Hypertension Intervention to Reduce Osteonecrosis in Chil... | NCT04401267

ID	Type	Description	Link
1K08CA250418	U.S. NIH Grant/Contract		View source
NCI-2020-03603	Registry Identifier	NCI Clinical Trial Registration Program

Name	Class
National Cancer Institute (NCI)	NIH

Description Module

Brief Summary

This is a randomized unblinded 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).

Primary Objective

Compare the frequency of radiographically extensive osteonecrosis in patients receiving intensive compared to conventional antihypertensive therapy.

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.
Compare the frequency of clinically significant and radiographically extensive osteonecrosis in patients receiving antihypertensive therapy and historical controls.
Compare blood pressures achieved in intensive and conventional arms using both pressures obtained as part of routine patient care and ambulatory blood pressure monitoring.
Compare levels of vascular dysfunction as measured physiologically, radiographically, and in blood samples in patients receiving intensive compared to standard antihypertensive therapy.

Exploratory Objectives

Identify predictive patterns of blood biomarkers which identify patients at high- risk of developing clinically significant osteonecrosis.
Identify MRI findings during late induction which correlate with osteonecrosis lesions seen during reinduction.
Identify patterns of diurnal blood pressure variation as measured by ambulatory blood pressure monitoring associated with the later development of osteonecrosis.
Compare induction blood pressure control and intervention arm to echocardiographic changes at reinduction II.
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.

Label	Type	Description	Intervention Names
Intensive Antihypertensive Therapy	Experimental	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.	Drug: Intensive Antihypertensive Therapy Other: Symptom Survey Other: Semi-structured interview
Conventional Antihypertensive Therapy	Active Comparator	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.	Drug: Conventional Antihypertensive Therapy Other: Symptom Survey Other: Semi-structured interview

Name	Type	Description	Arm Group Labels	Other Names
Intensive Antihypertensive Therapy	Drug	Receives intensive antihypertensive therapy	Intensive Antihypertensive Therapy

Measure	Description	Time Frame
Extensive Radiographic Osteonecrosis	Involvement of >=30% of the epiphyseal surface of either the hip or knee by prospective MRI during reinduction II	during reinduction II therapy, approximately 9 months into therapy.

Measure	Description	Time Frame
Rate of Clinically Significant Osteonecrosis	CTCAE grade 2 or high osteonecrosis	any time during leukemia therapy, approximately 2.5 years
Rate of Clinically Significant Osteonecrosis vs. Historical Control

Name	Affiliation	Role
Seth E. Karol, MD	St. Jude Children's Research Hospital	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital		Charlotte	North Carolina	28204	United States

Label	URL
St. Jude Children's Research Hospital	View source
ClinicalTrials Open at St. Jude	View source

ID	Title	Description
FG000	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Mar 1, 2021

ID	Title	Description
BG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
BG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00025 BG00125 BG00250

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Extensive Radiographic Osteonecrosis

Involvement of >=30% of the epiphyseal surface of either the hip or knee by prospective MRI during reinduction II

There were 21 of the 25 patients in conventional group, and 23 of the 25 patients in Intensive group reached reinduction II and had the MRI measurement during reinduction II.

Posted

Count of Participants

Participants

during reinduction II therapy, approximately 9 months into therapy.

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants	OG00021 OG00123

Title

Denominators

Categories

<30%

Title	Measurements
	OG00020 OG00121

>=30%

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Fisher Exact		0.7139														Superiority

Secondary

Rate of Clinically Significant Osteonecrosis

CTCAE grade 2 or high osteonecrosis

Not Posted

any time during leukemia therapy, approximately 2.5 years

Participants

Secondary

Rate of Clinically Significant Osteonecrosis vs. Historical Control

CTCAE grade 2 or high osteonecrosis vs. Total 16 matched controls

Not Posted

any time during leukemia therapy, approximately 2.5 years

Participants

Secondary

Blood Pressure Control on Trial

Comparison of repeated systolic and diastolic blood pressure measures between randomized treatment arms

Three patients on the Conventional Arm did not have the required measurement. Four patients on the Intensive Arm did not have the required measurement.

Posted

Median

Full Range

mmHg

first 9 months of therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarkers of Vascular Dysfunction - eNO Synthetase (pg/mL)

Comparison between randomized treatment arms

Seven patients on the Conventional Arm and Intensive Arm, Week3, did not have the required measurement. Fourteen patients on the Conventional Arm and Intensive Arm, Month9, did not have the required measurement.

Posted

Median

Full Range

pg/mL

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - Von Willebrand Factor (%)

Comparison between randomized treatment arms

Nine patients on the Conventional Arm and 10 on the Intensive Arm, Week3, did not have the required measurement. Four patients on the Conventional Arm and Intensive Arm, Month9, did not have the required measurement.

Posted

Median

Full Range

percentage (%)

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - TNF-alpha (pg/mL)

Comparison between randomized treatment arms

One patient on the Conventional Arm and 2 patients on the Intensive Arm, Week3, did not have the required measurement. Five patients on the Conventional Arm and Intensive Arm, Month9, did not have the required measurement.

Posted

Median

Full Range

pg/mL

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - D-dimer (µg/mL)

Comparison between randomized treatment arms

Nine patients on the Conventional Arm and 8 patients on the Intensive Arm, Week3, did not have the required measurement. Four patients on the Conventional Arm and 5 patients on the Intensive Arm, Month9, did not have the required measurement.

Posted

Median

Full Range

µg/mL

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - PAI-1 (AU/mL)

Comparison between randomized treatment arms

Nine patients on the Conventional Arm and the Intensive Arm, Week3, did not have the required measurement. Four patients on the Conventional Arm and 7 patients on the Intensive Arm, Month9, did not have the required measurement.

Posted

Median

Full Range

AU/mL

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - E-selectin (ng/mL)

Comparison between randomized treatment arms

One patient on the Conventional Arm and 2 patients on the Intensive Arm, Week3, did not have the required measurement. Five patients on the Conventional Arm and the Intensive Arm, Month9, did not have the required measurement.

Posted

Median

Full Range

ng/mL

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - ICAM-1 (ng/mL)

Comparison between randomized treatment arms

Posted

Median

Full Range

ng/mL

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - Arterial Elasticity (ml/mmHg)

Comparison between randomized treatment arms

Two patients on the Conventional Arm and Intensive Arm, Week3, did not have the required measurement. Seven patients on the Conventional Arm and 8 patients on the Intensive Arm, Month3, did not have the required measurement.

Posted

Median

Full Range

ml/mmHg

3 weeks and 3 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Biomarker of Vascular Dysfunction - Pulse Wave Velocity (m/Sec)

Comparison between randomized treatment arms

Two patients on the Conventional Arm and 3 patients on the Intensive Arm, Week3, did not have the required measurement. Eight patients on the Conventional Arm and on the Intensive Arm, Month3, did not have the required measurement.

Posted

Median

Full Range

m/sec

3 weeks and 3 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.
OG001	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.

Units	Counts
Participants

Secondary

Magnetic Resonance Imaging (MRI) of Right and Left Hip and Knee

Comparison between randomized treatment arms on proportions of MRI identified lesions >= 30%.

Four Conventional Arm patients and 2 Intensive Arm patients did not have Week3 right hip (R hip), left hip (L hip), right knee (R knee) and left knee (L knee) MRI.

Five Conventional and Intensive Arm patients did not have Month9 R hip MRI. Four Conventional Arm patients and 5 Intensive Arm patients did not have a Month9 L hip and R knee MRI.

Three Conventional Arm patients and 5 Intensive Arm patients did not have a Month9 L knee MRI.

Posted

Count of Participants

Participants

3 weeks and 9 months into therapy

ID	Title	Description
OG000	Conventional (Standard) Antihypertensive Therapy-Magnetic Resonance Imaging (MRI)-Right Hip	Conventional (Standard) Antihypertensive Therapy-Magnetic resonance imaging (MRI) of Right Hip
OG001	Intensive Antihypertensive Therapy-MRI-Right Hip	Intensive Antihypertensive Therapy-MRI of Right Hip
OG002	Conventional (Standard) Antihypertensive Therapy-MRI-Left Hip	Conventional (Standard) Antihypertensive Therapy-MRI of Left Hip

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Disseminated intravascular coagulation	Blood and lymphatic system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Febrile neutropenia	Blood and lymphatic system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0006 events4 affected25 at risk EG00114 events9 affected25 at risk
Cardiac disorders - Other	Cardiac disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Abdominal pain	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0012 events2 affected25 at risk
Colitis	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Constipation	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Pancreatic necrosis	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Pancreatitis	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0004 events4 affected25 at risk EG0014 events4 affected25 at risk
Vomiting	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0003 events3 affected25 at risk EG0012 events2 affected25 at risk
Fever	General disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0011 events1 affected25 at risk
Multi-organ failure	General disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Allergic reaction	Immune system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0011 events1 affected25 at risk
Catheter related infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Eye infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Infections and infestations - Other	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0013 events3 affected25 at risk
Lung infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0011 events1 affected25 at risk
Mucosal infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Sepsis	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0014 events2 affected25 at risk
Skin infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Tooth infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Upper respiratory infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0013 events2 affected25 at risk
Wound infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Vascular access complication	Injury, poisoning and procedural complications	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0011 events1 affected25 at risk
Blood antidiuretic hormone abnormal	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0013 events2 affected25 at risk
Blood bilirubin increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Lipase increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0011 events1 affected25 at risk
Serum amylase increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Dehydration	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0003 events3 affected25 at risk EG0010 events0 affected25 at risk
Hyperglycemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0014 events4 affected25 at risk
Hypoglycemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Hypokalemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Metabolism and nutrition disorders - Other	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Tumor lysis syndrome	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0014 events4 affected25 at risk
Encephalopathy	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Headache	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0003 events3 affected25 at risk EG0010 events0 affected25 at risk
Hydrocephalus	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Intracranial hemorrhage	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0011 events1 affected25 at risk
Seizure	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0013 events3 affected25 at risk
Syncope	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0012 events1 affected25 at risk
Anxiety	Psychiatric disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0011 events1 affected25 at risk
Mania	Psychiatric disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk
Acute kidney injury	Renal and urinary disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0013 events3 affected25 at risk
Renal calculi	Renal and urinary disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Laryngospasm	Respiratory, thoracic and mediastinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0010 events0 affected25 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0013 events2 affected25 at risk
Hypotension	Vascular disorders	NCI CTCAE v4.0	Systematic Assessment	EG0004 events3 affected25 at risk EG0014 events4 affected25 at risk
Thromboembolic event	Vascular disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0012 events2 affected25 at risk
Visceral arterial ischemia	Vascular disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0011 events1 affected25 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Alanine aminotransferase increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG00033 events13 affected25 at risk EG00127 events13 affected25 at risk
Hyponatremia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG00024 events10 affected25 at risk EG00120 events10 affected25 at risk
Hypertriglyceridemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG00018 events13 affected25 at risk EG00117 events10 affected25 at risk
Hyperglycemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG00013 events6 affected25 at risk EG00112 events8 affected25 at risk
Mucositis oral	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0009 events7 affected25 at risk EG00113 events10 affected25 at risk
Avascular necrosis	Musculoskeletal and connective tissue disorders	NCI CTCAE v4.0	Systematic Assessment	EG0008 events8 affected25 at risk EG00114 events14 affected25 at risk
Upper respiratory infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0007 events7 affected25 at risk EG0018 events7 affected25 at risk
Aspartate aminotransferase increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0009 events6 affected25 at risk EG0015 events5 affected25 at risk
Hypertension	Vascular disorders	NCI CTCAE v4.0	Systematic Assessment	EG0007 events7 affected25 at risk EG0016 events5 affected25 at risk
Dehydration	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0005 events5 affected25 at risk EG0015 events5 affected25 at risk
Cholesterol high	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0004 events4 affected25 at risk EG0015 events3 affected25 at risk
Serum amylase increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0017 events4 affected25 at risk
Thromboembolic event	Vascular disorders	NCI CTCAE v4.0	Systematic Assessment	EG0006 events4 affected25 at risk EG0013 events3 affected25 at risk
Blood bilirubin increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0003 events3 affected25 at risk EG0015 events3 affected25 at risk
Vascular access complication	Injury, poisoning and procedural complications	NCI CTCAE v4.0	Systematic Assessment	EG0004 events3 affected25 at risk EG0013 events3 affected25 at risk
Hypoalbuminemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0003 events2 affected25 at risk EG0014 events2 affected25 at risk
Hypokalemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0004 events2 affected25 at risk EG0013 events3 affected25 at risk
Hypophosphatemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0016 events4 affected25 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0004 events2 affected25 at risk EG0012 events2 affected25 at risk
Febrile neutropenia	Blood and lymphatic system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0013 events2 affected25 at risk
Mucosal infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0003 events2 affected25 at risk EG0012 events2 affected25 at risk
Skin infection	Infections and infestations	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0013 events2 affected25 at risk
Hypocalcemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0003 events3 affected25 at risk EG0012 events2 affected25 at risk
Abdominal pain	Gastrointestinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0003 events2 affected25 at risk EG0011 events1 affected25 at risk
Lipase increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0013 events3 affected25 at risk
Tumor lysis syndrome	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0013 events3 affected25 at risk
Hypotension	Vascular disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0013 events3 affected25 at risk
Fever	General disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0012 events2 affected25 at risk
General disorders and administration site conditions - Other	General disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0013 events2 affected25 at risk
GGT increased	Investigations	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0012 events2 affected25 at risk
Hyperuricemia	Metabolism and nutrition disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0013 events2 affected25 at risk
Headache	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0012 events2 affected25 at risk
Neuralgia	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0001 events1 affected25 at risk EG0012 events2 affected25 at risk
Peripheral motor neuropathy	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0011 events1 affected25 at risk
Adrenal insufficiency	Endocrine disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0012 events2 affected25 at risk
Allergic reaction	Immune system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0012 events2 affected25 at risk
Back pain	Musculoskeletal and connective tissue disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0012 events2 affected25 at risk
Syncope	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0012 events2 affected25 at risk
Pulmonary edema	Respiratory, thoracic and mediastinal disorders	NCI CTCAE v4.0	Systematic Assessment	EG0000 events0 affected25 at risk EG0012 events2 affected25 at risk
Peripheral sensory neuropathy	Nervous system disorders	NCI CTCAE v4.0	Systematic Assessment	EG0002 events2 affected25 at risk EG0010 events0 affected25 at risk

ID	Term
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D001847	Bone Diseases
D009140	Musculoskeletal Diseases
D009336	Necrosis
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D007945	Leukemia, Lymphoid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D008232	Lymphoproliferative Disorders
D008206	Lymphatic Diseases
D007160	Immunoproliferative Disorders
D007154	Immune System Diseases

ID	Term
D011795	Surveys and Questionnaires
D007407	Interviews as Topic

ID	Term
D003625	Data Collection
D004812	Epidemiologic Methods
D008919	Investigative Techniques
D017531	Health Care Evaluation Mechanisms
D011787	Quality of Health Care
D017530	Health Care Quality, Access, and Evaluation
D011634	Public Health
D004778	Environment and Public Health

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Intensive Antihypertensive Therapy	Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.	0	25	22	25	24	25
EG001	Conventional (Standard) Antihypertensive Therapy	Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II.	1	25	22	25	24	25

ID	Term
D006973	Hypertension
D010020	Osteonecrosis
D054198	Precursor Cell Lymphoblastic Leukemia-Lymphoma