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3-Week Parathyroid Hormone-related Protein (PTHrP) Dose Escalation Study in Post-Menopausal Women

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: NCT00222872
Recruitment Status : Completed
First Posted : September 22, 2005
Last Update Posted : April 28, 2014
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Department of Health and Human Services
Information provided by (Responsible Party):
Mara Horwitz, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE September 9, 2005
First Posted Date  ICMJE September 22, 2005
Last Update Posted Date April 28, 2014
Study Start Date  ICMJE July 2005
Actual Primary Completion Date September 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
Subjects will receive PTHrP without Dose Limiting Toxicity Events as established by safety parameters consisting of one major criteria or two minor criteria. [ Time Frame: 3 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 19, 2005)
  • Safety parameters: measurements of:
  • total ionized calcium
  • serum calcium,
  • phosphorus,
  • creatinine,
  • albumin;
  • other safety parameters include blood pressure,
  • pulse,
  • and subjective symptom ratings,
  • collected on a weekly basis.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
Efficacy measurements including (but not limited to): measurements of 25-hydroxy vitamin D, 1,25 (OH)2 vitamin D, PTH, PTHrP, osteocalcin, bone specific alkaline phosphatase, procollagen peptide-1, CTx, NTx, IgF and serum DPD. [ Time Frame: 3 week ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2005)
  • Efficacy will be investigated by examining:
  • changes in markers of bone metabolism
  • (e.g., CTx,
  • NTx,
  • P1NP
  • and others),
  • PTH(1-34),
  • 25-hydroxy Vitamin D,
  • and 1,25 (OH)2 Vitamin D
  • between the groups of subjects receiving:
  • placebo,
  • 500 micrograms PTHrP
  • and the maximum safely tolerated dose of PTHrP
  • (30 total, 10 per group)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 3-Week Parathyroid Hormone-related Protein (PTHrP) Dose Escalation Study in Post-Menopausal Women
Official Title  ICMJE A Three Week Dose Escalation Study of PTHrP(1-36) in Postmenopausal Women
Brief Summary The main purpose of this study is to determine the safety and effectiveness of three week daily subcutaneous injections of Parathyroid Hormone-related Protein (1-36). Previous studies indicated that PTHrP has a skeletal 'anabolic' or bone-building effect, and has shown to increase bone mineral density in postmenopausal women with osteoporosis. Safety of PTHrP will be determined by measurements of blood pressure and pulse, serum blood calcium levels and subjective symptoms. Effectiveness will be measured by changes in measurements of blood and urine markers of bone turnover.
Detailed Description

Parathyroid Hormone-related Protein (1-36) or PTHrP is a neuroendocrine peptide which shares significant homology with the only currently FDA approved anabolic agent for the treatment of osteoporosis: parathyroid hormone(1-34) or PTH. PTH, when given alone, has shown to increase lumbar spine bone mass by 12-15% over a 2-3 year period.

Previous studies indicate PTHrP may have a pure anabolic effect on bone. Postmenopausal women taking estrogen with osteoporosis who received daily subcutaneous PTHrP for 3 months exhibited a 4.7% increase in bone mineral density compared to those taking placebo. There were no side effects associated with PTHrP, despite the fact that the doses given were 20 times the usual doses of PTH. In another study, young healthy volunteers received a single, one-time subcutaneous doses of PTHrP in amounts up to 2 mg without any dose limiting toxicities.

This study will directly compare the effect of placebo and escalating doses of PTHrP given subcutaneously to postmenopausal women for three weeks. Each subject will have four outpatient visits and one inpatient 24-hour visit on the last day. 20 women in phase I will receive either placebo or 500 micrograms/day of PTHrP. 500 micrograms/day was selected as the lowest dose because it is similar to the dose used in our previous 3 month placebo controlled study. In Phase II, the doses of PTHrP will be increased in increments of approximately 30% for each successive group, i.e., 750, 1000, 1250, and 1500 micrograms. After the first group of 10 successfully receives 500 micrograms/day for 21 days, increased doses will be given to groups of three subjects until evidence of dose limiting toxicity (DLT) occurs, or a maximum dose of 1,500 micrograms is reached. Dose limiting toxicities are specified in the protocol and comprise either one major criteria: hypotension, orthostatic hypotension, tachycardia, hypertension, hypercalcemia or hypophosphatemia; or two minor criteria: flushing, nausea/vomiting, abdominal or muscle cramps, dizziness/lightheadedness, palpitations, or any other unpleasant subjective symptom.

If a particular dose of PTHrP causes a dose-limiting toxicity, the immediately preceding lower dose will be defined as the maximum safely tolerated dose. Once the maximum safely tolerated dose is determined, it will be given to a total of ten healthy subjects to ensure that is is safe and well tolerated.

Study methods include outpatient visits on days 1, 5, 10, 15, and an in-patient visit on day 21 for lab collection and patient examination. Blood and urine safety labs consist of serum ionized calcium, total calcium, creatinine, phosphorus and albumin. Efficacy labs consist of urine and blood measurements of 25-hydroxy vitamin D, 1,25 vitamin D, PTH, osteocalcin, bone specific alkaline phosphatase, procollagen peptide-1, C-telopeptide (CTx), N-telopeptide (NTx), Insulin-like growth factors (IgF) and serum free deoxypyridinoline (DPD).

Subject population includes up to 48 healthy 50-75 year old postmenopausal women who are Caucasian, Asian, and Hispanic. African-Americans are excluded from the study since it is well documented that African-Americans have clear quantitative differences in bone density and sensitivity to parathyroid hormone. No bone densitometry scans are done during this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Osteoporosis
  • Osteoporosis, Postmenopausal
Intervention  ICMJE
  • Drug: Parathyroid Hormone-related Protein
    PTHrP(1-36) starting at 500 micrograms, then increasing by 125 micrograms up to a maximum of 1,500 micrograms.
    Other Name: study drug
  • Drug: Placebo
    Placebo drug via subcutaneous injection in single blinded fashion daily for 3 weeks
    Other Name: Placebo group
Study Arms  ICMJE
  • Active Comparator: 1 - PTHrP Group
    Group receiving study drug: PTHrP(1-36)
    Intervention: Drug: Parathyroid Hormone-related Protein
  • Placebo Comparator: 2 - Single Blind Placebo Group
    Receives placebo injections daily via subcutaneous injection
    Intervention: Drug: Placebo
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: November 4, 2008)
61
Original Enrollment  ICMJE
 (submitted: September 19, 2005)
48
Actual Study Completion Date  ICMJE September 2008
Actual Primary Completion Date September 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Women
  • Caucasian
  • Hispanic
  • Asian
  • One year past onset of menopause
  • Weigh between 50 and 90 kilograms

Exclusion Criteria:

  • Taking bisphosphonates in the last 2 years
  • Estrogen replacement hormones in last year
  • SERMS in last year
  • One weeks worth of PTHrP, PTH or an analog of PTH in past year
  • Recent non-traumatic bone fracture within last year
  • Significant uncontrolled cardiac, vascular, renal, pulmonary, endocrine or rheumatologic disease
  • History of malignancy
  • Anemia
  • Significant alcohol or drug abuse
  • Receiving any investigational drug within past 90 days
  • Medications that interfere with metabolism or renal clearance of study drug, oral or systemic glucocorticoids of > 5 mg/day prednisone (or equivalent) over the past year
  • Thiazide-type diuretics
  • Abnormal screening labs (calcium, vit D and PTH, CBC)
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 50 Years to 75 Years   (Adult, Older 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 NCT00222872
Other Study ID Numbers  ICMJE IRB # 0503166
NIH RO - DK 51081
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mara Horwitz, University of Pittsburgh
Study Sponsor  ICMJE University of Pittsburgh
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • Department of Health and Human Services
Investigators  ICMJE
Principal Investigator: Mara J. Horwitz, M.D. University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date April 2014

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