PDF: ALISAH
(2012)Objective
To investigate the safety and tolerability of 25% human albumin in patients with subarachnoid hemorrhage and determine the maximum tolerated dose
Study Summary
• Outcomes trended toward better responses in Tier 2 (1.25 g/kg) compared to Tier 1 (OR 3.05) and IHAST cohort (OR 3.15)
• Higher doses (1.875 g/kg) were associated with pulmonary edema, leading to early study termination
Intervention
25% human albumin administered intravenously daily for 7 days at escalating doses: Tier 1 (0.625 g/kg/day), Tier 2 (1.25 g/kg/day), Tier 3 (1.875 g/kg/day), and planned Tier 4 (2.5 g/kg/day)
Inclusion Criteria
Adult patients with aneurysmal subarachnoid hemorrhage treated within 72 hours of symptom onset, aneurysm secured, no stupor or coma, age <80 years
Study Design
Arms: Three dose escalation tiers: Tier 1 (0.625 g/kg/day), Tier 2 (1.25 g/kg/day), Tier 3 (1.875 g/kg/day)
Patients per Arm: Tier 1: 20, Tier 2: 20, Tier 3: 7
Outcome
• Glasgow Outcome Scale 0-1 at 3 months: Tier 1 65%, Tier 2 85%, Tier 3 43%
• Modified Rankin Scale ≤1 at 3 months: Tier 1 55%, Tier 2 75%, Tier 3 43%
Bottom Line
Albumin doses up to 1.25 g/kg/day for 7 days were safe and tolerated in SAH patients without major dose-limiting complications. Outcomes trended toward better functional recovery at this dose level, suggesting potential neuroprotective effects, though higher doses were associated with pulmonary edema.
Major Points
- Open-label, dose-escalation Phase I pilot study of 25% human albumin in SAH patients
- 47 patients enrolled across 6 North American centers from May 2006 to May 2010
- Doses up to 1.25 g/kg/day×7 days were well tolerated
- Study terminated early after 7 patients in Tier 3 due to 2 SAEs of pulmonary edema related to albumin
- Serum albumin concentrations increased and remained elevated 7 days post-treatment
- Tier 2 patients showed better functional outcomes compared to Tier 1 and historical IHAST controls
- Low incidence of delayed cerebral ischemia (17% overall, 15% in Tier 2)
- Only 3 serious adverse events out of 17 total SAEs were adjudicated as related to albumin
- Treatment protocol was feasible and successfully implemented at multiple international centers
Study Design
- Study Type
- Open-label, dose-escalation, Phase I pilot study
- Randomization
- No
- Blinding
- None - open-label study. Independent Data and Safety Monitoring Board reviewed unblinded data. Medical Safety Monitor adjudicated adverse events
- Sample Size
- 47
- Follow-up
- 90 days (3 months)
- Centers
- 6
- Countries
- United States, Canada
Primary Outcome
Definition: Maximum tolerated dose of albumin based on rate of severe-to-life-threatening heart failure or anaphylactic reaction related to albumin treatment
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Tier 1: 1 SAE possibly related (pulmonary edema) in 20 patients; Tier 2: 2 SAEs related (1 possibly, 1 definitely pulmonary edema) in 20 patients; Tier 3: 2 SAEs related (1 definitely, 1 possibly pulmonary edema) in 7 patients - study terminated | - |
Limitations & Criticisms
- Open-label, non-randomized design without concurrent controls limits interpretation
- Small sample size (47 patients total, only 7 in Tier 3)
- Not powered to test for efficacy - primarily a safety and feasibility study
- Early termination of study after Tier 3 enrollment prevented assessment of higher dose tiers
- Comparison with historical IHAST cohort is post-hoc and exploratory, not pre-specified
- Potential selection bias due to low enrollment rate (12.3% of screened patients)
- No head CT scans obtained immediately after aneurysm treatment, limiting ability to determine timing of cerebral infarctions
- Infarction volume not measured, preventing assessment of severity of radiological injury
- Study initially planned for 3 years but required 4 years due to investigator transfers and site initiation delays
- Fluid management protocol was modified mid-study after DSMB recommendation, potentially affecting consistency
- Predominantly conducted at North American centers, limiting generalizability to other populations
Citation
Stroke. 2012;43:683-690