A Phase 2/3 Study of GLASSIA for the Treatment of Acute GvHD

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the safety and efficacy of GLASSIA as an add-on biopharmacotherapy to standard-of-care steroid treatment as the first-line treatment in participants with acute GvHD with lower GI involvement.

Official Title
-----------------
A Two-Part, Multi-Center, Prospective, Phase 2/3 Clinical Study to Evaluate the Safety and Efficacy of GLASSIA as an Add-On Biopharmacotherapy to Conventional Steroid Treatment in Subjects With Acute Graft-Versus-Host Disease With Lower Gastrointestinal Involvement

Conditions
-----------------
Graft Versus Host Disease

Intervention / Treatment
-----------------
* Biological: GLASSIA
* Drug: methylprednisolone or equivalent steroid
* Biological: Albumin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female participants aged ≥18 years at the time of screening Recipient of an hematopoietic stem cell transplantation (HSCT) The disease indication for which the participant required HSCT must be in remission Newly diagnosed acute graft-versus-host disease (GvHD), including lower Gastrointestinal (GI) involvement (modified International Bone Marrow Transplant Registry [IBMTR] Severity Stage 1 to 4 [>500 mL diarrhea/day]), with or without other organ system involvement. Willing to undergo or must have had a lower GI biopsy within 7 days of informed consent to confirm GI GvHD. Biopsy results are not needed to initiate treatment; however, if biopsy results are not consistent with aGvHD, treatment with GLASSIA will be discontinued. Participants must be receiving systemic corticosteroids. Treatment with methylprednisolone/systemic steroids must have been initiated within 72 hours prior to the first dose of study treatment after enrollment Evidence of myeloid engraftment (absolute neutrophil count ≥0.5 x 10^9/L) Lower GI GvHD manifested by diarrhea must have other causes of diarrhea ruled out (eg, negative for Clostridium difficile or cytomegalovirus [CMV] infection or oral magnesium administration) Karnofsky Performance Score ≥50% If female of childbearing potential, participant presents with a negative blood pregnancy test Females of childbearing potential with a fertile male sexual partner must agree to employ adequate contraception for the duration of the study. Males must use adequate contraception and must not donate sperm for the duration of the study. Participant is willing and able to comply with the requirements of the protocol Exclusion Criteria: Participant with manifestations of chronic GvHD Participant with acute/chronic GvHD overlap syndrome Participant whose GvHD developed after donor lymphocyte infusion Participant with myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to the first dose of study treatment, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant Participant with evidence of recurrent malignancy Participant with veno-occlusive disease (ie, sinusoidal obstruction syndrome) Participant receiving GvHD treatment other than continued prophylaxis (eg, cyclosporine and/or mycophenolate mofetil, etc) or corticosteroid therapy. In addition, a participant who received the first dose of corticosteroid therapy for acute GvHD with lower GI involvement more than 72 hours before the first dose of study treatment is not eligible for the study Participant with severe sepsis involving at least 1 organ failure Participant who is seropositive or positive in the nucleic acid test for human immunodeficiency virus (HIV) Participant with active hepatitis B or C Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study If female, participant is pregnant or lactating at the time of enrollment, or has plans to become pregnant during the study Participant with a serious medical or psychiatric illness likely to interfere with participation in the study Participant is a family member or employee of the investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Part 1 - All Participants - GLASSIA<br>Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion) | Biological: GLASSIA<br>* GLASSIA [Alpha1-Proteinase Inhibitor (Human)]<br>* Other names: alpha-1 proteinase inhibitor;Drug: methylprednisolone or equivalent steroid<br>* The conventional steroid treatment (methylprednisolone or equivalent steroid) will be supplied by the investigators per their institutional practice.<br>|
| Experimental: Study Part 2 - GLASSIA<br>Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion) | Biological: GLASSIA<br>* GLASSIA [Alpha1-Proteinase Inhibitor (Human)]<br>* Other names: alpha-1 proteinase inhibitor;Drug: methylprednisolone or equivalent steroid<br>* The conventional steroid treatment (methylprednisolone or equivalent steroid) will be supplied by the investigators per their institutional practice.<br>|
| Placebo Comparator: Study Part 2 - Albumin (Control)<br>Participants to receive control (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion) | Drug: methylprednisolone or equivalent steroid<br>* The conventional steroid treatment (methylprednisolone or equivalent steroid) will be supplied by the investigators per their institutional practice.<br>Biological: Albumin<br>* The control vials contain human albumin 20% in 50 mL normal saline solution in glass vials (for non-United States (US) Countries), or Flexbumin 25% in 50 mL in normal saline solution in plastic IV bags (for US).<br>* Other names: Human Albumin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Overall Response (OR) At Day 28 | OR was defined as graft-versus-host disease (GvHD) complete response (CR) + partial response (PR), defined as: - GvHD CR was complete resolution of all signs and symptoms of acute GvHD in all organs without intervening salvage and GvHD PR was improvement of 1 stage in 1 or more organs involved in GvHD without progression in other organs. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Gastrointestinal (GI) Response at Day 28 | GI response was defined as complete response (CR) + partial response (PR), defined as: - GI CR was able to eat; not requiring parenteral nutrition, and passing primarily formed stools - GI PR was decrease in need for parenteral nutrition to less than or equal to (<=) 50% of required calories; and reduction of stool volume by greater than or equal to (>=) 50%, without ileus. | Day 28 | 
| Percentage of Participants Achieving Overall Response at Day 56 | Overall response was defined as graft-versus-host disease (GvHD) complete response (CR) + partial response (PR), defined as: - GvHD CR was complete resolution of all signs and symptoms of acute GvHD in all organs without intervening salvage - GvHD PR was improvement of 1 stage in 1 or more organs involved in GvHD without progression in other organs. | Day 56 | 
| Acute Graft-versus-host Disease (GvHD) Grading at Days 28, 56 and 180 | Grading of GvHD was performed by the investigator according to the modified International Bone Marrow Transplant Registry (IBMTR) grading system which classifies the degree of involvement of each organ system by stage on a scale of 0 to 4. The degree of skin involvement was staged depending upon degree and severity of the lesions: Stage 1: Maculopapular rash over less than (<) 25% of body area, Stage 2: Maculopapular rash over 25 to 50% of body area, Stage 3: Generalized erythroderma, Stage 4: Generalized erythroderma with bullous formation. Degree of GI involvement was staged based on severity of diarrhoea: Stage 1: 500 to 1000 mL/day,Stage 2: 1000 to 1500 mL/day, Stage 3: 1500 to 2000 mL/day, Stage 4: greater than (>) 2000 mL/day OR pain OR ileus. Degree of liver involvement was staged based upon serum total bilirubin level as follows: Stage 1: 2 to 3 mg/dL, Stage 2: 3 to 6 mg/dL, Stage 3: 6 to 15 mg/dL, Stage 4: >15 mg/dL. | Days 28, 56 and 180 | 
| Incidence of Chronic Graft-versus-host Disease (GvHD) | Incidence of chronic GvHD at Days 180 and 365 was reported. | Days 180 and 365 | 
| Duration of Overall Response (OR) | OR was defined as GvHD CR + PR, defined as: - GvHD CR was complete resolution of all signs and symptoms of acute GvHD in all organs without intervening salvage - GvHD PR was improvement of 1 stage in 1 or more organs involved in GvHD without progression in other organs. Duration of OR was not assessed due to the termination of the study. | Baseline up to Day 365 | 
| Duration of Gastrointestinal (GI) Response | GI response was defined as CR + PR, defined as: - GI CR was able to eat; not requiring parenteral nutrition, and passing primarily formed stools - GI PR was decrease in need for parenteral nutrition to <= 50% of required calories; and reduction of stool volume by >= 50%, without ileus. Duration of GI response was not assessed due to the termination of the study. | Baseline up to Day 365 | 
| Overall Survival (OS) - Percentage of Participants With an Event | OS was defined as the time from the date of randomization to the date of death due to any cause. | Days 100, 180 and 365 | 
| Transplant-related Mortality | Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant). | Days 28, 56, 100 and 180 | 
| Failure-free Survival - Percentage of Participants With an Event | Failure-free survival was defined as the absence of all of the following criteria: Need for second-line treatment for acute GvHD, Non-relapse mortality (death during continuous complete remission) and recurrent malignancy. | Days 100 and 180 | 
| Graft-versus-host Disease (GvHD)-Free Survival - Percentage of Participants With an Event | GVHD-free survival was defined as being alive without previous onset of acute GVHD or chronic GVHD requiring immunosuppressive therapy. | Days 28, 56, 100, 180 and 365 | 
| Infection-related Mortality - Percentage of Participants With an Event | Infection-related mortality was determined by the investigator (any deaths considered related to infection [including infections related to hematopoietic stem cell transplant {HSCT}]). | Days 28, 56, 100 and 180 | 
| Graft-versus-host Disease (GvHD)-Related Mortality - Percentage of Participants With an Event | Graft-versus-host disease (GvHD)-related mortality was determined by the investigator (any deaths considered related to GvHD). | Days 28, 56, 100 and 180 | 
| All-cause Mortality - Percentage of Participants With an Event | All-cause mortality was defined as the time from HSCT to death due to any cause. | Days 28, 56, 100 and 180 | 
| Number of Participants With Adverse Events (AEs), Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs and Temporally-associated AEs | An AE was defined as any untoward medical occurrence in a participant administered an investigational product (IP) that does not necessarily have a causal relationship with the treatment. An SAE was defined as an untoward medical occurrence that at any dose meets one or more of the following criteria: outcome was fatal/results in death, life-threatening, required inpatient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. | From start of study drug administration up to 371 days | 
| Number of Participants With Clinically Significant Changes in Clinical Laboratory Assessments | Clinical laboratory assessments such as hematology, clinical chemistry, lipid and coagulation panels and urinalysis were performed. | Baseline up to Day 56 | 
| Number of Participants With Clinically Significant Changes in Vital Signs | Vital signs included body temperature, respiratory rate, pulse rate and systolic and diastolic blood pressure. | Baseline up to Day 56 | 
| Number of Participants With Recurrence of Primary Malignancies | Incidence of recurrence of primary malignancies was reported. | Baseline up to Day 365 | 
| Area Under the Plasma Concentration Curve (AUC0-inf) From Time Zero to Infinity | AUC of GLASSIA was reported. | Day 1: through 48 hours; Day 13: through 48 hours; Day 22 and Day 50: through approximately 168 hours | 
| Area Under the Plasma Concentration Curve From Time Zero to Time t AUC(0-t) of GLASSIA | AUC(0-t) of GLASSIA was reported. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours | 
| Systemic Clearance at Steady State (CLss) of GLASSIA | CLss of GLASSIA was reported. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours | 
| Maximum Observed Plasma Concentration (Cmax) of GLASSIA | Cmax of GLASSIA was reported. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours | 
| Apparent Volume of Distribution at Steady State (Vss) of GLASSIA | Vss of GLASSIA was reported. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours | 
| Apparent Terminal Half-life (t1/2) of GLASSIA | Apparent terminal half-life (hour), determined as ln2/lambda-z. lambda-z is the apparent terminal rate constant (one per hour), determined by linear regression of the terminal points of the log-linear concentration-time curve. Visual assessment will be used to identify the terminal linear phase of the concentration-time profile. A minimum of 3 data points will be used for determination. t1/2 of GLASSIA was reported. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours | 
| Mean Residence Time (MRT) of GLASSIA | MRT of GLASSIA was not calculated. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours | 
| Trough Plasma Concentration at Steady State (Ctrough) of GLASSIA | Ctrough of GLASSIA was not assessed due to the termination of the study. | Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours |