Tissue Kallikrein for Ischemic Stroke (ReMEDy2 Trial)
Recruiting in Palo Alto (17 mi)
+24 other locations
Overseen ByScott Kasner, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: DiaMedica Therapeutics Inc
Prior Safety Data
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This is a Phase 2/3 study evaluating the safety and efficacy of DM199 (rinvecalinase alfa) in treating participants with moderate stroke severity, who present within 24 hours of Acute Ischemic Stroke (AIS) onset due to small and medium vessel occlusions. This study focuses on participants with limited treatment options. Participants who have or will receive mechanical thrombectomy (MT) are not eligible for participation. Additionally, participants who have received fibrinolytics are excluded unless they experience a persistent neurological deficit of moderate severity six or more hours after fibrinolytic treatment. Participants considered for this trial should not be denied the use of standard of care (SoC) AIS therapies, such as fibrinolytics or MT, when appropriate. The double-blinded study will be randomized and placebo-controlled at up to approximately 100 sites.
Will I have to stop taking my current medications?
The trial requires participants who are currently taking an ACE inhibitor (a type of blood pressure medication) to switch to another blood pressure medication for the duration of the study. If you are on an ACE inhibitor, you must not have taken it within 24 hours before starting the study drug.
What data supports the effectiveness of the drug Recombinant human tissue kallikrein (DM199) for ischemic stroke?
Research suggests that tissue kallikrein can help improve blood flow and reduce brain damage after a stroke by promoting the production of kinins, which are substances that widen blood vessels. Studies in animals have shown that kallikrein can reduce stroke-related brain injury and inflammation, suggesting it may be beneficial for treating ischemic stroke in humans.
12345How is the drug DM199 different from other treatments for ischemic stroke?
DM199, a form of recombinant human tissue kallikrein, is unique because it enhances blood flow by generating kinins, which are natural vasodilators (substances that widen blood vessels). Unlike standard treatments that focus on removing blood clots, DM199 promotes long-term vascular health and has anti-inflammatory and anti-oxidative properties, offering neuroprotection even when administered after a stroke.
13678Eligibility Criteria
Adults over 18, weighing between 50-160 kg, who've had an Acute Ischemic Stroke within the last 24 hours but can't have clot-dissolving drugs or mechanical clot removal. They should have a moderate stroke severity score and be in good health before the stroke. Pregnant women and those on certain blood pressure meds are excluded.Inclusion Criteria
I am 18 years old or older.
I am 18 years old or older.
My weight is between 50 kg and 160 kg.
Exclusion Criteria
I have not been part of a drug study or taken experimental drugs in the last 30 days.
I have alpha 1-antitrypsin deficiency.
I am currently hospitalized or need IV treatment for an infection.
I have trouble with veins for receiving treatment or drawing blood.
I have received or will receive clot-dissolving medication for my stroke.
I have symptoms or imaging results that suggest a stroke in the back part of my brain.
I am receiving or will receive mechanical thrombectomy for my stroke.
Participant Groups
The ReMEDy2 Trial is testing DM199 (recombinant human tissue kallikrein) for safety and effectiveness in treating strokes when standard treatments aren't suitable. Participants will either receive DM199 or a placebo at random, without knowing which one they're getting.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: DM199Experimental Treatment1 Intervention
DM199 administered by a single intravenous (IV) dose followed by subcutaneous (SC) doses at 2 hours (+10 hours) of the IV dose completion and then 2 times per week up to Day 21.
Group II: Placebo for DM199 Solution for InjectionPlacebo Group1 Intervention
Placebo administered by a single intravenous (IV) dose followed by subcutaneous (SC) doses at 2 hours (+10 hours) of the IV dose completion and then 2 times per week up to Day 21.
Recombinant human tissue kallikrein is already approved in China for the following indications:
🇨🇳 Approved in China as KLK1 for:
- Ischemic stroke
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Ballad HealthJohnson City, TN
Parkview Research CenterFort Wayne, IN
Northwell Health Physician Partners - Neurology at Lenox HillNew York, NY
Guilford Neurologic Associates, Inc.Greensboro, NC
More Trial Locations
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Who is running the clinical trial?
DiaMedica Therapeutics IncLead Sponsor
References
Human tissue kallikrein in the treatment of acute ischemic stroke. [2020]Acute ischemic stroke (AIS) remains a major cause of death and disability throughout the world. The most severe form of stroke results from large vessel occlusion of the major branches of the Circle of Willis. The treatment strategies currently available in western countries for large vessel occlusion involve rapid restoration of blood flow through removal of the offending blood clot using mechanical or pharmacological means (e.g. tissue plasma activator; tPA). This review assesses prospects for a novel pharmacological approach to enhance the availability of the natural enzyme tissue kallikrein (KLK1), an important regulator of local blood flow. KLK1 is responsible for the generation of kinins (bradykinin and kallidin), which promote local vasodilation and long-term vascularization. Moreover, KLK1 has been used clinically as a direct treatment for multiple diseases associated with impaired local blood flow including AIS. A form of human KLK1 isolated from human urine is approved in the People's Republic of China for subacute treatment of AIS. Here we review the rationale for using KLK1 as an additional pharmacological treatment for AIS by providing the biochemical mechanism as well as the human clinical data that support this approach.
Expression and characterization of human tissue kallikrein variants. [2006]Human tissue kallikrein is a serine protease implicated in the pathology of various inflammatory disorders. As one of the two principal enzymes that generate proinflammatory kinin peptides in vivo, tissue kallikrein represents an attractive target for therapeutic intervention in diseases such as asthma, pancreatitis, and rheumatoid arthritis. Three distinct human tissue kallikrein variants, differing in one or two amino acid substitutions, are predicted to exist based on genomic or cDNA nucleotide sequences derived from different tissues. The effects of these substitutions on the biochemical properties of tissue kallikrein are unknown but could, in principle, confer tissue-specific functions on the enzyme or affect the clinical utility of specific kallikrein inhibitors. All three variants, as well as a deglycosylated derivative, were expressed in high yield as recombinant proteins in Pichia pastoris. The recombinant kallikrein variants and natural urinary kallikrein all hydrolyzed synthetic peptides with similar specificity and efficiency and released kallidin from kininogen at comparable rates. Similarly, no significant differences were observed in the interactions between kallikrein variants and protein inhibitors such as SBTI, alpha1-PI, and aprotinin. We conclude that the known tissue kallikrein variants represent allelic variants and are not likely to have tissue-specific activity related to the amino acid substitutions.
Experimental therapy with tissue kallikrein against cerebral ischemia. [2019]Tissue kallikrein is a serine proteinase capable of cleaving kininogen substrate to produce the potent vasodilator kinin peptide. Kinin mediates a complex set of physiological actions through its receptor signaling. Systemic delivery of the kallikrein gene in an adenoviral vector significantly reduced stroke-induced mortality rate, blood pressure elevation, and aortic hypertrophy in hypertensive Dahl-salt sensitive rats fed a high salt diet. Using a focal cerebral ischemic rat model induced by middle cerebral artery occlusion, intravenous or intracerebroventricular kallikrein gene delivery significantly reduced ischemia/repefusion (I/R)-induced neurological deficits, cerebral infarction, neuronal and glial cell apoptosis, and inflammatory cell infiltration, while promoting angiogenesis and neurogenesis in the ischemic brain. A continuous infusion of a sub-depressor dose of tissue kallikrein protein through implanted minipump decreased I/R-induced neurological dysfunction and cerebral infarction, inflammation and oxidative stress independent of kallikrein's blood pressure-lowering effect. Moreover, kallikrein offered neuroprotection even when delivered at one day after the onset of stroke. Kallikrein's protective effects were blocked by the kinin B2 receptor antagonist icatibant. The role of the kinin B2 receptor in mediating the protective effect against ischemic brain injury was further confirmed by increases in mortality rate and post-ischemic brain injury in kinin B2 receptor-deficient mice. Taken together, these results suggest a novel function of kallikrein as an anti-inflammatory and anti-oxidative agent in protecting the brain against ischemic stroke-induced injuries. These findings also raise the possibility that tissue kallikrein may have value in the treatment of acute ischemic stroke.
Tissue Kallikrein Activity, Detected by a Novel Method, May Be a Predictor of Recurrent Stroke: A Case-Control Study. [2022]Tissue kallikrein (TK) protein content in plasma has been shown to be negatively associated with both incident and recurrent strokes. The aims of this study were to develop a novel method for detecting TK activity and to investigate its association with event-free survival over 5 years in Chinese first-ever stroke patients.
Isolation and characterization of human tissue kallikrein produced in Escherichia coli: biochemical comparison to the enzymatically inactive prokallikrein and methionyl kallikrein. [2013]This report describes bacterial expression, isolation, and characterization of human tissue kallikrein recombinantly produced in Escherichia coli. Successful production of enzymatically active recombinant human kallikrein requires the following processes: expression, solubilization and refolding of prokallikrein, thermolysin activation, and chromatographic separation. All experimental data confirmed that bacterially derived human kallikrein is properly folded and exhibits expected biochemical functions. As confirmed by SDS-PAGE and reverse-phase HPLC, recombinant kallikrein is apparently pure and is devoid of reduced or other partially folded kallikrein forms. Recombinant kallikrein behaves as a monomeric molecule in solution and exhibits full enzymatic activity in hydrolyzing peptide substrates. The molecule can bind to aprotinin to form kallikrein-inhibitor complex at a 1:1 molar ratio. Peptide mapping analysis derived from pepsin digestion of recombinant kallikrein assigned five disulfide bonds which match those of porcine kallikrein predicted from X-ray structure. Peptides containing unpaired cysteines or mispaired disulfide bonds were not detected. Both properly folded prokallikrein and methionyl kallikrein, containing a propeptide and an initiator methionine at their N-termini, respectively, were also produced and isolated. These two molecules are structurally similar to recombinant kallikrein, but are not enzymatically active.
Expression and preliminary characterization of recombinant human tissue kallikrein in egg white of laying hens. [2020]Human tissue kallikrein (hK1) plays an important role in regulation of blood pressure, electrolyte and glucose transport, and renal function. To evaluate the feasibility of expression of recombinant human tissue kallikrein (rhK1) in the egg whites of laying hens, human tissue kallikrein gene (hKLK1) cDNA was subcloned into the chicken oviduct-specific expression vector (pOV3), and the resultant recombinant vector pOV3K was injected into laying hens via wing vein after mixing with polyethyleneimine. Following injection twice with the recombinant vector, the enzymatic activity at a maximal level of 59 U/mL was detected in the egg whites, which lasted for more than 7 d. The expression level of rhK1 in the egg whites in the 3-mg group was relatively higher than that in the 2-mg group, but the significant differences were identified on d 7 and 8 (P 0.05). Western blot analysis of the egg whites from vector-injected hens showed the rhK1 was recognized by a polyclonal antibody specific for hK1 with molecular weights of 37 and 43 kDa, which probably corresponded to the mature and preenzyme, respectively. Biochemical studies showed that the recombinant enzyme had a similar thermostability, optimal pH, hypotensive effect, and sensitivity to different ions to the natural enzymes in human and porcine tissues. These data indicate that the chicken oviduct-specific transient expression system can produce relatively high level and authentic recombinant enzyme with a potential for further development for therapeutic use.
Immunoassays for the determination of human tissue kallikrein (TK) in different body fluids based on monoclonal antibodies. [2019]A monoclonal antibody produced against human tissue kallikrein was used to develop solid phase immunoassays for the determination of total immunoreactive tissue kallikrein, of the complex of tissue kallikrein with alpha 1-proteinase inhibitor, and of enzymatically active tissue kallikrein. The assays permit the specific determination of various forms of tissue kallikrein in body fluids and should be very useful in studies on the biological function of tissue kallikrein-kinin systems.
Recombinant avian adeno-associated virus-mediated oviduct-specific expression of recombinant human tissue kallikrein. [2020]Human tissue kallikrein (hK1) plays an important role in regulation of blood pressure, electrolyte and glucose transport, and renal function. To evaluate the feasibility of viral vector-mediated expression of recombinant human tissue kallikrein (rhK1) in the egg white of laying hens, human tissue kallikrein gene (hKLK1) cDNA-expression cassette was subcloned into avian adeno-associated virus (AAAV) transfer vector pAITR and transfected into AAV-293 cells with AAAV helper vector pcDNA-ARC and adenovirus helper vector pHelper. The recombinant viral particles with a typical AAAV morphology and relatively high titer were generated and identified by PCR and electron microscopy. After 1 intravenous injection of each laying hen with 2 x 10(10) viral particles, oviduct-specific expression of hKLK1 cDNA was demonstrated by reverse transcription-PCR. Secretion of rhK1 into the egg white was detected by enzymatic assay from d 2, reaching the highest level of 107 U/mL in wk 3, and lasted for more than 6 wk after injection. Western blotting showed that the oviduct-expressed rhK1 had the same molecular mass with the natural enzyme. These data suggest that rAAAV can mediate high level and long-lasting transgene expression in oviduct cells, and the established expression system is useful for production of other recombinant proteins.