NCT04401267

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

Completed Phase 2 Results posted Last updated 3 November 2025

What this trial tests

Phase 2 trial testing Intensive Antihypertensive Therapy in Hypertension in 51 participants. Completed in 7 October 2025.

Timeline

15 October 2020

Primary endpoint
25 September 2023

7 October 2025

Quick facts

Lead sponsor	St. Jude Children's Research Hospital
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	single
Primary purpose	treatment
Enrollment	51
Start date	15 October 2020
Primary completion	25 September 2023
Estimated completion	7 October 2025
Sites	2 locations across United States

Drugs / interventions tested

• Intensive Antihypertensive Therapy — full drug profile →
• Conventional Antihypertensive Therapy — full drug profile →
• Symptom Survey
• Semi-structured interview

Conditions studied

• Hypertension — all drugs for Hypertension →
• Osteonecrosis — all drugs for Osteonecrosis →
• Osteonecrosis Due to Drug — all drugs for Osteonecrosis Due to Drug →

Sponsor

St. Jude Children's Research Hospital

Who can join

10 and older, any sex, with Hypertension or Osteonecrosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Extensive Radiographic Osteonecrosis Primary · during reinduction II therapy, approximately 9 months into therapy.

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

<30%

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	20
Intensive Antihypertensive Therapy	21

>=30%

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	1
Intensive Antihypertensive Therapy	2

Blood Pressure Control on Trial Secondary · first 9 months of therapy

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

Systolic Blood at Pressure at Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	114.00	103.00 – 127.00
Intensive Antihypertensive Therapy	117.00	91.00 – 139.00

Diastolic Blood Pressure at Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	70.00	60.00 – 82.00
Intensive Antihypertensive Therapy	74.00	54.00 – 87.00

Biomarkers of Vascular Dysfunction - eNO Synthetase (pg/mL) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	187.78	12.68 – 2030.13
Intensive Antihypertensive Therapy	267.03	11.87 – 226392.20

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	193.28	87.49 – 1096.74
Intensive Antihypertensive Therapy	266.53	32.89 – 435387.25

Biomarker of Vascular Dysfunction - Von Willebrand Factor (%) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	195.00	143.00 – 420.00
Intensive Antihypertensive Therapy	191.00	118.00 – 420.00

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	211.00	59.00 – 420.00
Intensive Antihypertensive Therapy	164.00	82.00 – 352.00

Biomarker of Vascular Dysfunction - TNF-alpha (pg/mL) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	0.87	0.25 – 1.73
Intensive Antihypertensive Therapy	0.79	0.36 – 1.86

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	1.56	0.51 – 3.45
Intensive Antihypertensive Therapy	1.44	0.41 – 26.32

Biomarker of Vascular Dysfunction - D-dimer (µg/mL) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	0.85	0.30 – 2.00
Intensive Antihypertensive Therapy	0.60	0.27 – 2.77

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	0.44	0.27 – 4.28
Intensive Antihypertensive Therapy	0.29	0.27 – 1.10

Biomarker of Vascular Dysfunction - PAI-1 (AU/mL) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	17.85	2.00 – 293.00
Intensive Antihypertensive Therapy	15.80	3.10 – 71.90

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	38.00	2.00 – 100.00
Intensive Antihypertensive Therapy	41.10	2.00 – 138.50

Biomarker of Vascular Dysfunction - E-selectin (ng/mL) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	23.53	6.36 – 56.64
Intensive Antihypertensive Therapy	23.24	8.30 – 100.14

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	65.16	19.37 – 144.30
Intensive Antihypertensive Therapy	53.68	28.86 – 163.90

Biomarker of Vascular Dysfunction - ICAM-1 (ng/mL) Secondary · 3 weeks and 9 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	328.79	166.05 – 515.52
Intensive Antihypertensive Therapy	314.22	207.09 – 632.73

Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	629.13	344.67 – 1620.85
Intensive Antihypertensive Therapy	639.25	244.27 – 1511.56

Biomarker of Vascular Dysfunction - Arterial Elasticity (ml/mmHg) Secondary · 3 weeks and 3 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	11.60	3.30 – 24.30
Intensive Antihypertensive Therapy	10.70	3.00 – 21.00

Month3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	12.30	6.80 – 18.80
Intensive Antihypertensive Therapy	10.40	3.40 – 25.40

Biomarker of Vascular Dysfunction - Pulse Wave Velocity (m/Sec) Secondary · 3 weeks and 3 months into therapy

Comparison between randomized treatment arms

Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	5.00	0.50 – 8.30
Intensive Antihypertensive Therapy	5.35	3.80 – 8.40

Month3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy	5.00	3.00 – 6.10
Intensive Antihypertensive Therapy	5.30	3.10 – 6.10

Magnetic Resonance Imaging (MRI) of Right and Left Hip and Knee Secondary · 3 weeks and 9 months into therapy

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

>=30% at Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy-Magnetic Resonance Imaging (MRI)-Right Hip	1
Intensive Antihypertensive Therapy-MRI-Right Hip	2
Conventional (Standard) Antihypertensive Therapy-MRI-Left Hip	1
Intensive Antihypertensive Therapy-MRI-Left Hip	2
Conventional (Standard) Antihypertensive Therapy-MRI-Right Knee	1
Intensive Antihypertensive Therapy-MRI-Right Knee	1
Conventional (Standard) Antihypertensive Therapy-MRI-Left Knee	1
Intensive Antihypertensive Therapy-MRI-Left Knee	1

<30% at Week3

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy-Magnetic Resonance Imaging (MRI)-Right Hip	20
Intensive Antihypertensive Therapy-MRI-Right Hip	21
Conventional (Standard) Antihypertensive Therapy-MRI-Left Hip	20
Intensive Antihypertensive Therapy-MRI-Left Hip	21
Conventional (Standard) Antihypertensive Therapy-MRI-Right Knee	20
Intensive Antihypertensive Therapy-MRI-Right Knee	22
Conventional (Standard) Antihypertensive Therapy-MRI-Left Knee	20
Intensive Antihypertensive Therapy-MRI-Left Knee	22

<30% at Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy-Magnetic Resonance Imaging (MRI)-Right Hip	17
Intensive Antihypertensive Therapy-MRI-Right Hip	16
Conventional (Standard) Antihypertensive Therapy-MRI-Left Hip	18
Intensive Antihypertensive Therapy-MRI-Left Hip	16
Conventional (Standard) Antihypertensive Therapy-MRI-Right Knee	18
Intensive Antihypertensive Therapy-MRI-Right Knee	16
Conventional (Standard) Antihypertensive Therapy-MRI-Left Knee	19
Intensive Antihypertensive Therapy-MRI-Left Knee	16

>=30% at Month9

Group	Value	95% CI
Conventional (Standard) Antihypertensive Therapy-Magnetic Resonance Imaging (MRI)-Right Hip	3
Intensive Antihypertensive Therapy-MRI-Right Hip	4
Conventional (Standard) Antihypertensive Therapy-MRI-Left Hip	3
Intensive Antihypertensive Therapy-MRI-Left Hip	4
Conventional (Standard) Antihypertensive Therapy-MRI-Right Knee	3
Intensive Antihypertensive Therapy-MRI-Right Knee	4
Conventional (Standard) Antihypertensive Therapy-MRI-Left Knee	3
Intensive Antihypertensive Therapy-MRI-Left Knee	4

Adverse events — posted to ClinicalTrials.gov

Time frame: AEs will be collected approximately 9 months, until the end on reinduction.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Intensive Antihypertensive Therapy

Serious: 22/25 (88%)

Deaths: 0/25

Conventional (Standard) Antihypertensive Therapy

Serious: 22/25 (88%)

Deaths: 1/25

Serious adverse events (50 terms)

Reaction	System	Intensive Antihypertensive…	Conventional (Standard) An…
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Pancreatitis	Gastrointestinal disorders	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—
Tumor lysis syndrome	Metabolism and nutrition disorders	—	—
Hypotension	Vascular disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Infections and infestations - Other	Infections and infestations	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Seizure	Nervous system disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Allergic reaction	Immune system disorders	—	—
Lung infection	Infections and infestations	—	—
Sepsis	Infections and infestations	—	—
Upper respiratory infection	Infections and infestations	—	—
Blood antidiuretic hormone abnormal	Investigations	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Thromboembolic event	Vascular disorders	—	—
Disseminated intravascular coagulation	Blood and lymphatic system disorders	—	—
Cardiac disorders - Other	Cardiac disorders	—	—
Colitis	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Pancreatic necrosis	Gastrointestinal disorders	—	—
Fever	General disorders	—	—

Other adverse events (40 terms — click to expand)

Reaction	System	Intensive Antihypertensive…	Conventional (Standard) An…
Avascular necrosis	Musculoskeletal and connective tissue disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Hypertriglyceridemia	Metabolism and nutrition disorders	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—
Mucositis oral	Gastrointestinal disorders	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—
Upper respiratory infection	Infections and infestations	—	—
Hypertension	Vascular disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Cholesterol high	Investigations	—	—
Serum amylase increased	Investigations	—	—
Thromboembolic event	Vascular disorders	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—
Blood bilirubin increased	Investigations	—	—
Vascular access complication	Injury, poisoning and procedural complications	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—
Lipase increased	Investigations	—	—
Tumor lysis syndrome	Metabolism and nutrition disorders	—	—
Hypotension	Vascular disorders	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Mucosal infection	Infections and infestations	—	—
Skin infection	Infections and infestations	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Fever	General disorders	—	—
General disorders and administration site conditions - Other	General disorders	—	—
GGT increased	Investigations	—	—
Hyperuricemia	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Neuralgia	Nervous system disorders	—	—
Peripheral motor neuropathy	Nervous system disorders	—	—
Adrenal insufficiency	Endocrine disorders	—	—
Allergic reaction	Immune system disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Syncope	Nervous system disorders	—	—
Pulmonary edema	Respiratory, thoracic and mediastinal disorders	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—

Most-reported serious reactions: Febrile neutropenia, Pancreatitis, Hyperglycemia, Tumor lysis syndrome, Hypotension, Vomiting, Infections and infestations - Other, Dehydration.

Data from ClinicalTrials.gov NCT04401267 adverse events section.

Sponsor's own description

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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Bone health in childhood cancer survivors, is there really a problem? Pitfalls of assessment, calculating risk, and suggested surveillance and management for osteonecrosis and low and very low bone mineral density.
   de Winter DTC, Neggers SJCMM, van den Heuvel-Eibrink MM, van Atteveld JE. · · 2024 · cited 2× · PMID 39437150 · DOI 10.1530/ec-24-0487
2. Recent perspectives on the association between osteonecrosis and bone mineral density decline in childhood acute lymphoblastic leukemia.
   van Atteveld JE, de Winter DT, Pieters R, Neggers SJ, et al · · 2021 · cited 2× · PMID 34308423 · DOI 10.12703/r/10-57