One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study

NCT00580788 | Completed Early Phase 1 Results DMC

• 2 other identifiers: PRO07040081R01DK073039
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, that can be given safely over one week. The investigators plan to infuse low doses of intravenous PTHrP to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrp on markers of bone turnover, and plasma 1,25 (OH)2 vitamin D regulation in healthy human volunteers.

Conditions

Osteoporosis; Humoral Hypercalcemia of Malignancy; Hyperparathyroidism

Keywords

Endocrine System Diseases; MusculoSkeletal System Diseases; Hormones; Malignancy; Postmenopausal Women; Bone metabolism

Outcome Measures

Primary Outcomes (4)

• Dose Limiting Toxicity (DLT)

  DLT was defined as achieving one major criterion or two minor criteria rated at ≥ 2 on a scale of 0-5. The major criteria were defined as symptomatic orthostatic hypotension (systolic BP fall \>30 mm/hg), tachycardia (pulse \> 120), hypertension (systolic BP \>160 mm/hg on 2 occasions), hypercalcemia (serum calcium ≥ 12 mg/dl), and hypophosphatemia (serum phosphorous \< 1.5 mg/dl). Minor criteria included symptoms such as flushing, nausea, abdominal or muscle cramps, dizziness, lightheadedness, palpitations, etc.

  12 hours after the infusion was started then q 8 hours for 7 days

• Total Serum Calcium

  mg/dl

  12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete

• Ionized Serum Calcium

  mg/dl

  12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete

• Serum Phosphorous

  mg/dl

  12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete

Secondary Outcomes (9)

• 1,25 Vitamin D

  Baseline and Daily through day 8 then at follow-up visit

• 24 Hour Urine Calcium

  24 hours

• Tubular Maximum of Phosphorous (TmP/GFR)

  daily

• Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)

  Baseline, Daily, and 1 week follow-up

• Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)

  Baseline, Daily, and 1 week follow-up

Study Arms (4)

PTHrP(1-36) 2 pmol/kg/hr

EXPERIMENTAL

PTHrP(1-36) at 2 picomoles/kg/hr for one week.

Drug: PTHrP (1-36)

PTHrP (1-36) 4 pmol/kg/hr

EXPERIMENTAL

PTHrP(1-36) at 4 picomoles/kg/hr for one week.

Drug: PTHrP (1-36)

PTHrP(1-36) 5 pmol/kg/hr

EXPERIMENTAL

PTHrP(1-36) at 5 picomoles/kg/hr for one week.

Drug: PTHrP (1-36)

PTHrP(1-36) 6 pmol/kg/hr

EXPERIMENTAL

PTHrP(1-36) at 6 picomoles/kg/hr for one week.

Drug: PTHrP (1-36)

Interventions

PTHrP (1-36) DRUG

IND # 49,175

Also known as: Parathyroid Hormone-related Protein (1-36)

PTHrP (1-36) 4 pmol/kg/hr; PTHrP(1-36) 2 pmol/kg/hr; PTHrP(1-36) 5 pmol/kg/hr; PTHrP(1-36) 6 pmol/kg/hr

Eligibility Criteria

• Age: 24 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy caucasian subjects of both sexes between the ages of 24-35 years, who are able to spend one week on the Clinical \& Translational Research Center at the University of Pittsburgh Medical Center (UPMC) Montefiore

You may not qualify if:

• Pregnancy
• Any cardiac, renal, pulmonary, endocrine, musculoskeletal, hepatic, hematological, malignant or rheumatologic diseases
• Body mass index great than 30
• Anemia
• Significant alcohol or drug abuse
• Baseline hypotension or hypertension
• Abnormal screening labs
• Use of certain chronic medications excluding oral contraceptives
• Receiving an investigational drug in the last 90 days
• Previously receiving PTH or PTHrP
• African-American race

Sponsors & Collaborators

• University of Pittsburgh: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (27)

• Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991 Nov 15;254(5034):1024-6. doi: 10.1126/science.1658941.

  PMID: 1658941 BACKGROUND

• Orloff JJ, Wu TL, Heath HW, Brady TG, Brines ML, Stewart AF. Characterization of canine renal receptors for the parathyroid hormone-like protein associated with humoral hypercalcemia of malignancy. J Biol Chem. 1989 Apr 15;264(11):6097-103.

  PMID: 2539369 BACKGROUND

• Orloff JJ, Ribaudo AE, McKee RL, Rosenblatt M, Stewart AF. A pharmacological comparison of parathyroid hormone receptors in human bone and kidney. Endocrinology. 1992 Oct;131(4):1603-11. doi: 10.1210/endo.131.4.1327716.

  PMID: 1327716 BACKGROUND

• Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF. Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev. 1994 Feb;15(1):40-60. doi: 10.1210/edrv-15-1-40.

  PMID: 8156938 BACKGROUND

• Samuels MH, Veldhuis J, Cawley C, Urban RJ, Luther M, Bauer R, Mundy G. Pulsatile secretion of parathyroid hormone in normal young subjects: assessment by deconvolution analysis. J Clin Endocrinol Metab. 1993 Aug;77(2):399-403. doi: 10.1210/jcem.77.2.8345044.

  PMID: 8345044 BACKGROUND

• Prank K, Nowlan SJ, Harms HM, Kloppstech M, Brabant G, Hesch RD, Sejnowski TJ. Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls. J Clin Invest. 1995 Jun;95(6):2910-9. doi: 10.1172/JCI117998.

  PMID: 7769133 BACKGROUND

• Schmitt CP, Obry J, Feneberg R, Veldhuis JD, Mehls O, Ritz E, Schaefer F. Beta1-adrenergic blockade augments pulsatile PTH secretion in humans. J Am Soc Nephrol. 2003 Dec;14(12):3245-50. doi: 10.1097/01.asn.0000101240.47747.7f.

  PMID: 14638923 BACKGROUND

• Chapotot F, Gronfier C, Spiegel K, Luthringer R, Brandenberger G. Relationships between intact parathyroid hormone 24-hour profiles, sleep-wake cycle, and sleep electroencephalographic activity in man. J Clin Endocrinol Metab. 1996 Oct;81(10):3759-65. doi: 10.1210/jcem.81.10.8855835.

  PMID: 8855835 BACKGROUND

• Harms HM, Schlinke E, Neubauer O, Kayser C, Wustermann PR, Horn R, Kulpmann WR, von zur Muhlen A, Hesch RD. Pulse amplitude and frequency modulation of parathyroid hormone in primary hyperparathyroidism. J Clin Endocrinol Metab. 1994 Jan;78(1):53-7. doi: 10.1210/jcem.78.1.8288713.

  PMID: 8288713 BACKGROUND

• Ledger GA, Burritt MF, Kao PC, O'Fallon WM, Riggs BL, Khosla S. Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. J Clin Endocrinol Metab. 1995 Nov;80(11):3304-10. doi: 10.1210/jcem.80.11.7593443.

  PMID: 7593443 BACKGROUND

• el-Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA. The parathyroid hormone circadian rhythm is truly endogenous--a general clinical research center study. J Clin Endocrinol Metab. 1997 Jan;82(1):281-6. doi: 10.1210/jcem.82.1.3683.

  PMID: 8989274 BACKGROUND

• Plawner LL, Philbrick WM, Burtis WJ, Broadus AE, Stewart AF. Cell type-specific secretion of parathyroid hormone-related protein via the regulated versus the constitutive secretory pathway. J Biol Chem. 1995 Jun 9;270(23):14078-84. doi: 10.1074/jbc.270.23.14078.

  PMID: 7775469 BACKGROUND

• Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocana A, Stewart AF. Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers. J Clin Endocrinol Metab. 2003 Apr;88(4):1603-9. doi: 10.1210/jc.2002-020773.

  PMID: 12679445 BACKGROUND

• Syed MA, Horwitz MJ, Tedesco MB, Garcia-Ocana A, Wisniewski SR, Stewart AF. Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy. J Clin Endocrinol Metab. 2001 Apr;86(4):1525-31. doi: 10.1210/jcem.86.4.7406.

  PMID: 11297578 BACKGROUND

• Everhart-Caye M, Inzucchi SE, Guinness-Henry J, Mitnick MA, Stewart AF. Parathyroid hormone (PTH)-related protein(1-36) is equipotent to PTH(1-34) in humans. J Clin Endocrinol Metab. 1996 Jan;81(1):199-208. doi: 10.1210/jcem.81.1.8550752.

  PMID: 8550752 BACKGROUND

• Fraher LJ, Hodsman AB, Jonas K, Saunders D, Rose CI, Henderson JE, Hendy GN, Goltzman D. A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man. J Clin Endocrinol Metab. 1992 Aug;75(2):417-23. doi: 10.1210/jcem.75.2.1322424.

  PMID: 1322424 BACKGROUND

• Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocana A, Bisello A, Hollis BW, Rosen CJ, Wysolmerski JJ, Dann P, Gundberg C, Stewart AF. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. J Bone Miner Res. 2005 Oct;20(10):1792-803. doi: 10.1359/JBMR.050602. Epub 2005 Jun 6.

  PMID: 16160737 BACKGROUND

• Horwitz MJ, Tedesco MB, Sereika SM, Garcia-Ocana A, Bisello A, Hollis BW, Gundberg C, Stewart AF. Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study. Osteoporos Int. 2006 Feb;17(2):225-30. doi: 10.1007/s00198-005-1976-3. Epub 2005 Sep 7.

  PMID: 16151606 BACKGROUND

• Plotkin H, Gundberg C, Mitnick M, Stewart AF. Dissociation of bone formation from resorption during 2-week treatment with human parathyroid hormone-related peptide-(1-36) in humans: potential as an anabolic therapy for osteoporosis. J Clin Endocrinol Metab. 1998 Aug;83(8):2786-91. doi: 10.1210/jcem.83.8.5047.

  PMID: 9709948 BACKGROUND

• Stewart AF, Mangin M, Wu T, Goumas D, Insogna KL, Burtis WJ, Broadus AE. Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats. J Clin Invest. 1988 Feb;81(2):596-600. doi: 10.1172/JCI113358.

  PMID: 3339131 BACKGROUND

• Burtis WJ, Wu T, Bunch C, Wysolmerski JJ, Insogna KL, Weir EC, Broadus AE, Stewart AF. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151-6.

  PMID: 3584110 BACKGROUND

• Stewart AF, Wu T, Goumas D, Burtis WJ, Broadus AE. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987 Jul 31;146(2):672-8. doi: 10.1016/0006-291x(87)90581-x.

  PMID: 3619898 BACKGROUND

• Wu TL, Vasavada RC, Yang K, Massfelder T, Ganz M, Abbas SK, Care AD, Stewart AF. Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem. 1996 Oct 4;271(40):24371-81. doi: 10.1074/jbc.271.40.24371.

  PMID: 8798692 BACKGROUND

• Cosman F, Shen V, Xie F, Seibel M, Ratcliffe A, Lindsay R. Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers. Ann Intern Med. 1993 Mar 1;118(5):337-43. doi: 10.7326/0003-4819-118-5-199303010-00003.

  PMID: 8430979 BACKGROUND

• Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM. An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis. J Clin Invest. 1993 Mar;91(3):1138-48. doi: 10.1172/JCI116273.

  PMID: 8450043 BACKGROUND

• Fiaschi-Taesch NM, Stewart AF. Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences. Endocrinology. 2003 Feb;144(2):407-11. doi: 10.1210/en.2002-220818.

  PMID: 12538599 BACKGROUND

• Horwitz MJ, Tedesco MB, Sereika SM, Prebehala L, Gundberg CM, Hollis BW, Bisello A, Garcia-Ocana A, Carneiro RM, Stewart AF. A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover. J Bone Miner Res. 2011 Sep;26(9):2287-97. doi: 10.1002/jbmr.415.

  PMID: 21544866 DERIVED

MeSH Terms

Conditions

Osteoporosis; Humoral Hypercalcemia Of Malignancy; Hyperparathyroidism; Endocrine System Diseases; Musculoskeletal Diseases; Neoplasms

Interventions

parathyroid hormone-related peptide (1-36)

Condition Hierarchy (Ancestors)

Bone Diseases, Metabolic; Bone Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Parathyroid Diseases

Limitations and Caveats

Small number of subjects in each group Study limited to Caucasians Only one timepoint for follow-up was measure Study did not include saline infused controls

Results Point of Contact

• Title: Mara J Horwitz, MD
• Organization: University of Pittsburgh

horwitz@pitt.edu

4126922848

Study Officials

• Mara J Horwitz, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicne

Study Record Dates

• First Submitted: December 20, 2007
• First Posted: December 27, 2007
• Study Start: January 1, 2008
• Primary Completion: December 1, 2009
• Study Completion: December 1, 2009
• Last Updated: February 11, 2016
• Results First Posted: February 11, 2016

Record last verified: 2016-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)