7 Day Continuous Parathyroid Hormone IV Infusion

NCT00377312 | Completed Early Phase 1 Results DMC

• 2 other identifiers: 0606127R01DK073039
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Study consists of an eight day inpatient visit on the General Clinical Research Center. The investigators' specific aims are to:

1. 1.To define the maximum safe dose of a seven day continuous administration of parathyroid hormone \[PTH(1-34)\] in healthy human volunteers.
2. 2.To estimate the effect of a seven day continuous administration of parathyroid Hormone (PTH) in escalating doses on vitamin D metabolism, markers of bone turnover and fractional excretion of urine.

Conditions

Osteoporosis; Bone Diseases, Endocrine; Hyperparathyroidism

Keywords

Endocrine System Diseases; MusculoSkeletal System Disease; Hormone; Physiologic Properties

Outcome Measures

Primary Outcomes (4)

• Participants With Dose Limiting Toxicity

  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, daily up to Day 8 and follow-up

• Parathyroid Hormone (1-84)

  baseline, daily up to Day 8 and follow-up

• Fractional Excretion of Calcium

  baseline and daily

• 24 Hour Urine Calcium

  24 hours period from Day 7 to Day 8

• Tubular Maximum for Phosphorous

  baseline and daily

Study Arms (2)

Group 1

EXPERIMENTAL

Parathyroid Hormone (PTH) (1-34) 2 picomols/kg/hr for one week.

Drug: Parathyroid Hormone (1-34)

Group 2

EXPERIMENTAL

Parathyroid Hormone (PTH) (1-34)4 picomols/kg/hr for one week.

Drug: Parathyroid Hormone (1-34)

Interventions

Parathyroid Hormone (1-34) DRUG

PTH(1-34) IV given over a one week period

Also known as: IND 60,979

Group 1; Group 2

Eligibility Criteria

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

You may qualify if:

• Healthy Caucasian, Hispanic or Asian subjects
• Males and Females
• Non-smoker
• Ages 24 - 35 years old
• Subjects will be recruited either from the employee pool of the University of Pittsburgh or the University of Pittsburgh Medical Center (UPMC), or the general population living in the vicinity.
• Participation in this study by an employee or a potential employee at the University of Pittsburgh or UPMC has no effect on their employment or potential employment.
• Participants in the study will be required to discontinue all vitamins and health food supplements two weeks prior to the study.

You may not qualify if:

• Cardiac, hypertensive, vascular, renal (serum creatinine of \>1.5), pulmonary, endocrine, musculoskeletal, hepatic, hematologic or malignant or rheumatologic disease
• Body Mass Index (BMI) \> 30,
• Anemia (hematocrit less than 36% in women, less than 40% in men),
• Pregnancy (all women will have a urine pregnancy test performed immediately before starting the study and must not be pregnant)
• Significant alcohol or drug abuse or
• Baseline hypotension (systolic blood pressure less than 90 mm/Hg).
• Subjects will be excluded for abnormal levels of any of the screening labs including: ionized and total serum calcium, phosphorus, creatinine, albumin, 25-hydroxyvitamin D, and PTH. Pregnancy
• Subjects taking any chronic medications except oral contraceptives and stable doses of thyroid hormone, or those who have received any investigational drug in past 90 days will be excluded from the study.
• Subjects may not participate in this study more than once.
• Any subject who has previously received PTH or PTHrP, a related peptide, may not participate in this study.

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)

• Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, Stewart AF. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2003 Feb;88(2):569-75. doi: 10.1210/jc.2002-021122.

  PMID: 12574182 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

• 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

• 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

• Henry JG, Mitnick M, Dann PR, Stewart AF. Parathyroid hormone-related protein-(1-36) is biologically active when administered subcutaneously to humans. J Clin Endocrinol Metab. 1997 Mar;82(3):900-6. doi: 10.1210/jcem.82.3.3811.

  PMID: 9062504 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, Cain RL, Burr DB, Jacob D, Turner CH, Hock JM. Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroid hormone 893. J Bone Miner Res. 2000 Aug;15(8):1517-25. doi: 10.1359/jbmr.2000.15.8.1517.

  PMID: 10934650 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

• 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

• 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

• 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

• 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

• 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; Bone Diseases, Endocrine; Hyperparathyroidism; Endocrine System Diseases; Musculoskeletal Diseases

Interventions

Parathyroid Hormone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

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
• Organization: University of Pittsburgh

horwitz@pitt.edu

412-692-2848

Study Officials

• Mara J. Horwitz, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• 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: September 14, 2006
• First Posted: September 18, 2006
• Study Start: September 1, 2006
• Primary Completion: December 1, 2007
• Study Completion: December 1, 2007
• Last Updated: March 22, 2016
• Results First Posted: March 22, 2016

Record last verified: 2016-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)