REACT: Clinical Research Study With Clazosentan to Evaluate Its Effects on Preventing Complications Due to the Narrowing of the Blood Vessels (Vasospasm) in the Brain, Caused by Bleeding Onto the Surface of the Brain

Sponsor

Idorsia Pharmaceuticals Ltd. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03585270

Collaborator

(none)

409

Enrollment

Locations

Arms

48.4

Anticipated Duration (Months)

5.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate if clazosentan (on top of normal routine medical care) can reduce the risk of developing complications related to cerebral vasospasm and permanent brain damage as compared to normal routine medical care alone.

Condition or Disease	Intervention/Treatment	Phase
Aneurysmal Subarachnoid Hemorrhage	Drug: Clazosentan Drug: Placebo	Phase 3

Detailed Description

When a blood vessel just outside the brain bursts and causes bleeding onto its surface, the space surrounding the brain (the subarachnoid space) fills with blood. This condition is called subarachnoid hemorrhage. The bleeding due to the rupture of a pouch-like structure or a bulge (called an aneurysm) that formed on one of the blood vessels is condition called aneurysmal subarachnoid hemorrhage (aSAH).

In this study, clazosentan is being tested against normal routine medical care to determine if clazosentan can reduce the risk of developing complications related to vasospasm and permanent brain damage.

Participation will last for approximately 6 months from the episode of bleeding. For subjects randomized in the high-risk prevention group, treatment will start within 96 hours following the time of the aneurysm rupture, and be administered where possible, for 14 days. For subjects randomized in the early treatment group, treatment must begin within 24 hours of the time of the angiogram documenting the cerebral vasospasm necessary for entry into the study. Treatment will be administered for a minimum of 6 days and a maximum of 14 days. Recruitment in the early treatment group has been discontinued.

The end-of-study will be conducted as a telephone interview 6 months after the episode of bleeding.

Study Design

Study Type:

Interventional

Actual Enrollment :

409 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This study will be performed in a double-blind fashion. The investigator, study personnel, subjects, clinical research associates (CRAs), sponsor personnel, and vendor / Contract Research Organization (CRO) personnel involved in the conduct of the study will remain blinded to the study treatment received by the subjects during the double-blind treatment period until study closure

Primary Purpose:

Prevention

Official Title:

A Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase 3 Study to Assess the Efficacy and Safety of Clazosentan in Preventing Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI), in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage (aSAH)

Actual Study Start Date :

Dec 15, 2018

Actual Primary Completion Date :

Jun 13, 2022

Anticipated Study Completion Date :

Dec 28, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Clazosentan Participants will receive clazosentan for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH).	Drug: Clazosentan Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days. Other Names: ACT-108475
Placebo Comparator: Placebo Participants will receive clazosentan matching-placebo for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH).	Drug: Placebo Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

Arm

Intervention/Treatment

Experimental: Clazosentan

Participants will receive clazosentan for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH).

Drug: Clazosentan

Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days.

Other Names:

ACT-108475

Placebo Comparator: Placebo

Participants will receive clazosentan matching-placebo for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH).

Drug: Placebo

Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

Outcome Measures

Primary Outcome Measures

Occurrence of clinical deterioration due to delayed cerebral ischemia (DCI) from study drug initiation up to 14 days post-study drug initiation [Up to 14 days post-study drug initiation]
Clinical deterioration due to DCI is defined as a worsening of at least 2 points compared to the reference score, on the mGCS or the aNIHSS, lasting for at least 2 hours, which cannot be entirely attributed to causes other than cerebral vasospasm. It is centrally adjudicated by the CEC based on a written charter and review of clinical data, case narratives, angiograms and CT scans.

Secondary Outcome Measures

Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation [At Day 16 post study drug initiation]
A clinical relevant cerebral infarction is defined as: all-cause cerebral infraction ≥ 5 cm3 or cerebral infarction < 5 cm3 in subjects with clinical deterioration due to delayed cerebral ischemia (DCI). Cerebral infarction refers to new or worsened infarcts and is determined by central radiology review comparing the total volume of infarcts on the computed tomography (CT) scan performed 16 days after study drug initiation with the CT performed just prior to randomization.
Long-term clinical outcome assessed by the modified Rankin Scale (mRS) at Week 12 post-aSAH, dichotomized into poor outcome (score ≥ 3) and good outcome (score < 3) [At Week 12 post-aSAH]
Long-term clinical outcome assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 post-aSAH, dichotomized as follows: poor outcome (score ≤ 4) and good outcome (score > 4) [At Week 12 post-aSAH]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent to participate in the study must be obtained from the subject or proxy/legal representative at any time from hospital admission to prior to initiation of any study-mandated procedure,
Males and females aged 18 to 70 years (inclusive, at hospital admission),
Subjects with a ruptured saccular aneurysm, angiographically confirmed by DSA or CTA, which has been successfully secured within 72 hours of rupture, by surgical clipping or endovascular coiling,
WFNS (World Federation of Neurosurgical Societies) grades 1-4 (based on Glasgow Coma Scale [GCS]) assessed after recovery from the aneurysm-securing procedure and after external ventricular drainage for hydrocephalus, if required.
Subjects must meet the criteria for the high-risk prevention group: Subjects with a "thick and diffuse clot" (thick and diffuse is defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more basal cisterns) on the hospital admission CT scan, absence of cerebral vasospasm at the time of randomization, and possibility to start study drug in the ICU (or equivalent environment where all protocol assessments can be performed and the Patient Management Guidelines followed), within 96 hours after the time of the aneurysm rupture.
The recruitment into the early treatment group, i.e. subjects without a thick and diffuse clot on the hospital admission CT scan who develop asymptomatic or minimally symptomatic moderate to severe angiographic vasospasm, within the 14-day period post-aneurysm rupture, and for whom it is possible to start study drug in the ICU (or equivalent environment where all protocol assessments can be performed and the Patient Management Guidelines followed), within 24 hours of this angiographic diagnosis, has been discontinued.
Presence of a cerebral CT scan performed at least 8 hours post aneurysm securing procedure and within 24 hours prior to randomization.
Absence of a significant (e.g., symptomatic or large) new or worsened cerebral infarct or re-bleeding of the repaired aneurysm on the post-procedure CT scan.
A woman of childbearing potential is eligible only if the pregnancy test performed during the screening period is negative. Agreement must be obtained to take the necessary precautions to avoid pregnancy from hospital discharge until 30 days post-study drug discontinuation. If breastfeeding, agreement must be obtained to refrain for the duration of the treatment with study drug and until 30 days post-study drug discontinuation.
Males are eligible for study participation only if they agree to take the necessary precautions to avoid pregnancy in a female partner from hospital discharge until 30 days post-study drug discontinuation.

Exclusion Criteria:

Aneurysmal subarachnoid hemorrhage (aSAH), aneurysm-securing procedure, vasospasm:
Subjects with SAH due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms, SAH associated with arterio-venous malformation, vertebral dissections),
Significant bleeding post aneurysm-securing procedure (e.g., due to intra-ventricular drain, intra-cerebral hemorrhage, epidural hematoma, vessel dissection or rupture, re-bleeding of the repaired aneurysm), based on investigator judgment,
Intra-or peri-aneurysm securing procedure complication requiring non-routine medical or interventional treatment such as administration of an antithrombotic or anti-platelet agent (e.g., abciximab), which is not completely resolved prior to randomization,
Intraventricular hemorrhage on the hospital admission CT scan, filling more than 50% of both lateral ventricles and with involvement of the 3rd and 4th ventricles.
Intracerebral hemorrhage on the hospital admission CT scan, with an approximate volume of > 50 mL,
Presence of cerebral vasospasm at hospital admission (initial admission or transfer from another hospital) believed to be associated with a prior bleed (i.e., occurring before the bleed for which the subject is currently hospitalized). Vasospasm occurring during the aneurysm securing procedure is not an exclusion criterion,
Neurological and functional status:
Subjects with a new major neurological deficit occurring post aneurysm-securing procedure which is attributable to the procedure and does not improve to pre-procedure status before randomization,
Subjects with a GCS score of ≤ 9 at the time of randomization and without intracranial pressure (ICP) monitoring,
Modified Rankin Score of 3 or higher, prior to the aSAH (i.e., due to a chronic condition),
Other clinical considerations:
Subjects with total bilirubin > 2 times the upper limit of normal, and/or a known diagnosis or clinical suspicion of liver cirrhosis or moderate to severe hepatic impairment,
Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) at time of randomization that is refractory to treatment,
Unresolved pulmonary edema or significant pneumonia still present at the time of randomization, or severe hypoxia at the time of randomization in intubated subjects, defined as PaO2/FiO2 ≤ 200,
High sustained ICP (> 25 mmHg lasting > 20 minutes) at time of randomization, despite optimal treatment, in subjects with ICP monitoring,
Severe cardiac failure requiring inotropic support at the time of random

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Hospital & Clinics - Stanford School of Medicine Dept. of Neurosurgery	Stanford	California	United States	94305
2	Mayo clinic, Dept of Neurosurgery	Jacksonville	Florida	United States	32224
3	University of Illinois - Department of Neurosurgery	Chicago	Illinois	United States	60612
4	University of Maryland Medical Systems - Neurosurgery	Baltimore	Maryland	United States	21201
5	Boston University School of Medicine / Boston University Medical Center	Boston	Massachusetts	United States	02118
6	Beth Israel Deaconess Medical Center Dept of Neurosurgery	Boston	Massachusetts	United States	02215
7	Northwell Health, Department of Neurosurgery	Manhasset	New York	United States	11030
8	Mt Sinai Hospital	New York	New York	United States	10029
9	Columbia University Medical Center Dept. of Neurology - Neurological Intensive Care Unit	New York	New York	United States	10032
10	University Hospitals Case Medical Center - Department of Neurosurgery	Cleveland	Ohio	United States	44106
11	The Ohio State University - Wexner Medical Center	Columbus	Ohio	United States	43210
12	Oklahoma University Health Sciences Center - Department of Neurology	Oklahoma City	Oklahoma	United States	73104
13	Oregon Health and Science University	Portland	Oregon	United States	97239
14	Penn State Milton S Hershey Medical Center, Neurosurgery	Hershey	Pennsylvania	United States	17033
15	Vanderbilt University Medical Center - Department of Neurosurgery	Nashville	Tennessee	United States	37232
16	Virginia Commonwealth University, Department of Neurosurgery	Richmond	Virginia	United States	23298
17	Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie	Innsbruck		Austria	6020
18	Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie	Linz		Austria	A-4020
19	Hospital Erasme, Service de Soins Intensifs	Brussels		Belgium	1070
20	Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie	Brussels		Belgium	1200
21	Neurology Department, University Hospital	Gent		Belgium	9000
22	University Hospital Sart Tilman Liege	Liège		Belgium	4000
23	University of Alberta Hospital Department of Neurological Surgery	Edmonton	Alberta	Canada	T6G 2B7
24	Winnipeg Regional Health Authority Health Sciences Centre	Winnipeg	Manitoba	Canada	R3A 1R9
25	Halifax Infirmary, Nova Scotia Health Authority	Halifax	Nova Scotia	Canada	B3H 3A7
26	Royal University Hospital Department of Neurology	Saskatoon	Saskatchewan	Canada	S7N 0W8
27	Fakultní nemocnice Brno Neurochirurgická klinika	Brno		Czechia	625 00
28	Fakultní nemocnice Ostrava Neurochirurgická klinika	Ostrava-Poruba		Czechia	708 52
29	University Hospital in Pilsen, Department of Neurosurgery	Plzen		Czechia	304 60
30	Ústřední vojenská nemocnice Praha Neurochirurgická klinika	Praha		Czechia	169 02
31	Masarykova nemocnice v Ústí nad Labem Neurochirurgie	Ústí Nad Labem		Czechia	401 13
32	Odense Universitets Hospital Neurokirurgisk afdelning	Odense		Denmark	5000
33	Helsingin yliopistollinen keskussairaala Neurokirurgian klinikka	Helsinki		Finland	00260
34	Kuopio University Hospital	Kuopio		Finland	70210
35	Tampereen yliopistollinen sairaala Neurokirurgian klinika	Tampere		Finland	33520
36	Turku University Hospital Neurosurgery, T-hospital	Turku		Finland	20520
37	Hôpital neurologique Pierre Wertheimer Service de Reanimation	Bron		France	69006
38	Hôpital Gabriel Montpied, ICU DEPT, Neuro reanimation departement	Clermont-Ferrand		France	63003
39	Hôpital de la Timone 2, Intensive Care Unit SAR 1	Marseille		France	13385
40	Hôpital Nord Laennec - CHU de Nantes	Nantes		France	44093
41	Hospital Lariboisiere Paris	Paris		France	75010
42	Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski	Paris		France	75013
43	Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital	Toulouse		France	31059
44	Klinik für Diagnostische Radiologie und Neuroradiologie, Augsburg	Augsburg		Germany	86156
45	Charite Universitätsmedizin Berlin - Klinik und Poliklinik für Neurochirurgie	Berlin		Germany	10117
46	Heinrich-Heine Universität Düsseldorf -Klinik für Neurochirugie	Düsseldorf		Germany	40225
47	University of Erlangen-Nürnberg, Dpt. of Neurosurgery	Erlangen		Germany	91054
48	University Hospital of Essen, Department of Neurosurgery	Essen		Germany	45147
49	Universitätsklinik Frankfurt, Klinik und Poliklinik für Neurochirurgie, Dept of neurosurgery	Frankfurt		Germany	60528
50	Bezirkskrankenhaus Günzburg - Klinik für Neurochirugie	Günzburg		Germany	89132
51	Asklepios Klinik St. Georg - Neurochirugie	Hamburg		Germany	20099
52	University Hospital of Hamburg-Eppendorf, Dpt. of Neurosurgery	Hamburg		Germany	20246
53	Neurochirurgische Universitätklinik des Heidelberg, Dept of Neurosurgery	Heidelberg		Germany	69120
54	Universitätsklinikum Schleswig Hollstein Lübeck (UKSH) Klinik für Neurochirugie	Lübeck		Germany	23538
55	University Regensburg, Dpt. of Neurosurgery	Regensburg		Germany	93053
56	Universitätsklinikum Rostock, Abteilung für Neurochirurgie	Rostock		Germany	18057
57	Debreceni Egyetem, Idegsebészet	Debrecen		Hungary	4032
58	Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika	Pécs		Hungary	7623
59	Rambam Healthcare Campus, Neurology Department	Haifa		Israel	3109601
60	Hadassah Medical Center	Jerusalem		Israel	9112001
61	Beilinson Hospital, Rabin Medical Center, Department of Neurosurgery	Petah tikva		Israel	4941492
62	The Chaim Sheba Medical Centre - Neurosurgery	Ramat Gan		Israel	5265601
63	ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica	Monza		Italy	20900
64	Azienda Ospedaliera Padova-Università degli Studi di Padova - Istituto di Anestesia e Rianimazione	Padova		Italy	35128
65	Azienda Ospedaliero Universitaria di Parma, struttura complessa Neurochirurgia	Parma		Italy	43126
66	Fondazione Policlinico Universitario Agostino Gemelli Università Cattolica del Sacro Cuore, UOS Terapia Intensiva Neurochirurgic	Rome		Italy	00168
67	Oddział Neurochirurgii i Neurotraumatologii z Pododdziałem Leczenia Chorób Naczyniowych Centralnego Układu Nerwowego	Poznań		Poland	60-355
68	Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie	Warszawa		Poland	02-097
69	Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego	Łódź		Poland	90-153
70	Hospital Universitario Germans Trias i Pujol - Neurology Department	Badalona		Spain	08916
71	Hospital Vall d'Hebron Departamento Neuroradiología	Barcelona		Spain	08035
72	Hospital Clinic Barcelona	Barcelona		Spain	08036
73	Hospital Universitari de Bellvitge	Hospitalet de Llobregat		Spain	08907
74	University Hospital of Gran Canaria Dr. Negrin	Las Palmas De Gran Canaria		Spain	35010
75	Hospital Universitario 12 de Octubre, Departamento Neurosurgery Division Neuroradiology	Madrid		Spain	28041
76	Hospital Universitari son Espases	Palma De Mallorca		Spain	07014
77	Corporació Sanitària Parc Taulí, Hospital Parc Taulí	Sabadell		Spain	08208
78	Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården	Göteborg		Sweden	41345
79	Linköping Universitetssjukhuset, Neurokirurgiska kliniken	Linköping		Sweden	58185
80	Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA	Lund		Sweden	22185

Sponsors and Collaborators

Idorsia Pharmaceuticals Ltd.

Investigators

Study Director: Clinical Trials, Idorsia Pharmaceuticals Ltd.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Idorsia Pharmaceuticals Ltd.

ClinicalTrials.gov Identifier:

NCT03585270

Other Study ID Numbers:

ID-054-304
2018-000241-39

First Posted:

Jul 12, 2018

Last Update Posted:

Jun 21, 2022

Last Verified:

Jun 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Subarachnoid Hemorrhage

Hemorrhage

Study Results

No Results Posted as of Jun 21, 2022