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

Primary Purpose

HIV Infection, Bone Loss, Osteopenia

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Zoledronic acid

About this trial

This is an interventional treatment trial for HIV Infection focused on measuring HAART, Antiresorptive drugs, HIV/AIDS, Bone loss

Eligibility Criteria

30 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.
Absence of history of non-HIV related active immunological or bone disorders such as:
- Bone marrow or organ transplantation
- Inflammatory bowel disease (ulcerative colitis, Crohn's disease)
- Multiple Myeloma
- Osteogenesis imperfecta
- Osteomalacia
- Osteosarcoma
- Paget's disease
- Postmenopausal osteoporosis
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Thyroid disorders (hyper/hypothyroidism)
Contraception requirements
1. Female Subjects of Reproductive Potential:
  Female subjects of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception while participating in the study. Acceptable methods of contraception include:
  - Condoms (male or female) with or without a spermicidal agent
  - Diaphragm or cervical cap with spermicide
  - Intrauterine device (IUD)
  - Hormone-based contraceptive (must contain at ≥ 35 mcg of ethinyl estradiol)
2. Female Subjects Who Are Not of Reproductive Potential.

Exclusion Criteria:

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.

Sites / Locations

Grady Infectious Diseases Clinic (Ponce Center)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Zoledronic acid

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Baseline-Adjusted Means of Osteocalcin

Osteocalcin was evaluated to examine the inhibitory effect of single dose zoledronic acid on HAART associated changes in markers of bone turnover. Osteocalcin is released from bone during resorption and higher levels in the circulatory system indicate increased bone turnover. HIV-infected individuals are expected to have increased bone resorption. The baseline-adjusted osteocalcin 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 the Week 144 clinic visit. Baseline-adjusted means of osteocalcin at week 144 are presented.

Full Information

NCT ID

NCT01228318

First Posted

October 23, 2010

Last Updated

June 21, 2018

Sponsor

Emory University

1. Study Identification

Unique Protocol Identification Number

NCT01228318

Brief Title

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

Acronym

BLIR-HIV

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2018

Overall Recruitment Status

Completed

Study Start Date

January 2011 (undefined)

Primary Completion Date

April 13, 2017 (Actual)

Study Completion Date

April 13, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Emory University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

Detailed Description

In a prospective, blinded placebo-controlled randomized trial, treatment naïve HIV-infected subjects initiating HAART will be assigned to HAART + zoledronic acid or HAART + placebo. Serial assessment of serum levels of bone markers, cellular expression of OPG/RANKL and other cytokines, cellular immune activation markers, serum bone regulating hormones, and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) scan will be undertaken at pre-defined time points from baseline through week 144 of HAART. In the primary analysis, changes in serum C-Terminal Telopeptide (CTx) level, BMD, and cellular OPG/RANKL expression from baseline through week 24 will be quantitated and subsequently compared between treatment arms. In addition, the impact of zoledronic acid administration on these covariates will be assessed at various study time points. The relationship between OPG/RANKL expression, immune activation, serum bone regulating hormonal levels, and bone turnover will be evaluated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infection, Bone Loss, Osteopenia, Osteoporosis

Keywords

HAART, Antiresorptive drugs, HIV/AIDS, Bone loss

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

63 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Zoledronic acid

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Zoledronic acid

Other Intervention Name(s)

Reclast

Intervention Description

A single dose of reclast containing 5 mg/100 mL ready-to-infuse zoledronic acid solution administered over 15-30 minutes. 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.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, Week 12 through Week 144

Secondary Outcome Measure Information:

Title

Baseline-Adjusted Means of Osteocalcin

Description

Time Frame

Baseline, Week 144

Other Pre-specified Outcome Measures:

Title

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

Description

Development of osteoporosis was assessed by examining bone mineral density (BMD) by DXA scan. Baseline-adjusted means of DXA scan Z-scores are presented for the lumbar spine (L1-L4), left hip, and femur neck. The baseline-adjusted BMD 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 the Week 144 clinic visit. Bone density Z-scores tell how close to the average that a person is (adjusted for age, race, and gender). A Z-score of 0 means the value matches that of the average person. Z-score values below 0 indicate lower than average bone density while values above 0 indicate higher bone density than the average person.

Time Frame

Baseline, Week 144

10. Eligibility

Sex

All

Minimum Age & Unit of Time

30 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Absence of history of non-HIV related active immunological or bone disorders such as: Bone marrow or organ transplantation Inflammatory bowel disease (ulcerative colitis, Crohn's disease) Multiple Myeloma Osteogenesis imperfecta Osteomalacia Osteosarcoma Paget's disease Postmenopausal osteoporosis Rheumatoid arthritis Systemic lupus erythematosus Thyroid disorders (hyper/hypothyroidism) Contraception requirements Female Subjects of Reproductive Potential: Female subjects of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception while participating in the study. Acceptable methods of contraception include: Condoms (male or female) with or without a spermicidal agent Diaphragm or cervical cap with spermicide Intrauterine device (IUD) Hormone-based contraceptive (must contain at ≥ 35 mcg of ethinyl estradiol) Female Subjects Who Are Not of Reproductive Potential. Exclusion Criteria: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Igho Ofotokun, MD, MSc

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Mervyn N Weitzmann, PhD

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Grady Infectious Diseases Clinic (Ponce Center)

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30308

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

20643942

Citation

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.

Results Reference

background

PubMed Identifier

20844427

Citation

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.

Results Reference

background

PubMed Identifier

27193748

Citation

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.

Results Reference

result

PubMed Identifier

31621838

Citation

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.

Results Reference

derived

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

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