Alpha-proteinase Inhibitor for Eosinophilic Esophagitis
(ZEEPS Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Children's Hospital Medical Center, Cincinnati
Must not be taking: Anticoagulants, Systemic steroids
Disqualifiers: COPD, IgA deficiency, Cancer, others
No Placebo Group
Prior Safety Data
Approved in 5 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial is testing Zemaira, a medication that protects tissues from damage, in patients with Eosinophilic Esophagitis. These patients have chronic inflammation in their esophagus due to an overactive immune response. Zemaira works by blocking harmful enzymes to reduce inflammation and prevent further damage.
Will I have to stop taking my current medications?
The trial does not require you to stop your current medications if they are stable and related to Eosinophilic Esophagitis. You must keep the same dosage for certain medications like proton pump inhibitors and leukotriene inhibitors during the study.
What data supports the effectiveness of the drug Alpha-proteinase inhibitor for treating eosinophilic esophagitis?
Research indicates that the drug Alpha-1 antitrypsin (a type of Alpha-proteinase inhibitor) can inhibit experimental eosinophilic esophagitis, suggesting it may help manage this condition by balancing protease activity in the esophagus.
12345Is Alpha-proteinase Inhibitor safe for human use?
Alpha-proteinase Inhibitor, used under various names like Prolastin and Zemaira, has been used safely for over 20 years to treat conditions like alpha-1-antitrypsin deficiency and cystic fibrosis. Studies show it is well tolerated, with a low incidence of treatment-related adverse events and no documented viral transmission.
678910How does the drug Alpha-proteinase inhibitor differ from other treatments for eosinophilic esophagitis?
Alpha-proteinase inhibitor is unique because it is primarily used to protect tissues from damage by enzymes like elastase, which is different from typical treatments for eosinophilic esophagitis that focus on reducing inflammation or suppressing the immune response. This drug's novel approach may help address tissue damage in eosinophilic esophagitis by balancing protease activity, which is not the focus of standard treatments.
811121314Eligibility Criteria
Adults aged 18-70 with Eosinophilic Esophagitis (EoE) who've had moderate to severe abdominal/chest pain or swallowing difficulties at least twice a week, and whose symptoms weren't controlled by standard treatments. Participants must be willing to maintain their current diet and medical management for EoE throughout the study.Inclusion Criteria
Willing and able to comply with study visits and activities
Willing to maintain current dietary regimen throughout the course of the study. Diet must have been stable for 8 weeks prior to baseline endoscopy
My esophagus has inflammation with more than 15 eosinophils per high powered field, not caused by another known condition.
+5 more
Exclusion Criteria
I do not have Crohn's, inflammatory bowel disease, or Celiac disease.
Known immunoglobulin A (IgA) deficiency (i.e., IgA level < 8 mg/dL at screening)
I am taking blood thinners other than aspirin or NSAIDs.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
12 weeks
Treatment
Participants receive weekly intravenous infusions of Zemaira (120 mg/kg body weight) for 4 weeks
4 weeks
4 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
Participant Groups
The trial is testing Zemaira (alpha-1 trypsin inhibitor) in patients with Eosinophilic Esophagitis. It's an open-label study, meaning both researchers and participants know what treatment is being given, focusing on how effective this drug is for treating EoE.
1Treatment groups
Experimental Treatment
Group I: Active DrugExperimental Treatment1 Intervention
Zemaira alpha-proteinase inhibitor
Alpha-proteinase inhibitor is already approved in United States, United States, United States, United States, European Union for the following indications:
🇺🇸 Approved in United States as Aralast for:
- Chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)
🇺🇸 Approved in United States as Glassia for:
- Chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe hereditary deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)
🇺🇸 Approved in United States as Prolastin-C for:
- Chronic augmentation and maintenance therapy in adults with clinical evidence of emphysema due to severe hereditary deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)
🇺🇸 Approved in United States as Zemaira for:
- Chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)
🇪🇺 Approved in European Union as Alpha-1-proteinase inhibitor for:
- Congenital Alpha1–Proteinase Inhibitor deficiency
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The National Institutes of HealthBethesda, MD
Cincinnati Children's Hospital Medical CenterCincinnati, OH
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Who Is Running the Clinical Trial?
Children's Hospital Medical Center, CincinnatiLead Sponsor
CSL BehringIndustry Sponsor
National Institutes of Health (NIH)Collaborator
References
Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis. [2022]Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven, inflammatory disease of the esophagus and is associated with impaired barrier function. Evidence is emerging that loss of esophageal expression of the serine peptidase inhibitor, kazal type 7 (SPINK7), is an upstream event in EoE pathogenesis. Here, we provide evidence that loss of SPINK7 mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Overexpression of KLK5 in differentiated esophageal epithelial cells recapitulated the effect of SPINK7 gene silencing, including barrier impairment and loss of desmoglein-1 expression. Conversely, KLK5 deficiency attenuated allergen-induced esophageal protease activity, modified commensal microbiome composition, and attenuated eosinophilia in a murine model of EoE. Inhibition of PAR2 blunted the cytokine production associated with loss of SPINK7 in epithelial cells and attenuated the allergen-induced esophageal eosinophilia in vivo. Clinical samples substantiated dysregulated PAR2 expression in the esophagus of patients with EoE, and delivery of the clinically approved drug α1 antitrypsin (A1AT, a protease inhibitor) inhibited experimental EoE. These findings demonstrate a role for the balance between KLK5 and protease inhibitors in the esophagus and highlight EoE as a protease-mediated disease. We suggest that antagonizing KLK5 and/or PAR2 has potential to be therapeutic for EoE.
Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. [2022]Although eosinophilic esophagitis is recognized increasingly, outcome data guiding therapy are limited. We conducted a prospective randomized trial comparing oral prednisone (P) and swallowed fluticasone (F) for histologic and clinical response.
Montelukast Does not Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis. [2021]Montelukast, a cysteinyl leukotriene type-1 receptor blocker, has been shown in small retrospective studies to reduce symptoms in patients with eosinophilic esophagitis (EoE). We performed a randomized, placebo-controlled, double-blind trial to determine whether montelukast maintains symptomatic remission induced by topical steroid therapy in patients with EoE.
Management of pediatric eosinophilic esophagitis: an update. [2021]Eosinophilic esophagitis is an important chronic esophageal disorder with gastroesophageal reflux disease (GERD)-like symptoms, prominent esophageal mucosal eosinophilia, strongly associated with allergic disorders and unresponsive to anti-GERD therapy. Treatment of eosinophilic esophagitis has been successful with the use of dietary restrictions and topical corticosteroids. A subset of patients benefits from concurrent anti-GERD therapy; those with demonstrable esophageal strictures report variable duration symptom relief after esophageal dilation. At the current time, anti-interleukin-5 monoclonal antibody agents are being investigated in multicenter trials, and it is hoped that future therapy may be targeted against mediators of esophageal remodeling and fibrosis in eosinophilic esophagitis.
Topically applied mometasone furoate improves dysphagia in adult eosinophilic esophagitis - results from a double-blind, randomized, placebo-controlled trial. [2021]Topical corticosteroids are considered a cornerstone in the treatment of patients with eosinophilic esophagitis. The aim of this study was to evaluate the benefit of using mometasone furoate spray versus placebo on dysphagia and health-related quality of life in these patients.
Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. [2019]Augmentation therapy with a plasma derived alpha l-Proteinase Inhibitor (alpha1 -PI) has been demonstrated to be effective in restoring serum Alpha1 -antitrypsin (AAT)* levels in individuals with AAT Deficiency (note: alpha1 PI and AAT are synonymous). The objective of this study was to demonstrate that the steady-state trough serum alphal-PI levels, achieved by a new plasma derived alpha,-PI (Zemaira, study drug, ZLB Behring LLC, King of Prussia, Pennsylvania, USA), were bioequivalent to those achieved by the currently available alpha-PI therapy, Prolastin (control drug, Bayer Corporation, Berkeley, California, USA), and maintained weekly trough serum antigenic alpha1-PI levels above the protective threshold of 11 microM. This multi-center, controlled study randomized a total of 44 subjects to receive either study or control drug for a 10-week double-blind phase. The control group was then crossed over to receive the study drug for the remainder of the study (14 weeks). The difference in mean trough serum antigenic alpha1-PI level between the treatment groups was 1.45 microM (90% CI-2.77, -0.13), signifying bioequivalence. The mean trough serum antigenic alpha1-PI level in the study drug group was greater than the therapeutic threshold of 11 microM, achieving a level of 17.7 microM during the steady-state period. Treatment-related adverse events (AEs) were seen in 7% and 21% of study and control drug treated subjects, respectively. No documented viral transmission occurred. These results demonstrate that the new plasma derived alpha1-PI (Zemaira) is bioequivalent to the currently available product Prolastin, is well tolerated, and safe with respect to the risk of viral transmission.
Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha₁-antitrypsin deficiency: a randomized study. [2021]Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha₁-PI) and may lead to emphysema. Alpha₁-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha₁-Proteinase Inhibitor [Human]) to increase the levels of alpha₁-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha₁-PI product, designated Prolastin®-C (Alpha₁-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency.
A pilot study comparing the purity, functionality and isoform composition of alpha-1-proteinase inhibitor (human) products. [2006]Alpha-1-proteinase deficiency predisposes affected individuals to early onset pulmonary emphysema, and is treated with an alpha-1-proteinase inhibitor (A1-PI) from pooled human plasma. The objective of this pilot study was to assess analytical parameters of the three A1-PI products (Aralast, Prolastin, Zemaira) that may impact on clinical efficacy, safety, and convenience. These included: purity of the preparation; nature of impurities; functionality; and isoform composition.
Alpha 1-antitrypsin augmentation therapy. [2005]Alpha 1-proteinase inhibitor (also known as alpha 1-antitrypsin) derived from pooled human serum (Prolastin, Miles Biologicals) has been available in the United States since 1988. Although no formal controlled prospective study has been performed to prove its efficacy, intravenous administration of Prolastin has been the accepted treatment for individuals with pulmonary emphysema due to alpha 1-antitrypsin deficiency. In addition, Prolastin has been used experimentally by inhalation for the treatment of cystic fibrosis. It has been administered with some success to treat the panniculitis associated with alpha 1-antitrypsin deficiency. As a greater number of severely impaired alpha 1-antitrypsin deficient patients receive lung transplantation, the role of Prolastin in the post-transplant therapy of these patients will need evaluation. Newer antiproteases may render Prolastin obsolete with respect to its route of administration and its pricing, however, the safety record of this drug has been impressive.
Prolastin aerosol therapy and sputum taurine in cystic fibrosis. [2013]Neutrophil elastase in the cystic fibrosis airways inhibits opsonophagocytosis and induces the expression of interleukin-8, a neutrophil chemoattractant. Prolastin is a therapeutic preparation of alpha-1 proteinase inhibitor (alpha1,-PI), a neutrophil elastase inhibitor. The objective of this study was to determine the effects of Prolastin aerosol therapy on airway inflammation in cystic fibrosis.
Purification of alpha 1 proteinase inhibitor from human plasma fraction IV-1 by ion exchange chromatography. [2013]Alpha-proteinase inhibitor (PI) protects the lungs from proteolytic damage caused by elastase and can be used to treat congenital emphysema. We describe an improved method of purification of alpha 1 PI from redissolved fraction IV-1 paste.
Immunomodulation by alpha(1)-proteinase inhibitor: lack of chemotactic effects of recombinant human alpha(1)-proteinase inhibitor from yeast on human peripheral blood granulocytes. [2021]Recombinant alpha(1)-proteinase inhibitor, clinically developed for inhalative augmentation therapy in patients with alpha(1)-proteinase inhibitor deficiency or cystic fibrosis, may directly contribute to leukocyte accumulation as it may function as a chemoattractant. The migratory effects of yeast-derived human recombinant alpha(1)-proteinase inhibitor on human peripheral blood neutrophils and eosinophils were therefore tested in vitro.
Treatment of atopic dermatitis with alpha 1-proteinase inhibitor. [2004]Alpha 1-proteinase inhibitor (alpha 1-PI), a serine protease inhibitor, was tested for its efficacy for the treatment of recalcitrant atopic dermatitis. Atopic dermatitis affects both children and adults and has no established etiology. We hypothesized that during inflammation there is an excess of serine proteases and a deficiency of their naturally occurring inhibitors at the local site of tissue injury, even though there is a normal serum level of serine protease inhibitors. This pilot study consisted of a nonblinded trial using alpha 1-PI at a concentration of 20 mg/mL in an aqueous solution in an alternate day schedule in conjunction with a 1% cream of alpha 1-PI (Stage I) and a 5% cream of alpha 1-PI for maintenance therapy (Stage II). Before enrollment in this trial all six patients failed to respond to high potency topical steroids. Safety was gauged by careful clinical monitoring of subjective complaints, objective findings of erythema, edema, and serial measurements of blood chemistries and complete blood counts. Wound healing was documented by serial photography. Written informed consent was obtained from each patient. All six patients showed significant clinical improvement within 6 to 21 days of initiation of alternate day therapy. Alpha 1-PI stopped pain, pruritus, and promoted tissue healing without scarring in all six patients. No adverse side effects of therapy were documented by clinical history, physical examination, or by blood studies after 120 days of therapy. Atopic dermatitis may be one example where inflammation is due to an imbalance of serine proteases and their naturally occurring inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
Alpha 1-antitrypsin deficiency: an overview. [2022]1. alpha 1-antitrypsin is an antiprotease that inhibits the neutrophil elastase enzyme, and belongs to a family of structurally related serine proteinase inhibitors (serpins). Its methionine358 residue determines the specificity for elastase. 2. The normal M-type alpha 1-antitrypsin is mainly synthesized in the liver parenchymal cells and transported to the plasma. Abnormal Z-mutant alpha 1-antitrypsin is retained in the endoplasmic reticulum, which leads to its intracellular accumulation and to markedly decreased plasma levels. 3. In normal conditions, alpha 1-antitrypsin protects the lungs from destruction by the proteolytic neutrophil elastase. A protease/antiprotease imbalance in the lung is responsible for the development of emphysema in severe alpha 1-antitrypsin deficiency and in cigarette smokers, and accounts for the marked acceleration of the lung disease in smoking alpha 1-antitrypsin deficient patients. Smoking has to be avoided in alpha 1-antitrypsin deficient patients. Replacement therapy with plasma-derived alpha 1-antitrypsin seems indicated in alpha 1-antitrypsin deficient patients with emphysema. 4. Intracellular accumulation of abnormal Z-alpha 1-antitrypsin molecules in liver parenchymal cells may lead to liver disease, ranging from neonatal cholestasis to adulthood cirrhosis and hepatocellular carcinoma. End-stage liver disease can be treated by liver transplantation, which is followed by a phenotypic conversion. 5. Diagnosis of alpha 1-antitrypsin deficiency related disease relies on the presence of a low serum concentration of alpha 1-antitrypsin, and of periodic-acid Schiff positive globules in the liver parenchymal cells. Isoelectric focusing of the serum identifies the protease inhibitor phenotype. The protease inhibitor phenotype is determined by the independent expression of the two parental alpha 1-antitrypsin alleles. It is determinant of the serum level and of the risk for development of lung or liver disease.