| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intraventricular haemorrhage |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bleeding in the spaces in the brain |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022840 |
| E.1.2 | Term | Intraventricular haemorrhage |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To define precisely the long-term effects of lysing ventricular blood clots with rt-PA on the functional outcomes of cerebral hemorrhage patients. We propose to test if this intervention promotes a recovery of function, as defined as a modified Rankin score of < 3 at 180 days post ictus, by facilitating more rapid clot resolution as compared to treatment with extraventricular drainage (EVD) with placebo. |
|
| E.2.2 | Secondary objectives of the trial |
| To test if mortality at 180 days is improved for subjects receiving rt-PA, if the amount of residual blood at 72 h correlates directly with the functional outcome at 180 days post bleed, and if rt-PA use in IVH patients leads to less intense ICU management, including fewer ICU days, shorter periods of CSF drainage, decreased intensity of ICP management, lower rate of needing permanent ventriculoperitoneal shunt, and fewer general critical care complications. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 18-80.
2. Symptom onset less than 24 hrs prior to diagnostic CT scan.
3. Spontaneous ICH ≤ 30 cc and IVH obstructing 3rd and/or 4th ventricles.
4. ICH clot stability: ICH must be ≤ 30 cc on initial presentation and not exceed 35 cc on subsequent pre-randomization stability scans. A CT scan performed 6 hours or more after IVC placement must be stable (difference is . 5 cc) compared to the most previous CT scan as determined by the (AxBxC)/2 method.
Temporary Criterion: If the clot is not stable (i.e., difference is > 5 cc), a repeat CT scan must be performed at least 6 hours later and compared to the most previous CT scan. Investigator may continue to screen every 12 hours up to 72 hours for the initial bleeding to stabilize, as long as the subject is able to be randomized within 72 hours of time of diagnostic CT scan and the clot remains ≤ 35 cc. If the size stabilizes (i.e., enlargement ≤ 5 cc between 2 sequential CT scans) and remains ≤ 35 cc,the patient is eligible.
5. IVH clot stability: The width of the lateral ventricle most compromised by blood clot must not increase by > 2 mm, allowing for movement of blood under influence of gravity.
Temporary Criterion: If the clot is not stable (i.e., difference is > 2 mm),
a repeat CT scan must be performed at least 6 hours later and compared
to the most previous CT scan. Investigator may continue to screen up to
72 hours for the initial bleeding to stabilize, as long as the subject is able
to be randomized within 72 hours of time of diagnostic CT scan. If the size stabilizes (i.e., enlargement ≤ 2mm between 2 sequential CT scans), the patient is eligible.
6. Catheter tract bleeding must be less than or equal to 5 cc on CT scan for stability.
Temporary criterion: If a catheter tract hemorrhage is present on the CT scan done 6 hours after IVC placement and is > 5 cc or > 5 mm, obtain a repeat CT scan 12 hours later. This includes any bleeding at the entry site or along the catheter tract that is 5 mm in diameter seen on any CT slice or is 5 mL on more than one CT slice. If the catheter tract hemorrhage further enlarges by > 5 cc or > 5 mm as compared to the most previous CT scan, the investigator may continue to screen by repeat CT scan every 12 hours for the bleeding to stabilize, as long as the subject is able to be randomized within 72 hours of time of diagnostic CT scan. If the size stabilizes (i.e., enlargement ≤ 5 cc or ≤ 5
mm between 2 sequential CT scans), the patient is eligible.
7. On stability CT scan, the 3rd and/or 4th ventricles are occluded with blood.
8. All patients randomized will have had EVD placed, ideally using no more than 2 complete passes (including "soft passes" using the original trajectory), on an emergent basis as defined by the "standard of care" neurosurgical/critical care decisions of the managing physicians. If more than 2 passes are required for placement, additional stabilization of IVC site will be determined with a CT performed at 24 hours after IVC placement.
Temporary criterion: If no IVC is in place at the time the patient is initially screened, the decision to place an IVC may occur after the patient is initially screened but an IVC must be in-place and stable at the time of randomization.
9. Patients with primary IVH are eligible (i.e. with ICH=0).
10. SBP < 200 mmHg sustained for the 6 h before drug administration
(closest to randomization).
Temporary criterion: Blood pressure inclusion criteria not met when the patient is screened: Most vital signs are stabilized within the time window for enrollment.
11. No test article may be administered until at least 12 hours after symptom onset.
12. Able to randomize within 72 h of CT scan diagnosing IVH (provided the time of symptom onset to diagnostic CT does not exceed 24 h).
Temporary criterion: The 72 hour limit may be extended with approval from the Coordinating Center to allow for clot stability (ICH, IVH, catheter tract), INR stability, or other valild reason.
13. Historical Rankin of 0 or 1. |
|
| E.4 | Principal exclusion criteria |
1. Suspected (unless ruled out by angiogram or MRA/MRI) or untreated ruptured cerebral aneurysm, ruptured intracranial AVM, or tumor. Treatment of an existing aneurysm or AVM must have occurred at least 3 months before the current onset.
Temporary criterion: This is especially important in primary IVH, when no ICH source is found. CT angiogram, angiogram, MRA/MRI, or general diagnostic study (prior to confirming patient eligibility in the protocol) is standard of care to rule out underlying etiology. If the CT angiogram, angiogram or MRA/MRI is negative, the patient is eligible. The PI must document rationale if imaging is not done.
2. Presence of a choroid plexus vascular malformation or Moyamoya disease.
3. Clotting disorders. Subjects requiring long-term anti-coagulation are excluded.
Temporary criterion: Reversing anticoagulation will be permitted where long-term anticoagulation is not required.
4. Use of Dabigatran, Apixaban, and/or Rivaroxaban (or a medication from the same medication class) prior to symptom onset.
5. Platelet count < 100,000, INR > 1.4.
Temporary criterion: Low platelet counts etc. on admission can normalize within 24 hours as can an INR normalize to < 1.4.
6. Pregnancy (positive serum or urine pregnancy test).
7. Infratentorial hemorrhage
8. Thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non-reactive pupils. Other (supranuclear) gaze abnormalities are not an exclusion. Note: Patients with a posterior fossa ICH or cerebellar hematomas are ineligible.
9. SAH at clinical presentation (an angiogram (angiogram, CTA, MRA/MRI) must be obtained when the diagnostic CT scan shows SAH or any hematoma location or appearance not strongly associated with hypertension. If the angiogram or other imaging does not detect a bleeding source to account for the hemorrhage, the patient is eligible for the study.) Subsequent appearance of cortical SAH secondary to clot lysis is not a dosing endpoint.
Temporary criterion: An angiogram must be obtained when the diagnostic CT scan demonstrates subarachnoid hemorrhage or any hematoma location suggestive of aneurysm or appearing not strongly associated with hypertension. If the angiogram/imaging does not demonstrate a bleeding source that accounts for the hemorrhage, the patient is eligible for the study.
10. ICH/IVH enlargement that cannot be stabilized in the treatment time window.
Temporary criterion: ICH enlargement during the 6-hour stabilization period (6 hours after IVC placement): It is permitted to screen up to 72 hours after diagnostic scan. If the ICH clot size stabilizes (i.e., enlarges no more than 5 cc) and does not exceed 35 cc (an ICH clot size of 35 cc allows for stabilization of a 5cc expansion for those patients at the upper limit of the ICH clot size limit), the patient is eligible.
11. Ongoing internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts. (Patient with prior bleeding that is clinically stable for 12 h or more without any coagulopathy or bleeding disorder is eligible).
12. Multi-focal, superficial bleeding, observed at multiple vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or site of recent surgical intervention.
13. Prior enrollment in the study.
14. Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated. Subjects who are not expected to survive to the day 180 visit due to co-morbidities and/or are DNR/DNI status prior to randomization are excluded.
Temporary criterion: Although these situations are often irreversible, under other conditions, change can occur over 24 hours.
15. Planned or simultaneous participation (between screening and Day-30) in another interventional medical investigation or clinical trial. Patients involved in observational, natural history, and/or epidemiological studies not involving an intervention are eligible.
16. No subject or legal representative to give written informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Dichotomized mRS 0-3 vs. 4-6 at 180 days |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Additional mRS Dichotomizations at 180 days (0-4 vs 5-6).
2. Ordinal mRS (0 – 6).
3. Mortality and Safety Events at 30 days.
4. Mortality at 180 days.
5. Functional Status: NIHSS, Barthel Index, GOS, extended GOS, mRS,
Personal Health Utility Assessment Interview.
6. Type and Intensity of ICU Management: ICU days, CSF drainage time,
ICP management intensity, EVD weaning time, number of critical care
complications.
7. Rate and extent of ventricular blood clot removal based on CT Imaging.
8. Quality of Life: Stroke Impact Scale, EQ-5D, PBSI, LOS (acute care + rehab); time at home during first 180 days. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 72 hours; 1, 3, 6, 9, and 12 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Canada |
| Germany |
| Hungary |
| Israel |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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