7 Day Continuous Parathyroid Hormone IV Infusion

Study Overview
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Brief Summary
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Study consists of an eight day inpatient visit on the General Clinical Research Center. The investigators' specific aims are to: To define the maximum safe dose of a seven day continuous administration of parathyroid hormone [PTH(1-34)] in healthy human volunteers. 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.

Detailed Description
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This study will expand upon earlier infusions studies that demonstrated: 1) There is a dose-related increase in 1,25 (OH)2 vitamin D in response to PTHrP and PTH over multiple days. 2) There is a markedly attenuated vitamin D response to PTHrP compared to PTH, particularly during the second 24 hours. 3) The increase in 1,25 (OH)2 vitamin D is almost certainly responsible for the greater calcemic effect of PTH compared to PTHrP. 4) PTHrP is obviously a weaker agonist of 1,25 (OH)2 vitamin D but does not result in its suppression as is seen in Humoral Hypercalcemia of Malignancy (HHM). Thus, the suppression of 1,25 (OH)2 vitamin D seen in HHM remained unexplained. In addition to assessing the effects of an infusion of PTHrP and PTH on calcium handling and 1,25(OH)2 vitamin D, we also measured their effects on markers of bone turnover. Given the clinical observations seen in Hyperparathyroidism (HPT) and HHM, we anticipated that PTH would stimulate both bone resorption and formation, while PTHrP would stimulate bone resorption but inhibit formation. However, we observed that infusions of PTHrP and PTH resulted in an equivalent, rapid increase in bone resorption as measured by N-telopeptide (NTx) and C-telopeptide (CTx), as well as a progressive decline in bone formation. There was no difference between PTH and PTHrP. We assumed that formation would ultimately increase with additional time, as seen in HPT, and therefore examined an additional group of subjects infused with PTHrP for 96 hours. However, N-terminal propeptide of type 1 procollagen (P1NP) continued to decline even further as is seen in HHM in contrast to HPT. We have not yet studied longer infusions of PTH. One of the reasons for doing this pilot study is to determine the optimal dosing of PTH over a week period of time. Intravenous PTH has never been infused into human beings for prolonged periods of time. The investigators question whether a prolonged continuous intravenous infusion of PTH will lead to a sustained and progressive suppression of bone formation as occurs in HHM or an increase in bone formation as occurs in HPT. They also want to assess the direct influence of long-term continuous PTH infusions on plasma 1,25 (OH)2 vitamin D regulation in healthy human volunteers. We have shown in our previous studies that doses of 8 picomoles (pmol)/kg/hr PTH given over 48 hours result in sustained mild serum hypercalcemia, with serum calcium seeming to plateau in the range of 11 - 11.5 mg/dL after 48 hours. A dose of 8 picomoles (pmol)/kg/hr has also been shown to cause desirable effects on serum 1,25(OH)2 vitamin D and markers of bone turnover, and may therefore be the ideal dose. However, we do not know whether serum calcium will plateau after an infusion of 48 hours with escalating doses or whether it will continue to increase over seven days. To determine what will happen with a prolonged infusion, we plan to start with doses lower than 8 picomoles (pmol)/kg/hr, and then gradually increase the dose of PTH in successive groups of subjects. In the event of a significant adverse effect, immediate action will be taken to reverse it. Protocols will be in place to follow in the event of expected adverse events such as hypotension, nausea, and muscle cramping. Severe sudden side effects are not anticipated; however, mild easily reversible side effects are to be expected as an outcome in order to determine the optimal dose of PTH. This study has been approved by the NIH and the Data Safety Monitoring Board (DSMB). Seventy five normal healthy men and women will be screened for an eight day in-patient admission to the General Clinical Research Center (GCRC). Thirty evaluable research participants will receive a seven day infusion of a predetermined dose of PTH. Vitals signs, blood pressure, blood and urine lab results will be monitored frequently as per the study flow sheet. The starting dose of PTH, 2 picomoles (pmol)/kg, will be given to three normal healthy subjects. The dose will be escalated in increments with successive groups of three subjects each, until early adverse effects (mild hypercalcemia, postural hypotension, tachycardia) are seen. This dose will then be used in future studies. The investigators with this study are trying to discover if a prolonged continuous intravenous infusion of PTH will lead to a sustained and progressive suppression of bone formation as occurs in HHM or an increase in bone formation as occurs in HPT. Subject Population will consist of healthy young adults, ages 24-35 years, as in our other safety and physiologic studies. It is anticipated that we will need to screen 75 subjects in order to obtain 30 evaluable subjects.

Official Title
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Determining the Maximal Safe Dose of a Continuous Infusion of Parathyroid Hormone(1-34): Effects on Bone Formation

Conditions
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Osteoporosis, Bone Diseases, Endocrine, Hyperparathyroidism

Intervention / Treatment
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* Drug: Parathyroid Hormone (1-34)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. Minority Inclusion/Exclusion Statement: We will not include African-Americans because this group has been demonstrated by a number of investigators to display resistance to PTH, and may create wider statistical variation and a need for larger numbers of study subjects per group.

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

Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Parathyroid Hormone (PTH) (1-34) 2 picomols/kg/hr for one week. | Drug: Parathyroid Hormone (1-34)<br>* PTH(1-34) IV given over a one week period<br>* Other names: IND 60,979;|
| Experimental: Group 2<br>Parathyroid Hormone (PTH) (1-34)4 picomols/kg/hr for one week. | Drug: Parathyroid Hormone (1-34)<br>* PTH(1-34) IV given over a one week period<br>* Other names: IND 60,979;|

What is the study measuring?
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Primary Outcome Measures

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1,25 Vitamin D | pg/ml | baseline, daily up to Day 8 and follow-up | 
| Parathyroid Hormone (1-84) | pg/ml | baseline, daily up to Day 8 and follow-up | 
| Fractional Excretion of Calcium | % = (S Creatinine X U Calcium)/(S Calcium X U Creatinine) | baseline and daily | 
| 24 Hour Urine Calcium | mg/gm creatinine | 24 hours period from Day 7 to Day 8 | 
| Tubular Maximum for Phosphorous | mg/dl | baseline and daily | 
| Serum Amino-terminal of Collagen- (sNTX) | % change from baseline | baseline, daily, one week follow-up | 
| Serum Carboxy-terminal of Collagen- 1(sCTX) | % change from baseline | baseline, daily, one week follow-up | 
| Amino-terminal Peptides of Procollagen- 1(P1NP) | % change from baseline | baseline, daily, one week follow-up | 
| Bone Specific Alkaline Phosphatase (BSAP) | % change from baseline | baseline, daily, one week follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endocrine System Diseases, MusculoSkeletal System Disease, Hormone, Physiologic Properties