A Phase II, Randomized, Placebo-Controlled A Phase II, Randomized, Placebo-Controlled Study of Once-Weekly Alendronate in HIV-Study of Once-Weekly Alendronate in HIV-

Infected Subjects with Decreased Bone Mineral Infected Subjects with Decreased Bone Mineral

Density Receiving Calcium and Vitamin DDensity Receiving Calcium and Vitamin D

Grace A McComsey, Michelle A Kendall, Pablo Tebas,Grace A McComsey, Michelle A Kendall, Pablo Tebas,Susan Swindells, Evelyn Hogg, Beverly Alston-Smith,Susan Swindells, Evelyn Hogg, Beverly Alston-Smith,

Carol Suckow, Geetha Gopalakrishnan, Carol Suckow, Geetha Gopalakrishnan, Constance Benson, and David A Wohl Constance Benson, and David A Wohl

on behalf of the ACTG A5163 teamon behalf of the ACTG A5163 team

BackgroundBackground Decreased bone mineral density (BMD) is prevalent Decreased bone mineral density (BMD) is prevalent

among persons living with HIV infection, as are among persons living with HIV infection, as are traditional risk factors for reduced BMD. traditional risk factors for reduced BMD.

Alendronate is a bisphosphonate that inhibits Alendronate is a bisphosphonate that inhibits osteoclast-mediated bone resorption and is FDA-osteoclast-mediated bone resorption and is FDA-approved for the treatment of osteoporosis in men approved for the treatment of osteoporosis in men and women. and women.

Small open-label studies of alendronate in Small open-label studies of alendronate in combination with calcium and vitamin D in HIV+ combination with calcium and vitamin D in HIV+ individuals suggested the drug increases lumbar individuals suggested the drug increases lumbar spine BMD and is well tolerated (Guaraldi 2004; spine BMD and is well tolerated (Guaraldi 2004; Mondy 2005; Negredo 2005).Mondy 2005; Negredo 2005).

Study DesignStudy Design

A5163 is a 48-week prospective, randomized, double A5163 is a 48-week prospective, randomized, double blinded, placebo-controlled trial to evaluate the blinded, placebo-controlled trial to evaluate the effects of alendronate versus placebo, with calcium effects of alendronate versus placebo, with calcium and vitamin D supplementation, on BMD in and vitamin D supplementation, on BMD in patients with HIV.patients with HIV.

Study DesignStudy Design

Alendronate + Calcium/Vitamin DAlendronate + Calcium/Vitamin Dn=42n=42

Placebo+ Calcium/Vitamin Dn=40

Study Regimen: 48 weeks

-Alendronate or matching placebo 70 mg weekly -Calcium carbonate/Vitamin D (500 mg/200 IU BID)

HIV+

Lumbar t-score ≤-1.5

VL <5000

CD4 > 100

Randomization was stratified by CD4+ cell count at screening (100-200 cells/mm3 or >200 cells/mm3)

Inclusion/Exclusion CriteriaInclusion/Exclusion Criteria

InclusionInclusion

Documented HIV Documented HIV

≥ ≥ 25 years 25 years

CD4 ≥ 100 cells/mmCD4 ≥ 100 cells/mm33

HIV-1 RNA ≤ 5,000 cps/mLHIV-1 RNA ≤ 5,000 cps/mL

Lumbar spine t-score ≤ -1.5Lumbar spine t-score ≤ -1.5

Stable ARV for ≥ 12 wksStable ARV for ≥ 12 wks

No plan to alter ARV, exercise No plan to alter ARV, exercise habits, or diethabits, or diet

Exclusion Exclusion

Pregnancy or breast-feedingPregnancy or breast-feeding

Untreated hypogonadism or Untreated hypogonadism or hyperthyroidismhyperthyroidism

25-OH vitamin D <15 ng /mL 25-OH vitamin D <15 ng /mL

Hepatitis CHepatitis C

PTH > 80 pg/mLPTH > 80 pg/mL

Chronic systemic steroidsChronic systemic steroids

Treatment for osteoporosisTreatment for osteoporosis

Recent bone fractureRecent bone fracture

Esophageal pathologyEsophageal pathology

A5163 Main ObjectivesA5163 Main Objectives To examine the efficacy of once-weekly alendronate To examine the efficacy of once-weekly alendronate

and daily calcium and vitamin D in the treatment of and daily calcium and vitamin D in the treatment of HIV-associated decreased BMD, as assessed by HIV-associated decreased BMD, as assessed by percent change in lumbar spine BMD from baseline to percent change in lumbar spine BMD from baseline to week 48 in week 48 in men men receiving alendronate versus placeboreceiving alendronate versus placebo

To assess the safety and tolerability of once-weekly To assess the safety and tolerability of once-weekly alendronate in HIV-infected subjectsalendronate in HIV-infected subjects

To examine gender interactions in the efficacy of To examine gender interactions in the efficacy of once-weekly alendronate and daily calcium and once-weekly alendronate and daily calcium and vitamin D in the treatment of HIV-associated vitamin D in the treatment of HIV-associated decreased BMD decreased BMD

Statistical ConsiderationsStatistical Considerations

Study powered (80% power; 2-sided alpha = 0.05) Study powered (80% power; 2-sided alpha = 0.05) to detect an absolute difference of 3.5% in the to detect an absolute difference of 3.5% in the mean percent change mean percent change betweenbetween arms in arms in menmen. An . An additional 20% enrolled to account for possible additional 20% enrolled to account for possible drop-out and unevaluable DXA scans for a total of drop-out and unevaluable DXA scans for a total of 27-30 men per arm . 27-30 men per arm .

To test for moderate treatment/sex interactions, To test for moderate treatment/sex interactions, 10-13 women per arm were also included (total 10-13 women per arm were also included (total n=80)n=80)

Baseline CharacteristicsBaseline CharacteristicsAlendronate

N=42

Placebo

N=40

AgeAge 48 (33-63) 46 (30-68)

Men Men 71% 70%

% White% White 69% 85%

CD4 cell countCD4 cell count 482 (105-1387) 463 (189-1237)

HIV RNA < 400 cps/mLHIV RNA < 400 cps/mL 90% 93%

Current smokingCurrent smoking 36% 35%

BMIBMI 23.9 (20.1-38.6) 24.2 (19.1-35.1)

PI at study entryPI at study entry

Tenofovir at entryTenofovir at entry

Lumbar spine t-scoreLumbar spine t-score

Lumbar spine t-score < -2.5Lumbar spine t-score < -2.5

69%

38%

-2.15 (-3.3, -1.5)

24%

63%

38%

-1.95 (-3.0, -1.5)*

18%

*p=0.05

BMD Lumbar Spine (men and women)

Week

0 24 48

% ch

ang

e from

baselin

e

0

1

2

3

4

5

Vitamin D + Ca + Alendronate

Vitamin D + Ca

* p=0.0006

* significant within arms† significant between arms

* p=0.0003

* p=0.02

† p=0.03

BMD Total Hip (men and women)

Week

0 24 48

% c

han

ge

fro

m b

asel

ine

0

1

2

3

4

5

Vitamin D + Ca + Alendronate

Vitamin D + Ca

* p<0.0001

* p<0.0001

* significant within arms† significant between arms

* p=0.009

* p=0.03

† p=0.004

† p=0.05

BMD Trochanter (Men and Women)

Week

0 24 48

% c

han

ge

fro

m b

asel

ine

0

1

2

3

4

5

Vitamin D + Ca + Alendronate

Vitamin D + Ca

* p=0.0002

* p=0.002

* significant within arms† significant between arms

† p=0.007

ResultsResults

Two traumatic fractures occurred during the Two traumatic fractures occurred during the study (one per arm)study (one per arm)

ResultsResults Two traumatic fractures occurred during the study Two traumatic fractures occurred during the study

(one per arm).(one per arm). No evidence of a treatment/sex interaction when we No evidence of a treatment/sex interaction when we

considered the % change from baseline to week 48 considered the % change from baseline to week 48 in BMD assessed at the lumbar spine, total hip, or in BMD assessed at the lumbar spine, total hip, or trochanter (p=0.41, 0.82, and 0.19, respectively).trochanter (p=0.41, 0.82, and 0.19, respectively).

Changes from 0 Changes from 0 24 weeks strongly predicted 24 weeks strongly predicted changes from 0 changes from 0 48 weeks 48 weeks

In a multivariable model correcting for treatment, In a multivariable model correcting for treatment, BMI and baseline L-spine BMD, black race was BMI and baseline L-spine BMD, black race was associated with a smaller % change from baseline in associated with a smaller % change from baseline in lumbar spine BMD with alendronate (p=0.003)lumbar spine BMD with alendronate (p=0.003)

ResultsResults Two traumatic fractures occurred during the study Two traumatic fractures occurred during the study

(one per arm).(one per arm). No evidence of a treatment/sex interaction when we No evidence of a treatment/sex interaction when we

considered the % change from baseline to week 48 considered the % change from baseline to week 48 in BMD assessed at the lumbar spine, total hip, or in BMD assessed at the lumbar spine, total hip, or trochanter (p=0.41, 0.82, and 0.19, respectively).trochanter (p=0.41, 0.82, and 0.19, respectively).

Changes from 0 Changes from 0 24 weeks strongly predicted 24 weeks strongly predicted changes from 0 changes from 0 48 weeks 48 weeks

In a multivariable model correcting for treatment, In a multivariable model correcting for treatment, BMI and baseline L-spine BMD, black race was BMI and baseline L-spine BMD, black race was associated with a smaller % change from baseline in associated with a smaller % change from baseline in lumbar spine BMD with alendronate (p=0.003)lumbar spine BMD with alendronate (p=0.003)

ResultsResults Two traumatic fractures occurred during the study Two traumatic fractures occurred during the study

(one per arm).(one per arm). No evidence of a treatment/sex interaction when we No evidence of a treatment/sex interaction when we

considered the % change from baseline to week 48 considered the % change from baseline to week 48 in BMD assessed at the lumbar spine, total hip, or in BMD assessed at the lumbar spine, total hip, or trochanter (p=0.41, 0.82, and 0.19, respectively).trochanter (p=0.41, 0.82, and 0.19, respectively).

Changes from 0 Changes from 0 24 weeks strongly predicted 24 weeks strongly predicted changes from 0 changes from 0 48 weeks 48 weeks

In a multivariable model correcting for treatment, In a multivariable model correcting for treatment, BMI and baseline L-spine BMD, black race was BMI and baseline L-spine BMD, black race was associated with a smaller % change from baseline in associated with a smaller % change from baseline in lumbar spine BMD with alendronate (p=0.003)lumbar spine BMD with alendronate (p=0.003)

Safety/TolerabilitySafety/Tolerability

More signs/symptoms of Grade More signs/symptoms of Grade 3 in the placebo 3 in the placebo arm (15% versus 0% in the alendronate arm; arm (15% versus 0% in the alendronate arm; p=0.01)p=0.01)

No difference between treatment arms in Grade No difference between treatment arms in Grade 3 laboratory toxicities (15% on placebo arm 3 laboratory toxicities (15% on placebo arm versus 17% on alendronate; p>0.9) versus 17% on alendronate; p>0.9)

No discontinuation related to toxicityNo discontinuation related to toxicity

Study LimitationsStudy Limitations

Osteopenia may not require treatmentOsteopenia may not require treatment Duration relatively short Duration relatively short

need longer term efficacy and tolerabilityneed longer term efficacy and tolerability 21% changed ARV during study (5 TDF)21% changed ARV during study (5 TDF)

results unchanged when these 5 subjects results unchanged when these 5 subjects were excluded were excluded

ConclusionsConclusions

Alendronate given with calcium/vitamin D led to Alendronate given with calcium/vitamin D led to significant increases in lumbar spine, total hip significant increases in lumbar spine, total hip and trochanter BMD and trochanter BMD

Calcium/vitamin D alone led to modest increases Calcium/vitamin D alone led to modest increases in BMDin BMD

Alendronate was well tolerated, without Alendronate was well tolerated, without significant adverse eventssignificant adverse events

There was no evidence of treatment/sex There was no evidence of treatment/sex interactions at any of the bone sites examinedinteractions at any of the bone sites examined

AcknowledgmentsAcknowledgments David WohlDavid Wohl Pablo TebasPablo Tebas Michelle KendallMichelle Kendall Janet AndersenJanet Andersen Evelyn HoggEvelyn Hogg Lynette PurdueLynette Purdue Susan Swindells Susan Swindells Geetha GopalakrishnanGeetha Gopalakrishnan Melissa G. KerkauMelissa G. Kerkau Marjorie BusbyMarjorie Busby Carol SuckowCarol Suckow Amy SbrollaAmy Sbrolla Enid VazquezEnid Vazquez Jennifer NowakJennifer Nowak Murray AbramsonMurray Abramson Anne E. de PappAnne E. de Papp Mary E. MeltonMary E. Melton

All Participating ACTU Sites and Study Participants!

Merck for alendronate/placebo