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Safety and Effectiveness of Alendronate for Bone Mineral Density in HIV-infected Children and Adolescents

This study has been completed.
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00921557
First received: June 12, 2009
Last updated: May 15, 2017
Last verified: May 2017
June 12, 2009
May 15, 2017
November 2009
January 2016   (Final data collection date for primary outcome measure)
  • Percent Change From Baseline to Weeks 24 and 48 in Lumbar Spine BMD [ Time Frame: Weeks 0, 24 and 48 ]
    Percent change was calculated as (measurement at time T - measurement at baseline)/measurement at baseline * 100%. Results for Groups 1A and 1B combined as both were on alendronate for the first 48 weeks.
  • Percentage of Participants Developing New Signs, Symptoms, Hematology or Chemistry Laboratory Values Greater Than or Equal to Grade 3 or New Cases of Jaw Osteonecrosis, Atrial Fibrillation, or Non-healing Fractures [ Time Frame: Week 0 to 48 ]
    Signs, symptoms, and laboratory values were graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0 (December 2004). Results for Groups 1A and 1B were combined as both were on alendronate for the first 48 weeks.
  • Pre-treatment levels in BMD of the lumbar spine after 24 and 48 weeks of versus participants receiving placebo [ Time Frame: At Weeks 24 and 48 ]
  • Safety of of alendronate use as measured by the incidence of new ≥ Grade 3 hematology or chemistry laboratory values, signs or symptoms, or new cases of jaw osteonecrosis, atrial fibrillation, or non-healing fractures [ Time Frame: Throughout study ]
Complete list of historical versions of study NCT00921557 on ClinicalTrials.gov Archive Site
  • Percent Change From Baseline to Weeks 24 and 48 in Whole Body (With Head) BMD [ Time Frame: Weeks 0, 24 and 48 ]
    Percent change was calculated as (measurement at time T - measurement at baseline)/measurement at baseline * 100%. Results for Groups 1A and 1B were combined as both were on alendronate for the first 48 weeks.
  • Percent Change From Baseline to Week 96 in Lumbar Spine BMD [ Time Frame: Weeks 0 and 96 ]
    Percent change was calculated as (measurement at week 96 - measurement at baseline)/measurement at baseline * 100%. Includes Groups 1A and 1B only.
  • Percent Change From Baseline to Week 96 in Whole Body (With Head) BMD [ Time Frame: Weeks 0 and 96 ]
    Percent change was calculated as (measurement at week 96 - measurement at baseline)/measurement at baseline * 100%. Includes Groups 1A and 1B only.
  • Safety as Measured by the Incidence of New Signs, Symptoms, Hematology or Chemistry Laboratory Values Greater Than or Equal to Grade 3 or New Cases of Jaw Osteonecrosis, Atrial Fibrillation, or Non-healing Fractures [ Time Frame: Weeks 0 to 144 ]
    Signs, symptoms, and laboratory values were graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0 (December 2004).
  • Effect of Other Known Bone Mineral Determinants (Age, Gender, Race/Ethnicity, Steroid Use, Depo-Provera, Tenofovir, Pubertal Stage, Bone Age, Vitamin D Status) and Inflammatory Cytokine Levels on Changes in Lumbar Spine BMD [ Time Frame: Weeks 0, 24 and 48 ]
    A slope was fit for each participant to their percent change [(measurement at time T - measurement at baseline)/measurement at baseline)*100%] in lumbar spine BMD from baseline. Results represent average changes in lumbar spine BMD over one year. Results are summarized for age, gender, ethnicity, tenofovir use, Tanner stage, bone age and vitamin D level. Only one participant was on steroids and none were using Dep-Provera. Inflammatory cytokine levels were not assayed. Results were combined for Groups 1A and 1B as both were on alendronate for the first 48 weeks.
  • Effect of Other Known Bone Mineral Determinants (Age, Gender, Race/Ethnicity, Steroid Use, Depo-Provera, Tenofovir, Pubertal Stage, Bone Age, Vitamin D Status) and Inflammatory Cytokine Levels on Changes in Whole Body (With Head) BMD. [ Time Frame: Weeks 0, 24 and 48 ]
    A slope was fit for each participant to their percent change [(measurement at time T - measurement at baseline)/measurement at baseline)*100%] in whole body (with head) BMD from baseline. Results represent average changes in whole body (with head) BMD over one year. Results are summarized for age, gender, ethnicity, tenofovir use, Tanner stage, bone age and vitamin D level. Only one participant was on steroids and none were using Dep-Provera. Inflammatory cytokine levels were not assayed. Results were combined for Groups 1A and 1B as both were on alendronate for the first 48 weeks.
  • Percent Change From Week 48 to Week 96 (Group 1B), Week 48 to Week 144 (Group 1B), and Week 96 to 144 (Group 2) in Lumbar Spine BMD [ Time Frame: Weeks 48, 96 and 144 ]
    Percent change was calculated as (measurement at time T2 - measurement at time T1)/measurement at Time T1 * 100%.
  • Percent Change From Week 48 to Week 96 (Group 1B), Week 48 to Week 144 (Group 1B), and Week 96 to 144 (Group 2) in Whole Body (With Head) BMD [ Time Frame: Weeks 48, 96 and 144 ]
    Percent change was calculated as (measurement at time T2 - measurement at time T2)/measurement at time T1 * 100%.
  • Change From Baseline to Week 48 in Bone Marker Turnover [ Time Frame: Weeks 0 and 48 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Correlation of Changes in Bone Marker Turnover With Changes in Lumbar Spine and Whole Body (With Head) BMD [ Time Frame: Weeks 0 and 48 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Change From Baseline to Week 48 in Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin (RANKL/OPG) Ratio [ Time Frame: Weeks 0 and 48 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Correlation of Changes in RANKL/OPG Ratio With Changes in Lumbar Spine and Whole Body (With Head) BMD [ Time Frame: Weeks 0 and 48 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Change From Baseline to Week 48 in Central Fat Content [ Time Frame: Weeks 0 and 48 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Correlation of Changes in Central Fat Content With Changes in Lumbar Spine and Whole Body (With Head) BMD [ Time Frame: Weeks 0 and 48 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Percent of Participants With HIV-1 RNA <= 400 Copies/ml [ Time Frame: Weeks 0, 48, 96 and 144 ]
    Percent calculated as number of participants with HIV-1 RNA <= 400 copies/ml relative to the number of participants with HIV-1 RNA measured at that time point.
  • Change in CD4 Percent From Baseline [ Time Frame: Weeks 0, 48, 96 and 144 ]
    Change in percentage of lymphocytes that are CD4 cells calculated as measurement at each time point minus baseline measurement
  • Change in Centers for Disease Control (CDC) HIV Disease Category [ Time Frame: Weeks 144 ]
    Percentage of participants advancing in CDC HIV disease category from baseline throughout study follow-up
  • Percent of Participants With Detectable Urinary Alendronate [ Time Frame: Weeks 48, 96 and 144 ]
    Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported.
  • Changes from pre-treatment levels in whole body BMD after alendronate treatment versus placebo [ Time Frame: At Weeks 24 and 48 ]
  • Changes from pre-treatment levels in whole body and lumbar spine BMD alendronate treatment versus 48 weeks of alendronate followed by 48 weeks of placebo [ Time Frame: At Weeks 48 and 96 ]
  • Safety of alendronate use as measured by the incidence of new ≥ Grade 3 hematology or chemistry laboratory values, signs or symptoms, or new cases of jaw osteonecrosis, atrial fibrillation, or non-healing fractures [ Time Frame: Throughout study ]
  • Effect of other known bone mineral determinants (age, gender, race/ethnicity, steroid use, Depo-Provera, tenofovir, pubertal stage, bone age, vitamin D status) and inflammatory cytokine levels on changes in BMD after alendronate treatment [ Time Frame: At Weeks 48 and 96 ]
  • Changes in BMD after completion of 48 weeks of alendronate therapy [ Time Frame: At Weeks 48 and 96 ]
  • Alterations in pre-treatment bone marker turnover, RANKL/OPG ratio, central fat content (by whole body DXA) after 48 weeks of alendronate therapy and determine if the changes in these outcomes correlate with changes in BMD [ Time Frame: At study entry and Week 48 ]
  • Effect of alendronate therapy on changes in HIV status (as measured by changes in viral load, CD4% and CDC disease category) and determine if the changes in these outcomes correlate with changes in BMD [ Time Frame: Throughout study ]
  • Duration of detectable urinary alendronate in adolescent participants who have completed 48 and 96 weeks of alendronate therapy [ Time Frame: Throughout study ]
Not Provided
Not Provided
 
Safety and Effectiveness of Alendronate for Bone Mineral Density in HIV-infected Children and Adolescents
Impact of Oral Alendronate Therapy on Bone Mineral Density in HIV-infected Children and Adolescents With Low Bone Mineral Density
HIV-infected children, youth, and adults have lower bone mineral density (BMD) than would be expected for HIV-uninfected people of similar age, weight and race. As the majority of perinatally HIV-infected U.S. children are entering or in adolescence, the potential for HIV-related impaired BMD during the adolescent peak of bone mass acquisition is of particular concern. The primary purpose of this study was to compare changes from pre-treatment levels of BMD of the lumbar spine after 24 and 48 weeks of alendronate treatment with placebo in HIV-infected children and adolescents.

Puberty is a time when the foundation is laid for healthy bone mass. Over the course of puberty, 26% of bone mass is established in the 4-year period of peak height velocity and up to 60% of adult peak bone mass is established. Factors that affect normal bone mineralization include calcium intake, vitamin D status, degree of physical and weight bearing activities, hormones, genetics, body weight, and general health and nutrition status. HIV-infected children, youth, and adults have lower bone mineral density (BMD) than would be expected for healthy people of similar age, weight, and race. As the majority of perinatally HIV-infected U.S. children are entering or in adolescence, the potential for HIV-related impaired BMD during the adolescent peak of bone mass acquisition is of particular concern. The purpose of this study was to compare changes in BMD of the lumbar spine from pre-treatment levels to 24 and 48 weeks after alendronate treatment or placebo in HIV-infected children and adolescents.

Participants were randomized equally into one of three groups: Group 1A received alendronate for 96 weeks; Group 1B received alendronate for 48 weeks followed by placebo for 48 weeks; Group 2 received placebo for 48 weeks followed by alendronate for 48 weeks. All three groups were followed off treatment for an additional 48 weeks. Participants also received vitamin D/calcium for the duration of the study and were asked to perform 60 minutes of weight-bearing exercise each day.

Clinic visits were scheduled every 12 weeks after entry, with telephone contact visits one, four, and 28 weeks after entry and the week 48 visit. A physical exam and dental assessment was conducted at each clinic visit, and a history of adverse events collected. Dual Energy X-ray absorptiometry (DXA), hematology and chemistry panels were conducted at entry and weeks 24, 48, 72, 96 and 144. Lumbar spine and whole body (with head) BMD was measured using Hologic DXA scanners (QDR4500A, QDR4500W or Delphi A models).

The primary analysis compared changes from entry to 24 and 48 weeks in lumbar spine BMD between Groups 1A and 1B combined (both on alendronate for initial 48 weeks) vs. Group 2 (on placebo for 48 weeks). Study participants were unblinded after 96 weeks of follow-up (the primary completion date) but remained on study, off study treatment, for an additional 48 weeks.

Secondary laboratory outcomes listed in the protocol (bone marker turnover and Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin (RANKL/OPG) Ratio) and central fat content, which required application for additional funding for laboratory testing, will not be performed and no results will be available.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Participant, Care Provider
Primary Purpose: Treatment
HIV Infection
  • Drug: Alendronate
    Oral tablet taken once weekly: 70 mg if participant greater than 30 kg or 35 mg if participant less than or equal to 30 kg
    Other Name: Fosamax
  • Drug: Placebo
    Oral tablet taken once weekly
  • Dietary Supplement: Calcium carbonate/vitamin D
    Tablet taken once or twice daily: calcium carbonate (600 mg) and vitamin D (400 IU) once daily for participants with 25-OH-vitamin D levels greater than or equal to 20 ng/mL or twice daily for those with 25-OH-vitamin D levels less than 20 ng/mL
  • Experimental: 1A: Alendronate/Alendronate
    Participants received alendronate for 96 weeks and calcium carbonate/vitamin D for 144 weeks
    Interventions:
    • Drug: Alendronate
    • Dietary Supplement: Calcium carbonate/vitamin D
  • Experimental: 1B: Alendronate/Placebo
    Participants received alendronate for 48 weeks followed by placebo for 48 weeks and calcium carbonate/vitamin D for 144 weeks
    Interventions:
    • Drug: Alendronate
    • Drug: Placebo
    • Dietary Supplement: Calcium carbonate/vitamin D
  • Experimental: 2: Placebo/Alendronate
    Participants received placebo for 48 weeks followed by alendronate for 48 weeks and calcium carbonate/vitamin D for 144 weeks
    Interventions:
    • Drug: Alendronate
    • Drug: Placebo
    • Dietary Supplement: Calcium carbonate/vitamin D

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
52
January 2017
January 2016   (Final data collection date for primary outcome measure)

Inclusion Criteria (Version 2.0 of protocol):

  • Documentation of HIV-1 infection
  • HIV-infection acquired before puberty
  • For participants receiving antiretroviral therapy, must have been on the same antiretroviral agents for at least 12 weeks prior to study entry and have a viral load less than 10,000 copies/mL. For participants not receiving antiretroviral therapy, must have not been on antiretroviral agents for at least 12 weeks prior to study entry and have no indication for therapy
  • Lumbar spine DXA BMD z-score less than -1.5 or history of fragility fracture within the prior 12 months (regardless of DXA result).
  • Available for routine dental exam and care every 6 months
  • Demonstrated ability and willingness to swallow study medications
  • Females of reproductive potential must have had a negative pregnancy test at screening and within 48 hours prior to study entry. They must also have agreed to avoid pregnancy while on the study and if engaging in sexual activity, use at least two forms of contraception.
  • Parent or legal guardian able and willing to provide signed informed consent for children who could not provide consent for themselves.

Exclusion Criteria (Version 2.0 of protocol):

  • Body weight more than 300 lbs.
  • For female participants: if on Depo-Provera, they must have been on it for at least 1 year prior to study entry; if not on Depa-Provera, they must have not been on it for at least 1 year prior to study entry.
  • Anticonvulsant therapy
  • Proven growth hormone deficiency
  • Use of growth hormone in the 12 months prior to entry
  • Primary hyperparathyroidism
  • Hypoparathyroidism
  • Renal failure
  • Cushing syndrome
  • Active dental infection
  • Dental or periodontal disease expected to require more than basic restorative care
  • Pregnancy or lactation
  • Esophageal or gastric ulcer, chronic nonsteroidal anti-inflammatory drug (NSAID) use, or aspirin use
  • Tenofovir disoproxil fumarate (TDF): if on TDF, they must have been on it for at least 6 months prior to study entry; if not on TDF, they must have not been on it for at least 6 months prior to study entry.
  • Hemoglobin less than 10 g/dL
  • Any past pharmacologic treatment (except vitamin D and/or calcium supplementation) for low bone density
  • Inability to stand or sit upright for at least 30 minutes
  • Hypersensitivity to any component of alendronate
  • Hypocalcemia (less than the lower limit of normal established by the local laboratory in which it was performed)
  • Known abnormalities of the esophagus that delay esophageal emptying such as stricture or achalasia
  • 25-OH vitamin D less than 10 ng/mL in combination with elevated intact PTH above the upper limit of normal for the local laboratory in which it was performed
Sexes Eligible for Study: All
11 Years to 24 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
Brazil,   Puerto Rico,   United States
 
 
NCT00921557
P1076
10669 ( Registry Identifier: DAIDS-ES Registry Number )
IMPAACT P1076
Yes
Not Provided
Plan to Share IPD: No
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study Chair: George K. Siberry, MD Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Allergy and Infectious Diseases (NIAID)
May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP