Clinical Trial: 7 Day Continuous Parathyroid Hormone IV Infusion

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: 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 Summary:

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 i
Sponsor: University of Pittsburgh

Current Primary Outcome:

  • 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: Blood collections for safety measurements including serum ionized and total calcium, phosphorus and creatinine

Current Secondary Outcome:

  • 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: 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.

Information By: University of Pittsburgh

Dates:
Date Received: September 14, 2006
Date Started: September 2006
Date Completion:
Last Updated: March 18, 2016
Last Verified: March 2016