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7 Day Continuous Parathyroid Hormone IV Infusion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00377312
Recruitment Status : Completed
First Posted : September 18, 2006
Results First Posted : March 22, 2016
Last Update Posted : March 22, 2016
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Mara Horwitz, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE September 14, 2006
First Posted Date  ICMJE September 18, 2006
Results First Submitted Date  ICMJE April 25, 2014
Results First Posted Date  ICMJE March 22, 2016
Last Update Posted Date March 22, 2016
Study Start Date  ICMJE September 2006
Actual Primary Completion Date December 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
  • 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.
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: September 14, 2006)
Blood collections for safety measurements including serum ionized and total calcium, phosphorus and creatinine
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
  • 1,25 Vitamin D [ Time Frame: baseline, daily up to Day 8 and follow-up ]
    pg/ml
  • Parathyroid Hormone (1-84) [ Time Frame: baseline, daily up to Day 8 and follow-up ]
    pg/ml
  • Fractional Excretion of Calcium [ Time Frame: baseline and daily ]
    % = (S Creatinine X U Calcium)/(S Calcium X U Creatinine)
  • 24 Hour Urine Calcium [ Time Frame: 24 hours period from Day 7 to Day 8 ]
    mg/gm creatinine
  • Tubular Maximum for Phosphorous [ Time Frame: baseline and daily ]
    mg/dl
  • Serum Amino-terminal of Collagen- (sNTX) [ Time Frame: baseline, daily, one week follow-up ]
    % change from baseline
  • Serum Carboxy-terminal of Collagen- 1(sCTX) [ Time Frame: baseline, daily, one week follow-up ]
    % change from baseline
  • Amino-terminal Peptides of Procollagen- 1(P1NP) [ Time Frame: baseline, daily, one week follow-up ]
    % change from baseline
  • Bone Specific Alkaline Phosphatase (BSAP) [ Time Frame: baseline, daily, one week follow-up ]
    % change from baseline
Original Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2006)
Blood collections analyzed for measurements of PTH(1-34), PTH(1-84), 25-hydroxy Vitamin D, 1,25 (OH)2 vitamin D and markers of bone turnover.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 7 Day Continuous Parathyroid Hormone IV Infusion
Official Title  ICMJE Determining the Maximal Safe Dose of a Continuous Infusion of Parathyroid Hormone(1-34): Effects on Bone Formation
Brief Summary

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.
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  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Condition  ICMJE
  • Osteoporosis
  • Bone Diseases, Endocrine
  • Hyperparathyroidism
Intervention  ICMJE Drug: Parathyroid Hormone (1-34)
PTH(1-34) IV given over a one week period
Other Name: IND 60,979
Study Arms  ICMJE
  • Experimental: Group 1
    Parathyroid Hormone (PTH) (1-34) 2 picomols/kg/hr for one week.
    Intervention: Drug: Parathyroid Hormone (1-34)
  • Experimental: Group 2
    Parathyroid Hormone (PTH) (1-34)4 picomols/kg/hr for one week.
    Intervention: Drug: Parathyroid Hormone (1-34)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 18, 2016)
11
Original Enrollment  ICMJE
 (submitted: September 14, 2006)
75
Actual Study Completion Date  ICMJE December 2007
Actual Primary Completion Date December 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 24 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00377312
Other Study ID Numbers  ICMJE 0606127
R01DK073039 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Mara Horwitz, University of Pittsburgh
Study Sponsor  ICMJE University of Pittsburgh
Collaborators  ICMJE National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE
Principal Investigator: Mara J. Horwitz, MD University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP