CompletedNCT00580788Updated Feb 11, 2016Results posted

One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study

An Early Phase 1 interventional study of PTHrP (1-36) in Osteoporosis, Humoral Hypercalcemia of Malignancy and Hyperparathyroidism, sponsored by University of Pittsburgh. Completed at 1 site in United States. Open to participants aged 24 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2016-02-11.

Sponsored by University of Pittsburgh · Early Phase 1 and Interventional

Phase: Early Phase 1
Study type: Interventional
Enrollment: 14
Allocation: Non-randomized
Ages: 24 Years to 35 Years
Sex: All

Study summary

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.

Read the detailed description

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.

Conditions studied

Osteoporosis
Humoral Hypercalcemia of Malignancy
Hyperparathyroidism

Browse trials for

Keywords

Endocrine System Diseases
MusculoSkeletal System Diseases
Hormones
Malignancy
Postmenopausal Women
Bone metabolism

Who can participate

Ages eligible: 24 Years to 35 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Healthy caucasian subjects of both sexes between the ages of 24-35 years, who are able to spend one week on the Clinical \& Translational Research Center at the University of Pittsburgh Medical Center (UPMC) Montefiore

Exclusion criteria

Exclusion Criteria:

Pregnancy
Any cardiac, renal, pulmonary, endocrine, musculoskeletal, hepatic, hematological, malignant or rheumatologic diseases
Body mass index great than 30
Anemia
Significant alcohol or drug abuse
Baseline hypotension or hypertension
Abnormal screening labs
Use of certain chronic medications excluding oral contraceptives
Receiving an investigational drug in the last 90 days
Previously receiving PTH or PTHrP
African-American race

Study design

Phase: Early Phase 1
Allocation: Non-randomized
Intervention model: Single group
Masking: Single (Participant)
Enrollment: 14 participants (actual)

Study arms

Experimental
PTHrP(1-36) 2 pmol/kg/hr
PTHrP(1-36) at 2 picomoles/kg/hr for one week.
Drug: PTHrP (1-36)
Experimental
PTHrP (1-36) 4 pmol/kg/hr
PTHrP(1-36) at 4 picomoles/kg/hr for one week.
Drug: PTHrP (1-36)
Experimental
PTHrP(1-36) 5 pmol/kg/hr
PTHrP(1-36) at 5 picomoles/kg/hr for one week.
Drug: PTHrP (1-36)
Experimental
PTHrP(1-36) 6 pmol/kg/hr
PTHrP(1-36) at 6 picomoles/kg/hr for one week.
Drug: PTHrP (1-36)

Interventions

DrugPTHrP (1-36)
IND # 49,175
Also known as: Parathyroid Hormone-related Protein (1-36)

What researchers measure

Primary outcomes

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.
Time frame: 12 hours after the infusion was started then q 8 hours for 7 days
Total Serum Calcium
mg/dl
Time frame: 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
Time frame: 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
Time frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete

Secondary outcomes

1,25 Vitamin D
pg/ml
Time frame: 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
Time frame: 24 hours
Tubular Maximum of Phosphorous (TmP/GFR)
mg/dl calculated from daily second morning void
Time frame: daily
Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Amino-terminal Peptides of Procollagen 1 (P1NP)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Bone Specific Alkaline Phosphatase (BSAP)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Parathyroid Hormone (1-84)
pg/ml
Time frame: Baseline and Daily
Fractional Excretion of Calcium
% calculated from daily second morning void
Time frame: daily

Results

Posted Feb 11, 2016

Limitations and caveats

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

Participant flow

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.

Participant flow — Overall Study
Milestone	Group 1	Group 2	Group 3	Group 4
Started	3	6	3	2
Completed	3	6	3	1
Not completed	0	0	0	1
Withdrew: Adverse event	0	0	0	1

Outcome measures

PrimaryDose 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.

Time frame:: 12 hours after the infusion was started then q 8 hours for 7 days
Reported as:: Number · participants

Dose Limiting Toxicity (DLT)
participants	Group 1	Group 2	Group 3	Group 4
Dose Limiting Toxicity (DLT)	0	0	2	2

Secondary1,25 Vitamin D

pg/ml

Time frame:: Baseline and Daily through day 8 then at follow-up visit
Reported as:: Mean · pg/ml

1,25 Vitamin D
pg/ml	Group 1	Group 2	Group 3	Group 4
baseline	34.13 ± 3.03	45.08 ± 4.24	39.0 ± 4.09	—
Day 2	38.40 ± 5.12	45.88 ± 1.53	39.77 ± 2.69	—
Day 3	30.13 ± 4.57	36.58 ± 4.17	36.73 ± 2.75	—
Day 4	32.23 ± 2.32	40.38 ± 4.18	35.17 ± 2.63	—
Day 5	32.27 ± 1.80	46.40 ± 6.12	32.07 ± 3.79	—
Day 6	42.77 ± 4.23	34.90 ± 4.91	35.37 ± 2.98	—
Day 7	40.53 ± 4.38	37.12 ± 3.58	31.17 ± 6.84	—
Day 8	32.37 ± 3.17	33.43 ± 3.13	30.63 ± 4.79	—
follow-up	40.10 ± 4.01	45.78 ± 4.72	36.33 ± 2.11	—

Statistical analysis

Group 1 vs Group 3 · Mixed Models Analysis · p = >0.05 (The reported p-value corresponds to change over time for the PTHrP 2 and PTHrP 5 pmol groups)The level of statistical significance was set at .05 (two-tailed)
Group 2 · Mixed Models Analysis · p = 0.01 (the reported p value corresponds to a decrease by Day 8 compared to baseline in the PTHrP 4 pmol group)The level of statistical significance was set at .05 (two-tailed)

Secondary24 Hour Urine Calcium

mg/gm creatinine collected on day 7 of PTHrP infusion

Time frame:: 24 hours
Reported as:: Mean · mg/gm creatinine

24 Hour Urine Calcium
mg/gm creatinine	Group 1	Group 2	Group 3	Group 4
24 Hour Urine Calcium	121.64 ± 9.87	283.43 ± 30.93	320.23 ± 41.32	—

SecondaryTubular Maximum of Phosphorous (TmP/GFR)

mg/dl calculated from daily second morning void

Time frame:: daily
Reported as:: Mean · mg/dl

Tubular Maximum of Phosphorous (TmP/GFR)
mg/dl	Group 1	Group 2	Group 3	Group 4
Baseline	3.43 ± 0.26	3.91 ± 0.23	3.38 ± 0.35	—
Day 2	4.48 ± 0.20	4.08 ± 0.23	3.47 ± 0.46	—
Day 3	4.28 ± 0.30	3.74 ± 0.26	3.25 ± 0.50	—
Day 4	4.42 ± 0.31	3.75 ± 0.31	3.15 ± 0.45	—
Day 5	4.43 ± 0.02	3.95 ± 0.34	3.37 ± 0.45	—
Day 6	4.90 ± 0.08	3.98 ± 0.11	3.38 ± 0.35	—
Day 7	4.15 ± 0.08	3.98 ± 0.19	2.95 ± 0.28	—

Statistical analysis

Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = 0.61 (The reported p-value corresponds to all Arms/Groups at all time points compared to baseline)The level of statistical significance was set at .05 (two-tailed)

PrimaryTotal Serum Calcium

mg/dl

Time frame:: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
Reported as:: Mean · mg/dl

Total Serum Calcium
mg/dl	Group 1	Group 2	Group 3	Group 4
baseline	9.37 ± 0.07	9.58 ± 0.12	9.2 ± 0.25	—
11P DAY 1	9.67 ± 0.09	9.80 ± 0.16	9.67 ± 0.20	—
7A DAY 2	9.4 ± 0.17	10.05 ± 0.19	10.17 ± 0.20	—
3P DAY 2	9.57 ± 0.09	10.28 ± 0.14	10.47 ± 0.30	—
11P DAY 2	9.67 ± 0.09	10.32 ± 0.14	10.23 ± 0.26	—
7A DAY 3	9.6 ± 0.10	10.40 ± 0.18	10.73 ± 0.57	—
3P DAY 3	9.73 ± 0.09	10.42 ± 0.14	10.67 ± 0.27	—
11P DAY 3	9.40 ± 0.17	9.73 ± 0.10	9.93 ± 0.38	—
7A DAY 4	9.47 ± 0.03	10.00 ± 0.24	10.3 ± 0.23	—
3P DAY 4	9.40 ± 0.17	9.92 ± 0.21	10.33 ± 0.34	—
11P DAY 4	9.37 ± 0.09	9.48 ± 0.11	10.00 ± 0.15	—
7A DAY 5	9.30 ± 0.12	9.62 ± 0.12	10.53 ± 0.15	—
3P DAY 5	9.50 ± 0.15	9.83 ± 0.20	10.27 ± 0.44	—
11P DAY 5	9.43 ± 0.09	9.45 ± 0.13	9.80 ± 0.20	—
7A DAY 6	9.57 ± 0.07	9.83 ± 0.20	10.53 ± 0.22	—
3P DAY 6	9.43 ± 0.15	10.08 ± 0.12	10.83 ± 0.27	—
11P DAY 6	9.43 ± 0.13	9.67 ± 0.21	10.43 ± 0.47	—
7A DAY 7	9.40 ± 0.10	10.13 ± 0.28	10.90 ± 0.46	—
3P DAY 7	9.70 ± 0.15	10.22 ± 0.32	10.70 ± 0.46	—
11P DAY 7	9.60 ± 0.15	10.27 ± 0.28	10.73 ± 0.50	—
7A DAY 8	9.83 ± 0.13	10.67 ± 0.40	11.17 ± 0.35	—
FOLLOW-UP	9.33 ± 0.07	9.80 ± 0.12	9.17 ± 0.24	—

Statistical analysis

Group 2 · Mixed Models Analysis · p = <0.0001 (The reported p-value corresponds to the increase over time for the PTHrP 4 pmol group.)Value The level of statistical significance was set at .05 (two-tailed)

PrimaryIonized Serum Calcium

mg/dl

Time frame:: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
Reported as:: Mean · mg/dl

Ionized Serum Calcium
mg/dl	Group 1	Group 2	Group 3	Group 4
baseline	4.79 ± 0.03	4.72 ± 0.08	4.55 ± 0.15	—
11P DAY 1	4.51 ± 0.05	4.77 ± 0.08	4.75 ± 0.04	—
7A DAY 2	4.77 ± 0.07	4.98 ± 0.10	5.07 ± 0.07	—
3P DAY 2	4.52 ± 0.02	4.99 ± 0.06	5.07 ± 0.06	—
11P DAY 2	4.48 ± 0.08	5.04 ± 0.07	4.84 ± 0.00	—
7A DAY 3	4.77 ± 0.15	5.31 ± 0.08	5.25 ± 0.13	—
3P DAY 3	4.73 ± 0.11	4.99 ± 0.10	4.91 ± 0.16	—
11P DAY 3	4.41 ± 0.15	4.58 ± 0.15	4.83 ± 0.14	—
7A DAY 4	4.75 ± 0.14	4.90 ± 0.13	5.11 ± 0.09	—
3P DAY 4	4.45 ± 0.16	4.68 ± 0.14	4.72 ± 0.17	—
11P DAY 4	4.47 ± 0.07	4.46 ± 0.12	4.69 ± 0.06	—
7A DAY 5	4.71 ± 0.07	4.82 ± 0.09	4.97 ± 0.12	—
3P DAY 5	4.61 ± 0.20	4.67 ± 0.12	4.87 ± 0.40	—
11P DAY 5	4.60 ± 0.13	4.58 ± 0.07	4.79 ± 0.09	—
7A DAY 6	4.63 ± 0.03	4.77 ± 0.10	5.25 ± 0.09	—
3P DAY 6	4.72 ± 0.13	4.83 ± 0.07	5.35 ± 0.03	—
11P DAY 6	4.32 ± 0.06	4.72 ± 0.09	5.19 ± 0.21	—
7A DAY 7	4.55 ± 0.22	5.01 ± 0.09	5.55 ± 0.27	—
3P DAY 7	4.84 ± 0.16	5.04 ± 0.17	5.25 ± 0.31	—
11P DAY 7	4.56 ± 0.12	4.87 ± 0.19	5.24 ± 0.02	—
7A DAY 8	5.00 ± 0.11	5.43 ± 0.18	5.69 ± 0.10	—
FOLLOW-UP	4.68 ± 0.08	4.83 ± 0.05	4.80 ± 0.06	—

Statistical analysis

Group 2 · Mixed Models Analysis · p = <0.0001 (The reported p-value corresponds to the increase over time for the PTHrP 4 pmol group.)The level of statistical significance was set at .05 (two-tailed)

PrimarySerum Phosphorous

mg/dl

Time frame:: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
Reported as:: Mean · mg/dl

Serum Phosphorous
mg/dl	Group 1	Group 2	Group 3	Group 4
baseline	3.55 ± 0.15	3.63 ± 0.14	3.55 ± 0.45	—
11P DAY 1	3.87 ± 0.26	3.90 ± 0.16	4.03 ± 0.12	—
7A DAY 2	4.07 ± 0.15	4.20 ± 0.15	3.63 ± 0.44	—
3P DAY 2	3.63 ± 0.33	3.50 ± 0.23	3.70 ± 0.20	—
11P DAY 2	4.13 ± 0.29	3.52 ± 0.19	3.63 ± 0.19	—
7A DAY 3	3.90 ± 0.26	3.77 ± 0.19	3.43 ± 0.39	—
3P DAY 3	3.53 ± 0.24	3.53 ± 0.18	3.60 ± 0.23	—
11P DAY 3	4.03 ± 0.26	3.58 ± 0.17	3.70 ± 0.15	—
7A DAY 4	4.07 ± 0.22	3.90 ± 0.13	3.30 ± 0.40	—
3P DAY 4	3.90 ± 0.10	3.37 ± 0.20	3.33 ± 0.32	—
11P DAY 4	3.67 ± 0.28	3.48 ± 0.14	3.63 ± 0.27	—
7A DAY 5	3.87 ± 0.19	4.02 ± 0.14	3.20 ± 0.30	—
3P DAY 5	3.57 ± 0.29	3.35 ± 0.20	3.10 ± 0.21	—
11P DAY 5	3.93 ± 0.23	3.45 ± 0.20	3.87 ± 0.32	—
7A DAY 6	4.00 ± 0.06	4.00 ± 0.10	3.63 ± 0.35	—
3P DAY 6	3.67 ± 0.03	3.80 ± 0.14	3.73 ± 0.19	—
11P DAY 6	3.93 ± 0.18	3.90 ± 0.10	3.93 ± 0.09	—
7A DAY 7	4.30 ± 0.10	4.28 ± 0.12	3.73 ± 0.38	—
3P DAY 7	4.07 ± 0.09	3.62 ± 0.20	3.50 ± 0.20	—
11P DAY 7	4.20 ± 0.26	3.62 ± 0.19	3.60 ± 0.30	—
7A DAY 8	4.43 ± 0.15	4.10 ± 0.10	3.40 ± 0.23	—
FOLLOW-UP	3.57 ± 0.38	3.48 ± 0.26	3.87 ± 0.09	—

Statistical analysis

Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = >.05 (The reported p-value corresponds to change over time from baseline for all Arms/groups)The level of statistical significance was set at .05 (two-tailed)

SecondarySerum Amino-terminal Telopeptide of Collagen -1 (sNTX)

% change from baseline

Time frame:: Baseline, Daily, and 1 week follow-up
Reported as:: Mean · % change

Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)
% change	Group 1	Group 2	Group 3	Group 4
baseline	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	—
Day 2	32.86 ± 23.41	87.75 ± 18.79	54.21 ± 10.64	—
Day 3	26.73 ± 23.19	91.53 ± 28.94	88.51 ± 19.99	—
Day 4	28.32 ± 20.26	90.86 ± 32.25	89.57 ± 20.22	—
Day 5	41.29 ± 20.06	82.36 ± 20.62	116.58 ± 13.85	—
Day 6	11.41 ± 12.63	123.08 ± 28.62	150.82 ± 48.26	—
Day 7	35.04 ± 21.44	161.55 ± 41.54	176.42 ± 50.08	—
Day 8	65.77 ± 30.43	214.90 ± 59.26	108.69 ± 34.29	—
follow-up	-14.95 ± 2.97	-3.33 ± 6.68	-9.02 ± 7.19	—

Statistical analysis

Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = <.008 (The reported p-value corresponds to the % increase compared to baseline in all Arms/groups on Days 2-8.)The level of statistical significance was set at .05 (two-tailed)
Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = >0.05 (The reported p-value corresponds the the % change from baseline at follow-up in all Arms/groups)The level of statistical significance was set at .05 (two-tailed)

SecondarySerum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)

% change from baseline

Time frame:: Baseline, Daily, and 1 week follow-up
Reported as:: Mean · % change

Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)
% change	Group 1	Group 2	Group 3	Group 4
baseline	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	—
Day 2	59.78 ± 18.14	147.12 ± 40.72	105.06 ± 11.54	—
Day 3	66.67 ± 32.24	180.27 ± 44.45	148.45 ± 36.80	—
Day 4	71.19 ± 18.88	167.01 ± 47.01	165.16 ± 40.29	—
Day 5	79.39 ± 23.89	167.27 ± 25.30	174.58 ± 47.26	—
Day 6	74.09 ± 26.72	239.51 ± 49.42	230.42 ± 54.10	—
Day 7	109.27 ± 29.39	283.15 ± 65.65	267.89 ± 104.52	—
Day 8	110.61 ± 30.92	368.31 ± 93.63	140.58 ± 78.58	—
follow-up	-35.73 ± 11.53	-8.60 ± 11.15	-41.33 ± 20.38	—

Statistical analysis

Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = <.0001 (The reported p-value corresponds to % change (increase) from baseline in all Arms/groups at Days 2-8.)The level of statistical significance was set at .05 (two-tailed)
Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = >0.05 (The reported p-value corresponds to the % change from baseline at follow-up in all Arms/groups)The level of statistical significance was set at .05 (two-tailed)

SecondaryAmino-terminal Peptides of Procollagen 1 (P1NP)

% change from baseline

Time frame:: Baseline, Daily, and 1 week follow-up
Reported as:: Mean · % change

Amino-terminal Peptides of Procollagen 1 (P1NP)
% change	Group 1	Group 2	Group 3	Group 4
baseline	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	—
Day 2	-1.05 ± 4.95	-17.49 ± 5.93	-23.88 ± 6.05	—
Day 3	-6.83 ± 2.78	-30.44 ± 7.10	-37.77 ± 6.56	—
Day 4	-12.16 ± 0.57	-25.66 ± 9.55	-39.44 ± 4.46	—
Day 5	-5.63 ± 2.27	-21.27 ± 8.01	-45.04 ± 3.07	—
Day 6	-8.42 ± 5.07	-31.71 ± 7.50	-39.55 ± 1.75	—
Day 7	-12.59 ± 6.17	-30.98 ± 8.87	-39.88 ± 2.78	—
Day 8	-16.03 ± 5.03	-36.60 ± 9.64	-38.53 ± 3.40	—
follow-up	-7.12 ± 2.29	0.60 ± 9.58	46.67 ± 17.34	—

Statistical analysis

Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = <.0001 (the reported p-value corresponds to % decrease compared to baseline at Days 2-8 in all Arms/groups)The level of statistical significance was set at .05 (two-tailed)
Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = 0.01 (the reported p-value corresponds to % change from baseline at the follow-up visit in all Arms/groups)The level of statistical significance was set at .05 (two-tailed)

SecondaryBone Specific Alkaline Phosphatase (BSAP)

% change from baseline

Time frame:: Baseline, Daily, and 1 week follow-up
Reported as:: Mean · % change

Bone Specific Alkaline Phosphatase (BSAP)
% change	Group 1	Group 2	Group 3	Group 4
baseline	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	—
Day 2	-12.53 ± 8.60	-1.17 ± 4.10	24.54 ± 7.01	—
Day 3	-6.35 ± 4.84	-1.44 ± 3.07	34.77 ± 6.53	—
Day 4	-5.82 ± 1.58	-3.79 ± 4.65	19.49 ± 8.23	—
Day 5	-0.33 ± 0.33	-9.64 ± 4.73	13.61 ± 9.76	—
Day 6	-8.16 ± 9.32	-10.88 ± 4.04	9.02 ± 8.94	—
Day 7	-11.91 ± 10.38	-16.78 ± 2.58	9.86 ± 4.01	—
Day 8	-7.80 ± 8.66	-14.01 ± 3.72	15.27 ± 11.63	—
follow-up	-1.25 ± 2.70	6.16 ± 3.81	18.23 ± 2.22	—

Statistical analysis

Group 2 · Mixed Models Analysis · p = 0.001 (the reported p-value correspond to the decrease compared to baseline over time in the PTHrP 4 pmol group.)The level of statistical significance was set at .05 (two-tailed)
Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = .01 (the reported p=value corresponds to % change compared to baseline at follow-up in all Arms/groups)The level of statistical significance was set at .05 (two-tailed)

SecondaryParathyroid Hormone (1-84)

pg/ml

Time frame:: Baseline and Daily
Reported as:: Mean · pg/ml

Parathyroid Hormone (1-84)
pg/ml	Group 1	Group 2	Group 3	Group 4
baseline	42.97 ± 2.86	30.70 ± 5.56	48.27 ± 15.93	—
Day 2	23.47 ± 1.48	7.82 ± 1.50	3.60 ± 0.50	—
Day 3	21.43 ± 3.65	5.23 ± 1.75	3.00 ± 0.00	—
Day 4	26.77 ± 3.24	7.88 ± 3.21	3.00 ± 0.00	—
Day 5	22.37 ± 5.10	7.54 ± 1.80	3.00 ± 0.00	—
Day 6	21.13 ± 5.88	6.57 ± 2.24	3.00 ± 0.00	—
Day 7	19.40 ± 4.03	5.67 ± 1.20	3.00 ± 0.00	—
Day 8	12.60 ± 3.58	3.00 ± 0.00	3.00 ± 0.00	—
follow-up	56.37 ± 5.18	31.60 ± 2.63	44.20 ± 10.87	—

Statistical analysis

Group 1 vs Group 2 vs Group 3 · Mixed Models Analysis · p = <0.05 (the reported p-values correspond to the decrease compared to baseline in all arms/groups at Days 2-8)The level of statistical significance was set at .05 (two-tailed)

SecondaryFractional Excretion of Calcium

% calculated from daily second morning void

Time frame:: daily
Reported as:: Mean · % of filtered load

Fractional Excretion of Calcium
% of filtered load	Group 1	Group 2	Group 3	Group 4
Baseline	1.93 ± 0.91	2.57 ± 0.73	2.38 ± 0.59	—
Day 2	1.31 ± 0.59	2.26 ± 0.46	4.11 ± 2.42	—
Day 3	1.07 ± 0.51	2.85 ± 0.61	3.27 ± 0.45	—
Day 4	1.57 ± 0.25	2.79 ± 0.76	2.14 ± 0.40	—
Day 5	3.05 ± 0.70	2.05 ± 0.46	3.12 ± 0.46	—
Day 6	3.37 ± 0.67	2.75 ± 0.25	5.42 ± 2.23	—
Day 7	2.72 ± 0.28	3.94 ± 0.38	4.13 ± 0.73	—

Statistical analysis

Group 2 · Mixed Models Analysis · p = .002 (the reported p-value corresponds to the increase comapred to baseline over time (days 2-8) in the PTHrP 4 pmol group)The level of statistical significance was set at .05 (two-tailed)

Adverse events

Collected over Subjects were systematically assessed every 8 hours for adverse events. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Group 1	—	0/3 (0%)	0/3 (0%)
Group 2	—	0/6 (0%)	0/6 (0%)
Group 3	—	0/3 (0%)	1/3 (33.3%)
Group 4	—	0/2 (0%)	2/2 (100%)

Most frequent other events

Most frequent other events
Event	Group 1	Group 2	Group 3	Group 4
hypercalcemiaEndocrine disorders	0/3	0/6	1/3	1/2
hypertensionEndocrine disorders	0/3	0/6	0/3	1/2
tachycardiaEndocrine disorders	0/3	0/6	0/3	1/2
migraineEndocrine disorders	0/3	0/6	1/3	0/2
lightheadedEndocrine disorders	0/3	0/6	1/3	0/2

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Group 1	Group 2	Group 3	Group 4	Total
<=18 years	0	0	0	0	0
Between 18 and 65 years	3	6	3	2	14
>=65 years	0	0	0	0	0

Sex: Female, Male
Sex: Female, Male(Participants)	Group 1	Group 2	Group 3	Group 4	Total
Female	2	3	2	0	7
Male	1	3	1	2	7

Region of Enrollment
Region of Enrollment(participants)	Group 1	Group 2	Group 3	Group 4	Total
United States	3	6	3	2	14

Study locations

1 site

University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania 15213, United States

References and documents

Publications

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. PubMed 1658941 ↗
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. PubMed 2539369 ↗
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. PubMed 1327716 ↗
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. PubMed 8156938 ↗
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. PubMed 8345044 ↗
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. PubMed 7769133 ↗
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. PubMed 14638923 ↗
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. PubMed 8855835 ↗
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. PubMed 8288713 ↗
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. PubMed 7593443 ↗
el-Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA. 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. PubMed 8989274 ↗
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. PubMed 7775469 ↗
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. PubMed 12679445 ↗
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. PubMed 11297578 ↗
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. PubMed 8550752 ↗
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. PubMed 1322424 ↗
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. PubMed 16160737 ↗
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. PubMed 16151606 ↗
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. PubMed 9709948 ↗
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. PubMed 3339131 ↗
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. PubMed 3584110 ↗
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. PubMed 3619898 ↗
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. PubMed 8798692 ↗
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. Erratum In: Ann Intern Med 1994 Apr 15;120(8):698. PubMed 8430979 ↗
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. PubMed 8450043 ↗
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. PubMed 12538599 ↗
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. PubMed 21544866 ↗

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT00580788
Lead sponsor: University of Pittsburgh
Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Responsible party: Mara Horwitz (Associate Professor of Medicne, University of Pittsburgh) — Principal investigator
First posted: Dec 27, 2007
Start date: Jan 2008
Primary completion: Dec 2009
Completion: Dec 2009
Results posted: Feb 11, 2016
Last update: Feb 11, 2016

Study contacts

Mara J Horwitz, MD

principal investigator · University of Pittsburgh

Oversight

Data monitoring committee: Yes

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One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study

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