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

Overview

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.

Full Title of Study: “Determining the Maximal Safe Dose of a Continuous Infusion of Parathyroid Hormone-related Protein(1-36): Effects on Bone Formation”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Masking: Single (Participant)
  • Study Primary Completion Date: December 2009

Detailed Description

During this research the investigators administer PTHrP to healthy young volunteers in a controlled, continuous intravenous manner. As research subjects complete the week-long study without adverse effects, the dose of PThrP will be increased in later subjects. In the event of a significant adverse effect, immediate action will be taken to reverse it. The investigators want to estimate the effect of a sustainable level of mild hypercalcemia achieved by a week-long intravenous infusion of PTHrP has on vitamin D metabolism, markers of bone turnover and fractional excretion of calcium.

Interventions

  • Drug: PTHrP (1-36)
    • IND # 49,175

Arms, Groups and Cohorts

  • Experimental: PTHrP(1-36) 2 pmol/kg/hr
    • PTHrP(1-36) at 2 picomoles/kg/hr for one week.
  • Experimental: PTHrP (1-36) 4 pmol/kg/hr
    • PTHrP(1-36) at 4 picomoles/kg/hr for one week.
  • Experimental: PTHrP(1-36) 5 pmol/kg/hr
    • PTHrP(1-36) at 5 picomoles/kg/hr for one week.
  • Experimental: PTHrP(1-36) 6 pmol/kg/hr
    • PTHrP(1-36) at 6 picomoles/kg/hr for one week.

Clinical Trial Outcome Measures

Primary Measures

  • Dose Limiting Toxicity (DLT)
    • Time Frame: 12 hours after the infusion was started then q 8 hours for 7 days
    • 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.
  • Total Serum Calcium
    • Time Frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
    • mg/dl
  • Ionized Serum Calcium
    • Time Frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
    • mg/dl
  • Serum Phosphorous
    • Time Frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
    • mg/dl

Secondary Measures

  • 1,25 Vitamin D
    • Time Frame: Baseline and Daily through day 8 then at follow-up visit
    • pg/ml
  • 24 Hour Urine Calcium
    • Time Frame: 24 hours
    • mg/gm creatinine collected on day 7 of PTHrP infusion
  • Tubular Maximum of Phosphorous (TmP/GFR)
    • Time Frame: daily
    • mg/dl calculated from daily second morning void
  • Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)
    • Time Frame: Baseline, Daily, and 1 week follow-up
    • % change from baseline
  • Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)
    • Time Frame: Baseline, Daily, and 1 week follow-up
    • % change from baseline
  • Amino-terminal Peptides of Procollagen 1 (P1NP)
    • Time Frame: Baseline, Daily, and 1 week follow-up
    • % change from baseline
  • Bone Specific Alkaline Phosphatase (BSAP)
    • Time Frame: Baseline, Daily, and 1 week follow-up
    • % change from baseline
  • Parathyroid Hormone (1-84)
    • Time Frame: Baseline and Daily
    • pg/ml
  • Fractional Excretion of Calcium
    • Time Frame: daily
    • % calculated from daily second morning void

Participating in This Clinical Trial

Inclusion Criteria

  • 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 Exclusion Criteria:

  • 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

Gender Eligibility: All

Minimum Age: 24 Years

Maximum Age: 35 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Pittsburgh
  • Collaborator
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Mara Horwitz, Associate Professor of Medicne – University of Pittsburgh
  • Overall Official(s)
    • Mara J Horwitz, MD, Principal Investigator, University of Pittsburgh

References

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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.

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.

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.

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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.

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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.

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.

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