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

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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

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.

Condition or disease Intervention/treatment Phase
Osteoporosis Osteoporosis, Postmenopausal Drug: Parathyroid Hormone-related Protein Drug: Placebo Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 61 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: A Three Week Dose Escalation Study of PTHrP(1-36) in Postmenopausal Women
Study Start Date : July 2005
Actual Primary Completion Date : September 2008
Actual Study Completion Date : September 2008

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 1 - PTHrP Group
Group receiving study drug: PTHrP(1-36)
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

Placebo Comparator: 2 - Single Blind Placebo Group
Receives placebo injections daily via subcutaneous injection
Drug: Placebo
Placebo drug via subcutaneous injection in single blinded fashion daily for 3 weeks
Other Name: Placebo group




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00222872


Locations
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United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pittsburgh
National Institutes of Health (NIH)
Department of Health and Human Services
Investigators
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Principal Investigator: Mara J. Horwitz, M.D. University of Pittsburgh

Additional Information:
Publications:

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Responsible Party: Mara Horwitz, Associate Professor of Medicne, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT00222872     History of Changes
Other Study ID Numbers: IRB # 0503166
NIH RO - DK 51081
First Posted: September 22, 2005    Key Record Dates
Last Update Posted: April 28, 2014
Last Verified: April 2014
Keywords provided by Mara Horwitz, University of Pittsburgh:
Endocrine System Diseases
MusculoSkeletal System Diseases
Hormone
Postmenopausal Women
Additional relevant MeSH terms:
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Osteoporosis
Osteoporosis, Postmenopausal
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Hormones
Parathyroid Hormone
Parathyroid Hormone-Related Protein
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Calcium-Regulating Hormones and Agents