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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Impact of Oral Alendronate Therapy on Bone Mineral Density in HIV-infected Children and Adolescents With Low Bone Mineral Density

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Drug: Alendronate
* Drug: Placebo
* Dietary Supplement: Calcium carbonate/vitamin D


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 11 Years
Maximum Age: 24 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1A: Alendronate/Alendronate<br>Participants received alendronate for 96 weeks and calcium carbonate/vitamin D for 144 weeks | Drug: Alendronate<br>* 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<br>* Other names: Fosamax;Dietary Supplement: Calcium carbonate/vitamin D<br>* 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<br>|
| Experimental: 1B: Alendronate/Placebo<br>Participants received alendronate for 48 weeks followed by placebo for 48 weeks and calcium carbonate/vitamin D for 144 weeks | Drug: Alendronate<br>* 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<br>* Other names: Fosamax;Drug: Placebo<br>* Oral tablet taken once weekly<br>Dietary Supplement: Calcium carbonate/vitamin D<br>* 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<br>|
| Experimental: 2: Placebo/Alendronate<br>Participants received placebo for 48 weeks followed by alendronate for 48 weeks and calcium carbonate/vitamin D for 144 weeks | Drug: Alendronate<br>* 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<br>* Other names: Fosamax;Drug: Placebo<br>* Oral tablet taken once weekly<br>Dietary Supplement: Calcium carbonate/vitamin D<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Weeks 24 and 48 in Lumbar Spine BMD | 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. | Weeks 0, 24 and 48 | 
| 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 | 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. | Week 0 to 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Weeks 24 and 48 in Whole Body (With Head) BMD | 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. | Weeks 0, 24 and 48 | 
| Percent Change From Baseline to Week 96 in Lumbar Spine BMD | Percent change was calculated as (measurement at week 96 - measurement at baseline)/measurement at baseline * 100%. Includes Groups 1A and 1B only. | Weeks 0 and 96 | 
| Percent Change From Baseline to Week 96 in Whole Body (With Head) BMD | Percent change was calculated as (measurement at week 96 - measurement at baseline)/measurement at baseline * 100%. Includes Groups 1A and 1B only. | Weeks 0 and 96 | 
| 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 | 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). | Weeks 0 to 144 | 
| 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 | 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. | Weeks 0, 24 and 48 | 
| 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. | 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. | Weeks 0, 24 and 48 | 
| 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 | Percent change was calculated as (measurement at time T2 - measurement at time T1)/measurement at Time T1 * 100%. | Weeks 48, 96 and 144 | 
| 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 | Percent change was calculated as (measurement at time T2 - measurement at time T2)/measurement at time T1 * 100%. | Weeks 48, 96 and 144 | 
| Change From Baseline to Week 48 in Bone Marker Turnover | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 0 and 48 | 
| Correlation of Changes in Bone Marker Turnover With Changes in Lumbar Spine and Whole Body (With Head) BMD | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 0 and 48 | 
| Change From Baseline to Week 48 in Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin (RANKL/OPG) Ratio | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 0 and 48 | 
| Correlation of Changes in RANKL/OPG Ratio With Changes in Lumbar Spine and Whole Body (With Head) BMD | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 0 and 48 | 
| Change From Baseline to Week 48 in Central Fat Content | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 0 and 48 | 
| Correlation of Changes in Central Fat Content With Changes in Lumbar Spine and Whole Body (With Head) BMD | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 0 and 48 | 
| Percent of Participants With HIV-1 RNA <= 400 Copies/ml | 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. | Weeks 0, 48, 96 and 144 | 
| Change in CD4 Percent From Baseline | Change in percentage of lymphocytes that are CD4 cells calculated as measurement at each time point minus baseline measurement | Weeks 0, 48, 96 and 144 | 
| Change in Centers for Disease Control (CDC) HIV Disease Category | Percentage of participants advancing in CDC HIV disease category from baseline throughout study follow-up | Weeks 144 | 
| Percent of Participants With Detectable Urinary Alendronate | Outcome measure required additional funding for laboratory testing which was not available, so this outcome is not reported. | Weeks 48, 96 and 144 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bone mineral density