The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage
The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage
For patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.
REACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.
In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH.
Aneurysmal subarachnoid hemorrhage (aSAH) occurs at a rate of 7.9 cases per 100,000 person-years  and it is associated with significant morbidity and mortality [2,3,4]. Despite early aneurysm repair by surgical clipping or endovascular coiling, patients remain at risk of developing cerebral vasospasm characterized by a reduction in the diameter of cerebral arteries . Up to 70% of patients with aSAH develop angiographic vasospasm [6,7,8,9]. Clinical deterioration due to delayed cerebral ischemia, so called delayed cerebral ischemia (DCI), has been reported in about 20–50% of patients in early studies [7, 10, 11] and a recent systematic review of aSAH clinical trials has reported a prevalence of 30% with no change observed over time within the last 2 decades . Cerebral vasospasm is a key contributing factor to the progression towards DCI and infarction [8, 13, 14], which leave many survivors with neurologic deficits, reduced quality of life, and cognitive impairment [7, 15].
Hemodynamic therapy consisting of the administration of IV fluids and vasopressors is the first step in the treatment of symptomatic vasospasm . The only approved drug for the prevention of DCI is the calcium channel blocker nimodipine, which has become standard of care in the US and the EU [1, 16]. Nimodipine has been shown to improve neurological outcomes but has little effect on vasospasm [17,18,19]. For patients with unresponsive severe vasospasm, the main treatment option currently available is endovascular therapy, an invasive procedure with variable clinical success rates , consisting of balloon angioplasty for accessible lesions of the proximal larger arteries including the internal carotid, middle cerebral, and basilar arteries, and intra-arterial administration of vasodilators for more distal vessels .
The pathogenesis of vasospasm after aSAH is thought to be initiated by clot hemolysis and the release of hemoglobin, oxyhemoglobin, and thrombin in the subarachnoid space resulting in an imbalance between vasoconstrictor (endothelin-1) and vasodilator substances (nitric oxide) [9, 21,22,23]. Endothelin-1 is one of the most potent vasoconstrictors known  and its binding to vasoconstricting receptor subtype A (ETA) has been implicated in the development of cerebral vasospasm following aSAH [25, 26]. Blocking this receptor is a promising therapeutic option that targets the root cause of vasospasm. Since its first description in 1997 , clazosentan, a selective ETA receptor antagonist, has been investigated for its anti-vasospastic properties in approximately 2000 patients with aSAH. Four Phase 2, proof of concept studies have investigated the potential of clazosentan to prevent and possibly reverse vasospasm, as well as decrease vasospasm severity [28,29,30,31]. A phase 2 dose finding study performed in Japanese and Korean patients and 2 phase 3 global studies have further supported the efficacy of the 10 mg/hour dose in Japanese patients and the 15 mg/hour dose in the global patient population [30, 32, 33]. Two phase 3 studies performed in Japanese patients with aSAH secured by endovascular coiling in one study and surgical clipping in the other  subsequently led to the approval of the 10 mg/hour clazosentan dose in Japan, in 2022, for the prevention of cerebral vasospasm, vasospasm-related cerebral infarction, and cerebral ischemic symptoms after aSAH surgery. In parallel, the 15 mg/hour dose was selected based on the results from the global phase 2 and 3 studies for further investigation in the ongoing REACT (pRevention and trEatment of vAsospasm with ClazosenTan) study in patients with a clipped or coiled aneurysm after aSAH. The design of this study is strongly supported by the knowledge that was gained over the years during the clinical development program of clazosentan. Across all clazosentan studies, the treatment effect of clazosentan 10 or 15 mg/hour on the composite vasospasm-related morbidity and all-cause mortality endpoint was driven by the vasospasm-related delayed ischemic neurological deficit component (also called clinical deterioration due to delayed cerebral ischemia). This endpoint which captures the immediate clinical manifestations of post-aSAH cerebral ischemia was selected as the primary endpoint of the REACT study. The previous studies also identified a population of patients who have a high risk for vasospasm-related ischemic complications because of extensive cisternal clot burdens at admission [31, 35]. This finding was used to implement a high-risk patient enrichment strategy in the REACT study to maximize the overall benefit/risk profile. The safety profile of clazosentan has been well-documented in past studies and the adverse events which are commonly reported for selective endothelin-A receptor antagonists (e.g., fluid retention and hypotension) are identified and can be managed following specific treatment guidelines.
The REACT study protocol is detailed in anticipation of the upcoming study results.
Study aim, design, and setting
The primary goal of the REACT study is to determine the efficacy of clazosentan in preventing clinical deterioration due to DCI up to 14 days post-study drug initiation. Secondary objectives include the evaluation of the effect of clazosentan on the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation and the impact on the long-term clinical outcome and cognition at Week 12, and on quality of life at Week 12 and 24 post-aSAH. The assessment of safety and tolerability up to 24 hours after study drug discontinuation is also a secondary objective. In addition, the study evaluates the effect of clazosentan on healthcare resource utilization.
REACT is a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group, phase 3 study. It aims to enroll 400 patients with aSAH from a ruptured brain aneurysm at approximately 100 sites (list available on Clinicaltrials.gov) in approximately 15 countries. After randomization to clazosentan vs. placebo, patients enter a double-blind treatment period for a maximum duration of 14 days, which is followed by a safety follow-up period of 24 hours, preceding any hospital discharge. The extended follow-up period includes an on-site visit 12 weeks after the aSAH, and a telephone interview 24 weeks after the aSAH (end-of-study visit) for safety and efficacy assessments (Fig. 1).
The REACT study enrolls a population of patients at high risk of developing cerebral vasospasm and DCI because they are required to have large amounts of subarachnoid blood at hospital admission based upon CT findings. The patients should have thick and diffuse clot, defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more basal cisterns (Additional file 2) . This enriched population is likely to present with greater vasospasm-related morbidity than the broader aSAH population, which has been investigated so far. A second group of high-risk patients, which included those patients who had already developed vasospasm with no significant neurological deterioration, was initially planned by protocol. However, recruitment into this so-called ‘Early Treatment group’ was discontinued because inclusion rates were low, making the contribution of these patients to the overall study futile (Additional file 3).
The inclusion and exclusion criteria are listed in Table 1 and Table 2, respectively.
Patient screening and randomization
The screening period starts with the signature of the informed consent form (Additional file 4) by the patient and/or his/her legally designated representative/proxy. If neither the patient nor his/her legally designated representative/proxy can sign the consent form, a deferral of consent process may be followed if allowed by local regulations and if study-specific approval is previously received. If the patient is not able to provide personal consent at the time the consent is obtained, then he/she must provide this consent as soon as possible once his/her clinical condition has improved to the extent that providing personal consent is possible, unless local regulations state otherwise. The screening period ends with randomization occurring within 96 hours after aSAH. Patients are randomized 1:1 to clazosentan or placebo, and they are stratified by World Federation of Neurological Societies (WFNS) grade (1–2 versus 3–5) and age at hospital admission (≤ 60 and > 60 years), which are both recognized factors for unfavorable outcome . Randomization is performed by the Interactive Response Technology system, which allocates a medication to the patient.
Patients receive clazosentan or placebo as a continuous 15 mg/hour intravenous (i.v.) infusion for up to 14 days with a minimum of 10 days, on top of the usual standard of care for the management of aSAH. The study drug infusion is administered in an intensive care unit in parallel to the administration of hemodynamic therapy as per the Patient Management Guidelines (Additional file 5). This study is performed in a double-blind fashion; the investigators and the personnel involved in the conduct of the study remain blinded to the study treatment received by the patients during the double-blind treatment period until study closure. The identity of the study treatment may be revealed (through the Interactive Response Technology system) only if the patient experiences an emergency medical event, the management of which would require knowledge of the blinded treatment assignment. Although the decision to unblind resides solely with the investigator, discussion with the Sponsor prior to any unblinding is recommended.
Study drug interruption/discontinuation
Study drug may be temporarily interrupted in response to an adverse event, a diagnostic or therapeutic procedure, a laboratory abnormality, or for administrative reasons. The Patient Management Guidelines (Additional file 5) also recommend temporarily interrupting study drug when the target blood pressure cannot be achieved (after the discontinuation of nimodipine, if applicable) or when pulmonary ventilation/perfusion ratio mismatch is suspected (or is persistent despite discontinuation of nimodipine, if applicable). Interruptions of study treatment should be kept as short as possible.
Study treatment may be discontinued in response to an adverse event, lack of efficacy (including disease progression, worsening of patient’s condition), a protocol deviation (including eligibility failure, non-compliance with study requirements), a diagnostic or therapeutic procedure, a laboratory abnormality, or for administrative reasons.
Allowed concomitant therapy
The usual standard of care for the management of aSAH, including oral or i.v. nimodipine, is allowed except for those therapies considered forbidden as described below. “Statins” (e.g., simvastatin, pravastatin) may only be administered if the patient was receiving them chronically for treatment of high cholesterol. Urgent endovascular rescue therapy for the treatment of refractory vasospasm (i.e., balloon angioplasty, intra-arterial/intrathecal/intracisternal/intraventricular vasodilators) can be administered at any time during the treatment period for refractory vasospasm but requires temporary interruption of study drug. Intravenous administration of vasodilators (e.g., nicardipine, milrinone) are allowed as rescue therapy only if preceded by intra-arterial administration of a vasodilator.
Vaccines (including those for Coronavirus disease 2019 [COVID-19]) may be administered at any time during the study.
The following treatments are not allowed until the primary endpoint is assessed due to their potential to interfere with the evaluation of efficacy or safety, or due to the potential for a drug-drug interaction with study drug: intra-aortic balloon device; lumbar and/or cisternal drainage for the prevention of cerebral vasospasm and/or DCI; i.v. milrinone, i.v. nicardipine (may be used for blood pressure control), and intrathecal/intra-cisternal/intra-ventricular vasodilators (e.g., nimodipine); i.v. magnesium, i.v. albumin, or plasma volume expander if administered specifically for the prevention of vasospasm and/or DCI; thrombolytics (except to open an occluded drain) and antifibrinolytics; i.v. hypertonic saline (in the absence of hyponatremia, brain edema, or high intracranial pressure [ICP]); i.v. mannitol (in the absence of brain edema or high ICP); strong inhibitors of organic anion transporting polypeptide (OATP)1B1 and OATP1B3 transporter proteins; other endothelin receptor antagonists; any investigational drugs, procedures, or devices; traditional medicines.
The primary efficacy endpoint (adjudicated by an independent Clinical Event Committee (CEC)) is the occurrence of clinical deterioration due to DCI, from 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 on the modified Glasgow Coma Scale (mGCS) or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which cannot be entirely attributed to causes other than cerebral vasospasm (Appendices 3 and 4).
Patients who die between study drug start up to and including 14 days post-study drug initiation are considered as presenting with clinical deterioration due to DCI. Patients who cannot be evaluated for neurological status at any time during this same period are considered as presenting with clinical deterioration due to DCI if either rescue therapy was administered for a relevant vasospasm or the reason for not being evaluable is vasospasm related.
Patients who are discharged from the study site prior to Day 14 post-study drug initiation have a follow-up visit or telephone call, covering their clinical status between discharge and Day 14 post-study drug start. If this follow-up reveals that the patient was re-hospitalized or transferred to another facility, and DCI cannot be ruled out as a primary or contributing cause, the patient is considered as meeting the primary endpoint. If a patient has less than 14 days of neurological scales available and there is an absence of follow-up information (including patients withdrawn from the study during the observation period) the primary endpoint is assessed based on the totality of available clinical data.
The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation defined as all cause cerebral infarction ≥ 5 cm3 or cerebral infarction < 5 cm3 in patients with clinical deterioration due to DCI. This definition was updated following protocol amendment (Additional file 3).
Cerebral infarction refers to new or worsened infarcts and is determined by central radiology review, comparing the total volume of infarcts on the CT scan performed 16 days after study drug initiation with the total volume on the CT scan performed just prior to randomization. If the CT scan cannot be performed on Day 16, then it is acceptable for the CT to be performed within 7 days following Day 16. If a patient is discharged from the hospital prior to Day 16, the CT scan is performed on the day of hospital discharge. Clinical deterioration due to DCI and cerebral infarctions ≥ 5 cm3 are confirmed by the CEC. Cerebral infarctions < 5 cm3 in patients with clinical deterioration due to DCI are derived from both the CEC data (primary endpoint) and the Independent Radiology Committee (IRC) data (for infarct size).
Other secondary endpoints include long-term clinical outcome, assessed at Week 12 post-aSAH by the modified Rankin scale (mRS)  dichotomized into poor outcome (score ≥ 3) and good outcome (score < 3) and the Glasgow Outcome Scale-Extended (GOSE) , dichotomized into poor outcome (score ≤ 4) and good outcome (score > 4).
Exploratory efficacy endpoints
Exploratory endpoints include cognitive status assessed with the Montreal Cognitive Assessment (MoCA; values at Day 14 after study drug initiation and at Week 12 post-aSAH, changes from baseline to Day 14 and to Week 12, and changes from Day 14 to Week 12).
Other efficacy endpoints include the number of episodes of clinical deterioration due to DCI from study drug initiation up to 14 days post-study drug initiation, and the occurrence of all-cause new or worsened cerebral infarction ≥ 5 cm3 in total volume (initially planned as main secondary endpoint, see Additional file 3), as adjudicated by the CEC.
Quality of life endpoints
Quality of life endpoints are assessed with 2 generic instruments including the EQ-5D (values at Week 12 post-aSAH, at Week 24, and change in index score and visual analog scale from Week 12 to Week 24) and the Oxford Participation and Activities Questionnaire (Ox-PAQ; values at Week 12). Quality of life is also evaluated with the Stroke Specific Quality of Life (SS-QOL; values at Week 12).
The pharmaco-economic endpoints describe the number and type of episodes of rescue therapy, and the number and type of specific medical treatments and therapies from randomization up to hospital discharge and from hospital discharge up to Week 12 post-aSAH. The length of initial and total intensive care unit stay, the length of total hospitalization, and duration in different hospital/institutional care units are recorded from randomization up to hospital discharge and from hospital discharge up to Week 12. The intensity of rehabilitation care up to Week 12 post-aSAH, the first post-hospital discharge location, and the duration of home care support post-initial hospital discharge are documented. The employment status is collected at Week 24 post-aSAH.
The area under the plasma concentration-time curve of the S100b protein from baseline to Day 10 and 14 post-study drug initiation is to be calculated. The S100b protein has emerged as a brain ischemia biomarker that is implicated in the pathogenic process of aSAH .
The safety endpoints include the occurrence of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of specific interest (i.e. pulmonary complications, hypotension, anemia, cerebral hemorrhage, cerebral edema, fluid retention, hepatic disorders, tachyarrhythmia), and treatment-emergent marked laboratory abnormalities up to 24 hours after study drug discontinuation (along with changes from baseline to end of study drug administration for selected centrally assessed laboratory parameters). TEAEs leading to premature discontinuation of study drug and death (all causes) up to week 24 post-aSAH are to be collected. The occurrence of rescue therapy-specific adverse events up to hospital discharge (or up to week 12, whichever is earlier) is also documented.
An overview of the timing of the assessments is presented in Table 3. For those patients who cannot return to the investigational site for the 12-week visit, the GOSE and quality of life assessments are conducted by telephone and post, respectively. Depending on local regulations, a study staff member from the investigative site may also conduct the week 12 visit at the patient’s place of residence. If the 24-week (end-of-study) visit cannot be conducted as a telephone interview, the patient is asked to return the completed data collection forms by post.
Glasgow Coma Scale (GCS) and modified Glasgow Coma Scale (mGCS)
The GCS (Additional file 6) describes levels of consciousness by testing eye opening, verbal, and motor response . The highest score (fully awake) is 15 and the lowest 3. If the motor response in the left and the right arm are not the same, then the best score out of the two scores is used to determine the total GCS score. The mGCS (Additional file 6) is used in conjunction with the aNIHSS (see below) to detect episodes of clinical deterioration due to DCI [42, 43]. It is performed the same way as the GCS. However, the worst motor response is used to enable the detection of any new focal deficits from one assessment to the next.
Abbreviated National Institutes of Health Stroke Scale (aNIHSS)
The aNIHSS (Additional file 7) is a measure of limb movement and strength and it only includes the motor section of the full NIHSS, which is a tool used to objectively quantify the impairment caused by a stroke . Four separate scores from 0 (best) to 4 (worst) are determined for each limb. The total score ranges from 0 (best) to 16 (worst).
Glasgow Outcome Scale-Extended (GOSE) and modified Rankin Scale (mRS)
The combined GOSE /mRS structured interview (Additional file 8) measures functional outcome and dependency with minimum bias and high inter-rater reliability [38, 39]. The GOSE score ranges from 1 (dead) to 8 (upper good recovery) and the mRS score from 0 (no symptoms) to 6 (dead).
World Federation of Neurological Societies (WFNS) grade
The WFNS grade is a clinical measure of disease severity; it is determined from the GCS score and the presence of motor deficit .
Oxford Participation and Activities Questionnaire (Ox-PAQ)
The Ox-PAQ is a patient-reported outcome measure, which assesses generic health-related quality of life . The instrument evaluates the ability of individuals to engage in activities (such as work, hobbies, daily routines) and the level of dependency an individual has on others. It is comprised of 23 questions that cover 3 domains (routine activities, emotional well-being, and social engagement). If the patient is unable to complete the questionnaire it is not completed by a proxy.
The EQ-5D is a patient-reported outcome measure developed to assess generic health-related quality of life . It is composed of 5 domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a visual analog scale assessing overall health. The 5L version is used. If the patient is unable to complete the questionnaire, a proxy (e.g., family member, caregiver, close friend) is asked to complete the questionnaire.
Height, weight, vital signs including intracranial pressure and central venous pressure (if monitored), body temperature, fluid balance, electrocardiogram parameters, laboratory test results are collected according to the schedule provided in Table 3. In case of episodes of clinical deterioration, a blood sample is drawn as close as possible to the time of the initial neurological deterioration, but no later than 1 hour after the confirmation of the deterioration or within 3 hours after the initial worsening. Serum sodium, creatinine, and arterial blood gases (arterial oxygen saturation, partial pressure of carbon dioxide and oxygen in arterial blood) and pH (if the patient is intubated/ventilated) must be included as a minimum. Adverse events and serious adverse events are collected throughout the study.
Four null hypotheses are tested according to a fixed sequence procedure (primary endpoint, main secondary endpoint, other secondary endpoints -mRS then GOSE-) at the two-sided significance level of 0.05 until first non-rejection.
Analyses of the study variables
The primary statistical analysis is performed on the full analysis set, which includes all patients from the randomized analysis set who have started the study treatment. This is in accordance with the intention-to-treat principle as a) randomized but untreated patients are rare and b) the decision whether or not to begin treatment cannot be influenced by knowledge of the assigned treatment. The primary endpoint is analyzed using a Cochran-Mantel-Haenszel test, stratified on WFNS grade (1–2 versus 3–5) and age at hospital admission (≤ 60 and > 60 years). The treatment effect (clazosentan versus placebo) is expressed in terms of odds ratios and also in terms of relative risk reduction of the active arm compared to placebo with corresponding 95% confidence limits.
Supportive analyses include logistic regression to estimate the treatment effect after adjusting for WFNS grade and age at hospital admission. Subgroup analyses are conducted for WFNS grade and age at hospital admission.
Similar analyses are performed for the primary and secondary efficacy endpoints.
The safety analysis provides descriptive statistics for each treatment arm.
No interim analyses are planned in this study.
The sample size is derived from the assumption that the true incidence of clinical deterioration due to DCI up to 14 days after study drug initiation is 28% in the placebo arm and 14% in the clazosentan arm ; a sample size of 176 patients in each treatment arm has 90% power to show the superiority in response of clazosentan compared to placebo using Pearson’s χ2 test with a 5% two-sided significance level. When taking an approximate 10% drop-out rate into account, 400 patients have to be enrolled in the study, with 200 patients randomized to each treatment arm.
Handling of missing data
The CEC provides a final assessment (yes or no) on the primary endpoint, indicating for each patient whether it has been met, therefore it is assumed that there are no missing data for the primary endpoint. In addition, the CEC distinguishes between the cases of clinical deterioration due to DCI and the cases imputed according to the substitution rules described for the primary endpoint.
The CEC provides a final assessment (yes or no) on the first component of the main secondary endpoint (infarcts ≥ 5 cm3), indicating for each patient whether it has been met and distinguishing between the true cases of cerebral infarction ≥ 5 cm3 and imputed cases (as per CEC charter). Regarding the second component, patients who met the primary endpoint as per CEC but with missing CT scan at Day 16 are considered to have met the secondary endpoint (i.e., the worst possible outcome is assumed).
Changes to the protocol
Changes to the protocol occurring after study start are listed in Additional file 3. Most importantly, the main secondary endpoint definition was updated to include clinically relevant infarcts < 5 cm3 in addition to all-cause infarcts ≥ 5 cm3 (as initially planned) at day 16 post-study drug initiation. The latter is to be analyzed as an exploratory endpoint. The mRS was formally included in the statistical hierarchical testing strategy, just before the GOSE.
Exceptional measures to ensure patient safety and counteract potential trial conduct disruption due to the COVID-19 pandemic
As a consequence of the Coronavirus disease 2019 (COVID-19) declared a pandemic by the World Health Organization (WHO) on 11 March 2020, Idorsia put the recruitment for the REACT study on hold temporarily, on 19 March 2020.
All protocol deviations related to the COVID-19 crisis are to be identified and tracked. This will allow, at the end of the trial, a reconstruction of the impact that such deviations had on the trial integrity and interpretability.
In case of logistical restrictions due to the COVID-19 pandemic, it is possible to postpone the Week 12 assessments up to Week 24 (at the latest) and to perform the safety follow-up of ongoing adverse event in an alternative hospital or local laboratory. It is reminded that if OATP inhibitors are used (e.g., for the treatment of a patient with COVID 19) then study drug must be permanently discontinued as per study protocol. It is possible to perform remote monitoring and source data verification if allowed locally, otherwise alternatives may be agreed with the principal investigator to ensure data integrity.
An Independent Data Monitoring Committee is responsible for monitoring unblinded safety and efficacy data at regular intervals.
An Independent Radiology Committee (IRC) composed of radiologists, who are independent from the study sponsor and blinded to treatment allocation, review all angiograms and CT scans to document and quantify specific radiological findings including clot size, cerebral vasospasm, and cerebral infarction.
An Independent Clinical Event Committee (CEC) composed of clinicians with expertise in aSAH, who are blinded to treatment allocation, determine whether the primary endpoint and the main secondary endpoints have been met. This committee reviews clinical and imaging data from all patients to determine which cases fulfill the definition of clinical deterioration due to DCI. It also adjudicates cases for the presence of a new or worsened cerebral infarct ≥ 5 cm3 based on the central review of CT scans performed by the IRC or other available data when the CT scan is missing at day 16 post-study drug initiation. Cerebral infarcts < 5 cm3 in patients with clinical deterioration due to DCI are derived from both the CEC data (primary endpoint) and IRC data (for infarct size).
Committee charters are available from the corresponding author upon reasonable request once trial results are published.
Data from source documents are reported in the patient electronic case report form using electronic data capture. Results from laboratory analyses are electronically sent to the sponsor. Adverse events and medical history are coded according to the latest Medical Dictionary for Regulatory Activities (MedDRA™) version used by the sponsor. Medications are coded according to the latest WHO Drug Dictionary version used by the sponsor.
All data and documentation related to the trial are stored on site for as long as is necessary to comply with the sponsor’s requirements and national and/or international regulations. Access to data is restricted to authorized trial personnel.
The sponsor representatives may audit the investigator site.
The planned recruitment of 400 patients was reached in May 2022 and the study was completed in November 2022.
Delayed cerebral ischemia contributes significantly to poor outcome after aSAH  and there is a high medical need for improved treatment options to avoid brain infarction, neurological complications and the need for additional endovascular therapy. Clazosentan has been shown to reduce the incidence and severity of cerebral vasospasm and to decrease vasospasm-related morbidity at 6 weeks, in patients with aSAH [29, 30, 32,33,34]. The effect of clazosentan on vasospasm-related morbidity is particularly noticeable in the patients who present with large amounts of blood clots on the initial CT scan , which has been associated with an increased risk for DCI and cerebral infarction . The objective of this ongoing, multicenter, randomized REACT study is to focus on in-hospital clinical deterioration due to DCI, assessed by central adjudication, in an enriched high-risk population including patients with thick and diffuse blood clots at admission. The clazosentan development program has shown that the clinical effect of clazosentan on vasospasm-related events is dose dependent and the 15 mg/hour dose, which was identified in global studies [29, 33] as the most efficacious dose when compared with the 1 and 5 mg/hour doses, is to be evaluated in the REACT trial.
The primary efficacy endpoint of the trial is the occurrence of clinical deterioration due to DCI, from study drug initiation up to 14 days post-study drug initiation. It is defined as a sustained worsening in neurological status that cannot be entirely attributed to causes other than cerebral vasospasm consistent with the recommendations of international multi-disciplinary aSAH research groups [42, 43]. The extension of the duration of the deterioration to 2 hours in the REACT protocol excludes transient fluctuations in clinical status and thus increases the robustness of the endpoint definition. The assessment period for the primary endpoint extends until 14 days after the initiation of treatment, thus covering the treatment period, and corresponding to the period during which DCI is most likely to occur. The proposed primary endpoint captures the most important clinical manifestations of post-aSAH cerebral ischemia that can be prevented by an anti-vasospastic treatment. This clinically relevant endpoint is predictive of cognitive impairment, quality of life deterioration, and poor long-term outcome [7, 15, 52,53,54]. Therefore, showing a significant reduction in the incidence of clinical deterioration due to DCI, supported by clinically relevant effects on the secondary and exploratory endpoints, is expected to demonstrate the clinically meaningful benefit of clazosentan in this disease indication.
The main secondary endpoint in the REACT study is the occurrence of clinically relevant cerebral infarction, a known complication of aSAH, which has been repeatedly shown to be a strong predictor of poor long-term clinical outcome [7, 55, 56]. A post-hoc analysis of the data from the CONSCIOUS-2 and CONSCIOUS-3 studies demonstrated that infarcts with a total cumulative volume ≥ 5 cm3 are mostly related to vasospasm and have a high association with poor clinical outcome at 3 months, as compared to those with a cumulative volume less than 5 cm3 . Therefore, the secondary endpoint definition as initially defined (all-cause new or worsened cerebral infarction of a total volume ≥ 5 cm3) only included those infarcts ≥ 5 cm3 in order to set a meaningful cut-off for infarct volume when considering all infarcts irrespective of cause. Since the determination of underlying infarct etiology based on CT scan assessment is often challenging, the 5 cm3 threshold serves as a proxy for vasospasm-related stroke. This endpoint also allowed the identification of ischemic events that are not detectable on clinical examination or that develop in patients who cannot be evaluated neurologically (e.g., due to sedation or very poor clinical status). However, routine blinded monitoring of the event rate during the REACT study revealed a lower-than-expected incidence of infarcts ≥ 5 cm3, resulting in insufficient power to detect a treatment effect. This led to an expansion of the endpoint definition to include cerebral infarcts < 5 cm3 if they occur in patients with clinical deterioration due to DCI. Although the infarcts < 5 cm3 have a lower association with vasospasm and prognosis, their vasospastic origin and their contribution to poor outcome cannot be completely excluded [58, 59]. Therefore, they are included in the secondary endpoint as long as DCI is present to avoid the inclusion of irrelevant infarcts, causing dilution of the treatment effect, as seen in the CONSCIOUS-1 trial .
Despite being correlated with the primary efficacy endpoint, the main secondary endpoint goes beyond clinical symptoms since deterioration due to DCI does not always result in the development of cerebral infarction. Conversely, cerebral infarction may be observed on a CT scan in the absence of clinical symptoms in up to 20% of aSAH patients [10, 60]. The assessment of this endpoint at day 16 post-study drug initiation allows for the detection of infarcts that may be the consequence of cerebral ischemia that occur up to day 14 (primary endpoint evaluation is up to day 14).
The other secondary endpoints of the REACT study are the mRS and GOSE scores at Week 12, which assess long-term clinical outcome. These scores have been chosen as secondary, rather than primary efficacy endpoints, because they are strongly driven by the initial hemorrhage and the complications of the aneurysm treatment procedure , on which clazosentan has no expected impact. However, the absence of a negative trend on these assessments would be an important part of the overall benefit/risk assessment of clazosentan in patients with aSAH. This justifies the use of mRS and GOSE as other secondary endpoints. The mRS has recently been recommended over the GOSE as the preferred scale for measuring the long-term clinical outcome of SAH by the international clinical experts of the SAH common data elements working group . Therefore, in REACT, the mRS was raised above the GOSE in the statistical hierarchical testing strategy, after protocol amendment (Additional file 3).
Finally, the REACT protocol includes a series of cognitive tests and patient reported outcome tools performed at 12 and/or 24 weeks after the aSAH with the objective to capture most of the aSAH-associated long-term disability.
A key feature of the REACT study is the enrolment of a selected population with a high risk of developing vasospasm-related ischemic complications. This risk is correlated with the amount of blood on the initial CT scan . Thus, the inclusion of patients who present with thick and diffuse clot at hospital admission is expected to increase the occurrence of clinical deterioration due to DCI, allowing the conduct of the study with a reasonable sample size. In the post-hoc analyses of the placebo arm of the CONSCIOUS-2, and CONSCIOUS-3 studies, the patients with thick and diffuse clot at admission, who represented approximately 50% of the overall patient population, had significantly increased risks for DCI and cerebral infarction (relative risk: 2.6 and 2.3, respectively, after adjustment for WFNS at admission) compared with the patients who had a lower amount of blood on the initial CT scan . These high-risk patients benefited most from clazosentan treatment and their relative risk for clinical deterioration due to DCI was significantly reduced by 57% compared with placebo . The REACT study design, which is based on an enriched population, focuses on those patients who are most likely to benefit from clazosentan. In addition, exclusion of patients with hypotension or hypoxia and protocol guidelines on hemodynamic management should reduce the frequency of clazosentan-related main adverse effects. Thus, the REACT study aims at assessing the benefit/risk profile of clazosentan in patients at high risk of vasospasm-related ischemic complications post-aSAH.
Clazosentan is known to reduce the occurrence and severity of vasospasm occurring after aSAH and was recently shown to decrease the combined incidence of vasospasm-related morbidity and all-cause mortality in two phase 3 studies conducted in Japan. The ongoing REACT study further investigates whether clazosentan can prevent the clinical deteriorations due to DCI and improve long-term outcome in an enriched patient population at high risk of vasospasm-related ischemic events.
Availability of data and materials
After completion of the study, the sponsor will post the summary of results within the required timelines on publicly accessible databases, as required by law and regulation. The study protocol and statistical analysis plan will be available at ClinicalTrials.gov.
The results of the study will be submitted for publication in a peer-reviewed journal. Authors of supported publications involving the REACT trial will have full access to available study data. There are currently no plans to share individual patient data.
Abbreviated National Institutes of Health Stroke Scale
Aneurysmal subarachnoid hemorrhage
Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage
Coronavirus disease 2019
Delayed cerebral ischemia
Glasgow Outcome Scale-Extended
(Modified) Glasgow Coma Scale
Modified Rankin Scale
Montreal Cognitive Assessment
Organic anion transporting polypeptide
Oxford Participation and Activities Questionnaire
PRevention and trEatment of vAsospasm with ClazosenTan
Stroke Specific Quality of Life
Treatment-emergent adverse events
World Federation of Neurological Societies
World Health Organization
Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43:1711–37.
Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8:635–42.
Frontera JA, Fernandez A, Schmidt JM, Claassen J, Wartenberg KE, Badjatia N, et al. Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke. 2009;40:1963–8.
Dankbaar JW, Rijsdijk M, van der Schaaf IC, Velthuis BK, Wermer MJ, Rinkel GJ. Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology. 2009;51:813–9.
Rigante L, van Lieshout JH, Vergouwen MDI, van Griensven CHS, Vart P, van der Loo L, et al. Time trends in the risk of delayed cerebral ischemia after subarachnoid hemorrhage: a meta-analysis of randomized controlled trials. Neurosurg Focus. 2022;52:E2.
Brami J, Chousterman B, Boulouis G, Dorze ML, Majlath M, Saint-Maurice JP, et al. Delayed cerebral infarction is systematically associated with a cerebral vasospasm of large intracranial arteries. Neurosurgery. 2020;86:e175–83.
Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G, et al. European stroke organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis. 2013;35:93–112.
Petruk KC, West M, Mohr G, Weir BK, Benoit BG, Gentili F, et al. Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial. J Neurosurg. 1988;68:505–17.
Hayashi K, Hirao T, Sakai N, Nagata I, group J-Ns. Current status of endovascular treatment for vasospasm following subarachnoid hemorrhage: analysis of JR-NET2. Neurol Med Chir (Tokyo). 2014;54(Suppl 2):107–12.
Kohno M, Yasunari K, Yokokawa K, Murakawa K, Horio T, Kanayama Y, et al. Thrombin stimulates the production of immunoreactive endothelin-1 in cultured human umbilical vein endothelial cells. Metabolism. 1990;39:1003–5.
Seifert V, Loffler BM, Zimmermann M, Roux S, Stolke D. Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage. Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma. J Neurosurg. 1995;82:55–62.
Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thome C, Ringel F, et al. Clazosentan (AXV-034343), a selective endothelin a receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg. 2005;103:9–17.
Fujimura M, Joo JY, Kim JS, Hatta M, Yokoyama Y, Tominaga T. Preventive effect of clazosentan against cerebral vasospasm after clipping surgery for aneurysmal subarachnoid hemorrhage in Japanese and Korean patients. Cerebrovasc Dis. 2017;44:59–67.
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10:618–25.
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43:1463–9.
Endo H, Hagihara Y, Kimura N, Takizawa K, Niizuma K, Togo O, et al. Effects of clazosentan on cerebral vasospasm-related morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients. J Neurosurg. 2022;137:1–11.
Mayer SA, Aldrich EF, Bruder N, Hmissi A, Macdonald RL, Viarasilpa T, et al. Thick and diffuse subarachnoid blood as a treatment effect modifier of Clazosentan after subarachnoid hemorrhage. Stroke. 2019;50:2738–44.
Aldrich EF, Higashida R, Hmissi A, Le EJ, Macdonald RL, Marr A, et al. Thick and diffuse cisternal clot independently predicts vasospasm-related morbidity and poor outcome after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2020;134:1–9.
Jaja BN, Cusimano MD, Etminan N, Hanggi D, Hasan D, Ilodigwe D, et al. Clinical prediction models for aneurysmal subarachnoid hemorrhage: a systematic review. Neurocrit Care. 2013;18:143–53.
Wilson JT, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, et al. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin scale. Stroke. 2002;33:2243–6.
Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41:2391–5.
Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, et al. A universal subarachnoid hemorrhage scale: report of a committee of the world federation of neurosurgical societies. J Neurol Neurosurg Psychiatry. 1988;51:1457.
Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–9.
Stienen MN, Geisseler O, Velz J, Maldaner N, Sebok M, Dannecker N, et al. Influence of the intensive care unit environment on the reliability of the Montreal cognitive assessment. Front Neurol. 2019;10:734.
Boosman H, Passier PE, Visser-Meily JM, Rinkel GJ, Post MW. Validation of the stroke specific quality of life scale in patients with aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2010;81:485–9.
Shen Y, Dong Z, Pan P, Shi H, Song Y. Risk factors for mild cognitive impairment in patients with aneurysmal subarachnoid hemorrhage treated with endovascular coiling. World Neurosurg. 2018;119:e527–e33.
Roux S, Kovats D, Mayer SA. Impact of infarct aetiology on lesion size and clinical outcome in high-risk patients for vasospasm with thick and diffuse aSAH (abstract). Paris: 11th EURONEURO Congress; 2021. p. 14–6. p. Poster no. 1016
Weidauer S, Lanfermann H, Raabe A, Zanella F, Seifert V, Beck J. Impairment of cerebral perfusion and infarct patterns attributable to vasospasm after aneurysmal subarachnoid hemorrhage: a prospective MRI and DSA study. Stroke. 2007;38:1831–6.
Schmidt JM, Wartenberg KE, Fernandez A, Claassen J, Rincon F, Ostapkovich ND, et al. Frequency and clinical impact of asymptomatic cerebral infarction due to vasospasm after subarachnoid hemorrhage. J Neurosurg. 2008;109:1052–9.
Zheng K, Zhong M, Zhao B, Chen SY, Tan XX, Li ZQ, et al. Poor-grade aneurysmal subarachnoid hemorrhage: risk factors affecting clinical outcomes in intracranial aneurysm patients in a multi-center study. Front Neurol. 2019;10:123.
Suarez JI, Sheikh MK, Macdonald RL, Amin-Hanjani S, Brown RD Jr, de Oliveira Manoel AL, et al. Common data elements for unruptured intracranial aneurysms and subarachnoid hemorrhage clinical research: a National Institute for neurological disorders and stroke and National Library of medicine project. Neurocrit Care. 2019;30:4–19.
The authors thank E. Maho and A Hmissi (Idorsia Pharmaceuticals Ltd.) for their contribution to the development of the statistical analysis plan.
The investigator/delegate must ensure that data confidentiality is maintained. On documents submitted to the sponsor or any vendors or Contract Research Organizations, patients must be identified only by number and never by their name or initials, date of birth, hospital numbers, or any other personal identifier.
This study is funded by Idorsia Pharmaceuticals Ltd. The study sponsor contributed to the design of the study and the writing of the manuscript. Editorial support was provided by Sylvie I. Ertel (Sundgau Medical Writers, France) and was funded by Idorsia Pharmaceuticals Ltd.
Authors and Affiliations
Department of Anesthesia and Critical Care, Hôpital de la Timone, Aix-Marseille Université, 264 rue St-Pierre, 13005, Marseille, France
Department of Neuro Interventional Radiology, University of California San Francisco Medical Center, San Francisco, USA
NB, RH, EFA, AM, SR and SM contributed to study design and protocol development, AM, SR, HSJ and CD developed and validated the statistical analysis plan, NB led the writing of the manuscript. All authors reviewed and approved the final manuscript.
The study is conducted in full compliance with the International Conference on Harmonization Good Clinical Practice Guideline, the principles of the Declaration of Helsinki, and the laws and regulations of the country in which it is performed. The REACT protocol and amendments have been approved by research ethics committees/institutional review boards in each participating investigational site (last amendment dated February 18, 2022, Additional file 3). It is the responsibility of the investigator to obtain written informed consent from all participants prior to enrolment in the study.
Consent for publication
NB, RH, EFA, and SAM have been consultants / scientific advisors for Idorsia Pharmaceuticals Ltd. and have received consulting fees.
HSJ, AM, and SR are employees of Idorsia Pharmaceuticals Ltd., and CD is an external contractor. Idorsia is the owner and developer of clazosentan.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glasgow Outcome Scale–Extended and Modified Rankin Scale.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Bruder, N., Higashida, R., Santin-Janin, H. et al. The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.
BMC Neurol22, 492 (2022). https://doi.org/10.1186/s12883-022-03002-8