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Tenofovir Disoproxil Fumarate Salvage Therapy in HIV-Infected Children and a Study of Its Effect on Bone Metabolism


Phase 2
N/A
N/A
Not Enrolling
Both
HIV Infections

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Trial Information

Tenofovir Disoproxil Fumarate Salvage Therapy in HIV-Infected Children and a Study of Its Effect on Bone Metabolism


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.

Inclusion 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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment

Authority:

United States: Federal Government

Study ID:

040234

NCT ID:

NCT00088309

Start Date:

June 2004

Completion Date:

May 2006

Related Keywords:

  • HIV Infections
  • Drug Resistance
  • HAART
  • Pamidronate
  • Osteopenia
  • Pediatric
  • HIV
  • Pediatrics
  • Treatment Experienced
  • HIV Infections
  • Acquired Immunodeficiency Syndrome

Name

Location

National Cancer Institute (NCI)Bethesda, Maryland  20892