A Study to Evaluate Steroid-free Treatment for Standard-Risk aGVHD (BMT CTN 1501)

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT02806947
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Cancer Institute (NCI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Marrow Donor Program (Other)
• Enrollment: 127
• Locations: 21
• Arms: 2
• Actual Duration (Months): 28.6
• Patients Per Site: 6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The study is a Phase II randomized, open label, multicenter trial designed to identify whether sirolimus is a potential alternative to prednisone as an up-front treatment for patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk stratification. This trial incorporates both a novel up front GVHD therapy (sirolimus) as well as a novel BMT CTN developed acute GVHD biomarker test.

Condition or Disease	Intervention/Treatment	Phase
Acute GVHD	Drug: Sirolimus; Drug: Prednisone	Phase 2

Detailed Description

The study is a Phase II randomized, open label, multicenter trial designed to identify whether sirolimus is a potential alternative to prednisone as an up-front treatment for patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk stratification.

Patients with previously untreated, standard-risk acute GVHD, according to the refined Minnesota Criteria, who are in need of systemic therapy, will have a 5 mL blood sample collected prior to randomization to assess their biomarker Ann Arbor Risk status. Ann Arbor scoring results will be provided 48-72 hours after randomization. Patients will begin their study treatment assignments within 24 hours of randomization. Those with biomarker results of combined AA1/2 risk will continue on their randomized study treatment and will be included for primary endpoint analysis (Day 28 complete or partial response) and all planned study procedures and assessments. In contrast, patients with AA3 biomarker risk and those patients with missing biomarker results may continue on their randomized therapies or start another therapy at their physicians' discretion. In addition, AA3 risk patients and those with missing results will not be considered in primary endpoint analysis, but will be included in a subset analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 127 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Phase II, Multicenter, Open Label, Study Evaluating Sirolimus and Prednisone in Patients With Refined Minnesota Standard Risk, Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease (BMT CTN 1501)
• Actual Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Aug 17, 2018
• Actual Study Completion Date: Feb 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sirolimus Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established.	Drug: Sirolimus; Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.; Other Names: Rapamycin Rapamune®
Active Comparator: Prednisone Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.	Drug: Prednisone; Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.; Other Names: Deltasone® Orasone® Cortan® Sterapred®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment [Days 28 and 56 Post-randomization]

   Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash on 25-50% of BSA Rash on >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: <2 mg/dL 2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL >15 mg/dL GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus

Secondary Outcome Measures

1. Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day [Day 28 Post-randomization]

   The proportion of patients with CR/PR and on a prednisone-equivalent steroid dose of 0.25 mg/kg/day or less is evaluated. CR/PR scoring is in comparison to acute GVHD status at randomization. CR is defined as staging of 0 in all target organs. PR is defined as improvement in some organ(s) without worsening in others. Death and initiation of steroid-free, systemic acute GVHD treatment beyond randomized therapy are considered failures for this endpoint. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 mg/dL GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus

2. Acute GVHD Response [Days 28 and 56 Post-randomization]

   Acute GVHD response is classified as CR, PR, mixed response (MR), no response (NR), and progression and scored by comparison to acute GVHD status at randomization. MR is defined as improvement in some organ(s) with worsening in another, progression as worsening in some organ(s) without improvement in others, and NR as absence of any improvement or worsening. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus

3. Percentage of Participants With Treatment Failure [Days 28 and 56 Post-randomization]

   Treatment failure is defined as either no response (NR) or progression and scored by comparison to acute GVHD status at randomization. Progression is defined as worsening in some target organ(s) without improvement in others and NR is defined as absence of any improvement or worsening in target organs. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus

4. Percentage of Participants With Overall Survival [6 and 12 Months Post-randomization]

   Overall survival is defined as survival of death from any cause.

5. Percentage of Participants With Disease-free Survival [6 and 12 Months Post-randomization]

   Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.

6. Proportion of Participants With Event-free Survival [6 and 12 Months Post-randomization]

   Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.

7. Percentage of Participants With Non-relapse Mortality [6 and 12 Months Post-randomization]

   Non-relapse mortality is defined as death due to any cause other than relapse of the underlying malignancy. The cumulative incidence of non-relapse mortality is described, with malignancy relapse treated as a competing risk.

8. Percentage of Participants With Malignancy Relapse [6 and 12 Months Post-randomization]

   The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.

9. Percentage of Participants With Chronic GVHD [6 and 12 Months Post-randomization]

   Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. The cumulative incidence of chronic GVHD is described, with death and malignancy relapse treated as competing risks.

10. Percentage of Participants With GVHD-free Survival [6 and 12 Months Post-randomization]

    GVHD-free survival is defined as freedom from acute GVHD, chronic GVHD, and death. The proportion of participants alive and free of both acute and chronic GVHD are described at 6 and 12 months post-randomization.

11. Percentage of Participants With Serious Infections [6 and 12 Months Post-randomization]

    The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with standard-risk acute GVHD, according to refined Minnesota Criteria. Refined Minnesota Criteria are available at https://redcap.ahc.umn.edu/surveys/?s=bNmFhseJIf.

Standard-risk acute GVHD according to the refined Minnesota Risk Criteria requires meeting one of the criteria below:

1. Single organ involvement (Stage 1-3 skin, Stage 1 upper GI, or Stage 1-2 lower GI)

2. Multiple organ involvement (Stage 1-3 skin plus stage 1 upper GI, Stage 1-3 skin plus stage 1 lower GI, Stage 1-3 skin plus stage 1 lower GI plus stage 1 upper GI, Stage 1-3 skin plus stage 1-4 liver, or Stage 1 lower GI plus stage 1 upper GI)

3. Acute Minnesota Standard Risk GVHD requiring systemic immune suppressive therapy.

4. Acute GVHD developing after allogeneic hematopoietic cell transplantation using either bone marrow, peripheral blood, or umbilical cord blood. Recipients of non-myeloablative, reduced intensity conditioning and myeloablative transplants are eligible. All allogeneic donor sources are permitted, including siblings, unrelated donors, human leukocyte antigen (HLA)-haploidentical related donors and umbilical cord blood.

5. Patients NOT receiving systemic immune suppressive therapy for treatment of active GVHD (topical skin and GI corticosteroids are allowed).

6. Ability to tolerate oral or enterically-administered medications.

7. Patients of all ages.

8. Absolute neutrophil count (ANC) greater than 500/µL.

9. Biopsy confirmation of GVHD is not required. Enrollment should not be delayed for biopsy or pathology results unless local institutional practice mandates biopsy confirmation to make a GVHD treatment decision.

10. Written informed consent and/or assent from patient, parent or guardian.

11. Collection of a 5 ml blood sample (red top for serum) from the patient for Ann Arbor Scoring and ready to be shipped immediately after randomization.

Exclusion Criteria:

1. Patients receiving sirolimus (for any indication including GVHD prophylaxis) within 14 days of screening for enrollment.

2. Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immune suppression.

3. Patients with acute GVHD developing after a donor lymphocyte infusion.

4. Active or recent (within 7 days) episode of transplant associated microangiopathy.

5. Patients with uncontrolled infections will be excluded. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

6. Patients unlikely to be available for evaluation at the transplant center on Day 28 and 56 of therapy.

7. A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment.

8. Patients receiving corticosteroids for any indication within 7 days before the onset of acute GVHD, except the following: Stable replacement doses of corticosteroids for adrenal insufficiency are permitted (e.g. hydrocortisone total dose of 10-12 mg/m^2/day or prednisone 5-7.5mg daily or equivalent). Corticosteroids administered as premedication before transfusion of blood products or before intravenous medications to prevent infusion reactions are allowed.

9. Patients who are pregnant or breastfeeding.

10. Females of childbearing potential (FCBP) or a man who has sexual contact with a FCBP and is unwilling to use effective birth control for the duration of the study.

11. Patients on dialysis.

12. Patients on mechanical ventilation.

13. Patients with severe hepatic sinusoidal obstruction syndrome who in the judgment of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment.

14. Patients with a history of hypersensitivity to sirolimus or any component of the formulation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	University of Florida College of Medicine (Shands)	Gainesville	Florida	United States	32610
4	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33612
5	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
6	Emory University	Atlanta	Georgia	United States	30322
7	Blood & Marrow Transplant Program at Northside Hospital	Atlanta	Georgia	United States	30342
8	University of Kansas Hospital	Kansas City	Kansas	United States	66160
9	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48105
10	University of Minnesota	Minneapolis	Minnesota	United States	55455
11	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
12	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri	United States	63110
13	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
14	Duke University Medical Center	Durham	North Carolina	United States	27705
15	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
16	Ohio State/Arthur G. James Cancer Hospital	Columbus	Ohio	United States	43210
17	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
18	University of Texas/MD Anderson Cancer Center	Houston	Texas	United States	77030
19	Virginia Commonwealth University MCV Hospitals	Richmond	Virginia	United States	23298
20	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
21	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Medical College of Wisconsin
• National Heart, Lung, and Blood Institute (NHLBI)
• National Cancer Institute (NCI)
• Blood and Marrow Transplant Clinical Trials Network
• National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research

Study Documents (Full-Text)

• Study Protocol - Jul 7, 2017
• Statistical Analysis Plan - Jun 7, 2018

More Information

Additional Information:

• Blood and Marrow Transplant Clinical Trials Network Website
• National Marrow Donor Program

Publications

• Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02806947
• Other Study ID Numbers: BMT CTN 1501; 2U10HL069294-11; 5U24CA076518
• First Posted: Jun 21, 2016
• Last Update Posted: Nov 1, 2021
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Medical College of Wisconsin: Acute GVHD; Standard-Risk; Sirolimus; Refined Minnesota Risk Criteria; Ann Arbor; Biomarker; Steroid-Free
• Additional relevant MeSH terms: Sirolimus; Prednisone

Study Results

Participant Flow

Pre-assignment Detail	The primary analysis population includes only participants with an AA score of 1 or 2 (n=64 on the prednisone arm, n=58 on the sirolimus arm). Three participants on the prednisone arm and two on the sirolimus arm were excluded because they had an AA score of 3 or missing.

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Period Title: Overall Study
STARTED	58	64
COMPLETED	53	63
NOT COMPLETED	5	1

Baseline Characteristics

Arm/Group Title	Sirolimus	Prednisone	Total
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.	Total of all reporting groups
Overall Participants	58	64	122
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58.0	52.4	54.6
Sex: Female, Male (Count of Participants)
Female	21 36.2%	31 48.4%	52 42.6%
Male	37 63.8%	33 51.6%	70 57.4%
Race/Ethnicity, Customized (Count of Participants)
American Indian / Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.7%	1 1.6%	2 1.6%
Hawaiian/Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.7%	2 3.1%	3 2.5%
White	55 94.8%	59 92.2%	114 93.4%
Multiracial	0 0%	0 0%	0 0%
Unknown	1 1.7%	2 3.1%	3 2.5%
Ann Arbor Biomarker Risk Score (Count of Participants)
1	38 65.5%	45 70.3%	83 68%
2	20 34.5%	19 29.7%	39 32%
Skin Abnormalities at Enrollment (Count of Participants)
No active GVHD rash	20 34.5%	19 29.7%	39 32%
Maculopapular Rash <25% body surface area	8 13.8%	11 17.2%	19 15.6%
Maculopapular Rash 25-50% body surface area	14 24.1%	13 20.3%	27 22.1%
Maculopapular Rash >50% body surface area	16 27.6%	21 32.8%	37 30.3%
Upper GI Abnormalities at Enrollment (Count of Participants)
No or Intermittent Nausea, Vomiting, or Anorexia	32 55.2%	36 56.3%	68 55.7%
Persistent Nausea, Vomiting, or Anorexia	26 44.8%	28 43.8%	54 44.3%
Lower GI Abnormalities at Enrollment (Count of Participants)
No Diarrhea	53 91.4%	46 71.9%	99 81.1%
Adult: <500 mL/day, Child: <10mL/kg/day	3 5.2%	10 15.6%	13 10.7%
Adult: 500-999mL/day, Child: 10-19.9mL/kg/day	2 3.4%	7 10.9%	9 7.4%
Adult: 1000-1500mL/day, Child: 20-30mL/kg/day	0 0%	1 1.6%	1 0.8%
Liver Abnormalities at Enrollment (Count of Participants)
Bilirubin <2.0mg/dL	58 100%	63 98.4%	121 99.2%
Bilirubin 2.0-3.0mg/dL	0 0%	1 1.6%	1 0.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment
Description	Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash on 25-50% of BSA Rash on >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: <2 mg/dL 2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL >15 mg/dL GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus
Time Frame	Days 28 and 56 Post-randomization

Outcome Measure Data

Analysis Population Description

CR/PR was evaluated in participants remaining on study until the assessment time point. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Yes	35 60.3%	46 71.9%
No	19 32.8%	17 26.6%
Yes	34 58.6%	50 78.1%
No	19 32.8%	13 20.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The primary objective of this Phase II trial was to describe the proportion of patients with Day 28 CR/PR in each treatment arm and to estimate the risk difference of these rates using a point estimate and 90% confidence interval. These estimates are used to inform about the efficacy of sirolimus in contrast to prednisone for potential future research.
	Type of Statistical Test	Other
	Comments	No formal hypothesis test was planned or performed for comparing Day 28 CR/PR proportions between arms. Rather, the risk difference is estimated by a point estimate and 90% confidence interval.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.082
	Confidence Interval	(2-Sided) 90%; -0.223 to 0.059
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.086
	Estimation Comments	The risk difference estimate is the observed proportion of Day 28 CR/PR in the sirolimus arm minus the proportion in the prednisone arm. A Wald confidence interval for this difference is given.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	A secondary objective of this Phase II trial was to describe the proportion of patients with Day 56 CR/PR in each treatment arm and to estimate the risk difference of these rates using a point estimate and 95% confidence interval. These estimates are used to inform about the efficacy of sirolimus in contrast to prednisone for potential future research.
	Type of Statistical Test	Other
	Comments	No formal hypothesis test was planned or performed for comparing Day 56 CR/PR proportions between arms. Rather, the risk difference is estimated by a point estimate and 95% confidence interval.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.152
	Confidence Interval	(2-Sided) 95%; -0.315 to 0.011
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	The risk difference estimate is the observed proportion of Day 56 CR/PR in the sirolimus arm minus the proportion in the prednisone arm. A Wald confidence interval for this difference is given.

2. Secondary Outcome

Title	Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day
Description	The proportion of patients with CR/PR and on a prednisone-equivalent steroid dose of 0.25 mg/kg/day or less is evaluated. CR/PR scoring is in comparison to acute GVHD status at randomization. CR is defined as staging of 0 in all target organs. PR is defined as improvement in some organ(s) without worsening in others. Death and initiation of steroid-free, systemic acute GVHD treatment beyond randomized therapy are considered failures for this endpoint. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 mg/dL GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus
Time Frame	Day 28 Post-randomization

Outcome Measure Data

Analysis Population Description

The endpoint was evaluated only in participants that remained on study until Day 28. One participant on the prednisone arm and four on the sirolimus arm were deemed unevaluable at Day 28 due to prior study withdrawal.

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	54	63
Yes	36 62.1%	20 31.3%
No	18 31%	43 67.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with CR/PR and steroid dose of 0.25mg/kg/day or less at Day 28 post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Z test comparing binomial proportions
	Comments

3. Secondary Outcome

Title	Acute GVHD Response
Description	Acute GVHD response is classified as CR, PR, mixed response (MR), no response (NR), and progression and scored by comparison to acute GVHD status at randomization. MR is defined as improvement in some organ(s) with worsening in another, progression as worsening in some organ(s) without improvement in others, and NR as absence of any improvement or worsening. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus
Time Frame	Days 28 and 56 Post-randomization

Outcome Measure Data

Analysis Population Description

Acute GVHD response was evaluated in participants remaining on study until the assessment day. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Complete Response (CR)	30 51.7%	39 60.9%
Partial Response (PR)	5 8.6%	7 10.9%
Mixed Response (MR)	1 1.7%	5 7.8%
No Response (NR)	16 27.6%	11 17.2%
Progression	2 3.4%	1 1.6%
Complete Response (CR)	30 51.7%	48 75%
Partial Response (PR)	4 6.9%	2 3.1%
Mixed Response (MR)	0 0%	0 0%
No Response (NR)	19 32.8%	10 15.6%
Progression	0 0%	3 4.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in classification of acute GVHD response at Day 28 post-randomization between participants on the sirolimus and prednisone arms. These classifications were compared between treatment arms using Fisher's exact test, due to the presence of small numbers of participants in some categories.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.320
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in classification of acute GVHD response at Day 56 post-randomization between participants on the sirolimus and prednisone arms. These classifications were compared between treatment arms using Fisher's exact test, due to the presence of small numbers of participants in some categories.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Percentage of Participants With Treatment Failure
Description	Treatment failure is defined as either no response (NR) or progression and scored by comparison to acute GVHD status at randomization. Progression is defined as worsening in some target organ(s) without improvement in others and NR is defined as absence of any improvement or worsening in target organs. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus
Time Frame	Days 28 and 56 Post-randomization

Outcome Measure Data

Analysis Population Description

Treatment failure was evaluated in participants remaining on study until the assessment day. At Day 28, one prednisone and four sirolimus arm participants were excluded from the analysis due to prior study withdrawal. At Day 56, one prednisone and five sirolimus arm participants were excluded from the analysis due to prior study withdrawal.

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Yes	18 31%	12 18.8%
No	36 62.1%	51 79.7%
Yes	19 32.8%	13 20.3%
No	34 58.6%	50 78.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with treatment failure at Day 28 post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.078
	Comments	Statistical significance was determine using a pre-specified threshold of 0.05
	Method	Z test comparing binomial proportions
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with treatment failure at Day 56 post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.068
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Z test comparing binomial proportions
	Comments

5. Secondary Outcome

Title	Percentage of Participants With Overall Survival
Description	Overall survival is defined as survival of death from any cause.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Overall Survival at 6 Months	81.9 141.2%	82.7 129.2%
Overall Survival at 12 Months	76.3 131.6%	73.2 114.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with overall survival between the sirolimus and prednisone arms during the 12 month period post-randomization. These proportions were compared between treatment arms using a log rank test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.785
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	Percentage of Participants With Disease-free Survival
Description	Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Disease-free Survival at 6 Months	72.8 125.5%	78.1 122%
Disease-free Survival at 12 Months	61.6 106.2%	70.2 109.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with disease-free survival between the sirolimus and prednisone arms during the 12 month period post-randomization. These proportions were compared between treatment arms using a log rank test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.340
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Log Rank
	Comments

7. Secondary Outcome

Title	Proportion of Participants With Event-free Survival
Description	Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Event-free Survival at 6 Months	47.3 81.6%	43.7 68.3%
Event-free Survival at 12 Months	35.9 61.9%	31.2 48.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with event-free survival between the sirolimus and prednisone arms during the 12 month period post-randomization. These proportions were compared between treatment arms using a log rank test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.713
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Log Rank
	Comments

8. Secondary Outcome

Title	Percentage of Participants With Non-relapse Mortality
Description	Non-relapse mortality is defined as death due to any cause other than relapse of the underlying malignancy. The cumulative incidence of non-relapse mortality is described, with malignancy relapse treated as a competing risk.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Non-relapse Mortality at 6 Months	12.7 21.9%	9.4 14.7%
Non-relapse Mortality at 12 Months	16.5 28.4%	14.2 22.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with non-relapse mortality between the sirolimus and prednisone arms during the 12 month period post-randomization, with malignancy relapse treated as a competing risk for non-relapse mortality. These proportions were compared between treatment arms using Gray's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.726
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Gray's test
	Comments

9. Secondary Outcome

Title	Percentage of Participants With Malignancy Relapse
Description	The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Malignancy Relapse at 6 Months	14.5 25%	12.5 19.5%
Malignancy Relapse at 12 Months	21.9 37.8%	15.7 24.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with malignancy relapse between the sirolimus and prednisone arms during the 12 month period post-randomization, with death treated as a competing risk for malignancy relapse. These proportions were compared between treatment arms using Gray's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.402
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Gray's test
	Comments

10. Secondary Outcome

Title	Percentage of Participants With Chronic GVHD
Description	Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. The cumulative incidence of chronic GVHD is described, with death and malignancy relapse treated as competing risks.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Chronic GVHD at 6 Months	25.7 44.3%	31.2 48.8%
Chronic GVHD at 12 Months	31.4 54.1%	40.6 63.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with chronic GVHD between the sirolimus and prednisone arms during the 12 month period post-randomization, with death and malignancy relapse treated as competing risks for chronic GVHD. These proportions were compared between treatment arms using Gray's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.296
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Gray's test
	Comments

11. Secondary Outcome

Title	Percentage of Participants With GVHD-free Survival
Description	GVHD-free survival is defined as freedom from acute GVHD, chronic GVHD, and death. The proportion of participants alive and free of both acute and chronic GVHD are described at 6 and 12 months post-randomization.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

GVHD-free survival was evaluated only in participants that remained on study until the assessment time point. One participant on the prednisone arm and five on the sirolimus arm were excluded from the analysis at 6 and 12 months due to prior study withdrawal.

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
GVHD-free Survival at 6 Months	45.3 78.1%	46.0 71.9%
GVHD-free Survival at 12 Months	50.9 87.8%	46.0 71.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with GVHD-free survival at 6 months post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.936
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Z test comparing binomial proportions
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with GVHD-free survival at 6 months post-randomization between the sirolimus and prednisone arms. These proportions were compared between treatment arms using a Z test of the difference of binomial proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.598
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Z test comparing binomial proportions
	Comments

12. Secondary Outcome

Title	Percentage of Participants With Serious Infections
Description	The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk.
Time Frame	6 and 12 Months Post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus	Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Measure Participants	58	64
Seirious Infections at 6 Months	30.4 52.4%	43.8 68.4%
Seirious Infections at 12 Months	39.6 68.3%	51.8 80.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus, Prednisone
	Comments	The null hypothesis is that there is no difference in the proportions of participants with serious infections between the sirolimus and prednisone arms during the 12 month period post-randomization, with death treated as a competing risk for serious infection. These proportions were compared between treatment arms using Gray's test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.221
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05
	Method	Gray's test
	Comments

Adverse Events

Time Frame	1 Year Post-randomization
Arm/Group Title	Sirolimus		Prednisone
Arm/Group Description	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Sirolimus: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.		Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. Prednisone: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
All Cause Mortality
	Sirolimus		Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/58 (20.7%)		17/64 (26.6%)
Serious Adverse Events
	Sirolimus		Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/58 (13.8%)		3/64 (4.7%)
Gastrointestinal disorders
Small intestinal obstruction	1/58 (1.7%)	1	0/64 (0%)	0
Hepatobiliary disorders
Hepatic cirrhosis	1/58 (1.7%)	1	0/64 (0%)	0
Infections and infestations
Appendicitis	1/58 (1.7%)	1	0/64 (0%)	0
Diverticulitis	1/58 (1.7%)	1	0/64 (0%)	0
Pneumonia	1/58 (1.7%)	1	0/64 (0%)	0
Metabolism and nutrition disorders
Failure to thrive	1/58 (1.7%)	1	0/64 (0%)	0
Psychiatric disorders
Delirium	0/58 (0%)	0	1/64 (1.6%)	1
Mental status changes	1/58 (1.7%)	1	0/64 (0%)	0
Renal and urinary disorders
Cystitis noninfective	0/58 (0%)	0	1/64 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/58 (0%)	0	1/64 (1.6%)	1
Pulmonary embolism	1/58 (1.7%)	1	0/64 (0%)	0
Other (Not Including Serious) Adverse Events
	Sirolimus		Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/64 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.