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

Primary Purpose

Hypertension, Osteonecrosis, Osteonecrosis Due to Drug

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Intensive Antihypertensive Therapy
Conventional Antihypertensive Therapy
Symptom Survey
Semi-structured interview
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypertension focused on measuring Acute Lymphoblastic Leukemia, Children, Hypertension, Osteonecrosis, Osteonecrosis Due to Drug

Eligibility Criteria

10 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
  • St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intensive Antihypertensive Therapy

Conventional Antihypertensive Therapy

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Rate of clinically significant osteonecrosis
CTCAE grade 2 or high osteonecrosis
Rate of clinically significant osteonecrosis vs. historical control
CTCAE grade 2 or high osteonecrosis vs. Total 16 matched controls
Blood pressure control on trial
Comparison of repeated systolic and diastolic blood pressure measures between randomized treatment arms
Biomarkers of vascular dysfunction - eNO synthetase (pg/mL)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - Von Willebrand Factor (%)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - TNF-alpha (pg/mL)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - D-dimer (µg/mL)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - PAI-1 (AU/mL)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - E-selectin (ng/mL)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - ICAM-1 (ng/mL)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - Arterial elasticity (ml/mmHg)
Comparison between randomized treatment arms
Biomarker of vascular dysfunction - Pulse Wave Velocity (m/sec)
Comparison between randomized treatment arms
Magnetic resonance imaging (MRI) of hip and knee
Comparison between randomized treatment arms

Full Information

First Posted
May 13, 2020
Last Updated
October 10, 2023
Sponsor
St. Jude Children's Research Hospital
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04401267
Brief Title
Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma
Official Title
Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 15, 2020 (Actual)
Primary Completion Date
September 25, 2023 (Actual)
Study Completion Date
March 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Osteonecrosis, Osteonecrosis Due to Drug
Keywords
Acute Lymphoblastic Leukemia, Children, Hypertension, Osteonecrosis, Osteonecrosis Due to Drug

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
Evaluation of the MRIs defining the primary endpoint will be performed by a blinded radiologist.
Allocation
Randomized
Enrollment
51 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intensive Antihypertensive Therapy
Arm Type
Experimental
Arm Description
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.
Arm Title
Conventional Antihypertensive Therapy
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Intensive Antihypertensive Therapy
Other Intervention Name(s)
Hypotensive Therapy
Intervention Description
Receives intensive antihypertensive therapy
Intervention Type
Drug
Intervention Name(s)
Conventional Antihypertensive Therapy
Other Intervention Name(s)
Hypotensive Therapy
Intervention Description
Receives conventional antihypertensive therapy
Intervention Type
Other
Intervention Name(s)
Symptom Survey
Other Intervention Name(s)
Survey
Intervention Description
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).
Intervention Type
Other
Intervention Name(s)
Semi-structured interview
Other Intervention Name(s)
Interview
Intervention Description
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.
Primary Outcome Measure Information:
Title
Extensive radiographic osteonecrosis
Description
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 Outcome Measure Information:
Title
Rate of clinically significant osteonecrosis
Description
CTCAE grade 2 or high osteonecrosis
Time Frame
any time during leukemia therapy, approximately 2.5 years
Title
Rate of clinically significant osteonecrosis vs. historical control
Description
CTCAE grade 2 or high osteonecrosis vs. Total 16 matched controls
Time Frame
any time during leukemia therapy, approximately 2.5 years
Title
Blood pressure control on trial
Description
Comparison of repeated systolic and diastolic blood pressure measures between randomized treatment arms
Time Frame
first 9 months of therapy
Title
Biomarkers of vascular dysfunction - eNO synthetase (pg/mL)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - Von Willebrand Factor (%)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - TNF-alpha (pg/mL)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - D-dimer (µg/mL)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - PAI-1 (AU/mL)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - E-selectin (ng/mL)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - ICAM-1 (ng/mL)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy
Title
Biomarker of vascular dysfunction - Arterial elasticity (ml/mmHg)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 3 months into therapy
Title
Biomarker of vascular dysfunction - Pulse Wave Velocity (m/sec)
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 3 months into therapy
Title
Magnetic resonance imaging (MRI) of hip and knee
Description
Comparison between randomized treatment arms
Time Frame
3 weeks and 9 months into therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Seth E. Karol, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
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.
IPD Sharing Time Frame
Data will be made available at the time of article publication.
IPD Sharing Access Criteria
Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
ClinicalTrials Open at St. Jude

Learn more about this trial

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

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