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CompletedNCT04401267Updated Jul 20, 2026Results posted

Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma

A Phase 2 interventional study of Intensive Antihypertensive Therapy and Conventional Antihypertensive Therapy in Hypertension, Osteonecrosis and Osteonecrosis Due to Drug, sponsored by St. Jude Children's Research Hospital. Completed at 2 sites in United States. Open to participants aged 10 Years and older. Per ClinicalTrials.gov, last updated 2026-07-20.

Sponsored by St. Jude Children's Research Hospital · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
51
Allocation
Randomized
Ages
10 Years and older
Sex
All
01

Study 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.
Read the detailed description

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). A target systolic blood pressure range will be chosen for each participant based on their randomization arm, age, sex, and height.

Patients will be randomized on day 4 of induction therapy to either conventional or intensive blood pressure goals. Patients will be treated with antihypertensive therapy to achieve blood pressure control as indicated by their randomized arm. Therapy will be adjusted every 3-4 days as needed to achieve targeted control based on the mean 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.

Patients will be asked to complete a symptom survey and a semi-structured interview.

02

Conditions studied

  • Hypertension
  • Osteonecrosis
  • Osteonecrosis Due to Drug

Keywords

  • Acute Lymphoblastic Leukemia
  • Children
  • Hypertension
  • Osteonecrosis
  • Osteonecrosis Due to Drug
03

Who can participate

Ages eligible
10 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • 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.
  • Patient is 10 years of age or older at the time of enrollment on TOT17.
  • Patient has completed ≤ 4 days of protocol therapy (patients are eligible on Day 4 of TOT17 therapy).

Exclusion criteria

Exclusion Criteria:

  • Moderate-severe renal dysfunction (glomerular filtration rate \<45 ml/min/1.73m2).
  • Down's syndrome (germline Trisomy 21) or other syndrome resulting in growth delay or alterations in stature.
  • Chronic inability to ambulate. Patients with limitations in movement due to acute complications of leukemia/lymphoma are not excluded.
  • Permanent contraindication to MRI evaluation.
  • Participants who are pregnant or lactating. Males or females of reproductive potential must agree to use effective contraception for the duration of study participation.
  • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Single (Outcomes assessor)
Enrollment
51 participants (actual)

Study arms

  • Experimental
    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.

    Drug: Intensive Antihypertensive Therapy · Other: Symptom Survey · Other: Semi-structured interview

  • Active comparator
    Conventional 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.

    Drug: Conventional Antihypertensive Therapy · Other: Symptom Survey · Other: Semi-structured interview

Interventions

  • DrugIntensive Antihypertensive Therapy

    Receives intensive antihypertensive therapy

    Also known as: Hypotensive Therapy

  • DrugConventional Antihypertensive Therapy

    Receives conventional antihypertensive therapy

    Also known as: Hypotensive Therapy

  • OtherSymptom Survey

    The symptom survey is 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).

    Also known as: Survey

  • OtherSemi-structured interview

    Patients will be interviewed by a trained examiner about their treatment and symptom burden on Week 49 of TOT17 Continuation Therapy. The interview will be recorded and will take about 30-45 minutes.

    Also known as: Interview

05

What researchers measure

Primary outcomes

  1. Extensive Radiographic Osteonecrosis

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

    Time frame: during reinduction II therapy, approximately 9 months into therapy.

Secondary outcomes

  1. Rate of Clinically Significant Osteonecrosis

    CTCAE grade 2 or high osteonecrosis

    Time frame: any time during leukemia therapy, approximately 2.5 years

  2. Rate of Clinically Significant Osteonecrosis vs. Historical Control

    CTCAE grade 2 or high osteonecrosis vs. Total 16 (TOTVXI-NCT00549848) matched controls

    Time frame: any time during leukemia therapy, approximately 2.5 years

  3. Blood Pressure Control on Trial

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

    Time frame: first 9 months of therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

  5. Biomarker of Vascular Dysfunction - Von Willebrand Factor (%)

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 9 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 3 months into therapy

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

    Comparison between randomized treatment arms

    Time frame: 3 weeks and 3 months into therapy

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

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

    Time frame: 3 weeks and 9 months into therapy

06

Results

Posted Jul 11, 2024

Participant flow

A total of 51 patients were enrolled into the study from 15OCT2020 to 28DEC2022. Of those, one patient was found to be ineligible to the study. Therefore, only 50 eligible patients will be included in the analyses of the study.

Participant flow — Overall Study
MilestoneIntensive Antihypertensive TherapyConventional (Standard) Antihypertensive Therapy
Started2625
Completed2122
Not completed53
Withdrew: Death01
Withdrew: Discontinuation of tot17 therapy42
Withdrew: Found to be ineligible10

Outcome measures

PrimaryExtensive Radiographic Osteonecrosis

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

Time frame:
during reinduction II therapy, approximately 9 months into therapy.
Reported as:
Count of participants · Participants
Extensive Radiographic Osteonecrosis
ParticipantsConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
<30%2021
>=30%12
Statistical analysis
  • Conventional (Standard) Antihypertensive Therapy vs Intensive Antihypertensive Therapy · Fisher Exact · p = 0.7139
SecondaryRate of Clinically Significant Osteonecrosis

CTCAE grade 2 or high osteonecrosis

Time frame:
any time during leukemia therapy, approximately 2.5 years
Reported as:
Count of participants · Participants
Rate of Clinically Significant Osteonecrosis
ParticipantsConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Grade 2 or higher osteonecrosis-Yes45
Grade 2 or higher osteonecrosis-No1815
Statistical analysis
  • Conventional (Standard) Antihypertensive Therapy vs Intensive Antihypertensive Therapy · Fisher Exact · p = 0.7
SecondaryRate of Clinically Significant Osteonecrosis vs. Historical Control

CTCAE grade 2 or high osteonecrosis vs. Total 16 (TOTVXI-NCT00549848) matched controls

Time frame:
any time during leukemia therapy, approximately 2.5 years
Reported as:
Count of participants · Participants
Rate of Clinically Significant Osteonecrosis vs. Historical Control
ParticipantsHYPERION Participants With Clinically Significant OsteonecrosisTOT16 Participants With Clinically Significant Osteonecrosis
Rate of Clinically Significant Osteonecrosis vs. Historical Control9103
Statistical analysis
  • HYPERION Participants With Clinically Significant Osteonecrosis vs TOT16 Participants With Clinically Significant Osteonecrosis · Chi-squared · p = 0.01
SecondaryBlood Pressure Control on Trial

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

Time frame:
first 9 months of therapy
Reported as:
Median · mmHg
Blood Pressure Control on Trial
mmHgConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Systolic Blood at Pressure at Month9114.00 (103.00 to 127.00)117.00 (91.00 to 139.00)
Diastolic Blood Pressure at Month970.00 (60.00 to 82.00)74.00 (54.00 to 87.00)
SecondaryBiomarkers of Vascular Dysfunction - eNO Synthetase (pg/mL)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · pg/mL
Biomarkers of Vascular Dysfunction - eNO Synthetase (pg/mL)
pg/mLConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week3187.78 (12.68 to 2030.13)267.03 (11.87 to 226392.20)
Month9193.28 (87.49 to 1096.74)266.53 (32.89 to 435387.25)
SecondaryBiomarker of Vascular Dysfunction - Von Willebrand Factor (%)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · percentage (%)
Biomarker of Vascular Dysfunction - Von Willebrand Factor (%)
percentage (%)Conventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week3195.00 (143.00 to 420.00)191.00 (118.00 to 420.00)
Month9211.00 (59.00 to 420.00)164.00 (82.00 to 352.00)
SecondaryBiomarker of Vascular Dysfunction - TNF-alpha (pg/mL)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · pg/mL
Biomarker of Vascular Dysfunction - TNF-alpha (pg/mL)
pg/mLConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week30.87 (0.25 to 1.73)0.79 (0.36 to 1.86)
Month91.56 (0.51 to 3.45)1.44 (0.41 to 26.32)
SecondaryBiomarker of Vascular Dysfunction - D-dimer (µg/mL)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · µg/mL
Biomarker of Vascular Dysfunction - D-dimer (µg/mL)
µg/mLConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week30.85 (0.30 to 2.00)0.60 (0.27 to 2.77)
Month90.44 (0.27 to 4.28)0.29 (0.27 to 1.10)
SecondaryBiomarker of Vascular Dysfunction - PAI-1 (AU/mL)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · AU/mL
Biomarker of Vascular Dysfunction - PAI-1 (AU/mL)
AU/mLConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week317.85 (2.00 to 293.00)15.80 (3.10 to 71.90)
Month938.00 (2.00 to 100.00)41.10 (2.00 to 138.50)
SecondaryBiomarker of Vascular Dysfunction - E-selectin (ng/mL)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · ng/mL
Biomarker of Vascular Dysfunction - E-selectin (ng/mL)
ng/mLConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week323.53 (6.36 to 56.64)23.24 (8.30 to 100.14)
Month965.16 (19.37 to 144.30)53.68 (28.86 to 163.90)
SecondaryBiomarker of Vascular Dysfunction - ICAM-1 (ng/mL)

Comparison between randomized treatment arms

Time frame:
3 weeks and 9 months into therapy
Reported as:
Median · ng/mL
Biomarker of Vascular Dysfunction - ICAM-1 (ng/mL)
ng/mLConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week3328.79 (166.05 to 515.52)314.22 (207.09 to 632.73)
Month9629.13 (344.67 to 1620.85)639.25 (244.27 to 1511.56)
SecondaryBiomarker of Vascular Dysfunction - Arterial Elasticity (ml/mmHg)

Comparison between randomized treatment arms

Time frame:
3 weeks and 3 months into therapy
Reported as:
Median · ml/mmHg
Biomarker of Vascular Dysfunction - Arterial Elasticity (ml/mmHg)
ml/mmHgConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week311.60 (3.30 to 24.30)10.70 (3.00 to 21.00)
Month312.30 (6.80 to 18.80)10.40 (3.40 to 25.40)
SecondaryBiomarker of Vascular Dysfunction - Pulse Wave Velocity (m/Sec)

Comparison between randomized treatment arms

Time frame:
3 weeks and 3 months into therapy
Reported as:
Median · m/sec
Biomarker of Vascular Dysfunction - Pulse Wave Velocity (m/Sec)
m/secConventional (Standard) Antihypertensive TherapyIntensive Antihypertensive Therapy
Week35.00 (0.50 to 8.30)5.35 (3.80 to 8.40)
Month35.00 (3.00 to 6.10)5.30 (3.10 to 6.10)
SecondaryMagnetic Resonance Imaging (MRI) of Right and Left Hip and Knee

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

Time frame:
3 weeks and 9 months into therapy
Reported as:
Count of participants · Participants
Magnetic Resonance Imaging (MRI) of Right and Left Hip and Knee
ParticipantsConventional (Standard) Antihypertensive Therapy-Magnetic Resonance Imaging (MRI)-Right HipIntensive Antihypertensive Therapy-MRI-Right HipConventional (Standard) Antihypertensive Therapy-MRI-Left HipIntensive Antihypertensive Therapy-MRI-Left HipConventional (Standard) Antihypertensive Therapy-MRI-Right KneeIntensive Antihypertensive Therapy-MRI-Right KneeConventional (Standard) Antihypertensive Therapy-MRI-Left KneeIntensive Antihypertensive Therapy-MRI-Left Knee
>=30% at Week312121111
<30% at Week32021202120222022
<30% at Month91716181618161916
>=30% at Month934343434

Adverse events

Collected over AEs will be collected approximately 9 months, until the end on reinduction. In addition, grade 2 or higher osteonecrosis AEs will be collected for approximately 2.5 years.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Intensive Antihypertensive Therapy0/25 (0%)22/25 (88%)24/25 (96%)
Conventional (Standard) Antihypertensive Therapy1/25 (4%)22/25 (88%)24/25 (96%)
Most frequent serious events
Showing 10 of 50
Most frequent serious events
EventIntensive Antihypertensive TherapyConventional (Standard) Antihypertensive Therapy
Febrile neutropeniaBlood and lymphatic system disorders4/259/25
PancreatitisGastrointestinal disorders4/254/25
HyperglycemiaMetabolism and nutrition disorders2/254/25
Tumor lysis syndromeMetabolism and nutrition disorders0/254/25
HypotensionVascular disorders3/254/25
VomitingGastrointestinal disorders3/252/25
Infections and infestations - OtherInfections and infestations2/253/25
DehydrationMetabolism and nutrition disorders3/250/25
HeadacheNervous system disorders3/250/25
SeizureNervous system disorders1/253/25
Most frequent other events
Showing 10 of 40
Most frequent other events
EventIntensive Antihypertensive TherapyConventional (Standard) Antihypertensive Therapy
Avascular necrosisMusculoskeletal and connective tissue disorders8/2514/25
Alanine aminotransferase increasedInvestigations13/2513/25
HypertriglyceridemiaMetabolism and nutrition disorders13/2510/25
HyponatremiaMetabolism and nutrition disorders10/2510/25
Mucositis oralGastrointestinal disorders7/2510/25
HyperglycemiaMetabolism and nutrition disorders6/258/25
Upper respiratory infectionInfections and infestations7/257/25
HypertensionVascular disorders7/255/25
Aspartate aminotransferase increasedInvestigations6/255/25
DehydrationMetabolism and nutrition disorders5/255/25

Baseline characteristics

Age, Continuous
Age, Continuous(years)Conventional (Standard) Antihypertensive TherapyIntensive Antihypertensive TherapyTotal
Mean13.96 ± 1.8614.27 ± 2.4214.11 ± 2.14
Age, Continuous
Age, Continuous(years)Conventional (Standard) Antihypertensive TherapyIntensive Antihypertensive TherapyTotal
Median13.93 (10.58 to 18.54)14.01 (10.07 to 18.43)13.98 (10.07 to 18.54)
Sex: Female, Male
Sex: Female, Male(Participants)Conventional (Standard) Antihypertensive TherapyIntensive Antihypertensive TherapyTotal
Female91019
Male161531
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Conventional (Standard) Antihypertensive TherapyIntensive Antihypertensive TherapyTotal
White131629
Black7613
Other415
Missing123
07

Study locations

2 sites
  • St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
    Charlotte, North Carolina 28204, United States
  • St. Jude Children's Research Hospital
    Memphis, Tennessee 38105, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Mar 1, 2021
  • Informed consent form · Mar 1, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

Supporting information: Study protocol, Sap, Icf

09

Registry details

Key details

Study ID
NCT04401267
Lead sponsor
St. Jude Children's Research Hospital
Collaborators
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
May 26, 2020
Start date
Oct 15, 2020
Primary completion
Sep 25, 2023
Completion
Oct 7, 2025
Results posted
Jul 11, 2024
Last update
Jul 20, 2026

Study contacts

Seth E. Karol, MD
principal investigator · St. Jude Children's Research Hospital

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
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