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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Osteoporosis, Humoral Hypercalcemia of Malignancy, Hyperparathyroidism

Intervention / Treatment
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* Drug: PTHrP (1-36)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 24 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTHrP(1-36) 2 pmol/kg/hr<br>PTHrP(1-36) at 2 picomoles/kg/hr for one week. | Drug: PTHrP (1-36)<br>* IND # 49,175<br>* Other names: Parathyroid Hormone-related Protein (1-36);|
| Experimental: PTHrP (1-36) 4 pmol/kg/hr<br>PTHrP(1-36) at 4 picomoles/kg/hr for one week. | Drug: PTHrP (1-36)<br>* IND # 49,175<br>* Other names: Parathyroid Hormone-related Protein (1-36);|
| Experimental: PTHrP(1-36) 5 pmol/kg/hr<br>PTHrP(1-36) at 5 picomoles/kg/hr for one week. | Drug: PTHrP (1-36)<br>* IND # 49,175<br>* Other names: Parathyroid Hormone-related Protein (1-36);|
| Experimental: PTHrP(1-36) 6 pmol/kg/hr<br>PTHrP(1-36) at 6 picomoles/kg/hr for one week. | Drug: PTHrP (1-36)<br>* IND # 49,175<br>* Other names: Parathyroid Hormone-related Protein (1-36);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endocrine System Diseases, MusculoSkeletal System Diseases, Hormones, Malignancy, Postmenopausal Women, Bone metabolism