Alpha-1 Antitrypsin for Graft-versus-Host Disease (MODULAATE Trial)
Palo Alto (17 mi)Age: Any Age
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: CSL Behring
Prior Safety Data
Trial Summary
What is the purpose of this trial?This study is a Phase 2/3 prospective, double-blind, randomized, multi-center, placebo-controlled study for prevention of acute GVHD (aGVHD) in subjects undergoing an allogeneic hematopoietic cell transplant (HCT).
Do I have to stop taking my current medications for this trial?The trial protocol does not specify whether you need to stop taking your current medications.
Is the drug Alpha-1 antitrypsin (AAT) a promising treatment for Graft-versus-Host Disease?Yes, Alpha-1 antitrypsin (AAT) is a promising treatment for Graft-versus-Host Disease. It has shown positive results in improving symptoms and survival rates in patients who do not respond to standard treatments. AAT helps reduce inflammation and supports the immune system, making it effective in treating severe cases of the disease.13457
What safety data exists for Alpha-1 Antitrypsin in treating Graft-versus-Host Disease?Alpha-1 Antitrypsin (AAT) has been evaluated in several studies for its safety in treating Graft-versus-Host Disease (GVHD). In a phase I/II study, AAT was well tolerated with no clinically relevant toxicities observed in patients with steroid-refractory acute GVHD. Another study reported that AAT is an effective and safe treatment option for steroid-resistant acute GVHD, with an overall response rate of 80%. Additionally, a multi-center study on Zemaira, a form of AAT, showed it to be well tolerated and safe, with treatment-related adverse events occurring in 7% of subjects. No viral transmission was documented. These studies suggest that AAT is generally safe for use in GVHD treatment.23457
What data supports the idea that Alpha-1 Antitrypsin for Graft-versus-Host Disease is an effective treatment?The available research shows that Alpha-1 Antitrypsin (AAT) can be effective for treating Graft-versus-Host Disease (GVHD), especially in cases where standard steroid treatments don't work. In one study, 8 out of 12 patients with severe GVHD showed improvement after receiving AAT, with 4 experiencing complete recovery. Another study found that 44% of patients with severe gut GVHD responded to AAT treatment, and 27% had a complete response. Additionally, a smaller study reported an 80% overall response rate in patients with steroid-resistant GVHD. These findings suggest that AAT can be a promising option for patients who do not respond to traditional treatments.34567
Eligibility Criteria
This trial is for males and females aged 12 or older (18+ in Germany) who are undergoing a bone marrow transplant due to blood cancers like leukemia, lymphoma, or myeloma. They must be planning an intense treatment regimen before the transplant. People with previous transplants or those getting certain T-cell treatments can't join.Inclusion Criteria
I am scheduled for a strong chemotherapy or radiation treatment before a stem cell transplant.
I am 12 or older (18+ in Germany) and having a transplant for blood cancer.
Exclusion Criteria
I have had a stem cell transplant before.
I am undergoing or planning to undergo a treatment that targets T-cells for graft-versus-host disease.
I am scheduled for a stem cell transplant using umbilical cord blood.
Treatment Details
The study tests if Alpha-1 Antitrypsin (AAT), compared to a placebo, can prevent acute Graft-Versus-host Disease after allogeneic hematopoietic cell transplant. It's double-blind meaning neither doctors nor patients know who gets AAT and who gets the placebo.
5Treatment groups
Experimental Treatment
Placebo Group
Group I: AAT (selected dose from open-label)Experimental Treatment1 Intervention
Double-blind. AAT is a lyophilized product for intravenous administration
Group II: AAT (medium dose)Experimental Treatment1 Intervention
Open label. AAT is a lyophilized product for intravenous administration
Group III: AAT (low dose)Experimental Treatment1 Intervention
Open label. Alpha-1 antitrypsin (AAT) is a lyophilized product for intravenous administration
Group IV: AAT (high dose)Experimental Treatment1 Intervention
Open label. AAT is a lyophilized product for intravenous administration
Group V: PlaceboPlacebo Group1 Intervention
Albumin solution administered intravenously
Alpha-1 antitrypsin (AAT) is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Alpha-1 antitrypsin for:
- Chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency
🇪🇺 Approved in European Union as Alpha-1 antitrypsin for:
- Chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency
Find a clinic near you
Research locations nearbySelect from list below to view details:
Duke University Medical CenterDurham, NC
Methodist HospitalSan Antonio, TX
University of Kansas Cancer CenterWestwood, KS
University of Michigan Medical CenterAnn Arbor, MI
More Trial Locations
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Who is running the clinical trial?
CSL BehringLead Sponsor
References
[Effect of alpha 1-protease inhibitor (alpha 1-antitrypsin) on the intensity of phytohemagglutinin stimulated lymphocyte transformation]. [2008]alpha 1-Antitrypsin (alpha 1-AT) decreases the intensity of human peripheral blood lymphocyte transformation stimulated by phytohemagglutinin. The degree of inhibition is influenced by the antiprotease activity of alpha 1-AT. It is shown that maximal inhibition of transplantation is 50%. Participation of alpha 1-AT in the control of biological activity of lymphoid tissue cells is suggested.
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.
Alpha-1 antitrypsin treatment of spontaneously diabetic nonobese diabetic mice receiving islet allografts. [2008]Alpha-1 antitrypsin (AAT) is a serine protease inhibitor able to prevent diabetes onset in nonobese diabetic (NOD) mice and to prolong islet allograft survival in a nonautoimmune murine model. In this study, we explored the effect of chronic administration of human AAT (hAAT) on allogeneic (C57BL/6) islet graft survival in spontaneously diabetic female NOD mice. Mice received intraperitoneal treatment with saline, Prolastin (1 or 2 mg/mouse) or Aralast (2 mg/mouse) on days -1, 0, 3, 6, and 9. Saline-treated mice rejected the grafts 10.0 +/- 2.5 days after transplantation (n = 9). Prolastin 1 mg (n = 9) and 2 mg (n = 3) resulted in rejection on 8.7 +/- 1.4 (not significant) and 13.0 +/- 4.3 days (P 100 days).
Response of Steroid-Refractory Acute GVHD to α1-Antitrypsin. [2022]α1-Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over a 15-day course. All patients had grades III or IV GVHD with stage 4 gut involvement. After treatment, plasma AAT levels increased in both cohorts and remained within 2 to 4 mg/mL for the duration of treatment. No clinically relevant toxicities attributable to AAT were observed. GVHD manifestations improved in 8 of 12 patients, and 4 responses were complete. Six patients (50%) were alive at last follow-up (>104 to >820 days). These findings show that AAT is well tolerated and has efficacy in the treatment of steroid-refractory severe acute GVHD. Further studies are warranted.
Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease. [2021]Almost one-half of patients developing graft-versus-host disease (GVHD) will not respond to standard first-line steroid treatment. Alpha-1 antitrypsin (AAT) is able to induce tolerance in preclinical models of GVHD. AAT alters the cytokine milieu, promotes a tolerogenic shift of dendritic cells, and skews effector T cells toward regulatory T cells. Gastrointestinal steroid-refractory (SR)-GVHD is a protein-losing enteropathy that might represent the optimal setting in which to use AAT. Here we analyze the outcomes of 16 patients treated with human-derived AAT in advanced-stage gut SR-GVHD, with two-thirds of the patients having failed at least 1 treatment for SR-GVHD. The overall response rate (ORR) was 44%, with a complete response (CR) rate of 27%. Gastrointestinal response was observed in 61% of patients. The median time to best response was 21 days (range, 6 to 26 days). At day 56 after AAT treatment, all CRs were maintained, and the ORR was 39%. The 1-year overall survival was 48% (95% confidence interval, 26% to 74%). Ancillary studies showed that AAT serum levels were in the normal range at the beginning of treatment, whereas fecal loss was elevated. AAT levels consistently rose after exogenous administration, but no correlation was found between serum levels and response. REG3α and IL-33 levels were associated with response while, in contrast to previous reports, regulatory T cells decreased during AAT treatment. This retrospective analysis supports a previous report of AAT as a promising agent in the management of gut SR-GVHD and should prompt its evaluation at an earlier stage.
Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin. [2022]Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.
Alpha-1-Antitrypsin Experience for Steroid-Resistant Acute Graft-Versus-Host Disease. [2023]Steroid-refractory acute graft-versus-host disease (SR-aGVHD) treatment has a low response rate and a high risk of infection in allogeneic hematopoietic stem cell transplantation. The standard approach to be applied in this situation is uncertain. This study aims to evaluate the effectiveness and safety of alpha-1-antitrypsin (AAT). In the study, the results of five SR-aGVHD patients received AAT evaluated. Complete response was seen 2 of four patients with gastrointestinal (GI) aGVHD, partial response in one GI and one liver aGVHD. The overall response rate was 80%. AAT is an effective and safe treatment option in SR-aGVHD.