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Table 3 Overview of study assessments

From: 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

PERIOD

Hospital admission

SCREENING Period

 

OBSERVATION Period (for 14 days post-study drug initiation irrespective of treatment duration)

24 h safety FU Period

Extended FU Period (From end of 24 h safety FU Period until EOS)

TREATMENT Period (min. 10, max. 14 days of treatment)

Timing / assessment

within 96 hours post-aSAH

for 14 days post-SD start

until 24 h post-SD stop

WEEK 12 VISIT

END OF STUDY (EOS)s

From ICF to randomization

Prior to study drug (SD) start

SD start

Daily in ICUh

During observation periodh

Worsening of ≥2 points on mGCS / aNIHSSh

End-of-Treatment (EOT)

84 days post-aSAH (± 7 d)

24 weeks (168 days ±14 days) post-aSAH

Informed consent

 

X

        

Demographics

 

X

       

Medical history

 

X

X

      

Incl./Excl. criteria

 

X

       

Height, weight

 

X

       

Vital signs (BP, HR, ICPa, CVPa)

  

X (within 60 min)

q6h (± 1 h)

q6h (± 1 h) (every 12 h if not in ICU)

    

Body temperature

  

X (within 60 min)

X (every 12 h ± 1 h)

    

Fluid balance (24 h)p

  

X

X

     

ECG parameters

  

X (within 60 min)

Xi

X (within 2 h post-SD stop)

  

Laboratory tests (local [l]/ central [c])

 

X (l)

X (c) (within 60 min)

Xj (c) (EOD for 14 days)

X (l) / SpO2

Xj (c) (within 2 h post-SD stop)

  

Biomarker

  

X (c) (within 60 min)

X (c) (EOD for 14 days)

X (c) if CNS cause

X (c) (within 2 h post-SD stop)

  

Pregnancy test

 

X (serum, (l))

     

X (urine)

 

Concomitant medicationsr

X

X

Non-drug treatments / interventions

  

X

X

WFNS

Xb

X, Xc

       

Total GCS

Xb

X, Xc

       

mGCS/aNIHSS

  

X (within 30 min)

q6hk (± 1 h)

Xl (± 1 h)

X (hourly ± 15 min for first 2 h)

   

Angiogram (DSA or CTA)

Xd

X (local standard of care, not assessed centrally)

   

X (if CNS cause)

   

CT scan

Xd

Xe

   

X (if CNS cause)

Xm (16 days post-SD start)

  

Subject narrative

     

X (14 days post-SD start)

   

MoCAf

 

Xg

 

X (14 ± 1 day post-SD start)q

  

X

 

GOSE

       

X

 

SS-QOL, Ox-PAQ

       

X

 

EQ-5D

        

X

X

Study drug administration

   

X

X

     

Adverse eventsn

 

X

 

X

Serious adverse eventso

 

X

X

Pharmaco-economic assessments

  

X

 

X

 

Employment status

     

X

  1. AE adverse event, aNIHSS abbreviated National Institutes of Health Stroke Scale, aSAH aneurysmal subarachnoid hemorrhage, BP blood pressure, CNS central nervous system, CT computerized tomography, CTA computerized tomography angiography, CVP central venous pressure, DSA digital subtraction angiography, ECG electrocardiogram, eCRF electronic case report form, EOD every other day, EOS End-of-Study, EOT End-of-Treatment, FU follow-up, GCS Glasgow Coma Scale, GOSE Glasgow Outcome Scale Extended, HR heart rate, ICF informed consent form, ICP intracranial pressure, ICU intensive care unit, mGCS modified Glasgow Coma Scale, MoCA Montreal Cognitive Assessment, Ox-PAQ Oxford Participation and Activities Questionnaire, SAE serious adverse event, SD study drug, SpO2 peripheral capillary oxygen saturation, SS-QOL Stroke Specific Quality of Life, WFNS World Federation of Neurological Societies
  2. aICP/CVP is measured and recorded for those patients with ICP and/or CVP monitoring in place
  3. bIf the patient was transferred from another hospital, the GCS score and WFNS grade correspond to the assessments made at the referral hospital, unless these were not done or not reliable
  4. cTwo assessments: post aneurysm-securing procedure and prior to randomization
  5. dIf performed at a referral hospital, is of acceptable quality, and is available in digital format at the investigational site at the time of screening, does not need to be repeated
  6. eThis CT scan is to be performed at least 8 hours after the aneurysm-securing procedure and within 24 hours prior to randomization
  7. fOnly performed if patient is GCS ≥ 13 and extubated (if applicable)
  8. gAs soon as possible after recovering from the aneurysm-securing procedure and prior to SD start
  9. hIf there is a worsening of at least 2 points in the mGCS and/or the aNIHSS the assessments in the “worsening” column must be performed on top of the regularly scheduled assessments. The mGCS and the aNIHSS must be repeated hourly for at least the first 2 hours after a 2-point worsening. If the deterioration is believed to be of CNS origin, a cerebral angiogram and a cerebral CT scan must be performed within 6 hours of the start of the symptoms and submitted for central review and a blood sample for S100b protein must be drawn within 1 hour of the confirmation of the neurological deterioration episode or no later than 3 hours from the initial worsening. Local lab tests should be obtained as close as possible to the time of the clinical worsening (max. 1 hour after time of confirmed worsening)
  10. iQT, QRS, PR, RR intervals, and HR are measured and recorded in the eCRF if patient experiences an AE related to cardiac rhythm abnormalities
  11. jAny clinically significant laboratory values must be reported as an AE/SAE as appropriate and those still abnormal at the time of the EOS assessment are followed up based on local routine standard of care. A local laboratory may be requested by the sponsor to document the event and its resolution, and the results recorded in the eCRF
  12. kAt least once per day for patients that require uninterrupted continuous sedation
  13. lAfter the end of the study drug infusion, the mGCS and aNIHSS continue to be assessed every 6 hours if the patient is still in the ICU (or equivalent ward), until 14 days after study drug initiation. They are assessed at least once per day if the patient requires continuous uninterrupted sedation. If the patient is no longer in the ICU (i.e., has been sent to a regular/general ward), the mGCS and aNIHSS are assessed at least once every 12 hours (± 1 h) until 14 days after study drug initiation. In the unavoidable situation where the patient is discharged from the study site before completing the observation period, their clinical status must be followed-up to cover the period between discharge and Day 14 post-study drug start. The follow-up should be performed on Day 14 post-study drug initiation or as soon as possible after. This follow-up is not required if the patient was discharged on Day 13 and there is at least one set of neurological assessment scales available on this day
  14. mIf the CT scan cannot be performed on the 16th day post-SD start, then it is acceptable if the CT scan is performed up to 7 days after Day 16. The CT scan is performed on the day of hospital discharge for those patients who are discharged from the hospital prior to 16 days after study drug start. If no CT scan is available at hospital discharge, the last CT scan performed prior to discharge may be used for this assessment
  15. nAll AEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other AEs are to be reported from SD initiation until 24 hours post-permanent SD discontinuation
  16. oAll SAEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other SAEs are to be reported from SD initiation until EOS. Waived SAEs do not require reporting to the sponsor’s Drug Safety department within 24 hours of the knowledge of its occurrence
  17. pApplicable during study drug administration only. Balance is captured if a urine catheter is present. Otherwise, 24-hour fluid intake is measured and recorded
  18. qThis MoCA is performed on the day of hospital discharge for those patients who are discharged from the hospital prior to 14 days after study drug start
  19. rFor details on the concomitant medication recording refer to text
  20. sThe EOS visit is conducted remotely as a telephone interview
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BMC Neurology

ISSN: 1471-2377

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