PROMISING RESULTS FROM CLINICAL TRIALS
A Phase 1 safety study of CIRARA was conducted in 2010. Following its successful completion, the GAMES-PILOT study was designed to test CIRARA in patients with large hemispheric infarction.
GAMES-PILOT was an open label trial in which 10 subjects were enrolled and treated at University of Maryland and the Massachusetts General Hospital between February 2011 and May 2012. At baseline, the median NIH Stroke Score (NIHSS) was 18, average lesion size, as centrally measured by diffusion-weighted magnetic resonance index (DWI), was 102 cm3, and median time to treatment was 8.7 hours.
In stark contrast, only 10% of CIRARA-treated patients died and the proportion of patients who survived without severe disability was 90%, a reversal of the dire natural history of patients with this large hemispheric infarction.
Follow up MRI images were notable for qualitative findings including absence of mass effect, and preservation of white matter. Imaging and blood biomarkers of blood–brain barrier breakdown and hemorrhagic conversion in patients treated with CIRARA were also reduced vs. historic controls.
The modified Rankin Scale (mRS) is a common outcome measure to determine the degree of disability or dependence in the daily activities of patients. The scale runs from 0 to 6, 0 being perfect health, to 6 indicating death. CIRARA treated subjects had Day 90 mRS 0-4 of 90% versus 50% in controls, mRS 0-3 of 40% vs. 25%, and mortality of 10% vs. 35%.
The GAMES pilot study (mentioned above) was open-label, had no placebo control arm, and the number of patients studied was small – but the results were impressive, thus warranting further clinical investigation to determine whether CIRARA could mitigate the devastating consequences associated with large hemispheric infarction and its resulting edema. As a result, Remedy Pharmaceuticals sponsored a larger Phase 2 trial, GAMES-RP.
GAMES-RP is a Phase 2 randomized, double-blinded, placebo-controlled, multicenter study, that, between June 2013 and April 2015, enrolled 77 subjects with large hemispheric infarction and centrally confirmed DWI lesions of 82-300 cm3. The median baseline NIH Stroke Score was 20 in the CIRARA arm and 20.5 in placebo, mean baseline lesion size was 154 cm3 in the CIRARA group and 159 cm3 in the placebo group. Treatment with CIRARA was commenced a median of 9.1 hours after LHI. Patients were randomized 1:1 to CIRARA or placebo.
Eighteen leading medical centers were involved in the GAMES-RP trial (in alphabetical order): Abington Memorial Hospital, Abington, PA; Cleveland Clinic, Cleveland, OH; Maine Medical Center, Portland, ME; Massachusetts General Hospital, Boston, MA; Medical University of South Carolina, Charleston, SC; Northwestern Memorial Hospital, Chicago, IL; Oregon Health & Science University Hospital, Portland, OR; Ohio State University/Wexner Medical Center, Columbus, OH; Rutgers (Robert Wood Johnson University Hospital), New Brunswick, NJ; Stanford University Medical Center, Stanford, CA; UMASS Memorial Medical Center, Worcester, MA; University of Arizona Medical Center - University Campus, Tucson, AZ; University of Florida, Jacksonville, FL; University of Louisville Hospital, Louisville, KY; University of Maryland Medical Center, Baltimore, MD; University of Utah Healthcare, Salt Lake City, UT; UPMC Presbyterian Hospital, Pittsburgh, PA; and Yale-New Haven Hospital, New Haven, CT.
Of the 77 patients in the primary analysis, there were 19 deaths within the first 30-day period, 6 of 41 in the CIRARA group (14%), versus 13 of 36 (36%) in the placebo group (p=0.03), corresponding to a reduction in mortality of 60%. Within the 90-day follow up period, there were a total of 20 deaths, 7 of 41 subjects in the CIRARA group (17%), versus 13 of 36 (36%) in the placebo group (p=0.06), a reduction in mortality of 53%.
A post hoc analysis found there were 16 patients dosed within 8 hours of onset of LHI, with 8 patients each in the CIRARA and placebo groups. Four of the 16 subjects died, all in the placebo group. There were no deaths in this CIRARA dosed subgroup.
Of the CIRARA group, 61% had a 90-day mRS of 0-4, versus 47% for the placebo group (p=0.23), or 29% more subjects in the CIRARA group. The median mRS in the CIRARA group was 4 versus 5 in the placebo arm. A “shift” analysis found improvement across the mRS scale (p=0.12). In subjects dosed within 8 hours, 63% (5/8) had a 90-day mRS of 0-3, versus 25% (2/8) of <8 hour placebo subjects.
Consistent with CIRARA’s mechanism of action, there was a 50% reduction in edema measured by mean midline shift at 72-96 hours of 4.4mm for CIRARA-treated patients, versus 8.8mm in the placebo group (p=0.0006).
While CIRARA did not reduce the incidence of decompressive craniectomy (DC),1 regardless of whether CIRARA patients underwent DC or not, they had substantially improved survival rates and mRS scores versus placebo patients.
An additional post hoc analysis found that in subjects ≤ 70 years old, mortality was reduced by 64% versus placebo (12% vs. 33%) and mRS 0-4 was improved by 32% versus placebo (69% vs. 47%). A “shift” analysis found improvement across the mRS scale (p=0.048).
CHARM (Cirara in large Hemispheric infarction Analyzed for modified Rankin scale and Mortality) is a Phase 3 randomized, double-blinded, placebo-controlled, multicenter study in large hemispheric infarction. CHARM is expected to begin recruitment in the first half of 2017.
If your center is interested in becoming part of the CHARM study, please CLICK HERE.
A Phase 2 human clinical trial in TBI was conducted at three centers in the United States: the University of California at San Diego, UPMC Presbyterian Hospital, Pittsburgh, PA and University of Maryland Medical Center, Baltimore, MD. The study was a randomized, double blind, placebo-controlled study of CIRARA, begun within 10 hours of moderate or severe TBI, with a primary objective of assessing whether CIRARA treated patients would show a decrease in MRI-defined edema and/or hemorrhage, compared to placebo treated patients.
The study was conducted by the INTRuST Consortium, funded by the U.S. Department of Defense. Enrollment was ended in January 2015. Data from this small TBI-pilot study involving 28 subjects is expected in late 2016.