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

Phase 2

Terminated

Conditions: Graft Versus Host Disease

Interventions: Biological: GLASSIA
Drug: methylprednisolone or equivalent steroid
Biological: Albumin

Registration Number: NCT02956122

Lead Sponsor: Baxalta now part of Shire

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Study Part 1 - All Participants - GLASSIA	methylprednisolone or equivalent steroid	Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)
Study Part 2 - GLASSIA	GLASSIA	Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)
Study Part 2 - GLASSIA	methylprednisolone or equivalent steroid	Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)
Study Part 1 - All Participants - GLASSIA	GLASSIA	Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)
Study Part 2 - Albumin (Control)	methylprednisolone or equivalent steroid	Participants to receive control (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)
Study Part 2 - Albumin (Control)	Albumin	Participants to receive control (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving Overall Response (OR) At Day 28	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.

Secondary Outcome Measures

Name	Time	Method
Incidence of Chronic Graft-versus-host Disease (GvHD)	Days 180 and 365	Incidence of chronic GvHD at Days 180 and 365 was reported.
Transplant-related Mortality	Days 28, 56, 100 and 180	Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant).
Percentage of Participants Achieving Overall Response at Day 56	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.
Acute Graft-versus-host Disease (GvHD) Grading at Days 28, 56 and 180	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.
Overall Survival (OS) - Percentage of Participants With an Event	Days 100, 180 and 365	OS was defined as the time from the date of randomization to the date of death due to any cause.
Percentage of Participants Achieving Gastrointestinal (GI) Response at Day 28	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.
Apparent Volume of Distribution at Steady State (Vss) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	Vss of GLASSIA was reported.
Duration of Overall Response (OR)	Baseline up to Day 365	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.
Graft-versus-host Disease (GvHD)-Free Survival - Percentage of Participants With an Event	Days 28, 56, 100, 180 and 365	GVHD-free survival was defined as being alive without previous onset of acute GVHD or chronic GVHD requiring immunosuppressive therapy.
Number of Participants With Clinically Significant Changes in Vital Signs	Baseline up to Day 56	Vital signs included body temperature, respiratory rate, pulse rate and systolic and diastolic blood pressure.
Number of Participants With Recurrence of Primary Malignancies	Baseline up to Day 365	Incidence of recurrence of primary malignancies was reported.
Maximum Observed Plasma Concentration (Cmax) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	Cmax of GLASSIA was reported.
Apparent Terminal Half-life (t1/2) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	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.
Duration of Gastrointestinal (GI) Response	Baseline up to Day 365	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.
Infection-related Mortality - Percentage of Participants With an Event	Days 28, 56, 100 and 180	Infection-related mortality was determined by the investigator (any deaths considered related to infection \[including infections related to hematopoietic stem cell transplant {HSCT}\]).
Number of Participants With Adverse Events (AEs), Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs and Temporally-associated AEs	From start of study drug administration up to 371 days	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.
Area Under the Plasma Concentration Curve From Time Zero to Time "t" AUC(0-t) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	AUC(0-t) of GLASSIA was reported.
Trough Plasma Concentration at Steady State (Ctrough) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	Ctrough of GLASSIA was not assessed due to the termination of the study.
Failure-free Survival - Percentage of Participants With an Event	Days 100 and 180	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.
Graft-versus-host Disease (GvHD)-Related Mortality - Percentage of Participants With an Event	Days 28, 56, 100 and 180	Graft-versus-host disease (GvHD)-related mortality was determined by the investigator (any deaths considered related to GvHD).
All-cause Mortality - Percentage of Participants With an Event	Days 28, 56, 100 and 180	All-cause mortality was defined as the time from HSCT to death due to any cause.
Number of Participants With Clinically Significant Changes in Clinical Laboratory Assessments	Baseline up to Day 56	Clinical laboratory assessments such as hematology, clinical chemistry, lipid and coagulation panels and urinalysis were performed.
Area Under the Plasma Concentration Curve (AUC0-inf) From Time Zero to Infinity	Day 1: through 48 hours; Day 13: through 48 hours; Day 22 and Day 50: through approximately 168 hours	AUC of GLASSIA was reported.
Systemic Clearance at Steady State (CLss) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	CLss of GLASSIA was reported.
Mean Residence Time (MRT) of GLASSIA	Day 1: through 48 hours, Day 13: through 48 hours, Day 22 and Day 50: through approximately 168 hours	MRT of GLASSIA was not calculated.