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

NCT ID: NCT00921557

Last Updated: 2021-11-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2017-01-31

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.

Conditions

HIV Infection

Keywords

Bone mineral density

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

1A: Alendronate/Alendronate

Participants received alendronate for 96 weeks and calcium carbonate/vitamin D for 144 weeks

Group Type: EXPERIMENTAL

Alendronate

Intervention Type: DRUG

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

Calcium carbonate/vitamin D

Intervention Type: DIETARY_SUPPLEMENT

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

1B: Alendronate/Placebo

Participants received alendronate for 48 weeks followed by placebo for 48 weeks and calcium carbonate/vitamin D for 144 weeks

Group Type: EXPERIMENTAL

Alendronate

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

Oral tablet taken once weekly

Calcium carbonate/vitamin D

Intervention Type: DIETARY_SUPPLEMENT

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

2: Placebo/Alendronate

Participants received placebo for 48 weeks followed by alendronate for 48 weeks and calcium carbonate/vitamin D for 144 weeks

Group Type: EXPERIMENTAL

Alendronate

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

Oral tablet taken once weekly

Calcium carbonate/vitamin D

Intervention Type: DIETARY_SUPPLEMENT

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

Interventions

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

Intervention Type: DRUG

Placebo

Oral tablet taken once weekly

Intervention Type: DRUG

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

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Fosamax

Eligibility Criteria

Inclusion Criteria

• 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

• 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

• Minimum Eligible Age: 11 Years
• Maximum Eligible Age: 24 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

George K. Siberry, MD

Role: STUDY_CHAIR

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Locations

David Geffen School of Medicine at UCLA NICHD CRS

Los Angeles, California, United States

Pediatric Perinatal HIV Clinical Trials Unit CRS

Miami, Florida, United States

USF - Tampa NICHD CRS

Tampa, Florida, United States

Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, United States

Johns Hopkins Univ. Baltimore NICHD CRS

Baltimore, Maryland, United States

WNE Maternal Pediatric Adolescent AIDS CRS

Worcester, Massachusetts, United States

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, United States

SOM Federal University Minas Gerais Brazil NICHD CRS

Belo Horizonte, Minas Gerais, Brazil

Univ. of Sao Paulo Brazil NICHD CRS

São Paulo, , Brazil

San Juan City Hosp. PR NICHD CRS

San Juan, , Puerto Rico

Countries

United States; Brazil; Puerto Rico

References

Clay PG, Voss LE, Williams C, Daume EC. Valid treatment options for osteoporosis and osteopenia in HIV-infected persons. Ann Pharmacother. 2008 May;42(5):670-9. doi: 10.1345/aph.1K465. Epub 2008 Apr 15.

Reference Type: BACKGROUND

PMID: 18413693 (View on PubMed)

McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, Suckow C, Gopalakrishnan G, Benson C, Wohl DA. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS. 2007 Nov 30;21(18):2473-82. doi: 10.1097/QAD.0b013e3282ef961d.

Reference Type: BACKGROUND

PMID: 18025884 (View on PubMed)

Stoch SA, Saag KG, Greenwald M, Sebba AI, Cohen S, Verbruggen N, Giezek H, West J, Schnitzer TJ. Once-weekly oral alendronate 70 mg in patients with glucocorticoid-induced bone loss: a 12-month randomized, placebo-controlled clinical trial. J Rheumatol. 2009 Aug;36(8):1705-14. doi: 10.3899/jrheum.081207. Epub 2009 Jun 1.

Reference Type: BACKGROUND

PMID: 19487264 (View on PubMed)

The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

Reference Type: BACKGROUND

Jacobson DL, Lindsey JC, Gordon C, Hazra R, Spiegel H, Ferreira F, Amaral FR, Pagano-Therrien J, Gaur A, George K, Benson J, Siberry GK. Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age. Clin Infect Dis. 2020 Aug 22;71(5):1281-1288. doi: 10.1093/cid/ciz957.

Reference Type: DERIVED

PMID: 31573608 (View on PubMed)

Other Identifiers

10669

Identifier Type: REGISTRY

Identifier Source: secondary_id

IMPAACT P1076

Identifier Type: -

Identifier Source: secondary_id

P1076

Identifier Type: -

Identifier Source: org_study_id