recombinant human growth hormone (r-hgh) to treat hiv-associated adipose redistribution syndrome...

Recombinant human Growth Hormone (r-hGH)

to treat HIV-associated Adipose Redistribution Syndrome (HARS): 12-Week Induction and

24-Week Maintenance TherapyCarl Grunfeld, MD, PhD

Professor of Medicine, UCSFChief, Metabolism and Endocrine Sections, VAMC

Veterans Affairs Medical CenterSan Francisco, CA

Melanie Thompson, Stephen Brown, Gary Richmond, Daniel Lee, Norma Muurahainen, Donald P. Kotler

and the Study 24380 Investigators Group

Background: HARS• Increased Visceral Adipose Tissue (VAT) often

accompanied by subcutaneous lipoatrophy

• Both have metabolic consequences

• Characterized by abdominal fat accumulation (truncal fat, primarily VAT); may occur with subcutaneous fat depletion

• Patients may also exhibit:- Dyslipidemia, insulin resistance, glucose

intolerance- Excess dorsocervical fat (“buffalo hump”)- Poor quality of life, particularly psychological

distress

Healthy HARS

SAT* Less SAT*

VAT More VAT

Visceral Adipose Tissue on Abdominal Cross-sectional CT Scan (L4-L5 Level)

*Subcutaneous Adipose Tissue (SAT)

Phase III Trial Design: Study 24380

o Double-Blindo Placebo-Controlledo N = 325o Duration 36 weeks:

o 12 Wks Induction o 24 Wks Maintenance (ARM A only)

PRE-SPECIFIED EFFICACY ENDPOINTS: INDUCTION PHASE: Reduction of VAT at Week 12 (GH 4 mg DD vs Placebo DD)

MAINTENANCE PHASE: During Weeks 12 to 36, less than 50% of pts on GH 2 mg AD regain >50% of VAT that they lost during the induction phase (baseline to Week 12)

Baseline 12 Wks 24 Wks 36 Wks

Randomized

3:1

Placebo DD

GH 2 mg AD

Placebo AD

Placebo AD Placebo ADGH 4 mg DD

GH 4 mg DD

GH 2 mg ADR

ARM A = 244

ARM B = 81

Weeks 0 - 12 Weeks 12-36

Ope

n-la

bel e

xten

sion

S

tudy

253

73

n = 92

n = 73

n = 93

n = randomized and received study drug

Endpoints & Eligibility: Study 24380

Induction and Maintenance Therapy Endpoints (EP):Primary EP:

• VAT at Week 12

Key Secondary EP:• Trunk fat on DXA• Fasting lipid profile• Maintain reduced

VAT

Eligibility Criteria• Documented HIV infection• Receiving antiretroviral therapy• Excess VAT by anthropometric

criteria• Men: WC > 88.2 cm and WHR

0.95• Women: WC > 75.3 cm and

WHR 0.90

• Not diabetic or receiving medications for diabetes

• Lipid-lowering agents permitted• Glucose tolerance criteria

• Fasting glucose < 110 mg/dL 2-hr glucose < 140 mg/dL after 75 g oral glucose load

VAT = Visceral Adipose Tissue on CT scan at L4-5

WC = Waist circumference

WHR = Waist:Hip Ratio

Baseline Characteristics: Study 24380

CharacteristicPlacebo(n=79)

4 mg DD (n=243) p-value

Age (yrs)* 45 ± 0.8 45 ± 0.4 0.365

% Female 11 (14) 36 (15) 0.846

CD4 (cells/mm3)* 493 ± 32 501 ± 18 0.814

BMI (kg/m2)* 27.8 ± 0.5 27.2 ± 0.2 0.629

% Body Fat 22 ± 1 22 ± 0.5 0.432

CT VAT (cm2)* 135 ± 7 136 ± 4 0.620

DXA Trunk Fat (kg)* 12.3 ± 0.5 11.8 ± 0.3 0.346

DXA Limb SAT (kg)* 6.1 ± 0.5 5.6 ± 0.2 0.289

Use of PI (n [%]) 50 (62) 152 (62) >0.999

Use of NRTI (n [%]) 81 (100) 228 (93) 0.015

Use of NNRTI (n [%]) 37 (46) 114 (47) 0.898

*Mean ± SEM

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VAT

SAT

% C

han

ge

fro

m b

asel

ine

*

*5% loss

Placebo r-hGH 4 mg DD

VAT & SAT (CT scan)

Primary and Secondary Endpoints,Baseline to Week 12: Study 24380

Decrease in VAT > SAT on r-hGH Decrease in Trunk Fat > Limb Fat on r-hGH

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Trunk fat

Limb SAT


*

*

% c

han

ge

fro

m b

asel

ine

*p < 0.001 for r-hGH vs. Placebo

Trunk Fat & Limb Fat (DXA scan)

-5

0

5

10

HDL

Cholesterol Profiles, Baseline to Week 12: Study 24380

*p < 0.001 for change from BL‡p < 0.05 for change from BL

Non-HDL & LDL Cholesterol

-15

-10

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0

5

10

Non-HDL

LDL


*% C

han

ge

fro

m b

asel

ine

*

‡

HDL Cholesterol

p = 0.018 for Non-HDL C

p = 0.031 for HDL-C

*

Mea

n C

ha

ng

e fr

om

bas

elin

e (m

g/d

L)


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VAT: Weeks 12 to 36 VAT: Baseline to Week 36

Maintenance Therapy: Study 24380

• Major efficacy EP for maintenance was met: Less than 50% on r-hGH maintenance regained more than 50% of VAT lost during induction

• Endpoint: Failure Rate = % who re-gained > 50% of VAT lost during induction

• Placebo FAILED;

53.7% regained more than 50% of VAT lost

• r-hGH 2 mg AD SUCCEEDED; 40.3% regained more than 50% of VAT lost

All Patients (ITT)

‡ from baseline, p = 0.295 between groups

Patients who lost VAT from Weeks 1 to 12


GH-Placebo

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p = 0.027‡

- 7.9 cm2

Mea

n C

han

ge

(cm

2 )

- 15.7 cm2

p < 0.001‡

GH-GH 2ADGH-Placebo

p <0.001‡

p = 0.008‡

-10.0 cm2

Mea

n C

han

ge

(cm

2 )-26.6 cm2

GH-GH 2AD

100

200

300

400

500

600

BL Wk 12 Wk 24 Wk 36

*p < 0.001

* *

24380 Safety: CD4, Fasting Glucose, IGF-I, Insulin AUC in those receiving r-hGH induction-maintenance (Baseline-Week 36)

80

90

100

110

120

BL Wk 2 Wk 4 Wk 12 Wk 16 Wk 24 Wk 26 Wk 28 Wk 36

Mean fasting glucose (mg/dL)

0

2000

4000

6000

8000

10000

BL Wk 12 Wk 24 Wk 36DD-PL-PL DD-AD-AD

Mean Insulin AUC (IU/mL-minute)Mean IGF-I (ng/mL)

Mean CD4 counts (cells/L)

200

300

400

500

600

700

BL Wk 12 Wk 36

Most Common Adverse Events (10%)*Week 12, Study 24380

Adverse Event, n (%)Placebo(n=81)

4 mg DD(n=244) p-value

Edema peripheral 4 (5) 113 (46) <0.001

Arthralgia 14 (17) 95 (39) <0.001

Pain in extremity 3 (4) 46 (19) <0.001

Headache 3 (4) 39 (16) 0.004

Hypoesthesia 0 34 (14) <0.001

Myalgia 3 (4) 34 (14) 0.014

Blood glucose increased 2 (3) 33 (14) 0.003

Paresthesia 3 (4) 25 (10) 0.107

*Overall, ~95% of events were only mild to moderate in severity.All serious adverse events were unlikely related, except for 1 possibly related SAE (migraine).

Most Common AEs (10%), n (%)

4DD-PL-PL(n=93)

4DD-2AD-2AD(n=92) p-value

Upper respiratory tract infection

15 (16) 7 (8) 0.110

4DD-PL-PL 4DD-2AD-2AD

Typical AEs, n (%) (n=93) (n=92) p-value

Edema peripheral 4 (4) 6 (7) 0.536Arthralgia 5 (5) 8 (9) 0.405Pain in extremity 5 (5) 2 (2) 0.444Headache 4 (4) 5 (5) 0.747Hypoesthesia 1 (1) 5 (5) 0.118Myalgia 2 (2) 2 (2) >0.999Blood glucose increased 3 (3) 6 (6) 0.330Paresthesia 4 (4) 4 (4) >0.999

Most Common AEs and Typical AEs*Weeks 12-36; Study 24380

*Overall, ~95% of events were mild to moderate in severity.All serious adverse events unrelated or unlikely related, except 1 possibly related SAE (basal cell skin carcinoma).

Induction Therapy (r-hGH 4 mg/day, Weeks 1-12) Significant reduction in VAT on r-hGH 4mg/day versus Placebo Reduction in trunk fat Improvement in cholesterol profile

Maintenance Therapy (r-hGH 2 mg alt day) Fewer than 50% of patients on r-hGH regain >50% of VAT lost during

induction therapy Improvement in cholesterol profile

Safety Profile of r-hGH: as anticipated AEs mostly mild to moderate Greater loss of VAT and trunk fat - than of abdominal SAT and limb

fat Transient increases in glucose, HbA1c, and insulin AUC

Summary & Conclusions: Study 24380

Thanks to all 24380 Study Subjects, Thanks to all 24380 Study Subjects, Study Personnel, Advisors, and InvestigatorsStudy Personnel, Advisors, and Investigators

Acknowledgements

Gary Blick, Norwalk, CTCynthia Brinson, Austin, TXStephen Brown, West Hollywood, CACalvin Cohen, Boston, MADaniel Coulston, Spokane, WAEric Daar, Los Angeles, CAGeorge Drusano, Albany, NYMichael Dube, Indianapolis, INJeffrey Fessel, San Francisco, CAMarshall Glesby, New York, NYCarl Grunfeld, San Francisco, CAKeith Henry, Minneapolis, MNDonald Kotler, New York, NYDaniel Lee, San Diego, CAKen Lichtenstein, Denver, COArdis Moe, Los Angeles, CA

Anne Morris, Springfield, MA Julio Montaner, Vancouver, BCRichard Pollard, Sacramento, CABruce Rashbaum, Washington, DCGary Richmond, Miami, FLMichael Saag, Birmingham, ALSteve Santiago, Miami, FLMorris Schambelan, San Francisco, CAMike Somero, Palm Springs, CACorklin Steinhart, Miami, FLAlan Tenorio, Chicago, ILMelanie Thompson, Atlanta, GAVilma Vega, Sarasota, FLChristine Wanke, Boston, MADavid Wheeler, Annandale, VAMichael Wohlfeiler, North Miami Beach, FL Antonio Urbina, New York, NY

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Baseline VAT & SAT in both studies

Study 24380

*Kotler et al., Letter, JAIDS, 2006 (in press)


Study 22388

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Mean Change in VAT & SAT during 12-Week Induction Therapy in Both Studies

Greater percent decrease in VAT than SAT on r-hGH

Study 24380

*p < 0.001 compared to placebo, corrected data (Kotler et al., Letter, JAIDS, 2006, in press)

*p < 0.001 compared to placebo

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HbA1c and HIV-1 RNA levels, Baseline to Week 36: Study 24380

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BL Wk 12 Wk 36

DD-PL-PL

DD-AD-AD

Mean HbA1c (%)

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Proportions of patients with HIV-1-RNA 400 copies/mL

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LDL

GH-Placebo GH-GH 2 mg AD

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GH-Placebo GH-GH 2 mg AD

Mean Change in Non-HDL and LDL Cholesterol, BL to Week 36: Study 24380

‡p < 0.05 for change from BL*p < 0.001 for change from BL

No significant differences - GH-GH 2 mg AD and GH-Placebo maintenance groups

Dyslipidemic at Baseline†

†Non-HDL-C 130 mg/dLLDL-C 100 mg/dL

-25

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LDL

Mea

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HDL

Dyslipidemic at Baseline†All Patients (ITT)

Mean Change in HDL Cholesterol, Baseline to Week 36: Study 24380

*p < 0.001 for change from BL

No significant differences - GH-GH 2 mg AD and GH-Placebo maintenance groups

*

Mea

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han

ge f

rom

ba

selin

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g/d

L)

GH-Placebo

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GH-GH 2 mg DD

†HDL-C <40 mg/dL

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g/d

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VAT: Weeks 12 to 36 Percent change VAT: BL to Week 36

Maintenance Therapy, Study 24380

• Major endpoint for Maintenance was met: No more than 50% of pts regained more than 50% of the VAT lost during induction therapy

• Pre-specified Endpoint:Failure Rate = Percentage of patients who (during Wks 12-36) regained > 50% of VAT lost during r-hGH induction therapy• Placebo FAILED; 53.7%

regained more than 50% of VAT lost

• r-hGH dosed 2 mg AD SUCCEEDED; 40.3% regained more than 50% of VAT lost

All Patients (ITT): 24380


Patients who lost VAT from Weeks 1 to 12

% C

han

ge

% C

han

ge


p < 0.001‡

p = 0.014‡

p = 0.018‡ p = 0.103‡

GH-GH 2ADGH-Placebo

GH-GH 2ADGH-Placebo

+3.1% -3.5%

+0.8% -14.7%

recombinant human growth hormone (r-hgh) to treat hiv-associated adipose redistribution syndrome...

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