7 Day Continuous Parathyroid Hormone IV Infusion

March 18, 2016 updated by: Mara Horwitz, University of Pittsburgh

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

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

  1. To define the maximum safe dose of a seven day continuous administration of parathyroid hormone [PTH(1-34)] in healthy human volunteers.
  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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

11

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh,, Pennsylvania, United States, 15213
        • University of Pittsburgh Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

24 years to 35 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: Single

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
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
12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
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
12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
Participants With Dose Limiting Toxicity
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.
12 hours after the infusion was started then q 8 hours for 7 days

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pittsburgh

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2006

Primary Completion (Actual)

December 1, 2007

Study Completion (Actual)

December 1, 2007

Study Registration Dates

First Submitted

September 14, 2006

First Submitted That Met QC Criteria

September 14, 2006

First Posted (Estimate)

September 18, 2006

Study Record Updates

Last Update Posted (Estimate)

March 22, 2016

Last Update Submitted That Met QC Criteria

March 18, 2016

Last Verified

March 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0606127
  • R01DK073039 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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