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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK073039 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, that can be given safely over one week. The investigators plan to infuse low doses of intravenous PTHrP to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrp on markers of bone turnover, and plasma 1,25 (OH)2 vitamin D regulation in healthy human volunteers.
During this research the investigators administer PTHrP to healthy young volunteers in a controlled, continuous intravenous manner. As research subjects complete the week-long study without adverse effects, the dose of PThrP will be increased in later subjects. In the event of a significant adverse effect, immediate action will be taken to reverse it. The investigators want to estimate the effect of a sustainable level of mild hypercalcemia achieved by a week-long intravenous infusion of PTHrP has on vitamin D metabolism, markers of bone turnover and fractional excretion of calcium.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PTHrP(1-36) 2 pmol/kg/hr | Experimental | PTHrP(1-36) at 2 picomoles/kg/hr for one week. |
|
| PTHrP (1-36) 4 pmol/kg/hr | Experimental | PTHrP(1-36) at 4 picomoles/kg/hr for one week. |
|
| PTHrP(1-36) 5 pmol/kg/hr | Experimental | PTHrP(1-36) at 5 picomoles/kg/hr for one week. |
|
| PTHrP(1-36) 6 pmol/kg/hr | Experimental | PTHrP(1-36) at 6 picomoles/kg/hr for one week. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PTHrP (1-36) | Drug | IND # 49,175 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose Limiting Toxicity (DLT) | 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. | 12 hours after the infusion was started then q 8 hours for 7 days |
| Total Serum Calcium | mg/dl | 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete |
| Ionized Serum Calcium | mg/dl | 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete |
| Serum Phosphorous | mg/dl | 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete |
| Measure | Description | Time Frame |
|---|---|---|
| 1,25 Vitamin D | pg/ml | Baseline and Daily through day 8 then at follow-up visit |
| 24 Hour Urine Calcium | mg/gm creatinine collected on day 7 of PTHrP infusion |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mara J Horwitz, MD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 1658941 | Background | Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991 Nov 15;254(5034):1024-6. doi: 10.1126/science.1658941. | |
| 2539369 | Background | Orloff JJ, Wu TL, Heath HW, Brady TG, Brines ML, Stewart AF. Characterization of canine renal receptors for the parathyroid hormone-like protein associated with humoral hypercalcemia of malignancy. J Biol Chem. 1989 Apr 15;264(11):6097-103. |
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24 subjects were screened and 14 were randomized in the study. Data from 2 subjects was not included in the analysis as there were not enough subjects in that group for analysis. 12 subjects were analyzed.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1 | PTHrP(1-36) 2 picomoles/kg/hr |
| FG001 | Group 2 | PTHrP(1-36) 4 picomoles/kg/hr |
| FG002 | Group 3 | PTHrP (1-36) 5 pmol/kg/hr |
| FG003 | Group 4 | PTHrP (1-36) 6 picomoles/kg/hr |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1 | PTHrP(1-36) 2 picomoles/kg/hr for one week. |
| BG001 | Group 2 | PTHrP(1-36) 4 picomoles/kg/hr for one week. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dose Limiting Toxicity (DLT) | 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. | Posted | Number | participants | 12 hours after the infusion was started then q 8 hours for 7 days |
|
Subjects were systematically assessed every 8 hours for adverse events
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group 1 | PTHrP(1-36) 2 picomoles/kg/hr for one week. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| hypercalcemia | Endocrine disorders | Systematic Assessment |
Small number of subjects in each group Study limited to Caucasians Only one timepoint for follow-up was measure Study did not include saline infused controls
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mara J Horwitz, MD | University of Pittsburgh | 4126922848 | horwitz@pitt.edu |
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| ID | Term |
|---|---|
| D010024 | Osteoporosis |
| C562390 | Humoral Hypercalcemia Of Malignancy |
| D006961 | Hyperparathyroidism |
| D004700 | Endocrine System Diseases |
| D009140 | Musculoskeletal Diseases |
| D009369 | Neoplasms |
| ID | Term |
|---|---|
| D001851 | Bone Diseases, Metabolic |
| D001847 | Bone Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C079957 | parathyroid hormone-related peptide (1-36) |
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|
| 24 hours |
| Tubular Maximum of Phosphorous (TmP/GFR) | mg/dl calculated from daily second morning void | daily |
| Serum Amino-terminal Telopeptide of Collagen -1 (sNTX) | % change from baseline | Baseline, Daily, and 1 week follow-up |
| Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX) | % change from baseline | Baseline, Daily, and 1 week follow-up |
| Amino-terminal Peptides of Procollagen 1 (P1NP) | % change from baseline | Baseline, Daily, and 1 week follow-up |
| Bone Specific Alkaline Phosphatase (BSAP) | % change from baseline | Baseline, Daily, and 1 week follow-up |
| Parathyroid Hormone (1-84) | pg/ml | Baseline and Daily |
| Fractional Excretion of Calcium | % calculated from daily second morning void | daily |
| 1327716 | Background | Orloff JJ, Ribaudo AE, McKee RL, Rosenblatt M, Stewart AF. A pharmacological comparison of parathyroid hormone receptors in human bone and kidney. Endocrinology. 1992 Oct;131(4):1603-11. doi: 10.1210/endo.131.4.1327716. |
| 8156938 | Background | Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF. Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev. 1994 Feb;15(1):40-60. doi: 10.1210/edrv-15-1-40. |
| 8345044 | Background | Samuels MH, Veldhuis J, Cawley C, Urban RJ, Luther M, Bauer R, Mundy G. Pulsatile secretion of parathyroid hormone in normal young subjects: assessment by deconvolution analysis. J Clin Endocrinol Metab. 1993 Aug;77(2):399-403. doi: 10.1210/jcem.77.2.8345044. |
| 7769133 | Background | Prank K, Nowlan SJ, Harms HM, Kloppstech M, Brabant G, Hesch RD, Sejnowski TJ. Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls. J Clin Invest. 1995 Jun;95(6):2910-9. doi: 10.1172/JCI117998. |
| 14638923 | Background | Schmitt CP, Obry J, Feneberg R, Veldhuis JD, Mehls O, Ritz E, Schaefer F. Beta1-adrenergic blockade augments pulsatile PTH secretion in humans. J Am Soc Nephrol. 2003 Dec;14(12):3245-50. doi: 10.1097/01.asn.0000101240.47747.7f. |
| 8855835 | Background | Chapotot F, Gronfier C, Spiegel K, Luthringer R, Brandenberger G. Relationships between intact parathyroid hormone 24-hour profiles, sleep-wake cycle, and sleep electroencephalographic activity in man. J Clin Endocrinol Metab. 1996 Oct;81(10):3759-65. doi: 10.1210/jcem.81.10.8855835. |
| 8288713 | Background | Harms HM, Schlinke E, Neubauer O, Kayser C, Wustermann PR, Horn R, Kulpmann WR, von zur Muhlen A, Hesch RD. Pulse amplitude and frequency modulation of parathyroid hormone in primary hyperparathyroidism. J Clin Endocrinol Metab. 1994 Jan;78(1):53-7. doi: 10.1210/jcem.78.1.8288713. |
| 7593443 | Background | Ledger GA, Burritt MF, Kao PC, O'Fallon WM, Riggs BL, Khosla S. Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. J Clin Endocrinol Metab. 1995 Nov;80(11):3304-10. doi: 10.1210/jcem.80.11.7593443. |
| 8989274 | Background | el-Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA; New Collective Author. The parathyroid hormone circadian rhythm is truly endogenous--a general clinical research center study. J Clin Endocrinol Metab. 1997 Jan;82(1):281-6. doi: 10.1210/jcem.82.1.3683. |
| 7775469 | Background | Plawner LL, Philbrick WM, Burtis WJ, Broadus AE, Stewart AF. Cell type-specific secretion of parathyroid hormone-related protein via the regulated versus the constitutive secretory pathway. J Biol Chem. 1995 Jun 9;270(23):14078-84. doi: 10.1074/jbc.270.23.14078. |
| 12679445 | Background | Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocana A, Stewart AF. Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers. J Clin Endocrinol Metab. 2003 Apr;88(4):1603-9. doi: 10.1210/jc.2002-020773. |
| 11297578 | Background | Syed MA, Horwitz MJ, Tedesco MB, Garcia-Ocana A, Wisniewski SR, Stewart AF. Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy. J Clin Endocrinol Metab. 2001 Apr;86(4):1525-31. doi: 10.1210/jcem.86.4.7406. |
| 8550752 | Background | Everhart-Caye M, Inzucchi SE, Guinness-Henry J, Mitnick MA, Stewart AF. Parathyroid hormone (PTH)-related protein(1-36) is equipotent to PTH(1-34) in humans. J Clin Endocrinol Metab. 1996 Jan;81(1):199-208. doi: 10.1210/jcem.81.1.8550752. |
| 1322424 | Background | Fraher LJ, Hodsman AB, Jonas K, Saunders D, Rose CI, Henderson JE, Hendy GN, Goltzman D. A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man. J Clin Endocrinol Metab. 1992 Aug;75(2):417-23. doi: 10.1210/jcem.75.2.1322424. |
| 16160737 | Background | Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocana A, Bisello A, Hollis BW, Rosen CJ, Wysolmerski JJ, Dann P, Gundberg C, Stewart AF. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. J Bone Miner Res. 2005 Oct;20(10):1792-803. doi: 10.1359/JBMR.050602. Epub 2005 Jun 6. |
| 16151606 | Background | Horwitz MJ, Tedesco MB, Sereika SM, Garcia-Ocana A, Bisello A, Hollis BW, Gundberg C, Stewart AF. Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study. Osteoporos Int. 2006 Feb;17(2):225-30. doi: 10.1007/s00198-005-1976-3. Epub 2005 Sep 7. |
| 9709948 | Background | Plotkin H, Gundberg C, Mitnick M, Stewart AF. Dissociation of bone formation from resorption during 2-week treatment with human parathyroid hormone-related peptide-(1-36) in humans: potential as an anabolic therapy for osteoporosis. J Clin Endocrinol Metab. 1998 Aug;83(8):2786-91. doi: 10.1210/jcem.83.8.5047. |
| 3339131 | Background | Stewart AF, Mangin M, Wu T, Goumas D, Insogna KL, Burtis WJ, Broadus AE. Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats. J Clin Invest. 1988 Feb;81(2):596-600. doi: 10.1172/JCI113358. |
| 3584110 | Background | Burtis WJ, Wu T, Bunch C, Wysolmerski JJ, Insogna KL, Weir EC, Broadus AE, Stewart AF. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151-6. |
| 3619898 | Background | Stewart AF, Wu T, Goumas D, Burtis WJ, Broadus AE. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987 Jul 31;146(2):672-8. doi: 10.1016/0006-291x(87)90581-x. |
| 8798692 | Background | Wu TL, Vasavada RC, Yang K, Massfelder T, Ganz M, Abbas SK, Care AD, Stewart AF. Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem. 1996 Oct 4;271(40):24371-81. doi: 10.1074/jbc.271.40.24371. |
| 8430979 | Background | Cosman F, Shen V, Xie F, Seibel M, Ratcliffe A, Lindsay R. Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers. Ann Intern Med. 1993 Mar 1;118(5):337-43. doi: 10.7326/0003-4819-118-5-199303010-00003. |
| 8450043 | Background | Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM. An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis. J Clin Invest. 1993 Mar;91(3):1138-48. doi: 10.1172/JCI116273. |
| 12538599 | Background | Fiaschi-Taesch NM, Stewart AF. Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences. Endocrinology. 2003 Feb;144(2):407-11. doi: 10.1210/en.2002-220818. |
| 21544866 | Derived | Horwitz MJ, Tedesco MB, Sereika SM, Prebehala L, Gundberg CM, Hollis BW, Bisello A, Garcia-Ocana A, Carneiro RM, Stewart AF. A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover. J Bone Miner Res. 2011 Sep;26(9):2287-97. doi: 10.1002/jbmr.415. |
| BG002 |
| Group 3 |
PTHrP(1-36) 5 picomoles/kg/hr for one week. |
| BG003 | Group 4 | PTHrP(1-36) 6 picomoles/kg/hr for one week. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
PTHrP(1-36) 4 picomoles/kg/hr for one week
| OG002 | Group 3 | PTHrP(1-36) 5 picomoles/kg/hr for one week |
| OG003 | Group 4 | PTHrP(1-36) 6 picomoles/kg/hr for one week |
|
|
| Secondary | 1,25 Vitamin D | pg/ml | Posted | Mean | Standard Error | pg/ml | Baseline and Daily through day 8 then at follow-up visit |
|
|
|
|
| Secondary | 24 Hour Urine Calcium | mg/gm creatinine collected on day 7 of PTHrP infusion | Posted | Mean | Standard Error | mg/gm creatinine | 24 hours |
|
|
|
| Secondary | Tubular Maximum of Phosphorous (TmP/GFR) | mg/dl calculated from daily second morning void | Posted | Mean | Standard Error | mg/dl | daily |
|
|
|
|
| Primary | Total Serum Calcium | mg/dl | Posted | Mean | Standard Error | mg/dl | 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete |
|
|
|
|
| Primary | Ionized Serum Calcium | mg/dl | Posted | Mean | Standard Error | mg/dl | 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete |
|
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|
|
| Primary | Serum Phosphorous | mg/dl | Posted | Mean | Standard Error | mg/dl | 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete |
|
|
|
|
| Secondary | Serum Amino-terminal Telopeptide of Collagen -1 (sNTX) | % change from baseline | Posted | Mean | Standard Error | % change | Baseline, Daily, and 1 week follow-up |
|
|
|
|
| Secondary | Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX) | % change from baseline | Posted | Mean | Standard Error | % change | Baseline, Daily, and 1 week follow-up |
|
|
|
|
| Secondary | Amino-terminal Peptides of Procollagen 1 (P1NP) | % change from baseline | Posted | Mean | Standard Error | % change | Baseline, Daily, and 1 week follow-up |
|
|
|
|
| Secondary | Bone Specific Alkaline Phosphatase (BSAP) | % change from baseline | Posted | Mean | Standard Error | % change | Baseline, Daily, and 1 week follow-up |
|
|
|
|
| Secondary | Parathyroid Hormone (1-84) | pg/ml | Posted | Mean | Standard Error | pg/ml | Baseline and Daily |
|
|
|
|
| Secondary | Fractional Excretion of Calcium | % calculated from daily second morning void | Posted | Mean | Standard Error | % of filtered load | daily |
|
|
|
|
| 0 |
| 3 |
| 0 |
| 3 |
| EG001 | Group 2 | PTHrP(1-36) 4 picomoles/kg/hr for one week. | 0 | 6 | 0 | 6 |
| EG002 | Group 3 | PTHrP(1-36) 5 picomoles/kg/hr for one week. | 0 | 3 | 1 | 3 |
| EG003 | Group 4 | PTHrP(1-36) 6 picomoles/kg/hr for one week. | 0 | 2 | 2 | 2 |
| hypertension | Endocrine disorders | Systematic Assessment |
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| migraine | Endocrine disorders | Systematic Assessment |
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| lightheaded | Endocrine disorders | Systematic Assessment |
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| tachycardia | Endocrine disorders | Systematic Assessment |
|
Not provided
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| D010279 | Parathyroid Diseases |
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| Day 3 |
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| Day 4 |
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| Day 5 |
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| Day 6 |
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| Day 7 |
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| Day 8 |
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| follow-up |
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| Mixed Models Analysis | The level of statistical significance was set at .05 (two-tailed) | 0.01 | the reported p value corresponds to a decrease by Day 8 compared to baseline in the PTHrP 4 pmol group | 2-Sided | Yes | Non-Inferiority or Equivalence | The study was designed as a standard dose-escalation study, dose-finding pilot study. The primary outcome measures were safety (hypercalcemia, hypophosphatemia and symptoms/hemodynamic measurements). A modified Fibronacci dose-escalation scheme was employed. |
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| Day 3 |
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| Day 6 |
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| Day 7 |
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| 7A DAY 2 |
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| FOLLOW-UP |
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| 7A DAY 6 |
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| 11P DAY 6 |
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| 7A DAY 7 |
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| 3P DAY 7 |
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| 7A DAY 8 |
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| FOLLOW-UP |
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| 7A DAY 2 |
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| 7A DAY 6 |
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| 7A DAY 7 |
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| 7A DAY 8 |
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| FOLLOW-UP |
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| Day 3 |
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| Day 4 |
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| Day 5 |
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| Day 6 |
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| Day 7 |
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| Day 8 |
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| follow-up |
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| Mixed Models Analysis | The level of statistical significance was set at .05 (two-tailed) | >0.05 | The reported p-value corresponds the the % change from baseline at follow-up in all Arms/groups | 2-Sided | Yes | Non-Inferiority or Equivalence | The study was designed as a standard dose-escalation study, dose-finding pilot study. The primary outcome measures were safety (hypercalcemia, hypophosphatemia and symptoms/hemodynamic measurements). A modified Fibronacci dose-escalation scheme was employed. |
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| Day 3 |
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| Day 4 |
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| Day 5 |
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| Day 6 |
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| Day 7 |
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| Day 8 |
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| follow-up |
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| Mixed Models Analysis | The level of statistical significance was set at .05 (two-tailed) | >0.05 | The reported p-value corresponds to the % change from baseline at follow-up in all Arms/groups | 2-Sided | Yes | Non-Inferiority or Equivalence | The study was designed as a standard dose-escalation study, dose-finding pilot study. The primary outcome measures were safety (hypercalcemia, hypophosphatemia and symptoms/hemodynamic measurements). A modified Fibronacci dose-escalation scheme was employed. |
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| Day 3 |
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| Day 4 |
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| Day 5 |
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| Day 6 |
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| Day 7 |
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| Day 8 |
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| follow-up |
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| Mixed Models Analysis | The level of statistical significance was set at .05 (two-tailed) | 0.01 | the reported p-value corresponds to % change from baseline at the follow-up visit in all Arms/groups | 2-Sided | Yes | Non-Inferiority or Equivalence | The study was designed as a standard dose-escalation study, dose-finding pilot study. The primary outcome measures were safety (hypercalcemia, hypophosphatemia and symptoms/hemodynamic measurements). A modified Fibronacci dose-escalation scheme was employed. |
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| Day 3 |
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| Day 4 |
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| Day 5 |
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| Day 6 |
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| Day 7 |
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| Day 8 |
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| follow-up |
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| Mixed Models Analysis | The level of statistical significance was set at .05 (two-tailed) | .01 | the reported p=value corresponds to % change compared to baseline at follow-up in all Arms/groups | 2-Sided | Yes | Non-Inferiority or Equivalence | The study was designed as a standard dose-escalation study, dose-finding pilot study. The primary outcome measures were safety (hypercalcemia, hypophosphatemia and symptoms/hemodynamic measurements). A modified Fibronacci dose-escalation scheme was employed. |
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| Day 3 |
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| Day 8 |
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| follow-up |
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| Day 5 |
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| Day 6 |
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| Day 7 |
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