Proof-of-concept Trial of Apraglutide in GVHD

Study Overview
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Brief Summary
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The aim of this trial is to assess safety and efficacy of apraglutide in subjects with steroid refractory gastrointestinal acute graft versus host disease (aGVHD).

Detailed Description
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This is an international, multicenter, randomized proof-of-concept trial to evaluate safety, tolerability, efficacy, durability of response, and clinical outcomes of apraglutide administration to subjects with steroid-refractory (SR) aGVHD of the lower GI tract being treated with systemic steroids (SS) and ruxolitinib (RUX).

Official Title
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A Randomized, Single-blind Trial to Evaluate the Safety and Efficacy of Apraglutide in Subjects With Grade II to IV (MAGIC) Steroid Refractory Gastrointestinal (GI) Acute Graft Versus Host Disease on Best Available Therapy

Conditions
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GVHD

Intervention / Treatment
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* Drug: Apraglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to give informed consent and agree to follow the details of participation as outlined in the protocol Male or female subjects aged 12 years or above at the time of consent and who weigh a minimum of 40 kg. Only subjects aged 18 years and above will be included in Germany. Clinically confirmed steroid refractory lower GI-aGVHD (MAGIC stage 1-4) prior to randomization Have undergone alloSCT from any donor source, any conditioning regimen Treated with SS plus RUX (RUX starts concomitantly to apraglutide or a maximum of 72 hours before apraglutide initiation) Women of childbearing potential (WOCBP): highly effective method of contraception and refrain from donating eggs during the trial and for 4 weeks after the End of Trial (EOT) visit Male subjects with partner WOCBP: contraception and abstention from sperm donation during the trial and for 2 weeks after the EOT visit Exclusion Criteria: Treatment with any systemic GVHD therapy other than SS and RUX including methotrexate and mycophenolate mofetil at the time of randomization / Day 0 Concomitant treatment with Janus kinase inhibitor other than RUX at the time of randomization Failed alloSCT due to relapse of underlying malignant disease Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-emptive treatment of malignancy recurrence Any use of enteral glutamine or GLP analogs or known ADA, within 6 months prior to randomization / Day 0 Significant organ system failures (respiratory renal hepatic and cardiac) Presence of relapsed primary malignancy or treatment for relapse after alloHSCT Presence or history of GI tumors (including the hepatobiliary system and pancreas) within the last five years before randomization Presence of colonic polyps not removed Active clinically uncontrolled infection or active tuberculosis Known chronic GVHD Known active GI inflammation not related to GI-aGVHD Major abdominal surgery in the last 6-months prior to randomization or history of clinically significant intestinal adhesions Abnormal liver function tests

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apraglutide Low Dose<br>Apraglutide SC injections, once weekly, for subjects with body weight of more than 50.0 kg. | Drug: Apraglutide<br>* Apraglutide is a new, synthetic glucagon-like peptide 2 (GLP-2) receptor agonist which acts as a gut targeted regenerative approach that is intestinotrophic with a mode of action that improves absorption and enhances gut barrier function.<br>|
| Experimental: Apraglutide High Dose<br>Apraglutide SC injections, once weekly, for subjects with body weight of more than 50.0 kg. | Drug: Apraglutide<br>* Apraglutide is a new, synthetic glucagon-like peptide 2 (GLP-2) receptor agonist which acts as a gut targeted regenerative approach that is intestinotrophic with a mode of action that improves absorption and enhances gut barrier function.<br>|
| Experimental: Apraglutide Standard Dose<br>Apraglutide SC injections, once weekly, for subjects with body weight between 40.0 kg to 49.9 kg. | Drug: Apraglutide<br>* Apraglutide is a new, synthetic glucagon-like peptide 2 (GLP-2) receptor agonist which acts as a gut targeted regenerative approach that is intestinotrophic with a mode of action that improves absorption and enhances gut barrier function.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AE) | System organ class, frequency and severity | From baseline to week 104 | 
| Occurrence of clinically relevant changes in vital signs | Systolic and diastolic blood pressure in mmHg | From baseline to week 104 | 
| Occurrence of clinically relevant changes in vital signs | Heart rate in Beats per Minute (BPM) | From baseline to week 104 | 
| Occurrence of clinically relevant changes in electrocardiogram | ECG QT Interval | From baseline to week 104 | 
| Occurrence of clinically relevant changes in electrocardiogram | ECG PR interval | From baseline to week 104 | 
| Occurrence of clinically relevant changes in electrocardiogram | ECG QRS interval | From baseline to week 104 | 
| Occurrence of clinically relevant changes in electrocardiogram | ECG rhythm | From baseline to week 104 | 
| Occurrence and titer anti-drug antibodies (ADA) | Number of subjects with anti-drug antibodies and their respective titers at specific time points. | From baseline to week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lower gastrointestinal-aGVHD response | Gastrointestinal-aGVHD response will be measured as a change of MAGIC stage for lower GI. Unit: Number of stools/day | At Days 14, 28, 56, 91, 119, 147, and 182 | 
| Overall response | Overall response will be measured as a change of MAGIC stage in any of the 4 organ systems. Measurement: MAGIC stage from 0 to 4 | At days 14, 28, 56, 91, 119, 147, and 182 | 
| Graft failure post-first dose of apraglutide | Incidence of graft failure | Baseline to 2 years | 
| Failure free survival post-first dose of apraglutide | The time from the date of randomization to the date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGVHD treatment. Unit: days | Baseline to 2 years | 
| Overall survival post-first dose of apraglutide |  | Baseline to 2 years | 
| Malignancy relapse/progression post-first dose of apraglutide | The time from date of randomization to hematologic disease relapse/progression. Unit:days | Baseline to 2 years | 
| Lower Gastrointestinal-GVHD relapse following complete GI response | Incidence of lower Gastrointestinal-aGVHD relapse following complete GI-response. Number of relapses Relapse is defined as GI flare: any increase in signs or symptoms of lower GI-aGVHD that is sustained for >24 h after an initial response (complete response or initial response) and requires re-escalation of immunosuppressive therapy. | Baseline to 2 years | 
| Absorption rate constant (ka) of apraglutide through population PK data analysis |  | Day 7 to day 56 | 
| Apparent clearance (CL/F) of apraglutide through population PK data analysis |  | Day 7 to day 56 | 
| Apparent volume of distribution (Vz/F) of apraglutide through population PK data analysis |  | Day 7 to day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft versus host disease, GVHD, GVHD, Acute, Steroid-refractory aGVHD, Gastrointestinal-GVHD, GI-GVHD