Alpha-1 Antitrypsin for Graft-versus-Host Disease

(MODULAATE Trial)

Recruiting at 61 trial locations

Overseen By Trial Registration Coordinator

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: CSL Behring

Must not be taking: Anti-T cell antibodies

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

222 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called Alpha-1 antitrypsin (AAT) to determine its effectiveness in preventing acute graft-versus-host disease (aGVHD). aGVHD can occur after a donor stem cell transplant when the donor's cells attack the recipient's body. The trial compares different doses of AAT with a placebo to identify the most effective treatment. It is suitable for individuals aged 12 and older undergoing a stem cell transplant for blood-related cancers such as leukemia or lymphoma. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that Alpha-1 antitrypsin (AAT) is generally safe for people. Previous studies found that AAT is well-tolerated in treating steroid-resistant acute graft-versus-host disease (aGVHD), with no serious safety issues reported.

AAT is also used for other conditions, such as emphysema, indicating its safety is well-established. However, this does not guarantee it will be free of side effects for everyone. As with any treatment, individual reactions may vary.

This study is in a later phase, indicating the treatment has already passed initial safety tests. This phase aims to further confirm the treatment's safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Alpha-1 antitrypsin (AAT) for graft-versus-host disease because it introduces a new approach to treatment by using a naturally occurring protein with anti-inflammatory properties. Unlike standard treatments that mainly involve immunosuppressants like corticosteroids, AAT works by protecting tissues from inflammation and damage, potentially reducing side effects associated with long-term steroid use. Additionally, AAT is administered intravenously in lyophilized form, which may offer a more targeted delivery method compared to some existing oral medications. This unique mechanism and administration route could lead to more effective management of graft-versus-host disease with fewer complications.

What evidence suggests that this trial's treatments could be effective for preventing acute GVHD?

Studies have shown that Alpha-1 antitrypsin (AAT) can help treat acute graft-versus-host disease (aGVHD), especially when steroids fail. Many patients who received AAT infusions experienced lasting improvements. In this trial, participants will receive different doses of AAT or a placebo to evaluate its effectiveness and safety. Research suggests that AAT may reduce inflammation, a major issue in aGVHD. Overall, AAT appears to be a promising treatment option for managing this condition. ^{1 2 5 6 7}

Who Is on the Research Team?

Study Physician

Principal Investigator

CSL Behring

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Alpha-1 antitrypsin (AAT)
• Placebo

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.

How Is the Trial Designed?

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

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

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. aetna.com aetna.com/cpb/medical/data/100_199/0145.html

Alpha1-Proteinase Inhibitors - Medical Clinical Policy ... Although alpha 1-antitrypsin inhibitor therapy (Prolastin, Aralast) has not been shown to prevent or reverse emphysema in these patients affected by AAT ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5865235/

α1-Antitrypsin infusion for treatment of steroid-resistant acute ... AAT infusion produced a high proportion of durable clinical responses in SR-aGVHD. AAT is associated with minimal toxicity and low rates of infection in ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01523821

Study Details | NCT01523821 | Alpha 1 Anti-Trypsin (AAT) ... This phase I/II trial evaluates the efficacy and adverse effects of alpha 1 anti-trypsin (AAT) for the treatment of acute graft-versus-host disease (GVHD)

4. ohsu.edu ohsu.edu/sites/default/files/2025-06/HS-MPS-Alpha-1-PI-04-25.pdf

Alpha-1-Proteinase Inhibitors: Aralast NP - Prolastin®-C Acute Graft Versus Host Disease (aGVHD): Coverage will be provided for a maximum of 8 doses. (4 weeks) and may NOT be renewed. II. Dosing Limits.

5. keystonefirstvipchoice.com keystonefirstvipchoice.com/content/dam/keystone-first/vip-choice/pdf/provider/resources/pharmacy/policies-20240801/Alpha_1-Antitrypsin_Therapy_(Prolastin-C,_Aralast_NP,_Glassia,_Zemaira).pdf.coredownload.inline.pdf

Alpha 1-Antitrypsin Therapy (eg, Prolastin-C, Aralast NP, ... Alpha 1-antitrypsin infusion for treatment of steroid-resistant acute graft- versus-host disease. Blood. 2018;131(12):1372-1379. Marciniuk, DD, Hernandez P, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03805789

Study Details | NCT03805789 | The Safety and Efficacy of ... This study is a phase 2 / 3 prospective, double-blind, randomized, multicenter, placebo-controlled study for prevention of acute GVHD (aGVHD) in ...

7. trasci.com trasci.com/article/S1473-0502(24)00243-X/abstract

What is the role of alpha-1 antitrypsin in the management of ... Alpha-1 antitrypsin is a protease inhibitor and has anti-inflammatory and immune regulatory properties. Here we report the outcomes and safety data of 17 ...