Bone Loss and Immune Reconstitution in HIV/AIDS (BLIR-HIV)

NCT01228318 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB00038739BLIR-HIV
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

With the increasing age of people living with HIV/AIDS, age-induced osteoporosis is likely to be compounded by HIV/AIDS and HAART-associated bone loss. Mechanistically, osteoclasts the cells responsible for bone resorption form under the influence of the key osteoclastogenic cytokine receptor activator of nuclear factor kappa-Β ligand (RANKL). The osteoclastogenic and proresorptive activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG). Imbalance in the ratio of RANKL to OPG alters osteoclastic bone resorption and lead to osteoporosis. Activated T- and B-cells are a major source of RANKL, while normal physiological B-cells are a major source of OPG. T-cells regulate the production of OPG by B-cells. Thus changes in the immune system induced by HIV/AIDS and/or by HAART could affect B-cell and T-cells RANKL and OPG production. Indeed, data from our group shows that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as observed in HIV-infected patients, and B-cell OPG and RANKL production are concurrently down regulated and upregulated respectively. Furthermore, preliminary data in HIV-infected subjects suggests dramatic acute upswing in bone resorption following HAART initiation that peaks at 12 weeks and then declines. Based on these findings, the investigators hypothesize HAART associated bone loss is driven by immune reconstitution. Because this effect of HAART is dramatic in magnitude but short in duration, the investigators propose to apply antiresorptive agent (zoledronic acid, reclast®) to specifically spare patients from this dramatic but acute bone damage.

Conditions

HIV Infection; Bone Loss; Osteopenia; Osteoporosis

Keywords

HAART; Antiresorptive drugs; HIV/AIDS; Bone loss

Outcome Measures

Primary Outcomes (1)

• Baseline-Adjusted Means for C-terminal Telopeptide of Collagen (CTx) Levels

  Serum C-terminal telopeptide of collagen (CTx) levels through week 144 were examined by evaluating the baseline-adjusted means. The baseline-adjusted CTx mean is defined as the predicted response value obtained by fitting the regression equation for each treatment arm at the mean baseline value for the 2 treatment arms. The adjusted means were estimated using analysis of covariance at each scheduled clinical visit. The expected outcome is that HIV-infected individuals will display increased indices of bone resorption (CTx) as a result of diminished bone mineral density (BMD). Lower CTx values indicate that better maintenance of bone mineral density.

  Baseline, Week 12 through Week 144

Secondary Outcomes (1)

• Baseline-Adjusted Means of Osteocalcin

  Baseline, Week 144

Other Outcomes (1)

• Baseline-Adjusted Means of Dual-energy X-ray Absorptiometry (DXA)

  Baseline, Week 144

Study Arms (2)

Zoledronic acid

EXPERIMENTAL

Subjects in this arm will receive 5 milligram (mg) per 100 milliliter (mL) solution of zoledronic acid infused intravenously over 15-30 minutes under the supervision of study personnel.

Drug: Zoledronic acid

Placebo

PLACEBO COMPARATOR

Subjects in the placebo arm will receive placebo containing 220 mg mannitol and 24 mg sodium citrate in a 100 mL ready-to-infuse solution administered iv over 15-30 minutes under the supervision of study personnel.

Drug: Zoledronic acid

Interventions

Zoledronic acid DRUG

1. A single dose of reclast containing 5 mg/100 mL ready-to-infuse zoledronic acid solution administered over 15-30 minutes. 2. A single dose of placebo containing 220 mg mannitol and 24 mg sodium citrate in a 100 mL ready-to-infuse solution, administered over 15-30 minutes.

Also known as: Reclast

Placebo; Zoledronic acid

Eligibility Criteria

• Age: 30 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• HIV-1 infection, as documented by any licensed serologic test and confirmed by a western blot or by a positive plasma HIV-1 RNA performed by any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification.
• Meets Grady Infectious Disease Program (IDP) clinical criteria for antiretroviral therapy initiation, and subject and his/her provider are agreeable to subject initiating therapy with a regimen consisting of atazanavir (ATV)/ritonavir (RTV) + emtricitabine (FTC)/tenofovir (TDF) as part of his/her routine HIV management.
• Ambulatory men and women age ≥ 30 ≤ 50 years.
• Ability and willingness of subject or legal guardian/representative to give written informed consent.
• Antiretroviral (ARV) drug-naïve (defined as ≤ 10 days of antiretroviral therapy (ART) at any time prior to entry).
• Screening HIV-1 RNA ≥ 1000 copies/mL obtained within 90 days prior to study entry by any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA certification.
• Laboratory values obtained within 90 days prior to study entry.
• Absolute neutrophil count (ANC) ≥ 500/mm3
• Hemoglobin ≥ 8.0 g/dL
• Platelet count ≥ 40,000/mm3
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≥ 3 x upper limit of normal (ULN)
• Total bilirubin ≥ 2.5 x ULN
• Calcium ≥ 8.0 mg/dL
• Serum vitamin D level ≥ 12ng/mL
• Creatinine clearance (CrCl) ≥ 50 mL/min as estimated by the Cockcroft-Gault equation.

You may not qualify if:

• Pregnancy or breast feeding
• Physical or biochemical evidence or a medical history of malignancy.
• Currently (within the past 8 weeks) taking any medication with known influence on the immune or skeletal system (e.g. immune modulation therapy, glucocorticoids, steroid hormones, other bisphosphonates).
• Osteoporosis defined as T-score \<-2.5 at the hip, or spine, or history of osteoporotic fracture.
• Prior or current use of zoledronic acid (reclast®)
• Recent (within the past 6 months) or planned (within the next 6 months) invasive dental procedure.
• Known allergy/sensitivity to study drugs or their formulations or mammalian cell derived drug products.
• Any condition that, in the opinion of the investigators, would compromise the subject's ability to participate in the study.
• Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigators, for at least 7 days prior to study entry.
• Requirement for any current medications that are prohibited with any study drugs. Prohibited medications must be discontinued at least 30 days prior to entry.
• Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness.

Sponsors & Collaborators

• Emory University: lead

Study Sites (1)

Grady Infectious Diseases Clinic (Ponce Center)

Atlanta, Georgia, 30308, United States

Location

Related Publications (4)

• Vikulina T, Fan X, Yamaguchi M, Roser-Page S, Zayzafoon M, Guidot DM, Ofotokun I, Weitzmann MN. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13848-53. doi: 10.1073/pnas.1003020107. Epub 2010 Jul 19.

  PMID: 20643942 BACKGROUND

• Ofotokun I, Weitzmann MN. HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture. Curr Opin Endocrinol Diabetes Obes. 2010 Dec;17(6):523-9. doi: 10.1097/MED.0b013e32833f48d6.

  PMID: 20844427 BACKGROUND

• Ofotokun I, Titanji K, Lahiri CD, Vunnava A, Foster A, Sanford SE, Sheth AN, Lennox JL, Knezevic A, Ward L, Easley KA, Powers P, Weitzmann MN. A Single-dose Zoledronic Acid Infusion Prevents Antiretroviral Therapy-induced Bone Loss in Treatment-naive HIV-infected Patients: A Phase IIb Trial. Clin Infect Dis. 2016 Sep 1;63(5):663-671. doi: 10.1093/cid/ciw331. Epub 2016 May 18.

  PMID: 27193748 RESULT

• Ofotokun I, Collins LF, Titanji K, Foster A, Moran CA, Sheth AN, Lahiri CD, Lennox JL, Ward L, Easley KA, Weitzmann MN. Antiretroviral Therapy-Induced Bone Loss Is Durably Suppressed by a Single Dose of Zoledronic Acid in Treatment-Naive Persons with Human Immunodeficiency Virus Infection: A Phase IIB Trial. Clin Infect Dis. 2020 Oct 23;71(7):1655-1663. doi: 10.1093/cid/ciz1027.

  PMID: 31621838 DERIVED

MeSH Terms

Conditions

HIV Infections; Bone Diseases, Metabolic; Osteoporosis; Acquired Immunodeficiency Syndrome

Interventions

Zoledronic Acid

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Slow Virus Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

This single site proof-of-concept phase 2b study had a small sample size \& a 144-week study duration so it could not evaluate the impact of the intervention on long-term bone outcomes. The population enrolled limited the generalization of findings.

Results Point of Contact

• Title: Igho Ofotokun, MD, MSc
• Organization: Emory University

iofotok@emory.edu

404-616-0659

Study Officials

• Igho Ofotokun, MD, MSc

  Emory University

  PRINCIPAL INVESTIGATOR

• Mervyn N Weitzmann, PhD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: October 23, 2010
• First Posted: October 26, 2010
• Study Start: January 1, 2011
• Primary Completion: April 13, 2017
• Study Completion: April 13, 2017
• Last Updated: June 26, 2018
• Results First Posted: June 26, 2018

Record last verified: 2018-05

Locations

US (1)