45131
101	Clinical Trial Site	Frankfurt am main		Germany	60528
102	Clinical Trial Site	Frankfurt		Germany	65929
103	Clinical Trial Site	Giessen		Germany	35392
104	Clinical Trial Site	Greifswald		Germany	17475
105	Clinical Trial Site	Göttingen		Germany	37075
106	Clinical Trial Site	Hamburg		Germany	22307
107	Clinical Trial Site	Hamburg		Germany	81377
108	Clinical Trial Site	Hanover		Germany	30625
109	Clinical Trial Site	Heidelberg		Germany	69120
110	Clinical Trial Site	Konstanz		Germany	78464
111	Clinical Trial Site	Lubeck		Germany	23538
112	Clinical Trial Site	Lünen		Germany	44534
113	Clinical Trial Site	Mannheim		Germany	68167
114	Clinical Trial Site	Minden		Germany	32429
115	Clinical Trial Site	Munich		Germany	81377
116	Clinical Trial Site	Murnau am Staffelsee		Germany	82418
117	Clinical Trial Site	Münster		Germany	48149
118	Clinical Trial Site	Osnabrück		Germany	49076
119	Clinical Trial Site	Regensburg		Germany	93053
120	Clinical Trial Site	Sanderbusch		Germany	26452
121	Clinical Trial Site	Stuttgart		Germany	70174
122	Clinical Trial Site	Tübingen		Germany	72076
123	Clinical Trial Site	Ulm		Germany	89081
124	Clinical Trial Site	Alexandroupoli		Greece	68100
125	Clinical Trial Site	Athens		Greece	12462
126	Clinical Trial Site	Heraklion		Greece	71003
127	Clinical Trial Site	Patras		Greece	26504
128	Clinical Trial Site	Thessaloniki		Greece	54636
129	Clinical Trial Site	Budapest		Hungary	1085
130	Clinical Trial Site	Budapest		Hungary	1106
131	Clinical Trial Site	Debrecen		Hungary	4032
132	Clinical Trial Site	Miskolc		Hungary	3526
133	Clinical Trial Site	Pécs		Hungary	7623
134	Clinical Trial Site	Tatabánya		Hungary	2800
135	Clinical Trial Site	Ashdod		Israel	7747629
136	Clinical Trial Site	Be'er Sheva		Israel	84101
137	Clinical Trial Site	Haifa		Israel	3109601
138	Clinical Trial Site	Jerusalem		Israel	9103102
139	Clinical Trial Site	Jerusalem		Israel	92100
140	Clinical Trial Site	Petah tikva		Israel	4941492
141	Clinical Trial Site	Ramat Gan		Israel	5262000
142	Clinical Trial Site	Tel Aviv-Yafo		Israel	7747629
143	Clinical Trial Site	Bologna		Italy	40133
144	Clinical Trial Site	Genova		Italy	16132
145	Clinical Trial Site	Milano		Italy	20132
146	Clinical Trial Site	Milano		Italy	20162
147	Clinical Trial Site	Monza		Italy	I-20900
148	Clinical Trial Site	Perugia		Italy	06129
149	Clinical Trial Site	Pisa		Italy	56124
150	Clinical Trial Site	Roma		Italy	00133
151	Clinical Trial Site	Roma		Italy	00152
152	Clinical Trial Site	Roma		Italy	00161
153	Clinical Trial Site	Roma		Italy	00168
154	Clinical Trial Site	Siena		Italy	I-53100
155	Clinical Trial Site	Riga		Latvia	LV-1002
156	Clinical Trial Site	Riga		Latvia	LV-1038
157	Clinical Trial Site	Vilnius		Lithuania	04130
158	Clinical Trial Site	Vilnius		Lithuania	08661
159	Clinical Trial Site	Amsterdam		Netherlands	1061 AE
160	Clinical Trial Site	Amsterdam		Netherlands	1105 AZ
161	Clinical Trial Site	Enschede		Netherlands	7512 KZ
162	Clinical Trial Site	Leiden		Netherlands	2333
163	Clinical Trial Site	Zwolle		Netherlands	8025 AB
164	Clinical Trial Site	Oslo		Norway	0450
165	Clinical Trial Site	Trondheim		Norway	N-7006
166	Clinical Trial Site	Gdańsk		Poland	80 - 803
167	Clinical Trial Site	Gmina Końskie		Poland	26-200
168	Clinical Trial Site	Grodzisk Mazowiecki		Poland	05-825
169	Clinical Trial Site	Katowice		Poland	40-635
170	Clinical Trial Site	Krakow		Poland	30-688
171	Clinical Trial Site	Lublin		Poland	20-718
172	Clinical Trial Site	Lublin		Poland	20-954
173	Clinical Trial Site	Sandomierz		Poland	27-600
174	Clinical Trial Site	Warsaw		Poland	02-957
175	Clinical Trial Site	Warsaw		Poland	03-242
176	Clinical Trial Site	Wejherowo		Poland	84-200
177	Clinical Trial Site	Coimbra	Centro Region	Portugal	3000-75
178	Clinical Trial Site	Faro		Portugal	8000-386
179	Clinical Trial Site	Feira		Portugal	4520-211
180	Clinical Trial Site	Guarda		Portugal	6300-858
181	Clinical Trial Site	Guimarães		Portugal	4835-044
182	Clinical Trial Site	Lisbon		Portugal	1349-019
183	Clinical Trial Site	Porto		Portugal	4200-319
184	Clinical Trial Site	Senhora da Hora		Portugal	4464-513
185	Clinical Trial Site	Vila Nova de Gaia		Portugal	4434-502
186	Clinical Trial Site	Albacete		Spain	02006
187	Clinical Trial Site	Barakaldo		Spain	48903
188	Clinical Trial Site	Barcelona		Spain	08035
189	Clinical Trial Site	Barcelona		Spain	08041
190	Clinical Trial Site	Barcelona		Spain	08907
191	Clinical Trial Site	León		Spain	24071
192	Clinical Trial Site	Lleida		Spain	25198
193	Clinical Trial Site	Madrid		Spain	28034
194	Clinical Trial Site	Madrid		Spain	28041
195	Clinical Trial Site	Santiago de Compostela		Spain	15706
196	Clinical Trial Site	Sevilla		Spain	41009
197	Clinical Trial Site	Sevilla		Spain	41013
198	Clinical Trial Site	Valencia		Spain	46026
199	Clinical Trial Site	Basel		Switzerland	CH-4031
200	Clinical Trial Site	Bern		Switzerland	3010
201	Clinical Trial Site	St. Gallen		Switzerland	9007
202	Clinical Trial Site	Zurich		Switzerland	CH-8091
203	Clinical Trial Site	Bury		United Kingdom	BL9 7TD
204	Clinical Trial Site	Cambridge		United Kingdom	CB2 0QQ
205	Clinical Trial Site	Glasgow		United Kingdom	G51 4TF
206	Clinical Trial Site	Harrow		United Kingdom	HA1 3UJ
207	Clinical Trial Site	Leeds		United Kingdom	LS1 3EX
208	Clinical Trial Site	Leicester		United Kingdom	LE1 5WW
209	Clinical Trial Site	London		United Kingdom	SW17 0QT
210	Clinical Trial Site	London		United Kingdom	WC1B 5EH
211	Clinical Trial Site	Newcastle Upon Tyne		United Kingdom	NE1 4LP
212	Clinical Trial Site	Nottingham		United Kingdom	NG12 3EL
213	Clinical Trial Site	Salford		United Kingdom	M6 8HD