Alpha-1 Antitrypsin for Graft-versus-Host Disease

(MODULAATE Trial)

Recruiting in Palo Alto (17 mi)

+47 other locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: CSL Behring

Must not be taking: Anti-T cell antibodies

Disqualifiers: Prior HCT, T-cell depleted, UCB transplant

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This study is a phase 2 / 3 prospective, double-blind, randomized, multicenter, placebo-controlled study for prevention of acute GVHD (aGVHD) in participants undergoing an unrelated (matched or single allele mismatched) or matched related allogeneic hematopoietic cell transplantation (HCT).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Alpha-1 Antitrypsin for treating graft-versus-host disease?

Research shows that Alpha-1 Antitrypsin (AAT) improved symptoms in patients with severe graft-versus-host disease (GVHD) who did not respond to steroids, with some achieving complete recovery. In one study, 8 out of 12 patients showed improvement, and in another, 80% of patients had a positive response, indicating AAT's potential as an effective treatment for GVHD. ^{1 2 3 4 5}

Is Alpha-1 Antitrypsin safe for use in humans?

Alpha-1 Antitrypsin (AAT) has been shown to be generally safe in humans, with studies reporting it as well tolerated and without significant toxicities. In various trials, including those for graft-versus-host disease and other conditions, no major safety concerns were observed, and treatment-related adverse events were relatively low. ^{1 3 4 5 6}

How is the drug Alpha-1 Antitrypsin unique in treating graft-versus-host disease?

Alpha-1 Antitrypsin (AAT) is unique because it has anti-inflammatory and immunomodulatory properties that help manage steroid-refractory graft-versus-host disease (GVHD), especially in patients who do not respond to standard steroid treatments. It works by altering immune responses and promoting tolerance, which is different from traditional treatments that primarily rely on steroids. ^{1 3 4 5 7}

Research Team

Study Physician

Principal Investigator

CSL Behring

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.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Alpha-1 Antitrypsin (AAT) or placebo intravenously to prevent acute GVHD

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of acute and chronic GVHD

24 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term with selected dose of AAT

Treatment Details

Interventions

• Alpha-1 antitrypsin (AAT) (Protein Replacement Therapy)
• Placebo (Immunotherapy)

Trial Overview 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.

Participant Groups

Group I: AAT (selected dose from open-label) Experimental Treatment 1 Intervention

Double-blind. AAT is a lyophilized product for IV administration

Group II: AAT (medium dose) Experimental Treatment 1 Intervention

Open label. AAT is a lyophilized product for IV administration

Group III: AAT (low dose) Experimental Treatment 1 Intervention

Open label. AAT is a lyophilized product for intravenous (IV) administration

Group IV: AAT (high dose) Experimental Treatment 1 Intervention

Open label. AAT is a lyophilized product for IV administration

Group V: Placebo Placebo Group 1 Intervention

Albumin solution administered intravenously

Who Is Running the Clinical Trial?

CSL Behring

Lead Sponsor

Trials

204

Recruited

1,207,000+

Dr. Paul McKenzie

CSL Behring

Chief Executive Officer since 2023

PhD in Chemical Engineering from Carnegie Mellon University, B.S. in Chemical Engineering from the University of Pennsylvania

Dr. Bill Mezzanotte

CSL Behring

Chief Medical Officer since 2021

MD from Duke University

Findings from Research

In a phase I/II study involving 12 patients with severe steroid-refractory acute graft-versus-host disease (GVHD), α1-antitrypsin (AAT) was administered safely with no significant toxicities observed, indicating its potential as a well-tolerated treatment option.

AAT treatment led to improvements in GVHD symptoms in 8 out of 12 patients, with 4 achieving complete responses, suggesting that AAT may be an effective salvage therapy for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of Steroid-Refractory Acute GVHD to α1-Antitrypsin. Marcondes, AM., Hockenbery, D., Lesnikova, M., et al.[2022]

The MAGIC algorithm can identify patients at high risk for developing steroid-refractory acute graft-versus-host disease (GVHD) as early as 7 days after hematopoietic cell transplantation (HCT) using serum biomarkers, allowing for timely intervention.

In a trial involving 30 high-risk patients treated with α-1-antitrypsin (AAT), the treatment was well tolerated but did not significantly reduce the incidence of steroid-refractory GVHD compared to a control group, indicating that this specific dosing and schedule of AAT may not be effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin. Gergoudis, SC., DeFilipp, Z., Özbek, U., et al.[2022]

In a study of 16 patients with advanced-stage gastrointestinal steroid-refractory graft-versus-host disease (GVHD), treatment with alpha-1 antitrypsin (AAT) resulted in a 44% overall response rate and a 27% complete response rate, indicating its potential efficacy in this challenging condition.

The treatment led to gastrointestinal responses in 61% of patients, with responses maintained at day 56, suggesting that AAT could be a promising option for patients who do not respond to standard steroid therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease. Giannoni, L., Morin, F., Robin, M., et al.[2021]

Chronic administration of human alpha-1 antitrypsin (hAAT) can significantly prolong islet graft survival in diabetic NOD mice, with the best results seen in those treated with Aralast, which extended survival to 13 days compared to 10 days in saline-treated controls.

However, repeated hAAT treatments led to sudden deaths in some treated mice, likely due to hypersensitivity reactions, a risk not observed in non-autoimmune mice, indicating a need for caution in its use in autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-1 antitrypsin treatment of spontaneously diabetic nonobese diabetic mice receiving islet allografts. Pileggi, A., Molano, RD., Song, S., et al.[2008]

In a study of five patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), alpha-1-antitrypsin (AAT) demonstrated an overall response rate of 80%, with complete responses in 2 out of 4 patients with gastrointestinal aGVHD.

AAT was found to be a safe treatment option for SR-aGVHD, showing effectiveness particularly in gastrointestinal and liver cases, suggesting it could be a viable alternative when standard treatments fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-1-Antitrypsin Experience for Steroid-Resistant Acute Graft-Versus-Host Disease. Koyun, D., Seval, GC., Kırcalı, E., et al.[2023]

A new plasma-derived alpha1-Proteinase Inhibitor (Zemaira) was shown to be bioequivalent to the existing treatment (Prolastin) in restoring serum Alpha1-antitrypsin levels in individuals with AAT deficiency, achieving levels above the protective threshold of 11 microM.

The study, involving 44 subjects over a 10-week double-blind phase, found that Zemaira was well tolerated with a lower incidence of treatment-related adverse events (7%) compared to Prolastin (21%), and there were no cases of viral transmission, indicating its safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. Stocks, JM., Brantly, M., Pollock, D., et al.[2019]

Alpha 1-antitrypsin (alpha 1-AT) significantly reduces the activation of human peripheral blood lymphocytes when stimulated by phytohemagglutinin, with a maximum inhibition of 50%.

The effectiveness of alpha 1-AT in inhibiting lymphocyte transformation is linked to its antiprotease activity, suggesting it plays a role in regulating the biological activity of lymphoid tissue cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of alpha 1-protease inhibitor (alpha 1-antitrypsin) on the intensity of phytohemagglutinin stimulated lymphocyte transformation]. Baranova, FS., Berman, AA., Zaretskaia, IuM.[2008]

References

1. United States pubmed.ncbi.nlm.nih.gov

Response of Steroid-Refractory Acute GVHD to α1-Antitrypsin. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Alpha-1 antitrypsin treatment of spontaneously diabetic nonobese diabetic mice receiving islet allografts. [2008]

5. India pubmed.ncbi.nlm.nih.gov

Alpha-1-Antitrypsin Experience for Steroid-Resistant Acute Graft-Versus-Host Disease. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. [2019]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Effect of alpha 1-protease inhibitor (alpha 1-antitrypsin) on the intensity of phytohemagglutinin stimulated lymphocyte transformation]. [2008]