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

Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04401267
• Other study ID #: HYPERION
• Secondary ID: 1K08CA250418NCI-
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 15, 2020
• Est. completion date: September 2025

Study information

• Verified date: April 2024
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 51
• Est. completion date: September 2025
• Est. primary completion date: September 25, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years and older

Eligibility

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:

• 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.

Related Conditions & MeSH terms

• Hypertension
• Leukemia
• Leukemia, Lymphoid
• Osteonecrosis
• Osteonecrosis Due to Drug
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Intensive Antihypertensive Therapy
Receives intensive antihypertensive therapy
• Conventional Antihypertensive Therapy
Receives conventional antihypertensive therapy

Other:
• Symptom 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).
• Semi-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.

Locations

Country	Name	City	State
United States	St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital	Charlotte	North Carolina
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Secondary	Rate of clinically significant osteonecrosis	CTCAE grade 2 or high osteonecrosis	any time during leukemia therapy, approximately 2.5 years
Secondary	Rate of clinically significant osteonecrosis vs. historical control	CTCAE grade 2 or high osteonecrosis vs. Total 16 matched controls	any time during leukemia therapy, approximately 2.5 years
Secondary	Blood pressure control on trial	Comparison of repeated systolic and diastolic blood pressure measures between randomized treatment arms	first 9 months of therapy
Secondary	Biomarkers of vascular dysfunction - eNO synthetase (pg/mL)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - Von Willebrand Factor (%)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - TNF-alpha (pg/mL)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - D-dimer (µg/mL)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - PAI-1 (AU/mL)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - E-selectin (ng/mL)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - ICAM-1 (ng/mL)	Comparison between randomized treatment arms	3 weeks and 9 months into therapy
Secondary	Biomarker of vascular dysfunction - Arterial elasticity (ml/mmHg)	Comparison between randomized treatment arms	3 weeks and 3 months into therapy
Secondary	Biomarker of vascular dysfunction - Pulse Wave Velocity (m/sec)	Comparison between randomized treatment arms	3 weeks and 3 months into therapy
Secondary	Magnetic resonance imaging (MRI) of hip and knee	Comparison between randomized treatment arms	3 weeks and 9 months into therapy

External Links

•   ClinicalTrials Open at St. Jude
•   St. Jude Children's Research Hospital