Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma
Phase: PHASE2
Conditions: Hypertension, Osteonecrosis, Osteonecrosis Due to Drug
Sponsor: St. Jude Children's Research Hospital

HYPERION
Revision 1.1, dated 02-15-2021 
Protocol document date: 02-15-2021
St. Jude
HYPERION-NCT04401267 
Initial version, dated: 02-06-2020. Resubmitted to IRB 02-19-2020. IRB approved 02-19-2020. 
Resubmitted to CT-SRC 05-06-2020
Amendment 1.0, dated 05-06-2020 (resubmitted to IRB for review of CT-SRC changes). IRB 
approved: 08-12-2020). Activation date: 08-28-2020
Revision 1.1, dated 02-15-2021 (IRB approved: 
). Activation date:
HYPERTENSION INTERVENTION TO REDUCE OSTEONECROSIS IN CHILDREN 
WITH ACUTE LYMPHOBLASTIC LEUKEMIA/ LYMPHOMA
Principal Investigator
Seth Karol, MD
Departmental of Oncology
Co-Investigators
Hiroto Inaba, MD, PhD1
Ching-Hon Pui, MD1
Noel Delos Santos2
Cara Morin, MD, PhD3
Sue Kaste, DO3
Daniel Mulrooney, MD, MS14
Kirsten K. Ness, PT, PhD4
Gary Beasley, MD2
Erica Kaye, MD1
Cheng Cheng, PhD5
Aaryani Tipirneni-Sajja, PhD3
1Department of Oncology, 2Department of Pediatric Medicine, 3Department of Diagnostic 
Imaging, 4Department of Epidemiology/Cancer Control, 5Department of Biostatistics
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, Tennessee 38105-3678
Telephone:  (901) 595-3300
Contents of this document may not be extracted without permission from the Principal Investigator.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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List of Collaborating Investigators/Institutions
Kenneth M. Heym, MD
Cook Children’s Medical Center
1500 Cooper St.
Fort Worth, TX 76104
 
Norman J. Lacayo, MD
Lucile Packard Children's Hospital 
Stanford University / Stanford Cancer Institute
725 Welch Rd.
Palo Alto, CA 94304
Deborah E. Schiff, MD
Rady Children’s Hospital-San Diego
3020 Children’s Way, MC 5035
San Diego, CA 92123
   
Jeffrey W. Taub, MD, FAAP
Children’s Hospital of Michigan
3901 Beaubien Blvd
Detroit, MI 48201
   
Jessica Bell, MD
Novant Health Hemby Children’s Hospital
301 Hawthorne Lane, Suite 100
Charlotte, NC
 
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
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Protocol Summary
HYPERION: Hypertension Intervention to Reduce Osteonecrosis in Children with Acute 
Lymphoblastic Leukemia
Principal Investigator: Seth Karol, MD
IND Holder: N/A
Brief Overview: This is a randomized Phase II clinical trial evaluating the impact of intensive 
antihypertensive control (targeted to the 50-75th percentile for age, sex, and height) compared to 
conventional antihypertensive control (targeted to the 90-95th percentile for age, sex, and height) 
on the incidence of radiographically extensive osteonecrosis in children and young adults 
receiving treatment for newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL).
Intervention: Patients will be treated for hypertension to achieve the goal systolic blood 
pressure indicated by their intervention arm.
Brief Outline of Treatment Plan: Patients will be randomized on day 4 of induction therapy to 
either conventional or intensive blood pressure goals. Patients will be treated with the long-
acting antihypertensive lisinopril to achieve blood pressure control as indicated by their 
randomized arm. Long-acting therapy will be adjusted every 3-4 days as needed to achieve 
targeted control based on the median of blood pressures obtained in that period. Treatment of 
hypertension to the target will continue until the completion of reinduction II therapy. Patients 
will be evaluated for osteonecrosis as indicated in their primary therapeutic protocol using MRI 
during reinduction II. 
Study Design: Randomized unblinded trial of conventional vs. intensive hypertensive control. 
Evaluation of the MRIs defining the primary endpoint will be performed by a blinded 
radiologist.
Sample Size: We will randomize 160 evaluable patients (180 total). 
Data Management: Data management and statistical analysis will be provided locally by the 
Comprehensive Cancer Center Hematological Malignancies Program and the Biostatistics 
Department at St. Jude Children’s Research Hospital.
Human Subjects: The risks to subject will be related to the toxicity of antihypertensive therapy. 
Side effects are anticipated to be mild and limited to reversible orthostatic/postural hypotension 
and transient increases in creatinine. Patients will be informed of this and other minor side 
effects during informed consent discussion. Adverse events will be monitored and reported and 
treated appropriately.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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Revision 1.1, dated 02-15-2021 
Protocol document date: 02-15-2021
TABLE OF CONTENTS
1.0
OBJECTIVES...................................................................................................................1
1.1
Primary Objective....................................................................................................1
1.2
Secondary Objectives ..............................................................................................1
1.3
Exploratory Objectives ............................................................................................1
2.0
BACKGROUND AND RATIONALE.............................................................................2
2.1
Background..............................................................................................................2
2.2
Rationale..................................................................................................................2
2.3
Background and Rationale for Ancillary and Exploratory Studies .........................3
3.0
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND ENROLLMENT.........4
3.1
Inclusion Criteria .....................................................................................................4
3.2
Exclusion Criteria ....................................................................................................4
3.3
Research Participant Recruitment and Screening....................................................5
3.4
Enrollment on Study at St. Jude ..............................................................................5
3.5
Enrollment Instructions for Collaborating Sites......................................................5
4.0
TREATMENT PLAN.......................................................................................................6
4.1
Treatment.................................................................................................................6
4.2
Participation of St. Jude Affiliates in the Treatment Plan .......................................9
4.3
Treatment Modifications for Collaborating Sites....................................................9
4.4
Supportive Care .......................................................................................................9
4.5
Symptom Survey and Semi-structured Interviews ................................................10
5.0
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ...............................12
5.1
Pre-Study Evaluations ...........................................................................................12
5.2
Evaluations during Therapy...................................................................................12
5.3
Response Evaluations ............................................................................................13
5.4
Off-Study Evaluations ...........................................................................................13
5.5
Long-Term Follow-up Evaluations .......................................................................13
5.6
Modifications for Collaborating Sites ...................................................................13
5.7
Participation of Affiliate Sites ...............................................................................13
6.0
EVALUATION CRITERIA...........................................................................................14
6.1
Response Criteria...................................................................................................14
6.2
Toxicity Evaluation Criteria ..................................................................................14
6.3
Missed Doses.........................................................................................................14
7.0
OFF TREATMENT AND OFF STUDY CRITERIA ....................................................14
7.1
Off-Study Criteria..................................................................................................14
7.2
Off-Therapy Criteria..............................................................................................15
8.0
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS.......................15
8.1
Reporting Adverse Experiences and Deaths to St. Jude IRB ................................15
8.2
Recording Adverse Events and Serious Adverse Events ......................................18
8.3
Process for Reporting Adverse Events To and From St. Jude and Collaborating 
Sites/Affiliates ................................................................................................................19
9.0
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY..........20
9.1
Data Collection ......................................................................................................20
9.2
Study Monitoring...................................................................................................21
9.3
Confidentiality .......................................................................................................21
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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10.0
STATISTICAL CONSIDERATIONS............................................................................22
10.1 Sample size and accrual.........................................................................................22
10.2 Randomization.......................................................................................................22
10.3 Monitoring .............................................................................................................22
10.4 Primary Objective..................................................................................................23
10.5 Secondary Objectives ............................................................................................25
10.6 Exploratory Objectives ..........................................................................................26
10.7 Anticipated Completion Dates...............................................................................26
10.8 Summary of Primary and Secondary Objectives...................................................27
11.0
OBTAINING INFORMED CONSENT.........................................................................28
11.1 Consent at Enrollment ...........................................................................................28
11.2 Consent at Age of Majority ...................................................................................28
11.3 Consent When English is Not the Primary Language ...........................................28
12.0
REFERENCES ...............................................................................................................29
APPENDIX I: Performance Status Criteria
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1.0
OBJECTIVES
1.1
Primary Objective
1.1.1
Compare the frequency of radiographically extensive osteonecrosis in patients 
receiving intensive compared to conventional antihypertensive therapy.
1.2
Secondary Objectives
1.2.1
Evaluate the efficacy of intensive antihypertensive control compared to 
conventional antihypertensive control in the prevention of clinically significant 
(CTCAE Grade 2 or higher) and radiologically extensive osteonecrosis, overall 
and stratified by joints.
1.2.2
Compare the frequency of clinically significant and radiographically extensive 
osteonecrosis in patients receiving antihypertensive therapy and historical controls.
1.2.3
Compare blood pressures achieved in intensive and conventional arms using both 
pressures obtained as part of routine patient care and ambulatory blood pressure 
monitoring.
1.2.4
Compare levels of vascular dysfunction as measured physiologically, 
radiographically, and in blood samples in patients receiving intensive compared to 
standard antihypertensive therapy.
1.3
Exploratory Objectives
1.3.1
Identify predictive patterns of blood biomarkers which identify patients at high-
risk of developing clinically significant osteonecrosis.
1.3.2
Identify MRI findings during late induction which correlate with osteonecrosis 
lesions seen during reinduction.
1.3.3
Identify patterns of diurnal blood pressure variation as measured by ambulatory 
blood pressure monitoring associated with the later development of osteonecrosis.
1.3.4
Compare induction blood pressure control and intervention arm to 
echocardiographic changes at reinduction II.
1.3.5
Evaluate patient-reported, health-related quality of life in patients during 
induction and after 1.5 years of therapy when many experience the symptoms of 
osteonecrosis.
St. Jude Children's Research Hospital
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2.0
BACKGROUND AND RATIONALE
2.1
Background
Advancements in the treatment of acute lymphoblastic leukemia (ALL) have pushed the 
cure rate to greater than 90%.1 Intensifying glucocorticoid use (i.e. prednisone and 
dexamethasone) has been key in accomplishing these outcomes. However, 
glucocorticoid-induced osteonecrosis (ON) is one of the most common dose-limiting 
toxicities of ALL therapy in children.2-6 Symptomatic cases (defined as Common 
Terminology Criteria for Adverse Events (CTCAE) grade 2-4) often occur during the 
first two years of treatment, and may result in early discontinuation of glucocorticoids 
from treatment. Age is the most significant risk factor, with ALL patients greater than 10 
years of age at higher risk of developing ON.2,3,5,6 The most common affected joints are 
the hip, knee, and shoulder.7-9 In both Total XV3 and Total XVI10, the rate of 
symptomatic osteonecrosis in children age 10 or older was ~40%.
Recent work has demonstrated that patients with ALL age 10 or older at diagnosis who 
develop hypertension during glucocorticoid containing phases of therapy were more 
likely to develop osteonecrosis. Among 235 children treated on Total XV and Total XVI, 
osteonecrosis occurred in 52% of the 94 who developed hypertension compared to 38% 
of those who were normotensive [p=0.037, odds ratio (OR) 1.75, 95% confidence interval 
(95% CI) 1.02-3.01.11 The association was maintained in a multivariable analysis of all 
known factors associated with either hypertension or osteonecrosis (p=0.03, OR 1.88, 
95% CI 1.1-3.22). When the analysis was restricted to osteonecrosis that developed 
during protocol therapy, 52% of patients with hypertension developed osteonecrosis 
compared to 34% of normotensive patients (p=0.006, OR 2.11, 95% CI 1.2-3.6). 
Hypertension was also associated with an increased frequency of extensive epiphyseal 
involvement (≥30% of the surface effected) of the hip and knee joints on screening MRIs; 
this is significant as this degree of involvement is associated with joint collapse and the 
need for surgical intervention.12,13
In preclinical models, dexamethasone and asparaginase produced hypertension as in 
patients with ALL. The use of either an angiotensin enzyme inhibitor or hydralazine 
reduced the frequency of osteonecrosis (15% vs. 38% and 3% vs. 36%, p<0.01 for both) 
through reductions in osteonecrosis-inducing arteriopathy.11 The same regimen did not 
impact the antileukemic efficacy of chemotherapy in vitro or in vivo.
2.2
Rationale
Based on the retrospective clinical and prospective preclinical data, undertreatment of 
hypertension is associated with an approximately 2-fold increased risk of developing 
osteonecrosis after accounting for other known risk factors. Data from both adult14,15 and 
pediatric16 populations shows a benefit to more intensive blood pressure control 
compared to conventional control. Due to the risks of complications from untreated 
hypertension (e.g. posterior reversible encephalopathy syndrome), it is both impractical 
and unethical to randomize patients to no treatment for their hypertension. We will 
therefore test the efficacy of intensive hypertensive control (targeted to the 50-75th 
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percentile for age, sex, and height, systolic) compared to conventional antihypertensive 
control (targeted to the 90-95th percentile for age, sex, and height, systolic). We have 
chosen slightly higher systolic blood pressure goals for the intensive arm compared to the 
ESCAPE trial16 due to the presence of anemia and risk for infection in pediatric ALL 
patients, both of which may predispose to an increased risk of symptomatic hypotension.
The Children’s Oncology Group AALL0232 and CCG1961 trials demonstrated 
differences in osteonecrosis in patients receiving dexamethasone instead of prednisone 
during induction, or continuous instead of alternate week dexamethasone during delayed 
intensification, respectively.2,5 These data support the critical role that these two steroid-
intensive phases of therapy (termed induction and reinduction in St. Jude Total Therapy 
protocols) play in the development of osteonecrosis. The planned intervention will 
therefore encompass these two periods.
Although TOT17 includes an optional randomization for vincristine and dexamethasone 
duration (49 weeks vs. 101 weeks), the primary endpoint in this study (Reinduction II 
MRI) occurs prior to that randomization. Thus, the randomization will not impact the 
primary outcome of the study. Furthermore, review of symptomatic osteonecrosis timing 
on TOTXVI suggests that the majority of patients develop symptoms prior to this 
timepoint. For secondary endpoints including CTCAE symptomatic osteonecrosis, we 
will consider dexamethasone duration as a covariate.
2.3
Background and Rationale for Ancillary and Exploratory Studies
Screening magnetic resonance imaging has a higher sensitivity than traditional 
radiographs for detecting early osteonecrosis.12,17 Data from prior Total Therapy studies 
indicates that involvement of ≥30% of the epiphyseal surface of either the hip or knee is 
associated with the need for surgical intervention and/or collapse of the articular 
surface.12(Inaba et al, in submission).
Blood pressures obtained as part of routine care have historically been the standard for 
evaluation of hypertension in children with ALL.11,18-20 However, ambulatory blood 
pressure monitoring (ABPM) has been shown to better predict end-organ damage in 
patients with hypertension and to identify patients with masked hypertension during 
office visits.21-23 This modality has not been previously evaluated in children receiving 
leukemia treatment and so its predictive value in this population is unknown. These data 
also demonstrate echocardiographic changes seen in patients with hypertension detected 
by ABPM would not have been predicted by clinical monitoring.
Measurements of small and large elasticity are associated with cardiovascular events in 
the general population24,25 and are feasible in childhood cancer survivors.26 These 
vascular properties change across age and vary between boys and girls.27 We will 
measure these vascular properties non-invasively to assess their changes during therapy 
as well as their association with osteonecrosis and other vascular biomarkers.
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Plasma markers of vascular health have been associated with a variety of adverse 
cardiovascular outcomes. Synthesis of nitric oxide, a potent vasodilator, acts as a marker 
of cardiovascular stent re-stenosis risk.28 Other plasma markers shown to predict adverse 
cardiovascular events include von Willebrand Factor, tumor necrosis factor alpha,29, D-
dimer, 30 PAI-1, E-selectin, and ICAM-1.31 These markers of endothelial function and 
vascular health have not been previously studied in this population and so their 
association with osteonecrosis risk remains unknown.
Although osteonecrosis is considered a significant contributor to the intermediate- and 
long-term morbidity of ALL therapy, patient perspectives on the impact of osteonecrosis 
are lacking. We will thus evaluate the impact of therapy and osteonecrosis on the patient 
experience using the validated patient-reported tool PROMIS tools.32-35 We will further 
assess the impacts of therapy on patient quality of life with semi-structured interviews.36,37
3.0
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND ENROLLMENT 
According to institutional and NIH policy, the study will accession research participants 
regardless of gender and ethnic background.  Institutional experience confirms broad 
representation in this regard.
3.1
Inclusion Criteria
3.1.1
Patient is being treated for newly diagnosed acute lymphoblastic leukemia or 
lymphoma (ALL) on the TOT17 protocol. Patients do not need to be hypertensive 
to enroll.
3.1.2
Patient is 10 years of age or older at the time of enrollment on TOT17.
3.1.3
Patient has completed < 4 days of protocol therapy (patients are eligible on Day 4 
of TOT17 therapy).
3.2
Exclusion Criteria
3.2.1
Moderate-severe renal dysfunction (glomerular filtration rate <45 ml/min/1.73m2).
3.2.2
Down’s syndrome (germline Trisomy 21) or other syndrome resulting in growth 
delay or alterations in stature.
3.2.3
Chronic inability to ambulate. Patients with limitations in movement due to acute 
complications of leukemia/lymphoma are not excluded.
3.2.4
Permanent contraindication to MRI evaluation.
3.2.5
Participants who are pregnant or lactating. Males or females of reproductive 
potential must agree to use effective contraception for the duration of study 
participation. 
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3.2.6
Inability or unwillingness of research participant or legal guardian/representative 
to give written informed consent. 
3.3
Research Participant Recruitment and Screening
Five institutions will collaborate in the proposed project: St. Jude Children's Research 
Hospital (SJCRH); Cook Children’s Medical Center; Stanford University; Children’s 
Hospital of Michigan; Rady Children’s Hospital – San Diego and Novant Health Hemby 
Children’s Hospital – Charlotte NC.
3.4
Enrollment on Study at St. Jude
A member of the study team will confirm potential participant eligibility and complete all 
sections of the Participant Eligibility checklist, print, and sign. If the enrollment will be 
entered by Clinical Trials Operations (CTO), then the study team must send the 
completed checklist to CTO by email 
or fax 
 (follow fax by a phone call to 
 to ensure receipt). 
The Study Team or CTO will enter the Eligibility checklist information into the central 
enrollment system and release an informed consent form. The study team will provide a 
copy of the study informed consent form (ICF) to the participant family for their 
consideration and reference. The entire signed ICF must forwarded to CTO: 
 or faxed 
 so that the enrollment will 
show in the protocol Milli tab and for study-specific orders to be generated in Milli. 
To assist with enrollments and consent release, the CTO staff is available during office 
hours. After hours, weekends, and holiday patient enrollment issues please call the St. 
Jude study coordinator or refer to the CTO intranet site for additional resources and 
instructions: 
. 
3.5
Enrollment Instructions for Collaborating Sites
Before the collaborating or enrolling affiliate sites screen or enroll a study participant, the 
site completes a RIN request form and submits it to CTO by e-mail: 
 or fax 
(follow fax by a phone call to 
 
 to ensure receipt). A RIN is an eight-digit automated number beginning with an 
“R”. Once the form is received, St. Jude will register the research participant and then 
email the RIN to the email address provided on your registration form. This will register 
the participant only; it will not enroll the participant on the study. After hours, holidays, 
and weekends the site RIN request will be answered by the Patient Registration team. 
To enroll the study participant, after the RIN is obtained, the site study team will 
complete an eligibility checklist and fax it to 
or by email 
(follow with a phone call to 
 to ensure 
receipt). The CTO will enter the Eligibility Checklist information into the central 
enrollment system to officially enroll the participant on the trial. Collaborating sites are 
not required to forward a fully executed (signed) Informed Consent Form to St. Jude. 
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4.0
TREATMENT PLAN
4.1
Treatment
Following enrollment and randomization, a target systolic blood pressure range will be 
chosen for each participant based on their randomization arm, age, sex, and height. Target 
blood pressures for girls randomized to standard and intensive blood pressure control are 
shown in Tables 1a and 1b, respectively. Target blood pressures for boys randomized to 
standard and intensive blood pressure control are shown in Tables 2a and 2b, respectively. 
For patients ages 10-12 years, select the height column closest to their true height. If two 
columns are equidistant from their true height, select the lower height.
Patient randomization will be stratified based on patient’s location (Memphis vs. other), 
use of antihypertensives prior to randomization, and factors known to influence 
osteonecrosis risk, specifically sex and self-declared race (non-Hispanic white vs. other).
Patients will begin antihypertensive therapy to achieve the targeted blood pressure on day 
4. Patients already receiving antihypertensive therapy prior to day 4 should have their 
therapy adjusted according to the guidelines below. Patients requiring an 
antihypertensive should be started on lisinopril (initial dose 2.5mg daily) unless there is 
a contraindication to its use. Lisinopril dose may be escalated as indicated. Recommended 
second line agents for use when lisinopril is contraindicated include angiotensin receptor 
blockers (e.g. losartan 25mg daily), beta-blockers (e.g. carvedilol 3.125mg BID or, if 
cardiac rate control is required, metoprolol 12.5mg BID) or a calcium channel blocker 
(e.g. amlodipine 2.5mg daily).
Table 1a: Girls’ Standard Arm Systolic Blood Pressure Targets
Age/Height (cm)
Height 
5%
Height 
10%
Height 
25%
Height 
50%
Height 
75%
Height 
90%
Height 
95%
10 years
130 cm
132 cm
136 cm
141 cm
146 cm
150 cm
153 cm
Standard Low End Target 
(mmHg)
109
110
111
112
113
115
116
Standard High End Target 
(mmHg)
113
114
114
116
117
119
120
11 years
136 cm
138 cm
143 cm
148 cm
153 cm
157 cm
160 cm
Standard Low End Target 
(mmHg)
111
112
113
114
116
118
120
Standard High End Target 
(mmHg)
115
116
117
118
120
123
124
12 years
143 cm
146 cm
150 cm
155 cm
160 cm
164 cm
166 cm
Standard Low End Target 
(mmHg)
114
115
116
118
120
122
122
Standard High End Target 
(mmHg)
118
119
120
122
124
125
126
13+ years
All heights
Standard Low End Target 
(mmHg)
130
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Standard High End Target 
(mmHg)
135
Table 1b: Girls’ Intensive Arm Systolic Blood Pressure Targets
Age/Height (cm)
Height 
5%
Height 
10%
Height 
25%
Height 
50%
Height 
75%
Height 
90%
Height 
95%
10 years
130 cm
132 cm
136 cm
141 cm
146 cm
150 cm
153 cm
Intensive Low End Target 
(mmHg)
96
97
98
99
101
102
103
Intensive High End Target 
(mmHg)
103
103
105
106
108
109
110
11 years
136 cm
138 cm
143 cm
148 cm
153 cm
157 cm
160 cm
Intensive Low End Target 
(mmHg)
98
99
101
102
104
105
106
Intensive High End Target 
(mmHg)
105
106
107
109
110
112
113
12 years
143 cm
146 cm
150 cm
155 cm
160 cm
164 cm
166 cm
Intensive Low End Target 
(mmHg)
102
102
104
105
107
108
108
Intensive High End Target 
(mmHg)
108
109
110
112
113
114
114
13+ years
All heights
Intensive Low End Target 
(mmHg)
110
Intensive High End Target 
(mmHg)
120
Table 2a: Boys’ Standard Arm Systolic Blood Pressure Targets
Age/Height (cm)
Height 
5%
Height 
10%
Height 
25%
Height 
50%
Height 
75%
Height 
90%
Height 
95%
10 years
130 cm
133 cm
137 cm
141 cm
146 cm
150 cm
153 cm
Standard Low End Target 
(mmHg)
108
109
111
112
113
115
116
Standard High End Target 
(mmHg)
112
113
114
116
118
120
121
11 years
135 cm
137 cm
142 cm
146 cm
151 cm
156 cm
159 cm
Standard Low End Target 
(mmHg)
110
111
112
114
116
117
118
Standard High End Target 
(mmHg)
114
114
116
118
120
123
124
12 years
140 cm
143 cm
148 cm
153 cm
158 cm
163 cm
166 cm
Standard Low End Target 
(mmHg)
113
114
115
117
119
121
122
Standard High End Target 
(mmHg)
116
117
118
121
124
126
128
13+ years
All heights
Standard Low End Target 
(mmHg)
130
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Table 2a: Boys’ Standard Arm Systolic Blood Pressure Targets
Age/Height (cm)
Height 
5%
Height 
10%
Height 
25%
Height 
50%
Height 
75%
Height 
90%
Height 
95%
Standard High End Target 
(mmHg)
135
Table 2b: Boy’s Intensive Arm Systolic Blood Pressure Targets
Age/Height (cm)
Height 
5%
Height 
10%
Height 
25%
Height 
50%
Height 
75%
Height 
90%
Height 
95%
10 years
130 cm
133 cm
137 cm
141 cm
146 cm
150 cm
153 cm
Intensive Low End Target 
(mmHg)
97
98
99
100
101
102
103
Intensive High End Target 
(mmHg)
104
104
106
107
108
108
109
11 years
135 cm
137 cm
142 cm
146 cm
151 cm
156 cm
159 cm
Intensive Low End Target 
(mmHg)
99
99
101
102
103
104
106
Intensive High End Target 
(mmHg)
105
106
107
108
109
111
112
12 years
140 cm
143 cm
148 cm
153 cm
158 cm
163 cm
166 cm
Intensive Low End Target 
(mmHg)
101
101
102
104
106
108
109
Intensive High End Target 
(mmHg)
107
108
109
110
112
114
115
13+ years
All heights
Intensive Low End Target 
(mmHg)
110
Intensive High End Target 
(mmHg)
120
Patients will begin antihypertensive therapy to achieve the targeted blood pressure on Day 
4 of Remission Induction on TOT17. Patients already receiving antihypertensive therapy 
prior to Day 4 should have their therapy adjusted according to the guidelines below.
During outpatient visits, blood pressures measured should be performed after the patient 
has been sitting at rest for at least 10 minutes and is not experiencing pain or anxiety.
During induction, blood pressure adjustments will be made for each patient based on the 
mean blood pressure over the preceding 4 days (minimum 2 measurements) unless 
indication for immediate change is met (listed below). Blood pressures obtained while a 
patient is sedated for procedures should not be included in the evaluated blood pressures 
when determining whether to adjust antihypertensive medications. Patients with mean 
blood pressures outside of the target range should have antihypertensive therapy adjusted 
in an attempt to reach the goal range. However, if prior changes to medication have been 
made within 7 days and blood pressures are both 1) closer to the target range than at the 
time of prior medication change and 2) within 10mmHg of the goal range following that 
change, further modifications can be delayed until a subsequent visit.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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Immediate changes to antihypertensive therapy are indicated if:
1) systolic pressures are more than 15mmHg above the high end target,
2) patients are experiencing headache, vision changes, or neurologic symptoms 
attributable to hypertension, 
3) the patient has experienced an episode of syncope, 
4) the patient’s systolic pressure is below 90, or 
5) the patient is experiencing unacceptable toxicity from their current 
antihypertensive therapy.
Patients will continue antihypertensive therapy (as needed to achieve the targeted blood 
pressure range) during phases of therapy with scheduled glucocorticoids (i.e. Induction 
and Continuation, including Reinduction 1 & 2). Patients should continue 
antihypertensive therapy during other phases if tolerated. Caution is warranted in 
consolidation (due to the risk of altered renal perfusion or kidney injury) and during 
immunotherapy (due to the risk of cytokine release induced hypotension).
All antihypertensive agents are FDA approved and commercially available. See package 
inserts or published references or guidelines for drug information on individual 
medications. 
The completion of Reinduction II dexamethasone marks the completion of the 
intervention. Following this, physicians should discontinue antihypertensive therapy or 
continue treatment according to their clinical judgement.
Patients will be evaluated for variations in vascular function due to chemotherapy and the 
antihypertensive intervention according to the calendar in Table 3 (Section 5.2).
Adherence should be verified by the research team utilizing the proportion of days 
covered at least weekly.38
The term “day” does not refer to an absolute calendar day. It refers to a general 24-hour 
period. Variations in scheduled evaluations of up to 2 days outside the indicated time 
points are acceptable if needed for good patients care.
4.2
Participation of St. Jude Affiliates in the Treatment Plan 
Patients treated at affiliate sites will participate in the hypertension randomized 
intervention. They may participate in correlative studies based on the availability of 
required equipment at each affiliate institution. 
4.3
Treatment Modifications for Collaborating Sites 
Patients treated at collaborating sites will participate in the hypertension randomized 
intervention. They may participate in correlative studies based on the availability of 
required equipment at each collaborating institution. Induction MRI will only be 
performed for St. Jude patients.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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4.4
Supportive Care
Patients should receive supportive care per institutional standard and as directed in the 
TOT17 protocol.
4.5
Symptom Survey and Semi-structured Interviews
All patients will be asked to complete a symptom survey comprised of the PROMIS Ped 
25 profile, PROMIS pain interference 8a, PROMIS physical activity 8a, and PROMIS 
mobility 8a during induction (day 23-28), during week 17 of continuation (+/- 2 weeks), 
and continuation week 49 (+/- 3 weeks).
Patients electing to participate in patient interviews about their treatment and symptom 
burden will be contacted by a study team member. They will be asked to speak about the 
impact treatment and symptoms have had on their lives. The semi-structured interview 
will be recorded, with verbal consent at the time of the recording from the patient and, if 
present, family members confirming the written consent obtained at protocol entry. The 
semi-structured interview will include the following prompts:

Tell me about a time when your leukemia treatment changed the way that you did 
an activity.
o
e.g., Has your leukemia ever made it harder to do something that you 
wanted to do?
o
Has your leukemia ever prevented you from doing something that you 
wanted to do?
o
Conversely, has your leukemia ever made it easier to do something that 
you wanted to do?

Can you tell me a time when a side effect from treatment impacted your life?
o
e.g., Have you ever felt pain during treatment? If so, tell me about how 
this affected your ability to live your life.
o
Have you ever experienced nausea or vomiting during treatment? If so, tell 
me about how this affected your ability to live your life.
o
Are there other symptoms which have affected your ability to live your 
life?

What has been the hardest part of treatment for you?
o
What part of treatment has made you feel the most sad? 
o
What part of treatment has made you feel the most angry?
o
What part of treatment has made you feel the most frustrated or helpless?
o
As a last resort, if the interviewee is unable to come up with a response 
despite the question item and the above prompts:

Some people tell us that dealing with physical symptoms is the 
hardest part. Others tell us that feeling anxious or sad is the hardest 
part. Others say that being away from family/school/friends is the 
hardest part. And there are so many other things about treatment 
that are hard. What feels like the hardest part for YOU, personally?
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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
Tell me about something positive that has happened as a result of your treatment.
o
Has your treatment ever helped you feel better? Tell me about this 
experience.
o
Has your treatment ever helped you feel relieved? Tell me about this 
experience.
o
Has your treatment ever helped you feel hopeful? Tell me about this 
experience.
All interviews will be audio-recorded and transcribed into written narratives for grounded 
theory qualitative analysis. Patient specific identifiers will be replaced with a code for 
transcription.
Qualitative analysis of interviews will be performed using the well-described 
methodology of content analysis.36 Text transcripts will be reviewed in depth by multiple 
coders to discover similarities and trends related to each interview question item; this 
process will inform the development of an a priori coding schemata. Through a rigorous, 
iterative process of memoing and development of codes and code definitions, a 
preliminary codebook will be created. This codebook will be pilot tested through serial 
application across pre-selected rich transcripts by multiple coders, with subsequent 
assessment of inter-rater reliability (goal IRR >0.7). Based on pilot testing feedback, 
revisions will be made to the codebook to improve content and face validity. Following 
codebook finalization, codes will be applied across all transcripts by multiple coders 
working in silos to ensure at least 2 coders per transcript. The unit of analysis will be a 
segment inclusive of a single sentence or stand-alone phrase. Rigorous reconciliation 
processes will be conducted to reach consensus, with an objective third-party present to 
assist with adjudication. Codes will ultimately be organized and collapsed into broader 
categorized, with the goal of identifying emerging themes upon which to develop 
concepts and theories.37 As per the inclusion standard in qualitative methodology that 
investigates descriptive life experiences, if a theme occurs in one interview by one 
person, it is reported and considered legitimate.36 
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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5.0
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
5.1
Pre-Study Evaluations
All entry/eligibility studies must be performed within 10 days prior to entry onto the trial 
(unless otherwise specified). Evaluations performed as part of TOT17 evaluation and 
therapy should be used when feasible to avoid duplicate studies. 
5.2
Evaluations during Therapy
Evaluation
Timing during Induction
Timing post-Induction
Ambulatory blood pressure 
monitoring (ABPM)
Once for 12-30 hours on 
day 4-7, once for 12-30 
hours on day 23-28
-
Magnetic resonance imaging of 
hip and knee
Once during Days 23-28#
Reinduction 2 per Total 17 
protocol
Vasomotor testing (arterial 
elasticity, pulse wave velocity) #
Once during Days 23-28
Once between Early 
Intensification day 57 and 
Consolidation day 28, (optional) 
once Continuation week 120 ±2 
weeks
Serum for vascular biomarkers&
Day 22 +/- 2 days
Week 17 of Continuation 
(Reinduction II)
Echocardiogram
Once during week 17-19 of 
Continuation (Reinduction II)#
Symptom survey (PROMIS: Ped 
25 Profile, Pain interference 8a, 
Physical activity 8a, Mobility 8a)
Once on day 23-28
Week 17 of Continuation 
(Reinduction II) ± 2 weeks, week 
49 ± 3 weeks
Semi-structured interview of 
treatment and symptom burden #
Week 49 ± 3 weeks (with 
symptom survey)
All days/ weeks refer to the date of Total 17 therapy (i.e. day 22 refers to day 22 of Total 17, not the 22nd day since 
HYPERION entry or randomization).
**The St. Jude IRB requires that a female patient of childbearing potential must have a negative pregnancy test as a 
condition of clinical research eligibility.
Evaluation– must be obtained before 
enrollment
Within 10 days prior to enrollment
History and physical exam with height 
(cm), weight (kg), and BSA
X
Diagnosis of acute lymphoblastic 
leukemia/ lymphoma (ALL)
X
Laboratory studies: CBC with Diff, Chem 
18, Urinalysis, PT, PTT
X
Echocardiogram
X
Pregnancy test for females of childbearing 
potential
X
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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# SJCRH Memphis patients only
&See HYPERION Manual of Operations for collection, processing and shipping instructions.
Obtain other studies as needed for good patient care and per the TOT17 protocol.
5.3
Response Evaluations
Osteonecrosis will be graded according to CTCAE v4 (to coincide with CTCAE version 
used in TOT17). Patients will receive MRI screening during Reinduction II as prescribed 
in the TOT17 protocol. Pain will be ascribed to osteonecrosis or an alternative cause by 
the treating physician based on clinical history, radiographic findings, and response to 
therapeutic interventions. MRIs obtained at other times due to clinical 
concerns/symptoms will be recorded in the research database. MRIs will be evaluated by 
a pediatric radiologist blinded to the hypertension randomization.
Induction MRIs will only be performed in patients able to complete the study without 
sedation.
5.4
Off-Study Evaluations
A symptom survey (Pediatric PROMIS Ped 25 Profile, Pain interference 8a, Physical 
activity 8a, Mobility 8a) and a brief interview to assess patient symptom burden will be 
performed at week 49 ± 3 weeks.  Patients also have the option of completing vasomotor 
testing at week 120 ± 2 weeks.
5.5
Long-Term Follow-up Evaluations
Patients will be followed for the development of osteonecrosis as per the TOT17 protocol.
5.6
Modifications for Collaborating Sites
All sites will complete ambulatory blood pressure monitoring, Reinduction 2 MRI 
evaluations, serum vascular biomarkers, and symptom surveys for all patients. 
Vasomotor testing, echocardiography at week 17, and patient interviews will be 
performed only at St. Jude. Induction MRI may be performed at collaborating sites based 
on scanner design and sequence availability. Induction MRI may be performed at 
collaborating sites based on scanner design and sequence availability.
5.7
Participation of Affiliate Sites
All sites will complete ambulatory blood pressure monitoring, Reinduction 2 MRI 
evaluations, serum vascular biomarkers, and symptom surveys for all patients. 
Vasomotor testing, echocardiography at week 17, and patient interviews will be 
performed only at St. Jude.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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6.0
EVALUATION CRITERIA
6.1
Response Criteria
All patients will be evaluated clinically and radiographically for the development of 
osteonecrosis. Patients with radiographic (MRI or plain film x-ray) findings of 
osteonecrosis will be assessed for symptoms by the treating physician or designee. 
CTCAE version 4 criteria will be used to categorize the severity of osteonecrosis. MRI 
imaging will be centrally reviewed by a radiologist blinded to treatment assignment to 
assess the involvement of epiphyseal surfaces (0, <30%, ≥30%) which will be determined 
for each effected joint.
Blood pressures for each patient will be documented in the research database as the 
median of each week during induction and the median of each post-induction phase.
6.2
Toxicity Evaluation Criteria
CTCAE version 4 (to coincide with CTCAE criteria used in TOT17) will be used to 
document all toxicities which occur on study.
6.3
Missed Doses
For the planned analyses, patients within targeted blood pressure ranges (or below target 
without the use of any antihypertensives) at least 80% of the time will be considered as 
part of the per-protocol analysis. All patients will be evaluated in the intention to treat 
analysis regardless of the blood pressure range achieved or number of doses of 
antihypertensives given as long as imaging to assess osteonecrosis is available.
7.0
OFF TREATMENT AND OFF STUDY CRITERIA
7.1
Off-Study Criteria

Death

Lost to follow-up

Request of the patient/parent/LAR

Completion/discontinuation of Total 17 therapy

Discretion of the Study PI, such as the following 

The researcher decides that continuing in the study would be harmful, such as:
o
A treatment is needed that is not allowed on this study
o
The participant misses so many appointments that the data cannot be used 
in the study
o
The participant’s condition gets worse
o
New information is learned that a better treatment is available, or that the 
study is not in the participant’s best interest
o
Study evaluations are complete
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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7.2
Off-Therapy Criteria

Completion of prescribed therapy duration (completion of week 19 
dexamethasone).

Discontinuation of TOT17 therapy

Treatment with high-risk arm therapy (i.e. chimeric antigen receptor T-cell 
therapy, Reintensification, or transplant)

Development of unacceptable toxicity during treatment

Refusal of therapy

A research participant may also be taken off treatment or off of the study at 
the discretion of the study PI if persistent non-adherence with protocol 
directed therapy is documented.
8.0
 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
8.1
Reporting Adverse Experiences and Deaths to St. Jude IRB
Only “unanticipated problems involving risks to participants or others” referred to 
hereafter as “unanticipated problems” are required to be reported to the St. Jude IRB 
promptly, but in no event later than 10 working days after the investigator first learns of 
the unanticipated problem. Regardless of whether the event is internal or external (for 
example, an IND safety report by the sponsor pursuant to 21 CFR 312.32), only adverse 
events that constitute unanticipated problems are reportable to the St. Jude IRB. 
As further described in the definition of unanticipated problem, this includes any event 
that in the PI’s opinion was:

Unexpected (in terms of nature, severity, or frequency) given (1) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document, as well as other 
relevant information available about the research; (2) the observed rate of 
occurrence (compared to a credible baseline for comparison); and (3) the 
characteristics of the subject population being studied; and

Related or possibly related to participation in the research; and

Serious; or if not serious suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.
Unrelated, expected deaths do not require reporting to the IRB. Though death is 
“serious”, the event must meet the other two requirements of “related or possibly related” 
and “unexpected/unanticipated” to be considered reportable.
Deaths meeting reporting requirements are to be reported immediately to the St. Jude 
IRB, but in no event later than 48 hours after the investigator first learns of the death. 
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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The following definitions apply with respect to reporting adverse experiences: 
Serious Adverse Event: Any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria:

results in death;

is life-threatening (places the subject at immediate risk of death from the event as 
it occurred);

requires inpatient hospitalization or prolongation of existing hospitalization;

results in a persistent or significant disability/incapacity;

results in a congenital anomaly/birth defect; or

any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the other outcomes listed in this definition (examples of such 
events include:  any substantial disruption of the ability to conduct normal life 
functions, allergic bronchospasm requiring intensive treatment in the emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse), a 
congenital anomaly/birth defect, secondary or concurrent cancer, medication 
overdose, or is any medical event which requires treatment to prevent any of the 
medical outcomes previously listed.  
Unexpected Adverse Event: Any adverse event for which the specificity or severity is 
not consistent with the protocol-related documents, including the applicable investigator 
brochure, IRB approved consent form, Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) application, or other relevant sources of 
information, such as product labeling and package inserts; or if it does appear in such 
documents, an event in which the specificity, severity or duration is not consistent with 
the risk information included therein; or the observed rate of occurrence is a clinically 
significant increase in the expected rate (based on a credible baseline rate for 
comparison); or
The occurrence is not consistent with the expected natural progression of any underlying 
disease, disorder, or condition of the subject(s) experiencing the adverse event and the 
subject’s predisposing risk factor profile for the adverse event. 
Internal Events: Events experienced by a research participant enrolled at a site under the 
jurisdiction of St. Jude IRB for either multicenter or single-center research projects.
External Events: Events experienced by participants enrolled at a site external to the 
jurisdiction of the St. Jude Institutional Review Board (IRB) or in a study for which St. 
Jude is not the coordinating center or the IRB of record.
Unanticipated Problem Involving Risks to Subjects or Others: An unanticipated 
problem involving risks to subjects or others is an event which was not expected to occur, 
and which increases the degree of risk posed to research participants.  
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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Such events, in general, meet all of the following criteria:

unexpected; 

related or possibly related to participation in the research; and 

suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  An unanticipated problem involving risk to subjects or 
others may exist even when actual harm does not occur to any participant. 
Consistent with FDA and OHRP guidance on reporting unanticipated problems and 
adverse events to IRBs, the St. Jude IRB does not require the submission of external 
events, for example IND safety reports, nor is a summary of such events/reports required; 
however, if an event giving rise to an IND safety or other external event report constitutes 
an “unanticipated problem involving risks to subjects or others” it must be reported in 
accordance with this policy.  In general, to be reportable external events need to have 
implications for the conduct of the study (for example, requiring a significant and usually 
safety-related change in the protocol and/or informed consent form).
Although some adverse events will qualify as unanticipated problems involving risks to 
subjects or others, some will not; and there may be other unanticipated problems that go 
beyond the definitions of serious and/or unexpected adverse events. Examples of 
unanticipated problems involving risks to subjects or others include:

The theft of a research computer containing confidential subject information 
(breach of confidentiality); and 

The contamination of a study drug.  Unanticipated problems generally will 
warrant consideration of substantive changes in the research protocol or informed 
consent process/document or other corrective actions in order to protect the 
safety, welfare, or rights of subjects or others. 
The principal investigator has the obligation to report all serious adverse events to the 
FDA and IRB.
The following adverse events that are commonly observed in this patient population will 
not be reported as individual expedited reports, but with annual continuing review and 
progress reports:

Grade 3 or 4 infection or fever

Grade 3 or 4 fever and neutropenia with or without infection

Grade 3 or 4 elevation in hepatic transaminases, alkaline phosphatase, GGT, 
bilirubin, and triglycerides that resolve to less than grade 3 within 5 days

Grade 3 or 4 elevation of amylase or lipase

Grade 3 electrolyte disturbances and Grade 4 electrolyte disturbances that resolve 
to < grade 3 within 24 hours allowing for replacement as needed

Grade 3 and 4 electrolyte disturbances due to tumor lysis
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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
Grade 3 hyperglycemia or hypoglycemia and Grade 4 hyperglycemia or 
hypoglycemia that resolve to < grade 3 within 24 hours, allowing for replacement 
or insulin as needed

Grade 3 fatigue and nausea. 

Grade 3 vomiting or diarrhea that resolves to ≤ Grade 2 within 7 days with 
supportive care as needed (antiemetics, antidiarrheal medications)

Grade 3 or 4 hypotension explained by sepsis, pancreatitis, or infusion reaction

Grade 3 mucositis that resolves to ≤ Grade 2 within 14 days

Grade 3 anorexia

Grade 3 hypertension 

Grade 3 enterocolitis, typhlitis, or colitis

Grade 3 gastric hemorrhage, gastric ulcer, gastritis, and/or upper GI bleed 

Grade 3 glucose intolerance 

Grade 3 leukoencephalopathy and/or seizures secondary to intrathecal 
chemotherapy

Any Grade 3 event not specified above as an exception which resolves within 48 
hours

Any Grade 3 event secondary to an infectious process or thrombocytopenia
This is an investigator-initiated study. The principal investigator, Seth Karol and St. Jude 
are conducting the study and acting as the sponsor. Therefore, the legal/ethical 
obligations of the principal investigator include both those of a sponsor and those of an 
investigator.
8.2
Recording Adverse Events and Serious Adverse Events
Adverse events (AEs) will be evaluated and documented by the clinical staff and 
investigators throughout inpatient hospitalizations and each outpatient visit. CRAs are 
responsible for reviewing documentation related to AEs and entering directly into 
TrialMaster protocol-specific database. The data to be recorded are 1) the event 
description, 2) the NCI CTCAE v4.0 code and grade, 3) the onset date, 4) the resolution 
date (or ongoing), 4) action taken for event, 5) patient outcome 6) relationship of AE to 
protocol treatment/interventions, 7) if AE was expected or unexpected, and 8) comments, 
if applicable.
AEs that are classified as serious, unexpected, and at least possibly related will be notated 
as such in the database as “unanticipated problems”. 
Attribution of an Adverse Event
Not related – The lack of a temporal relationship of the event to study treatment makes a 
causal relationship not reasonably possible, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation. 
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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Unlikely related – The temporal relationship of the event to study treatment makes a 
causal relationship reasonably unlikely, and other drugs, therapeutic interventions or 
underlying conditions may not provide sufficient explanation for the observed event.
Possibly related – The temporal relationship of the event to study treatment makes a 
causal relationship reasonably possible, and the event is more likely explained by 
exposure to the study treatment than by other drugs, therapeutic interventions or 
underlying conditions.
A cumulative summary of all non-hematologic Grade 3-5 AEs, and expected/unrelated 
deaths that occur more than 30 days after protocol treatment will be reported to all sites 
with study progress report at the time of continuing review.
For the purpose of safety analyses, all AE’s that are classified as unlikely or possible will 
be considered treatment-related events.
8.3
Process for Reporting Adverse Events To and From St. Jude and 
Collaborating Sites/Affiliates 
Adverse events from collaborating sites will also be reviewed by the PI and discussed in 
study team meetings as described above. SAE reports from collaborating sites for AEs 
that are serious, unexpected, and at least possibly related to protocol treatment or 
interventions will be reported to site IRB and the St. Jude IRB within the reporting 
requirements described above. The PI will determine if this is an event that will need to 
be reported expeditiously to all participating sites, considering the following criteria:

Is the AE serious, unexpected, and related or possibly related to participation in 
the research?

Is the AE expected, but occurring at a significantly higher frequency or severity 
than expected?

Is this an AE that is unexpected (regardless of severity that may alter the IRB’s 
analysis of the risk versus potential benefit of the research and, as a result, 
warrant consideration of substantive changes in the research protocol or informed 
consent process/document?
With the submission of the “Reportable Event” in St. Jude iRIS application, the PI will 
indicate if all sites should be notified to report to their IRBs, and if the protocol and/or 
consent should be amended (consent will be amended if event is information that should 
be communicated to currently enrolled subjects). Generally, only events that warrant an 
amendment to the protocol and/or consent will be reported expeditiously to all sites. 
However, any event may be reported expeditiously to all sites at the discretion of the PI. 
A cumulative summary of all non-hematologic Grade 3-5 AEs, and expected/unrelated 
deaths that occur more than 30 days after protocol treatment will be reported to all sites 
with study progress report at the time of continuing review.
For collaborating sites: Serious AND unexpected events are to be reported to the St. Jude 
PI (Dr. Seth Karol) within 48-72 hours via fax or email.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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All treatment-related deaths and unexpected deaths must be reported to the St. Jude PI at 
HYPERION study team by e-mail or phone call to Dr. Karol within 24 hours of the 
event. A written report must follow.
The study team should be copied on all correspondence regarding the event. Sent report to:
Seth Karol, MD
Department of Oncology
Leukemia/Lymphoma Division
St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105
Phone: 
FAX: 
Email: 
Email: 
9.0
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY
9.1
Data Collection 
Electronic case report forms (e-CRFs) will be completed by the clinical trials staff from 
the Cancer Center Comprehensive Center, Hematological Malignancies Program. Data 
will be entered from record directly into a secure, protocol-specific TrialMaster database, 
developed and maintained by St. Jude Clinical Research Informatics. 
Data Management will be supervised by the Director of Clinical Trials Management, and 
Manager of Clinical Research Operations for the Hematological Malignancies Program, 
working with Dr. Karol or his designee. All protocol-specific data and non-hematologic 
grade 3-5 adverse events during glucocorticoid phases will be recorded by the clinical 
research associates into the protocol-specific database, ideally within 2-4 weeks of 
completion of study phase. Osteonecrosis (CTCAE Grade 2 or higher) will be recorded. 
All questions will be directed to the attending physician and/or PI and reviewed at 
regularly-scheduled working meetings. Data collection for adverse events will be 
captured for 4 weeks after participant is removed from treatment.
The attending physicians (or their designees) are responsible for keeping up-to-date 
roadmaps in the patient’s primary St. Jude medical chart. Regular (at least monthly) 
summaries of toxicity and protocol events will be generated for the PI and the department 
of Biostatistics to review.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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9.2
Study Monitoring
This study is considered moderate risk for monitoring purposes. Protocol and regulatory 
compliance, including essential regulatory documentation, will be assessed as well as the 
accuracy and completeness of data points related to the primary study objective semi- 
annually. If the study design has strata, accrual will be tracked continuously. The first 
two enrollees and then 10 % of participants will be monitored semi-annually.
The PI and study team are responsible for protocol and regulatory compliance, and for 
data accuracy and completeness. The study team will meet at appropriate intervals to 
review case histories or quality summaries on participants and retain copies of the 
minutes which are signed by the PI. 
Clinical Trials Operations (CTO) will verify informed consent documentation of and 
eligibility status for 50% of trial participants within 5 days of enrollment. Additionally, a 
quality review will be performed by CTO personnel on 100% of St. Jude participants’ 
informed consent forms to assure completeness. 
Overall study conduct, compliance with primary objectives, age of majority consenting, 
safety assessments and reporting, and the timeliness and accuracy of database entries are 
monitored routinely. Study documents routinely monitored on selected participants include 
medical records, database entries, study worksheets, and case report forms. Study 
documents are monitored for participant status, demographics, staging, subgroup 
assignment, treatments, investigational drug accountability, evaluations, responses, 
participant protocol status, off-study and off-therapy criteria, and for all other specifics as 
detailed in a separate study-specific monitoring plan. The study-specific monitoring plan 
may be revised over time, to adapt monitoring frequency and/ or intensity to a changing 
environment when appropriate (for example: new safety signals; positive history of 
compliance; all participants are in long term follow-up; or the enrollment period has ended). 
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness and 
appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate a formal 
report which is shared with the Principal Investigator (PI), study team and the Internal 
Monitoring Committee (IMC). 
Continuing reviews by the Institutional Review Board (IRB) and Scientific Review 
Committee (CT-SRC) will occur at least annually. In addition, unanticipated problems 
are reviewed in a timely manner by the IRB. 
9.3
Confidentiality
Research Identification numbers will be used in place of an identifier such as a medical 
record number. No research participant names will be recorded on the data collection 
forms. The list containing the study number and the medical record number will be 
maintained in a locked file and will be destroyed after all data have been analyzed. 
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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The medical records of study participants may be reviewed by the St. Jude IRB, FDA, 
and clinical research monitors.
10.0
STATISTICAL CONSIDERATIONS
10.1
Sample size and accrual
It is logistically realistic and statistically sound (see below) to randomize 160 patients 
(80/arm) to the intensive or the standard antihypertensive arms. Patients who are 
randomized but drop out due to reasons as defined in Sections 7.1 and 7.2 before ON is 
observed or before the reinduction 2 MRI, are considered as inevaluable for the primary 
endpoint, and should be replaced. Based on past experience, we anticipate ~60 eligible 
patients to be randomized annually. Conservatively postulating a 12% drop out rate, we 
need to randomize 180 patients altogether. We thus anticipate a full accrual within 3.5 
years. 
10.2
Randomization
Open-label, stratified block randomization with block size of 439. Randomization will be 
stratified by site (SJCRH and other), gender, self-declared race/ancestry (White Non-
Hispanic and other) and hypertension requiring >1 dose of medication before Day 4 
(Yes/No).
Analyses for the primary and secondary objectives will not be stratified. If it is 
determined that certain important factors are not balanced between the two treatment 
arms, appropriate regression models (such as logistic or integer response models) will be 
applied. The power assessment below is based on an unstratified Chi-square test.
10.3
Monitoring
To monitor the safety of therapy intensification, we will monitor for the following 
targeted toxicities: acute kidney injury (CTCAE grade 3 or higher not resolving to grade 
0-1 within 72 hours) and syncope resulting in any injury. We will count events occurring 
during glucocorticoid containing phases only. 
The intensive BP control arm (experimental) will be closely monitored for adverse effects 
and clinically suboptimal efficacy. The monitoring rules are constructed according to the 
Binomial group sequential design. We shall suspend the trial and investigate if any 
threshold defined in the rules is crossed. 
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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AE monitoring in the intensive treatment arm: Probabilities of suspending trial to 
monitor > 25% targeted AE:
Monitoring of missing the target in the intensive treatment arm: against <70%
Probability of stopping
Efficacy monitoring of failures at reinduction II MRI (failure defined as ≥30% 
involvement in any joint) against >50% failure rate.
10.4
Primary Objective
To compare the frequency of radiographically significant osteonecrosis in patients 
receiving intensive compared to conventional antihypertensive therapy.
The primary endpoint is the number of major joints (hips and knees) with extensive 
epiphyseal osteonecrosis (≥30% affected surface12,13,17) on MRI after approximately 9 
months of chemotherapy (during reinduction 2). All randomized patients with appropriate 
imaging are considered evaluable and all analyses will be done according to intent-to-treat. 
A chart review of 140 TOTXVI patients meeting the eligibility criteria of this study 
showed the following distribution of the number of affected joints in the low BP within-
target group vs. the above-target group:
True targeted AE probability
0.20
0.25
0.30
0.35
Suspend if number of AEs >7/20
0.03
0.07
0.23
0.40
Suspend if number of AEs >13/40
0.01
0.03
0.14
0.22
Suspend if number of AEs >25/80
0.00
0.01
0.12
0.18
True success probability
0.55
0.60
0.70
0.75
Suspend if number of successes <12/20
0.59
0.40
0.11
0.04
Suspend if number of successes <24/40
0.17
0.13
0.07
0.03
Suspend if number of failures <51/80
0.19
0.24
0.04
0.00
True success probability
0.35
0.40
0.45
0.50
0.55
Suspend if # successes <7/20
0.42
0.25
0.13
0.06
0.02
Suspend if # successes <16/40
0.31
0.23
0.13
0.05
0.01
Suspend if # successes <33/80
0.17
0.17
0.08
0.02
0.00
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IRB APPROVAL DATE: 03/01/2021

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Number of affected joints
0
1
2
3
4
Total
Above-target 
(proportion, n)
0.583, 70
0.083, 10
0.233, 28
0.017, 2
0.083, 10
120
Within-target 
(proportion, n)
0.80, 16
0.05, 1
0.10, 2
0.00, 0
0.05, 1
20
Clearly in each BP group the distribution is bi-modal with local modes at 0 and 2. 
The primary analysis will consist of two parts. In the first part the distribution of the 
number of affected joints will be compared by the exact one-sided Chi-square test 
comparing the probability of having at least 1 affected joint. Let P0(k) and P1(k) be the 
probability of k affected joints among patients above- and within-target respectively 
(k=0,1,2,3,4). We have noted in the preliminary data that the BP of 14.6% of the eligible 
patients was within target without any treatment. Therefore, the distribution of the 
number of affected joints in the control group is anticipated to be 
PC(k)=0.854*P0(k)+0.146*P1(k), and the distribution in the treatment group is 
anticipated to be PT(k)=P1(k), k=0,1,2,3,4. Applying the preliminary data displayed 
above to this model, we obtain the anticipated distribution in the control and treatment 
group as follows:
Number of affected joints k
0
1+
Control
0.615
0.385
Treatment
0.8
0.2
With n=80 subjects per group, the one-sided test has the exact power of 78.7% to detect 
the above anticipated difference at the 5% significance level. The power is calculated 
using Cytel Studio II. 
In the second part, the mean number of affected joints within the treatment and control 
group will be estimated by the sample mean and a 95% confidence interval based on the t 
statistic. Difference in the mean number of affected joints between the two groups will 
also be estimated by the point estimate of the difference of two sample means and the t-
statistic based 95% confidence interval. We note that although the sample space is 
discrete, the relatively large sample size (n=80/group) renders valid t statistic-based 
confidence intervals.
Bootstrap will be applied to check if the sample mean behaves similarly to a normally 
distributed random variable, and bootstrap confidence intervals will be applied if the t-
distribution approximation is questionable. Additionally, we will compare the two arms 
by the two-sided chi-square test for ordered columns.
Time frame: The analysis will begin within 6 months after the MRI assessments of the 
last randomized patient is completed.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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Responsible investigators: Seth Karol, Cheng Cheng
10.5
Secondary Objectives
Evaluate the efficacy of intensive antihypertensive control compared to conventional 
antihypertensive control in the prevention of clinically significant (CTCAE Grade 2 or 
higher) and radiologically extensive osteonecrosis, overall and stratified by joints.
A one-sided Chi-square test will be performed on a 2x2 contingency table similar to that 
in the primary objective, only now the columns are CTCAE Grade 2 ON (No/Yes). This 
analysis will also be performed for the knees and hips separately. MRI-defined extensive 
osteonecrosis will also be performed as described above, for knees and hip separately 
using Chi-square test on contingency tables. 
Compare the frequency of clinically and radiographically significant osteonecrosis 
between patients receiving antihypertensive intervention and historical controls.
The historical control cohort consists of all patients enrolled on TOT-XV and TOT-XVI 
studies with age at diagnosis 10 years or older. The rate of clinically significant (CTCAE 
Grade 2+) ON and radiographically significant findings (number of affected joints) will 
be compared between the intensive BP treatment arm and the historical cohort by Chi-
square tests.
Compare blood pressures achieved in intensive and conventional arms using both 
pressures obtained as part of routine patient care and ambulatory blood pressure 
monitoring.
The comparison will be done by regression modeling using mixed effect models to 
account for intra-patient repeated blood pressure measurements. The response variable is 
blood pressure, the explanatory variables include the BP control arm (intensive vs. 
conventional), age, sex, race and a random effect with AR(1) working covariance 
structure. 
Compare levels of vascular dysfunction as measured physiologically, radiographically, 
and in blood samples in patients receiving intensive compared to standard 
antihypertensive therapy.
The levels of vascular dysfunction are measured by markers such as MRI, eNO 
synthetase, Von Willebrand Factor, TNF-alpha, D-dimer, PAI-1, E-selectin and ICAM-1; 
the measurements are all continuous. Each marker will be compared between the 
intensive BP treatment arm and the standard care arm by Wilcoxon rank-sum test.
Time frame: The analysis will begin within 6 months after the MRI assessments of the 
last randomized patient is completed.
Responsible investigators: Seth Karol, Cheng Cheng
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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10.6
Exploratory Objectives
Identify predictive patterns of blood biomarkers which identify patients at high-risk of 
developing clinically significant osteonecrosis.
Associations between the blood biomarkers and CTCAE grade 2 or higher ON will be 
analyzed using mixed-effect logistic regression models. 
Identify MRI findings during late induction which correlate with osteonecrosis lesions 
seen during reinduction.
The MRI finding during late induction is represented by a 3-level ordinal variable (none, 
small, large). The ON lesions seen during reinduction are represented by a binary 
variable (large, less than large). The association will be tested by the Chi-square test on a 
3-by-2 contingency table with ordered rows.
Compare induction blood pressure control and intervention arm to echocardiographic 
changes at reinduction II.
Echocardiographic changes at reinduction II is measured by the LV strain which is a 
continuous variable. Comparison of the LV strain between the intensive BP treatment and 
standard care arms will be performed by Wilcoxon rank-sum test. 
Evaluate patient-reported, health-related quality of life in patients during induction and 
after 1.5 years of therapy when many experience the symptoms of osteonecrosis.
Survey response scores will be summarized by descriptive statistics including mean, 
standard deviation, minimum, maximum, quartiles, range and inter-quartile range. 
Time frame: The analysis will begin within 6 months after the MRI assessments of the 
last randomized patient is completed, except for the last exploratory objective for which 
the analysis will begin within 6 months after the last randomized patient is followed for 
1.5 years after completion of chemotherapy. 
Responsible investigators: Seth Karol, Cheng Cheng
10.7
Anticipated Completion Dates
Anticipated primary completion date: 3/2023
Anticipated study completion date: 3/2025
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021

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10.8
Summary of Primary and Secondary Objectives 
Objective#
Objective
Type
Analysis#
Resp
Party
Stat
Safety
Analysis
Measure
Analysis Title
Data Collection
Time Frame
# of 
Participants
1.1.1
P
1
SEK
CC
N
Patient  
Intensive vs. conventional 
hypertension control effect 
on osteonecrosis
Time on therapy
160
1.2.1
S
2
SEK
CC
N
Patient/ 
Joint
Antihypertensive 
intervention patients over 
time
Time on therapy/ 
Reinduction II
160
1.2.2
S
3
SCK/CM
CC
N
Patient/
Joint
Antihypertensive treated 
patients vs. historic control
Time on therapy/ 
Reinduction II
160
1.2.3
S
4
ND
CC
N
Patient
Blood pressure achieved by 
intervention arm
Through 
reinduction II
160
1.2.4
S
5
CM
CC
N
Patient
Induction MRI
Induction
80
1.2.4
S
6
DM
CC
N
Patient
Vascular function by 
vasomotor testing
Induction, 
consolidation, 
off therapy
80
1.2.4
S
7
SEK
CC
N
Patient
Blood markers of vascular 
dysfunction
Induction, 
reinduction II
160
1.3.1
E
7
SEK
CC
N
Patient
Blood markers of 
osteonecrosis risk
Induction, 
reinduction II
160
1.3.2
E
3/5
SCK/CM
CC
N
Patient
Early vs late MRI findings 
of osteonecrosis
Induction, 
Reinduction
80
1.3.3
E
8
ND
CC
N
Patient
ABPM blood pressures vs 
osteonecrosis
Induction
160
1.3.4
E
7
GB
CC
N
Patient
Echo changes at reinduction 
vs induction blood pressure
Reinduction II
80
1.3.5
E
9
EK
CC
N
Patient
HRQoL and symptom 
survey
Induction, 
reinduction II, 
week 49
160
1.3.5
E
10
EK
NA
N
Patient
Narrative symptom 
description
Week 49 
80
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11.0
OBTAINING INFORMED CONSENT
11.1
Consent at Enrollment 
The process of informed consent for HYPERION will follow institutional policy. The 
informed consent process is an ongoing one that begins at the time of enrollment and ends 
after the completion of therapy. Informed consent should be obtained by the attending 
physician or his/her designee, in the presence of at least one non-physician witness.
Throughout the entire treatment period, participants and their parents receive constant 
education from health professionals at St. Jude and are encouraged to ask questions 
regarding alternatives and therapy. All families have ready access to chaplains, 
psychologists, social workers, and the St. Jude ombudsperson for support, in addition to 
that provided by the primary physician and other clinicians involved in their care.
We will also obtain verbal assent from children 7 to 14 years old and written assent for 
all participants >14 years of age
11.2
Consent at Age of Majority
The age of majority in the state of Tennessee is 18 years old. Research participants must 
be consented at the next clinic visit after their 18th birthday. If an affiliate or collaborating 
site is located in a country or state where a different age of majority applies, that location 
must consent the participants according to their local laws.  
11.3
Consent When English is Not the Primary Language
When English is not the patient, parent, or legally authorized representative’s primary 
language, the Social Work department will determine the need for an interpreter. This 
information documented in the participant’s medical record. Either a certified interpreter 
or the telephone interpreter’s service will be used to translate the consent information. 
The process for obtaining an interpreter and for the appropriate use of an interpreter is 
outlined on the Interpreter Services, OHSP, and CTO websites. Collaborating sites should 
follow institutional policy.
St. Jude Children's Research Hospital
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IRB APPROVAL DATE: 03/01/2021

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12.0
REFERENCES
1. Pui CH, Campana D, Pei D, et al: Treating childhood acute lymphoblastic leukemia without 
cranial irradiation. N Engl J Med 360:2730-41, 2009
2. Karol SE, Yang W, Van Driest SL, et al: Genetics of glucocorticoid-associated osteonecrosis 
in children with acute lymphoblastic leukemia. Blood 126:1770-6, 2015
3. Kawedia JD, Kaste SC, Pei D, et al: Pharmacokinetic, pharmacodynamic, and 
pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic 
leukemia. Blood 117:2340-7; quiz 2556, 2011
4. Mattano LAJ, Devidas, M.; Winick, N.; Raetz, E.; Hunger, S. P.; Carroll, W. L.; Larsen, 
E.C.: Effects of dexamethasone (DEX) vs prednisone (PDN) and high-dose methotrexate 
(HD-MTX) vs Capizzi methotrexate/asparaginase (C-MTX/ASNase) on osteonecrosis (ON) 
incidence in children and young adults with high risk acute lymphoblastic leukemia (HR 
ALL): a report from the Children’s Oncology Group (COG) Study AALL0232. Blood ASH 
Abstract 665, 2012
5. Mattano LA, Jr., Devidas M, Nachman JB, et al: Effect of alternate-week versus continuous 
dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute 
lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 
13:906-15, 2012
6. Mattano LA, Jr., Sather HN, Trigg ME, et al: Osteonecrosis as a complication of treating 
acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin 
Oncol 18:3262-72, 2000
7. Mogensen SS, Harila-Saari A, Makitie O, et al: Comparing osteonecrosis clinical phenotype, 
timing, and risk factors in children and young adults treated for acute lymphoblastic 
leukemia. Pediatr Blood Cancer 65:e27300, 2018
8. Kuhlen M, Kunstreich M, Krull K, et al: Osteonecrosis in children and adolescents with 
acute lymphoblastic leukemia: a therapeutic challenge. Blood Advances 1:981-994, 2017
9. Powell C, Chang C, Gershwin ME: Current concepts on the pathogenesis and natural history 
of steroid-induced osteonecrosis. Clin Rev Allergy Immunol 41:102-13, 2011
10. Jeha S, Pei D, Choi J, et al: Improved CNS Control of Childhood Acute Lymphoblastic 
Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. J Clin Oncol 
37:3377-3391, 2019
11. Janke LJ, Van Driest SL, Portera MV, et al: Hypertension is a modifiable risk factor for 
osteonecrosis in acute lymphoblastic leukemia. Blood 134:983-986, 2019
12. Kaste SC, Pei D, Cheng C, et al: Utility of early screening magnetic resonance imaging for 
extensive hip osteonecrosis in pediatric patients treated with glucocorticoids. J Clin Oncol 
33:610-5, 2015
13. Karimova EJ, Wozniak A, Wu J, et al: How does osteonecrosis about the knee progress in 
young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res 468:2454-9, 2010
14. Group SR, Wright JT, Jr., Williamson JD, et al: A Randomized Trial of Intensive versus 
Standard Blood-Pressure Control. N Engl J Med 373:2103-16, 2015
15. Beddhu S, Chertow GM, Greene T, et al: Effects of Intensive Systolic Blood Pressure 
Lowering on Cardiovascular Events and Mortality in Patients With Type 2 Diabetes Mellitus 
on Standard Glycemic Control and in Those Without Diabetes Mellitus: Reconciling Results 
From ACCORD BP and SPRINT. J Am Heart Assoc 7:e009326, 2018
16. Group ET, Wuhl E, Trivelli A, et al: Strict blood-pressure control and progression of renal 
failure in children. N Engl J Med 361:1639-50, 2009
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17. Karimova EJ, Rai SN, Howard SC, et al: Femoral head osteonecrosis in pediatric and young 
adult patients with leukemia or lymphoma. J.Clin.Oncol. 25:1525-1531, 2007
18. Kamdem LK, Hamilton L, Cheng C, et al: Genetic predictors of glucocorticoid-induced 
hypertension in children with acute lymphoblastic leukemia. Pharmacogenet Genomics 
18:507-14, 2008
19. Louis CU, Butani L: High blood pressure and hypertension in children with newly diagnosed 
acute leukemia and lymphoma. Pediatr Nephrol 23:603-9, 2008
20. Schmiegelow K, Attarbaschi A, Barzilai S, et al: Consensus definitions of 14 severe acute 
toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet 
Oncol 17:e231-e239, 2016
21. Flynn JT: Differentiation between primary and secondary hypertension in children using 
ambulatory blood pressure monitoring. Pediatrics 110:89-93, 2002
22. Richey PA, DiSessa TG, Hastings MC, et al: Ambulatory blood pressure and increased left 
ventricular mass in children at risk for hypertension. Journal of Pediatrics 152:343-348, 2008
23. Gimpel C, Wuhl E, Arbeiter K, et al: Superior consistency of ambulatory blood pressure 
monitoring in children: implications for clinical trials. J Hypertens 27:1568-74, 2009
24. Mitchell GF, Hwang SJ, Vasan RS, et al: Arterial stiffness and cardiovascular events: the 
Framingham Heart Study. Circulation 121:505-11, 2010
25. Vlachopoulos C, Aznaouridis K, Stefanadis C: Prediction of cardiovascular events and all-
cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll 
Cardiol 55:1318-27, 2010
26. Mulrooney DA, Ness KK, Solovey A, et al: Pilot study of vascular health in survivors of 
Hodgkin lymphoma. Pediatr Blood Cancer 59:285-9, 2012
27. Senzaki H, Akagi M, Hishi T, et al: Age-associated changes in arterial elastic properties in 
children. Eur J Pediatr 161:547-51, 2002
28. Piatti P, Di Mario C, Monti LD, et al: Association of insulin resistance, hyperleptinemia, and 
impaired nitric oxide release with in-stent restenosis in patients undergoing coronary 
stenting. Circulation 108:2074-81, 2003
29. Ceconi C, Fox KM, Remme WJ, et al: ACE inhibition with perindopril and endothelial 
function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res 
73:237-46, 2007
30. Ceconi C, Fox KM, Remme WJ, et al: ACE inhibition with perindopril and biomarkers of 
atherosclerosis and thrombosis: results from the PERTINENT study. Atherosclerosis 
204:273-5, 2009
31. Massot A, Giralt D, Penalba A, et al: Predictive value of ankle-brachial index and PAI-1 in 
symptomatic intracranial atherosclerotic disease recurrence. Atherosclerosis 233:186-9, 2014
32. Hinds PS, Wang J, Cheng YI, et al: PROMIS pediatric measures validated in a longitudinal 
study design in pediatric oncology. Pediatr Blood Cancer 66:e27606, 2019
33. Cheng AL, Calfee R, Colditz G, et al: PROMIS Physical and Emotional Health Scores Are 
Worse in Musculoskeletal Patients Presenting to Physiatrists than to Other Orthopedic 
Specialists. PM R 11:604-612, 2019
34. Varni JW, Magnus B, Stucky BD, et al: Psychometric properties of the PROMIS (R) 
pediatric scales: precision, stability, and comparison of different scoring and administration 
options. Qual Life Res 23:1233-43, 2014
35. Hinds PS, Nuss SL, Ruccione KS, et al: PROMIS pediatric measures in pediatric oncology: 
valid and clinically feasible indicators of patient-reported outcomes. Pediatr Blood Cancer 
60:402-8, 2013
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36. Krippendorff K: Content Analysis: An Introduction to Its Methodology (ed Second). 
Thousand Oaks, SAGE Publications, 2004 
37. Ulin P RE, Tolley E: Qualitative Methods in Public Health: A Field Guide for Applied 
Research. San Francisco, Jossey-Bass Wiley Imprint, 2005 
38. (PQA) PQA: Adherence Measures [Internet]. 2018
39. Zelen M: The randomization and stratification of patients to clinical trials. J Chronic Dis 
27:365-75, 1974
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APPENDIX I: PERFORMANCE STATUS CRITERIA
PERFORMANCE STATUS CRITERIA
Karnofsky and Lansky performance scores are intended to be multiples of 10
ECOG (Zubrod)
Karnofsky
Lansky
Score
Description
Score
Description
Score
Description
100
Normal, no complaints, no 
evidence of disease
100
Fully active, normal
0
Fully active, able to 
carry on all pre-
disease performance 
without restriction
90
Able to carry on normal 
activity, minor signs or 
symptoms of disease
90
Minor restrictions in 
physically strenuous 
activity
80
Normal activity with 
effort; some signs or 
symptoms of disease
80
Active, but tires more 
quickly
1
Restricted in 
physically strenuous 
activity by ambulatory 
and able to carry out 
work of a light or 
sedentary nature, e.g., 
light housework, 
office work
70
Cares for self; unable to 
carry on normal activity or 
do active work
70
Both greater 
restriction of and less 
time spent in play 
activity
60
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs
60
Up and around, but 
minimal active play; 
keeps busy with 
quieter activities
2
Ambulatory and 
capable of self-care 
but unable to carry out 
any work activities; up 
and about more than 
50% of waking hours
50
Requires considerable 
assistance and frequent 
medical care
50
Gets dressed, but lies 
around much of the 
day; no active play, 
able to participate in 
all quiet play and 
activities
40
Disabled, requires special 
care and assistance
40
Mostly in bed; 
participates in quiet 
activities
3
Capable of only 
limited self-care, 
confined to bed or 
chair more than 50% 
of waking hours
30
Severely disabled, 
hospitalization indicated; 
death not imminent
30
In bed; needs 
assistance even for 
quiet play
20
Very sick, hospitalization 
indicated.  Death not 
imminent
20
Often sleeping; play 
entirely limited to 
very passive activities
4
Completely disabled; 
cannot carry on any 
self-care; totally 
confined to bed or 
chair
10
Moribund, fatal processes 
progressing rapidly
10
No play; does not get 
out of bed
St. Jude Children's Research Hospital
IRB NUMBER: 20-0420
IRB APPROVAL DATE: 03/01/2021