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Efficacy and Tolerability of an Individualized Dosing Regimen for Adult Growth Hormone Replacement Therapy in Comparison with Fixed Body Weight-Based Dosing

Veterans Affairs Palo Alto Health Care System and Stanford University Medical Center (A.R.H.), Palo Alto, California 94304; Innenstadt University Hospital (C.J.S.), 80336 Munich, Germany; and Lilly Research Laboratories (A.Z., W.F.B., A.K., M.L.H.), Eli Lilly and Company, Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Andrew R. Hoffman, Medical Service, Veterans Affairs Palo Alto Health Care System and Stanford University, 3801 Miranda Avenue, Palo Alto, California 94304. E-mail: arhoffman{at}stanford.edu.

To determine whether an individualized dose titration regimen (ID) for adult GH replacement therapy would have similar efficacy and better tolerability than a fixed body weight-based dosing regimen (FD), 387 adults with GH deficiency were randomized to FD (n = 200) or ID (n = 187) for 32 wk. In FD, subjects received sequentially 4, 8, and 12 µg/kg·d GH. ID was started at 0.2 mg/d and increased by 0.2-mg/d increments, based on clinical and serum IGF-I responses, to a maximum of 0.8 mg/d. Increases (mean ± SD) in serum IGF-I were similar in both groups (FD, 110.2 ± 87.8 vs. ID, 99.6 ± 77.7 µg/liter, P = 0.20) despite higher final GH doses in FD (0.70 ± 0.32 vs. 0.54 ± 0.22 mg/d, P < 0.001). Favorable changes in several efficacy measures were observed with no significant differences between the FD and ID groups: lean body mass increased; health-related quality of life improved; and abdominal fat mass, hip circumference, sum of skinfolds, and total and low-density lipoprotein cholesterol decreased. The decrease in fat mass was greater with FD than ID for men (–2.7 ± 2.7 kg vs. –1.8 ± 2.5 kg, P = 0.04) but not for women (–2.1 ± 2.4 vs. –2.0 ± 3.8 kg). The change in waist circumference was greater with FD than ID for women but not for men. There was a significant reduction of systolic blood pressure in ID but not in FD. The adverse event profile was similar between FD and ID except that ID had a lower occurrence of peripheral edema (9.1% vs. 16.5%, P = 0.03) and rash (1.1% vs. 5.5%, P = 0.02) than FD. In summary, the use of ID resulted in improved tolerability and similar efficacy compared with FD. We conclude that GH replacement therapy should be initiated at a low dose and titrated to a dose producing maximal benefits without adverse side effects and an IGF-I level within the age- and sex-adjusted normal range.

Present address for C.J.S.: Campus Charité Mitte, 10117 Berlin, Germany.

The members of the T002 Study Group were 1) France: Sylvie Arlot, Amiens; Yvan Bachelot, Grenoble; Francois P. Berthezene, Lyon; Francoise Borson-Chazot, Lyon; H. Hanaire Broutin, Toulouse; Philippe Chanson, Le Kremin Bicetre; Bruno Estour, Saint Etienne; Jacques Leclere, Nancy; Michel Pugeat, Lyon; Patrick Roger, Pessac; Charles Thivolet, Lyon; Gerard Turpin, Paris; and Andre Warnet, Paris; 2) Germany: H. C. Blossey, Kassel; B. Gerbert, Dresden; K. J. Graef, Berlin; Hans-Jurgen Heberling, Leipzig; H. Moenig, Kiel; K. G. Petersen, Freiburg; Stephan Petersenn, Hamburg; Ursula Plöckinger, Berlin; G. K. Stalla, Munich; Christian J. Strasburger, Berlin; K. H. Usadel, Frankfurt; and M. Ventz, Berlin; 3) Great Britain: Michael Cummings, Portsmouth; Trevor A. Howlett, Leicester; Richard Ross, Sheffield; David Russell-Jones, Guildford; Peter H. Sönksen, London; and Patricia Vice, Preston; 4) Italy: Antonio Barbarino, Rome; Franco Comanni, Turin; F. Cavagnini, Milan; G. Lombardi, Naples; Aldo Pinchera, Pisa; Alessandro Sartorio, Milan; Guido Tamburrano, Rome; and Ettore Degli Uberti, Ferrara; 5) United States: Jeanine Albu, New York, NY; Robert Alder, Richmond, VA; Francisco Aguilo, Jr., San Juan, Puerto Rico; Baha Arafah, Cleveland, OH; Beverly M. K. Biller, Boston, MA; Michael Carlson, Nashville, TN; John J. Cavanaugh, South Bend, IN; Robert Cohen, Cincinnati, OH; George E. Daily, La Jolla, CA; Richard Dorin, Albuquerque, NM; Lawrence Frohman, Chicago, IL; Andrew Hoffman, Palo Alto, CA; Silvio Inzucchi, New Haven, CT; Rashid A. Khairi, Indianapolis, IN; George R. Merriam, Tacoma, WA; Arshag D. Mooradian, St. Louis, MO; Phillip Orlander, Houston, TX; Lawrence S. Phillips, Atlanta, GA; Julio Rosentock, Dallas, TX; Daniel Spratt, Scarsborough, ME; David R. Sutton, Jacksonville, FL; and Ping Wang, Irvine, CA.

Abbreviations: ALS, Acid labile subunit; AO, adult onset; BIA, bioelectrical impedance analysis; BMD, bone mineral density; BP, blood pressure; CO, childhood onset; DXA, dual-energy x-ray absorptiometry; FD, fixed body weight-based dosing regimen; GHBP, GH binding protein; GHD, GH deficiency; HDL, high-density lipoprotein; ID, individualized dose titration regimen; IGFBP, IGF binding protein; LDL, low-density lipoprotein; NHP, Nottingham Health Profile; QLS, Questions on Life Satisfaction; QoL, health-related quality of life; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

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