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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Three Week Dose Escalation Study of PTHrP(1-36) in Postmenopausal Women

Conditions
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Osteoporosis, Osteoporosis, Postmenopausal

Intervention / Treatment
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* Drug: Parathyroid Hormone-related Protein
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 - PTHrP Group<br>Group receiving study drug: PTHrP(1-36) | Drug: Parathyroid Hormone-related Protein<br>* PTHrP(1-36) starting at 500 micrograms, then increasing by 125 micrograms up to a maximum of 1,500 micrograms.<br>* Other names: study drug;|
| Placebo Comparator: 2 - Single Blind Placebo Group<br>Receives placebo injections daily via subcutaneous injection | Drug: Placebo<br>* Placebo drug via subcutaneous injection in single blinded fashion daily for 3 weeks<br>* Other names: Placebo group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects will receive PTHrP without Dose Limiting Toxicity Events as established by safety parameters consisting of one major criteria or two minor criteria. |  | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | 3 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endocrine System Diseases, MusculoSkeletal System Diseases, Hormone, Postmenopausal Women