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Effect of Tenofovir DF on Bone Metabolism in Children

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Eye exam
Oral exam
CT scan
Neuropsychological testing
Electrocardiogram
Echocardiogram
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring Drug Resistance, HAART, Pamidronate, Osteopenia, Pediatric, HIV, Pediatrics, Treatment Experienced

Eligibility Criteria

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

INCLUSION CRITERIA: Cohort 1 - patients about to start tenofovir DF HIV-infected children between the ages of 4 years and less than 21 years. Clinical decision has been made to start the patient on tenofovir DF-containing antiretroviral regimen BSA greater than or equal to 0.85 m2 Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Not pregnant or breast feeding 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) Less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) AST and ALT less than or equal to 7.5 times the upper limit of normal Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Cohort 2 - patients already being treated with tenofovir DF who have baseline DEXA available HIV-infected children between the ages of 4 years and less than 21 years. Current tenofovir DF-containing antiretroviral regimen was started less than 6 months ago Baseline DEXA for L-spine BMD is available and was performed less than six months prior to or within the first week of starting tenofovir DF BSA greater than or equal to 0.85 m2 Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Not pregnant or breast feeding 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) Less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) AST and ALT less than or equal to 7.5 times the upper limit of normal Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Cohort 3 - patients already being treated with an antiretroviral regimen that includes tenofovir DF who DO NOT have baseline DEXA available HIV-infected children between the ages of 4 years and less than 21 years. Current antiretroviral regimen includes tenofovir DF Baseline (within prior 6 months) DEXA for L-spine BMD is NOT available BSA greater than or equal to 0.85 m2 Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Not pregnant or breast feeding 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) AST and ALT less than or equal to 7.5 times the upper limit of normal Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Eligibility criteria for pamidronate therapy (after enrollment on protocol) One of the following while on tenofovirDF-containing antiretroviral regimen: Greater than 6% loss in L-spine BMD in the presence of a BMD Z score less than -2.5 at 6 months compared to baseline Minimal trauma fracture BMD Z-score less than -3 AND One of the following while on tenofovirDF-containing antiretroviral regimen: Greater than or equal to 0.5 log decrease in VL from baseline Greater than or equal to 25% increase in absolute CD4 count from baseline Improvement in HIV-related signs or symptoms OR BMD Z-score less than -3 (i.e., pamidronate therapy will also be considered for subjects whose BMD Z score is less than -3 at baseline) Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Less than or equal to grade 1 serum phosphate, magnesium, and potassium (supplementation allowed) Not pregnant or breast feeding No history of hypersensitivity to bisphosphonates INCLUSION CRITERIA: Eligibility criteria for bone biopsy (after enrollment on protocol) No history of bleeding abnormality No history of hypersensitivity or intolerance to tetracycline or related drugs Normal CBC and PT/PTT BMD Z-score greater than -3 Informed consent: patient, parent or legal guardian must sign a separate informed consent to document their understanding of the investigational nature and the risks of the bone biopsy.

Sites / Locations

  • National Cancer Institute (NCI)

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
July 23, 2004
Last Updated
March 3, 2008
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00088309
Brief Title
Effect of Tenofovir DF on Bone Metabolism in Children
Official Title
Tenofovir Disoproxil Fumarate Salvage Therapy in HIV-Infected Children and a Study of Its Effect on Bone Metabolism
Study Type
Interventional

2. Study Status

Record Verification Date
May 2006
Overall Recruitment Status
Completed
Study Start Date
June 2004 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
May 2006 (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
This study will examine the long-term effects, particularly on bone metabolism, of the drug tenofovir DF in children with HIV infection. Tenofovir DF is approved for treating HIV-infected adults, but its use in children has not yet been approved. The drug may be helpful for children who have been treated with many other drugs and still have detectable HIV in their blood despite ongoing therapy. In a previous study, many children given tenofovir DF responded well, with increases in T-cell counts and decreases in viral load. However, many children also experienced bone thinning. This study will explore the problem of bone thinning in children taking tenofovir DF in combination with highly active antiretroviral therapy (HAART). HIV-infected patients from 4 to 20 years old who are taking tenofovir DF or for whom tenofovir DF treatment has been recommended may be eligible for this 3-year study. Participants take tenofovir DF every day in addition to their antiretroviral therapy. They have frequent follow-up visits for tests and procedures as follows: Study days 0, 2, and 4: blood tests. Screening and every study visit starting day 6: Physical exam, medical history, blood and urine tests. Baseline and every 48 weeks: Dental and eye examinations, kidney ultrasound, tuberculin skin testing, chest x-ray, electrocardiogram and echocardiogram, computed tomography (CT) scan, neuropsychological testing and neurologic assessment. The bone age hand x-rays are done every 24 weeks, unless the growth plates are fused (i.e. the child has stopped growing) DEXAs are done at 0, 12, 24 weeks and every 24 weeks thereafter. Dual energy x-ray absorptionometry (DEXA) scan is used to assess bone density. The patient lies still on a table while the spine and hip are scanned using a small amount of radiation. Only the spine and hip are scanned in the DEXA scan test. Baseline and week 24: Optional bone biopsy. Some patients are asked to undergo a bone biopsy to better understand the effect of Tenofovir DF on bone. For the procedure, the child is given a sedative. The skin over the hipbone is numbed with a small needle, a small incision is made and a larger needle is inserted into the bone. Some of the bone tissue is withdrawn through the needle and the incision is closed. Possible lumbar puncture (spinal tap): This optional procedure analyzes cerebrospinal fluid (CSF), the fluid that bathes the brain and spinal cord. The patient is given a local anesthetic and a needle is inserted into the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle. There is no specific schedule for this procedure if the patient opts for it. Patients who are benefiting from tenofovir DF therapy but show signs of bone effects are offered treatment with pamidronate (Aredia), a drug used to treat hypercalcemia (too much calcium in the blood). Patients who stop taking tenofovir DF because of bone toxicity continue to be followed on the regular study schedule. Those who stop the drug for toxicity other than bone toxicity or for toxicity not related to tenofovir DF are followed every 4 weeks until their laboratory test results improve.
Detailed Description
Tenofovir disoproxil fumarate (TDF) was approved for the treatment of HIV-infected adults in October 2001. In November 2001, we began enrollment to our phase I/II study of tenofovir DF in HIV-infected children (02-C-0006). That study has completed enrollment. The virologic and immunologic responses seen on that study in a group of heavily treatment-experienced children with multidrug resistant HIV were surprisingly good. The drug was well tolerated, but significant decreases in bone mineral density were seen in a minority of patients. With the current study we will enroll and systematically investigate HIV-infected children for whom tenofovir DF is being used as part of salvage combination HIV therapy. The primary objective of the study is to characterize the change in bone mineral density (BMD), as measured by lumbar spine dual-energy x-ray absorptiometry (DEXA), during and following treatment with tenofovir DF-containing antiretroviral therapy in HIV-infected children. The study will enroll 3 cohorts of children: 1) HIV-infected children about to start a tenofovir DF-containing antiretroviral regimen, 2) HIV-infected children already on tenofovir DF with available baseline DEXA results, and 3) HIV-infected children already on tenofovir DF but without baseline DEXA results who will come here for investigations of bone metabolism. Studies of bone metabolism will include periodic measurements of serum and urine calcium and phosphorus, PTH and vitamin D levels, bone resorption markers (urinary collagen cross-linked N-telopeptide and free deoxypyridinoline), bone formation markers (serum osteocalcin and bone specific alkaline phosphatase), IGF-1 levels, bone age, and DEXA scans. Patients about to start tenofovir DF (cohort 1) will be offered the option of having a transiliac crest core bone biopsy with tetracycline labeling performed at baseline and at 6 months to assess static and dynamic parameters of bone quality and turnover (histomorphometry). Subjects with substantial presumed tenofovir DF-related bone toxicity who are deriving benefit from their tenofovir DF-containing antiretroviral drug regimen will be offered the option of pamidronate therapy. The effects of pamidronate treatment on bone toxicity associated with tenofovir DF in these patients will be assessed in an exploratory fashion. It is expected that up to 40 patients with baseline BMD measurements will be enrolled onto this protocol. An additional 10 patients who are undergoing tenofovir DF treatment but who did not receive baseline BMD measurements will also be permitted to enroll in order to contribute to the data used to characterize changes in toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
Drug Resistance, HAART, Pamidronate, Osteopenia, Pediatric, HIV, Pediatrics, Treatment Experienced

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Enrollment
50 (false)

8. Arms, Groups, and Interventions

Intervention Type
Procedure
Intervention Name(s)
Eye exam
Intervention Type
Procedure
Intervention Name(s)
Oral exam
Intervention Type
Procedure
Intervention Name(s)
CT scan
Intervention Type
Procedure
Intervention Name(s)
Neuropsychological testing
Intervention Type
Procedure
Intervention Name(s)
Electrocardiogram
Intervention Type
Procedure
Intervention Name(s)
Echocardiogram

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Cohort 1 - patients about to start tenofovir DF HIV-infected children between the ages of 4 years and less than 21 years. Clinical decision has been made to start the patient on tenofovir DF-containing antiretroviral regimen BSA greater than or equal to 0.85 m2 Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Not pregnant or breast feeding 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) Less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) AST and ALT less than or equal to 7.5 times the upper limit of normal Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Cohort 2 - patients already being treated with tenofovir DF who have baseline DEXA available HIV-infected children between the ages of 4 years and less than 21 years. Current tenofovir DF-containing antiretroviral regimen was started less than 6 months ago Baseline DEXA for L-spine BMD is available and was performed less than six months prior to or within the first week of starting tenofovir DF BSA greater than or equal to 0.85 m2 Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Not pregnant or breast feeding 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) Less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) AST and ALT less than or equal to 7.5 times the upper limit of normal Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Cohort 3 - patients already being treated with an antiretroviral regimen that includes tenofovir DF who DO NOT have baseline DEXA available HIV-infected children between the ages of 4 years and less than 21 years. Current antiretroviral regimen includes tenofovir DF Baseline (within prior 6 months) DEXA for L-spine BMD is NOT available BSA greater than or equal to 0.85 m2 Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Not pregnant or breast feeding 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) AST and ALT less than or equal to 7.5 times the upper limit of normal Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Eligibility criteria for pamidronate therapy (after enrollment on protocol) One of the following while on tenofovirDF-containing antiretroviral regimen: Greater than 6% loss in L-spine BMD in the presence of a BMD Z score less than -2.5 at 6 months compared to baseline Minimal trauma fracture BMD Z-score less than -3 AND One of the following while on tenofovirDF-containing antiretroviral regimen: Greater than or equal to 0.5 log decrease in VL from baseline Greater than or equal to 25% increase in absolute CD4 count from baseline Improvement in HIV-related signs or symptoms OR BMD Z-score less than -3 (i.e., pamidronate therapy will also be considered for subjects whose BMD Z score is less than -3 at baseline) Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73. Less than or equal to grade 1 serum phosphate, magnesium, and potassium (supplementation allowed) Not pregnant or breast feeding No history of hypersensitivity to bisphosphonates INCLUSION CRITERIA: Eligibility criteria for bone biopsy (after enrollment on protocol) No history of bleeding abnormality No history of hypersensitivity or intolerance to tetracycline or related drugs Normal CBC and PT/PTT BMD Z-score greater than -3 Informed consent: patient, parent or legal guardian must sign a separate informed consent to document their understanding of the investigational nature and the risks of the bone biopsy.
Facility Information:
Facility Name
National Cancer Institute (NCI)
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
10228296
Citation
Sleasman JW, Nelson RP, Goodenow MM, Wilfret D, Hutson A, Baseler M, Zuckerman J, Pizzo PA, Mueller BU. Immunoreconstitution after ritonavir therapy in children with human immunodeficiency virus infection involves multiple lymphocyte lineages. J Pediatr. 1999 May;134(5):597-606. doi: 10.1016/s0022-3476(99)70247-7.
Results Reference
background
PubMed Identifier
11794218
Citation
Gortmaker SL, Hughes M, Cervia J, Brady M, Johnson GM, Seage GR 3rd, Song LY, Dankner WM, Oleske JM; Pediatric AIDS Clinical Trials Group Protocol 219 Team. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med. 2001 Nov 22;345(21):1522-8. doi: 10.1056/NEJMoa011157.
Results Reference
background
PubMed Identifier
10682153
Citation
Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, Margot NA, Anton KE, Cherrington JM. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir Ther. 1999;4(2):87-94. doi: 10.1177/135965359900400205.
Results Reference
background

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Effect of Tenofovir DF on Bone Metabolism in Children

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