Hypoparathyroidism
Conditions
Brief summary
This study is being conducted to characterize the effects of twice daily administration of rhPTH(1-84) on the way the body handles rhPTH(1-84) as well as its actions and safety and tolerability over the course of 24 hours as compared with the current once daily dosing regimen of marketed rhPTH(1-84) (marketed in the United States as Natpara® and in the EU as Natpar).
Interventions
DRUG25mcg rhPTH(1-84)
Participants will receive rhPTH(1-84) as twice-daily regimen (12 hours apart) of two 25mcg doses without calcium in cohort 1 and with calcium in cohort 3.
DRUG50mcg rhPTH(1-84)
Participants will receive rhPTH(1-84) as twice daily regimen (12 hours apart) of two 50mcg doses without calcium in cohort 2 and with calcium in cohort 4
DRUG100mcg rhPTH(1-84)
Participants will receive rhPTH(1-84) as once-daily regimen of one 100 mcg dose without calcium in cohort 1 and 2 and with calcium in cohort 3 and 4 in the morning.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. An understanding, ability, and willingness to fully comply with study procedures and restrictions. 2. Ability to voluntarily provide written, signed, and dated informed consent as applicable to participate in the study. 3. Adult men or women aged greater than or equal (\>=) 18 years at the time of consent. The date of participant signature of the informed consent is defined as the beginning of the Screening Period. The Screening Period for this study may encompass both the Administrative Screening Period (if needed) and the Clinical Screening Period. For purposes of this inclusion criterion, age will only be assessed at the time the informed consent is first signed by the study participant. 4. History of hypoparathyroidism for \>=12 months, post-diagnosis, inclusive of historical biochemical evidence of hypocalcemia with concomitant serum intact parathyroid hormone (PTH) concentrations below the lower limit of the laboratory normal range. 5. Requirement for supplemental oral calcium treatment \>=1000 milligrams (mg) elemental calcium per day. 6. Requirement for therapy with active forms of vitamin D at a minimum dose of \>=0.25 microgram (mcg) per day (that is, \>=0.25 mcg calcitriol or equivalent per day). 7. Serum calcium level within the laboratory normal reference range based on clinical chemistry lab results at the Clinical Screening Visit (based on central and/or local lab results) and Treatment Period 1, Day -2 (based on central and/or local lab results), or if outside of normal range, considered not clinically significant by the investigator. 8. Urinary calcium excretion \>=200mg (5 millimolar \[mmol\])/24 hour (h), based on a 24-hour collection, collected anytime during the Clinical Screening Period, but prior to check-in to the Clinical Research Center (CRC) at Treatment Period 1, Day -2 (based on central and/or local lab results). 9. Serum magnesium level within the laboratory normal range at the Clinical Screening Visit or, if outside of normal range, considered not clinically significant by the investigator. 10. Serum thyroid function tests within normal laboratory limits at the Clinical Screening Visit, or, if outside of normal range, considered as not clinically significant by the investigator. 11. Serum 25-hydroxyvitamin D (25(OH)D) level between the lower limit of normal and 1.5-fold the laboratory upper limit of normal, or, if outside of this range, considered not clinically significant by the investigator, at the Clinical Screening Visit. 12. Serum creatinine less than (\<) 1.5 mg/ decilitre (dL) (\<133 micromole \[mmol\]/ litre \[L\]) AND estimated creatinine clearance greater than (\>) 60 millilitre (mL)/minute (\>1.002mL/ Second \[s\]) at the Clinical Screening Visit, and serum creatinine \<1.5 mg/dL (\<133mmol/L) at Treatment Period 1, Day -2. 13. Male or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive requirements of the protocol or females of non-childbearing potential.
Exclusion criteria
1. Participation in any other investigational drug study in which the last dose of investigational drug occurred within 3 months prior to Day 1 of Treatment Period 1 (or within 5 half-lives, if elimination half-life is greater than 18 days). 2. Presence or history of a clinically significant disorder involving the cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine (with exception of the condition under study), or neurologic system(s) or psychiatric disease as determined by the investigator. 3. Known history of hypoparathyroidism resulting from an activation mutation in the calcium sensing receptor (CaSR) gene or impaired responsiveness to PTH (pseudohypoparathyroidism). 4. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism, including but not limited to, active hyperthyroidism; poorly controlled insulin-dependent diabetes mellitus or type 2 diabetes mellitus; severe and chronic cardiac, liver or renal disease; Cushing's syndrome; neuromuscular disease such as rheumatoid arthritis; myeloma; pancreatitis; malnutrition; rickets; recent prolonged immobility; active malignancy, bone metastases or a history of skeletal malignancies; primary or secondary hyperparathyroidism; a history of parathyroid carcinoma; hypopituitarism, acromegaly; or multiple endocrine neoplasia types 1 and 2, as determined by the investigator. 5 . In male and female rats, parathyroid hormone caused an increase in the incidence of osteosarcoma (a malignant bone tumor). The occurrence of osteosarcoma was dependent on parathyroid hormone dose and treatment duration. This effect was observed at parathyroid hormone exposure levels ranging from 3 to 71 times the exposure levels in humans receiving a 100 mcg dose of rhPTH(1-84). Therefore, participant who are at increased baseline risk for osteosarcoma such as participant with Paget's disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult participants with open epiphyses, participants with hereditary disorders predisposing to osteosarcoma or participant with a prior history of external beam or implant radiation therapy involving the skeleton are excluded. 6\. Participants who have a known history of hypercalcemia during initiation of treatment with PTH, PTH analogues or fragments of PTH. 7\. Participants who have a known history of hypocalcemia following abrupt withdrawal of treatment with PTH, PTH analogues or fragments of PTH. 8\. Participant dependent on regular parenteral calcium infusions (example, calcium gluconate) to maintain calcium homeostasis within 3 months prior to enrollment, as determined by the investigator. 9\. Use of the following medications prior to administration of investigational product within: 14 days- thiazide diuretics; 30 days - loop diuretics, lithium, systemic corticosteroids (medical judgment is required by the investigator. Primarily high doses of systemic corticosteroids \[example, prednisone\] should be excluded. Stable doses of hydrocortisone \[example, as treatment for Addison's disease\] may be acceptable); 3 months - calcitonin, cinacalcet hydrochloride, treatment with rhPTH(1-84) or N-terminal PTH or PTH-related peptide fragments or analogs; For females: changes in hormone replacement therapy within 3 months are excluded. Stable (\>=3 months) hormone replacement therapy is acceptable; 6 months - fluoride tablets, oral bisphosphonates, methotrexate, growth hormone, digoxin, raloxifene or similar selective estrogen receptor modulators (SERMs); 12 months - intravenous bisphosphonates, drug or alcohol abuse, as determined by the investigator. 10\. Presence of any clinically significant results from laboratory tests, vital signs assessments, or electrocardiograms (ECGs), as judged by the investigator. 11\. Twelve-lead ECG values (average of triplicate readings) demonstrating QTc\>450 millisecond (msec) (males) or \>470 msec (females) at the Clinical Screening Visit and/or any time points up to and including predose of Day 1 (Period 1). 12\. Any medical condition or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for this study. 13\. Positive test result for any of the following viral infections at the Clinical Screening Visit: Hepatitis B surface antigen; hepatitis C; human immunodeficiency virus (HIV) 14. Known significant bleeding diathesis that could preclude multiple venipunctures as determined by the investigator. 15\. Participants who have donated a total of 100 mL to 499 mL of whole blood within 30 days prior to dosing, or participants who have donated a total of more than 499 mL of whole blood within 56 days prior to dosing. 16\. A positive screen for drugs of abuse at the Clinical Screening Visit, and/or a positive screen for drugs of abuse and alcohol at check-in to the CRC at Treatment Period 1. Participants taking prescription medications that might be detected during the urine screen for drugs of abuse may be enrolled per the investigator's medical judgment. 17\. History of a clinically significant illness during the 4 weeks prior to dosing (as determined by the investigator). 18\. History of any clinically significant surgery or procedure within the past 8 weeks, as determined by the investigator. 19\. History of an allergic response(s) to PTH or PTH analogs, or other clinically significant allergies, as determined by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose | Total urinary excretion of calcium over 24 hours by Day1/Day 2 was reported. |
| Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose ; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. Tmax of baseline adjusted rhPTH(1-84) was reported. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure. |
| Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. Cmax of baseline adjusted rhPTH(1-84) was reported. |
| Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUClast of baseline adjsuted plasma rhPTH(1-84) was reported. |
| Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUCinf of baseline adjusted rhPTH(1-84) was reported. |
| Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUC0-24 of baseline adjusted rhPTH(1-84) was reported. |
| Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84) | BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUC0-12 of baseline adjusted rhPTH(1-84) was reported. AUC(0-12) was planned, analyzed and reported only in participants who received BID treatment ( Treatment A, Treatment C, Treatment D, Treatment F). |
| Area Under the Concentration Curve From Time of the Second Dose to 12 Hours Post the Second Dose (AUC12-24) of Baseline Adjusted rhPTH(1-84) | BID: 12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUC12-24 of baseline adjusted rhPTH(1-84) was reported. AUC(12-24) was planned, analyzed and reported only in participants who received BID treatment ( Treatment A, Treatment C, Treatment D, Treatment F). |
| Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose | Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. T1/2 of baseline adjusted rhPTH(1-84) was reported. |
| Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Day -1 | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCabove of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 was reported. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure. |
| Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Day -1 | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCbelow of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 was reported. |
| Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Day -1 | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. TEmax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 were reported. |
| Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Day -1 | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. Emax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 were reported. |
| Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCabove of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 were reported. |
| Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCbelow of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 was reported. |
| Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. TEmax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 were reported. |
| Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose | Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. Emax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 were reported. |
| Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | Day -1 | Total amount of urinary calcium excretion to total relative amount of creatinine over 24 hours by Day -1 was reported. |
| Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose | Total amount of urinary calcium excretion to total relative amount of creatinine over 24 hours by Day 1/ Day 2 was reported. |
| Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | Day -1 | Total urinary excretion of calcium over 24 Hours by Day -1 was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAE's) | From signing of informed consent up to follow up (up to Day 182) | An AE that occured during the study was considered a TEAE if it had a start date/time on or after the first dose of investigational product or if it had a start date before the date of the first dose of investigational product, but increased in severity on or after the date/time of the first dose of investigational product. Number of participants with TEAE's were reported. |
Countries
Canada, Denmark, Hungary, United States
Participant flow
Recruitment details
This study was conducted in North America and Europe between 04 March 2017 (first participant first visit) to 08 March 2019 (last participant last visit).
Pre-assignment details
A total of 34 participants were enrolled and 33 completed the study. The study consisted of two treatment periods (Treatment period I and II) with four cohorts. Cohort I included Sequence AB and BA. Cohort II included Sequence CB and BC. Cohort III included Sequence DE and ED, Cohort IV included Sequence FE and EF.
Participants by arm
| Arm | Count |
|---|---|
| Cohort I: Treatment A/B or Treatment B/A Participants received either 25 mcg rhPTH(1-84) BID with no calcium for treatment period 1 and 100 mcg rhPTH(1-84) QD with no calcium for treatment period 2; or 100 mcg rhPTH(1-84) QD with no calcium for treatment period 1 and 25 mcg rhPTH(1-84) BID with no calcium for treatment period 2 in the morning of Day 1 of respective treatment periods. The 2 treatment periods were separated by a washout period of \> or = 5 days but \< or = 30 days between the administration of rhPTH(1-84) or the first administration of rhPTH(1-84) in each period for QD or BID dosing, respectively. | 9 |
| Cohort II: Treatment C/B or Treatment B/C Participants received either 50 mcg rhPTH(1-84) BID with no calcium for treatment period 1 and 100 mcg rhPTH(1-84) QD with no calcium for treatment period 2; or 100 mcg rhPTH(1-84) QD with no calcium for treatment period 1 and 50 mcg rhPTH(1-84) BID with no calcium for treatment period 2 in the morning of Day 1 of respective treatment periods. The 2 treatment periods were separated by a washout period of \> or = 5 days but \< or = 30 days between the administration of rhPTH(1-84) or the first administration of rhPTH(1-84) in each period for QD or BID dosing, respectively. | 8 |
| Cohort III: Treatment D/E or Treatment E/D Participants received either 25 mcg rhPTH(1-84) BID with calcium for treatment period 1 and 100 mcg rhPTH(1-84) QD with calcium for treatment period 2; or 100 mcg rhPTH(1-84) QD with calcium for treatment period 1 and 25 mcg rhPTH(1-84) BID with calcium for treatment period 2 in the morning of Day 1 of respective treatment periods. The 2 treatment periods were separated by a washout period of \> or = 5 days but \< or = 30 days between the administration of rhPTH(1-84) or the first administration of rhPTH(1-84) in each period for QD or BID dosing, respectively. | 9 |
| Cohort IV: Treatment F/E or Treatment E/F Participants receive either 50 mcg rhPTH(1-84) BID with calcium for treatment period 1 and 100 mcg rhPTH(1-84) QD with calcium for treatment period 2; or 100 mcg rhPTH(1-84) QD with calcium for treatment period 1 and 50 mcg rhPTH(1-84) BID with calcium for treatment period 2 in the morning of Day 1 of respective treatment periods. The 2 treatment periods were separated by a washout period of \> or = 5 days but \< or = 30 days between the administration of rhPTH(1-84) or the first administration of rhPTH(1-84) in each period for QD or BID dosing, respectively. | 8 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort I: Treatment A/B or Treatment B/A | Cohort II: Treatment C/B or Treatment B/C | Cohort III: Treatment D/E or Treatment E/D | Cohort IV: Treatment F/E or Treatment E/F | Total |
|---|---|---|---|---|---|
| Age, Continuous | 42.6 Years STANDARD_DEVIATION 9.06 | 48.9 Years STANDARD_DEVIATION 13.48 | 52.4 Years STANDARD_DEVIATION 13.31 | 45.8 Years STANDARD_DEVIATION 9.02 | 47.4 Years STANDARD_DEVIATION 11.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 8 Participants | 9 Participants | 8 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 32 Participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 8 Participants | 7 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 8 | 0 / 17 | 0 / 8 | 0 / 8 | 0 / 17 |
| other Total, other adverse events | 3 / 9 | 1 / 8 | 4 / 17 | 5 / 8 | 3 / 8 | 7 / 17 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 | 0 / 17 | 0 / 8 | 0 / 8 | 0 / 17 |
Outcome results
Primary
Area Under the Concentration Curve From Time of the Second Dose to 12 Hours Post the Second Dose (AUC12-24) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUC12-24 of baseline adjusted rhPTH(1-84) was reported. AUC(12-24) was planned, analyzed and reported only in participants who received BID treatment ( Treatment A, Treatment C, Treatment D, Treatment F).
Time frame: BID: 12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration Curve From Time of the Second Dose to 12 Hours Post the Second Dose (AUC12-24) of Baseline Adjusted rhPTH(1-84) | 479.0 h*pg/mL | Geometric Coefficient of Variation 33.3 |
| Cohort II: Treatment C | Area Under the Concentration Curve From Time of the Second Dose to 12 Hours Post the Second Dose (AUC12-24) of Baseline Adjusted rhPTH(1-84) | 679.5 h*pg/mL | Geometric Coefficient of Variation 25.5 |
| Cohort I+II: Treatment B | Area Under the Concentration Curve From Time of the Second Dose to 12 Hours Post the Second Dose (AUC12-24) of Baseline Adjusted rhPTH(1-84) | 245.2 h*pg/mL | Geometric Coefficient of Variation 93.5 |
| Cohort III: Treatment D | Area Under the Concentration Curve From Time of the Second Dose to 12 Hours Post the Second Dose (AUC12-24) of Baseline Adjusted rhPTH(1-84) | 323.2 h*pg/mL | Geometric Coefficient of Variation 71.7 |
Primary
Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUC0-12 of baseline adjusted rhPTH(1-84) was reported. AUC(0-12) was planned, analyzed and reported only in participants who received BID treatment ( Treatment A, Treatment C, Treatment D, Treatment F).
Time frame: BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84) | 462.1 h*pg/mL | Geometric Coefficient of Variation 29.9 |
| Cohort II: Treatment C | Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84) | 665.2 h*pg/mL | Geometric Coefficient of Variation 42.3 |
| Cohort I+II: Treatment B | Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84) | 298.8 h*pg/mL | Geometric Coefficient of Variation 113.9 |
| Cohort III: Treatment D | Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84) | 220.2 h*pg/mL | Geometric Coefficient of Variation 354.7 |
Primary
Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUC0-24 of baseline adjusted rhPTH(1-84) was reported.
Time frame: QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | 944.6 h*pg/mL | Geometric Coefficient of Variation 29.9 |
| Cohort II: Treatment C | Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | 1357.6 h*pg/mL | Geometric Coefficient of Variation 31.3 |
| Cohort I+II: Treatment B | Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | 973.7 h*pg/mL | Geometric Coefficient of Variation 334.6 |
| Cohort III: Treatment D | Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | 577.6 h*pg/mL | Geometric Coefficient of Variation 94.3 |
| Cohort IV: Treatment F | Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | 606.3 h*pg/mL | Geometric Coefficient of Variation 135.3 |
| Cohort III + IV: Treatment E | Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) | 1106.8 h*pg/mL | Geometric Coefficient of Variation 59.3 |
Primary
Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCabove of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 was reported. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
Time frame: Day -1
Population: Pharmacodynamic (PD) analysis set consisted of all enrolled participants who did not have major protocol violations that affected the validity of the PD results, received at least 1 dose of rhPTH(1 84) and had at least 1 evaluable post-dose PD value available for 1 dose regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 2.714 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.5038 |
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 2.672 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.828 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 1.189 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.5482 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 1.190 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.3884 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.701 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 0.9478 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.616 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 0.8793 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.802 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 0.7234 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.934 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 0.792 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 1.470 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.7843 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 1.890 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.793 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.791 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 0.8162 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 1.162 hour*millimoles per Liter (h*mmol/L) | Standard Deviation 1.2725 |
Primary
Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCabove of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 were reported.
Time frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 1.222 h*mmol/L | Standard Deviation 1.2757 |
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 1.060 h*mmol/L | Standard Deviation 1.0398 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 1.084 h*mmol/L | Standard Deviation 0.8887 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.715 h*mmol/L | Standard Deviation 0.5001 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 1.645 h*mmol/L | Standard Deviation 1.1038 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 1.769 h*mmol/L | Standard Deviation 1.3569 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 2.860 h*mmol/L | Standard Deviation 4.1108 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 3.259 h*mmol/L | Standard Deviation 4.6635 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 1.468 h*mmol/L | Standard Deviation 1.5533 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 1.540 h*mmol/L | Standard Deviation 1.6227 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 2.610 h*mmol/L | Standard Deviation 1.552 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Above the Baseline, From Time 0 to 24 Hours (AUCabove) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 2.456 h*mmol/L | Standard Deviation 1.4576 |
Primary
Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCbelow of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 was reported.
Time frame: Day -1
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.283 h*mmol/L | Standard Deviation 0.5173 |
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.238 h*mmol/L | Standard Deviation 0.4379 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.380 h*mmol/L | Standard Deviation 0.3621 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.394 h*mmol/L | Standard Deviation 0.3259 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 1.291 h*mmol/L | Standard Deviation 1.8883 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 1.570 h*mmol/L | Standard Deviation 1.9043 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.637 h*mmol/L | Standard Deviation 1.0314 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.639 h*mmol/L | Standard Deviation 0.9601 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.434 h*mmol/L | Standard Deviation 0.6786 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.515 h*mmol/L | Standard Deviation 0.6182 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.816 h*mmol/L | Standard Deviation 0.9874 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.998 h*mmol/L | Standard Deviation 1.3267 |
Primary
Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. AUCbelow of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 was reported.
Time frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (Albumin-Corrected) | 1.085 h*mmol/L | Standard Deviation 1.1804 |
| Cohort I: Treatment A | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.944 h*mmol/L | Standard Deviation 1.1352 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (Albumin-Corrected) | 0.393 h*mmol/L | Standard Deviation 0.632 |
| Cohort II: Treatment C | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.362 h*mmol/L | Standard Deviation 0.3115 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (Albumin-Corrected) | 0.197 h*mmol/L | Standard Deviation 0.294 |
| Cohort I+II: Treatment B | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.320 h*mmol/L | Standard Deviation 0.5456 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (Albumin-Corrected) | 0.309 h*mmol/L | Standard Deviation 0.5883 |
| Cohort III: Treatment D | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.273 h*mmol/L | Standard Deviation 0.4174 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (Albumin-Corrected) | 0.548 h*mmol/L | Standard Deviation 0.6416 |
| Cohort IV: Treatment F | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.601 h*mmol/L | Standard Deviation 0.6863 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (Albumin-Corrected) | 0.316 h*mmol/L | Standard Deviation 0.5706 |
| Cohort III + IV: Treatment E | Area Under the Concentration-Time Curve That is Below the Baseline, From Time 0 to 24 Hours (AUCbelow) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.437 h*mmol/L | Standard Deviation 0.787 |
Primary
Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUCinf of baseline adjusted rhPTH(1-84) was reported.
Time frame: QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure and at specific category.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | 484.8 h*pg/mL | Geometric Coefficient of Variation 48.4 |
| Cohort II: Treatment C | Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | 677.7 h*pg/mL | Geometric Coefficient of Variation 22.9 |
| Cohort I+II: Treatment B | Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | 1567.6 h*pg/mL | Geometric Coefficient of Variation 36.7 |
| Cohort III: Treatment D | Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | 255.0 h*pg/mL | Geometric Coefficient of Variation 198.3 |
| Cohort IV: Treatment F | Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | 600.8 h*pg/mL | — |
| Cohort III + IV: Treatment E | Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) | 1043.5 h*pg/mL | Geometric Coefficient of Variation 50.4 |
Primary
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. AUClast of baseline adjsuted plasma rhPTH(1-84) was reported.
Time frame: QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure and at specific category.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | 496.0 hour*picogram per milliliter (h*pg/mL) | Geometric Coefficient of Variation 34.1 |
| Cohort II: Treatment C | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | 653.2 hour*picogram per milliliter (h*pg/mL) | Geometric Coefficient of Variation 25.5 |
| Cohort I+II: Treatment B | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | 901.1 hour*picogram per milliliter (h*pg/mL) | Geometric Coefficient of Variation 448.5 |
| Cohort III: Treatment D | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | 205.0 hour*picogram per milliliter (h*pg/mL) | Geometric Coefficient of Variation 106.6 |
| Cohort IV: Treatment F | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | 261.1 hour*picogram per milliliter (h*pg/mL) | Geometric Coefficient of Variation 77.6 |
| Cohort III + IV: Treatment E | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) | 1044.9 hour*picogram per milliliter (h*pg/mL) | Geometric Coefficient of Variation 58 |
Primary
Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. Emax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 were reported.
Time frame: Day -1
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: Treatment A | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.284 millimoles/Liter (mmol/L) | Standard Deviation 0.1495 |
| Cohort I: Treatment A | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.273 millimoles/Liter (mmol/L) | Standard Deviation 0.1874 |
| Cohort II: Treatment C | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.110 millimoles/Liter (mmol/L) | Standard Deviation 0.1098 |
| Cohort II: Treatment C | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.116 millimoles/Liter (mmol/L) | Standard Deviation 0.1066 |
| Cohort I+II: Treatment B | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.102 millimoles/Liter (mmol/L) | Standard Deviation 0.0892 |
| Cohort I+II: Treatment B | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.100 millimoles/Liter (mmol/L) | Standard Deviation 0.0921 |
| Cohort III: Treatment D | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.098 millimoles/Liter (mmol/L) | Standard Deviation 0.0539 |
| Cohort III: Treatment D | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.121 millimoles/Liter (mmol/L) | Standard Deviation 0.069 |
| Cohort IV: Treatment F | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.148 millimoles/Liter (mmol/L) | Standard Deviation 0.1398 |
| Cohort IV: Treatment F | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.197 millimoles/Liter (mmol/L) | Standard Deviation 0.1465 |
| Cohort III + IV: Treatment E | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 0.107 millimoles/Liter (mmol/L) | Standard Deviation 0.0783 |
| Cohort III + IV: Treatment E | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 0.127 millimoles/Liter (mmol/L) | Standard Deviation 0.0947 |
Primary
Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. Emax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 were reported.
Time frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: Treatment A | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 0.146 mmol/L | Standard Deviation 0.1031 |
| Cohort I: Treatment A | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.139 mmol/L | Standard Deviation 0.1029 |
| Cohort II: Treatment C | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 0.120 mmol/L | Standard Deviation 0.0746 |
| Cohort II: Treatment C | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.103 mmol/L | Standard Deviation 0.0489 |
| Cohort I+II: Treatment B | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 0.173 mmol/L | Standard Deviation 0.0825 |
| Cohort I+II: Treatment B | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.183 mmol/L | Standard Deviation 0.0993 |
| Cohort III: Treatment D | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 0.205 mmol/L | Standard Deviation 0.1999 |
| Cohort III: Treatment D | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.243 mmol/L | Standard Deviation 0.2247 |
| Cohort IV: Treatment F | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 0.160 mmol/L | Standard Deviation 0.0994 |
| Cohort IV: Treatment F | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.183 mmol/L | Standard Deviation 0.0873 |
| Cohort III + IV: Treatment E | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 0.216 mmol/L | Standard Deviation 0.1252 |
| Cohort III + IV: Treatment E | Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 0.207 mmol/L | Standard Deviation 0.1025 |
Primary
Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. Cmax of baseline adjusted rhPTH(1-84) was reported.
Time frame: QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | 136.9 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 50.9 |
| Cohort II: Treatment C | Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | 213.6 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 51.6 |
| Cohort I+II: Treatment B | Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | 339.1 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 137.8 |
| Cohort III: Treatment D | Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | 120.9 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 83.6 |
| Cohort IV: Treatment F | Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | 100.5 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 106.2 |
| Cohort III + IV: Treatment E | Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) | 240.8 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 69.6 |
Primary
Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. T1/2 of baseline adjusted rhPTH(1-84) was reported.
Time frame: QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose
Population: PK analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure and at specific category.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | 1.739 hours | Geometric Coefficient of Variation 39.461 |
| Cohort II: Treatment C | Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | 2.073 hours | Geometric Coefficient of Variation 38.704 |
| Cohort I+II: Treatment B | Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | 1.973 hours | Geometric Coefficient of Variation 42.421 |
| Cohort III: Treatment D | Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | 1.446 hours | Geometric Coefficient of Variation 62.293 |
| Cohort IV: Treatment F | Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | 1.773 hours | — |
| Cohort III + IV: Treatment E | Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) | 2.190 hours | Geometric Coefficient of Variation 38.206 |
Primary
Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84)
Baseline-adjusted rhPTH(1-84) concentrations (participant- and period-specific) were calculated by subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline was defined as premorning-dose endogenous rhPTH(1-84) level on Day 1 for each treatment period. Tmax of baseline adjusted rhPTH(1-84) was reported. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
Time frame: QD: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12,16 and 24 hours post-dose ; BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours,12 hour 10 minutes,12 hour 20 minutes,12 hour 30 minutes,13 hours, 13 hour 30 minutes,14,16,20,22,24,28 and 36 hours post-dose
Population: Pharmacokinetic (PK) analysis set consisted of all enrolled participants who did not have major protocol violations that affected the validity of the PK results, received at least 1 dose of rhPTH(1-84) and had at least 1 evaluable postdose PK concentration value available for 1 dose regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I: Treatment A | Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | 7.108 hours |
| Cohort II: Treatment C | Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | 7.083 hours |
| Cohort I+II: Treatment B | Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | 0.333 hours |
| Cohort III: Treatment D | Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | 1.000 hours |
| Cohort IV: Treatment F | Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | 12.167 hours |
| Cohort III + IV: Treatment E | Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) | 0.667 hours |
Primary
Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. TEmax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day -1 were reported.
Time frame: Day -1
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort I: Treatment A | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 8.000 hours |
| Cohort I: Treatment A | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 8.000 hours |
| Cohort II: Treatment C | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 13.583 hours |
| Cohort II: Treatment C | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 12.100 hours |
| Cohort I+II: Treatment B | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 6.000 hours |
| Cohort I+II: Treatment B | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 4.200 hours |
| Cohort III: Treatment D | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 7.317 hours |
| Cohort III: Treatment D | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 5.208 hours |
| Cohort IV: Treatment F | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 9.250 hours |
| Cohort IV: Treatment F | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 5.367 hours |
| Cohort III + IV: Treatment E | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Calcium (Albumin-Corrected) | 13.692 hours |
| Cohort III + IV: Treatment E | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 | Total Calcium | 13.692 hours |
Primary
Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2
Baseline-adjusted concentrations calculated by subtracting the appropriate baseline values from the raw concentrations at each time point. TEmax of baseline-adjusted serum calcium (albumin-corrected) and total calcium (calcium \[uncorrected\]) concentrations on Day 1/Day 2 were reported.
Time frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort I: Treatment A | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 11.667 hours |
| Cohort I: Treatment A | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 21.108 hours |
| Cohort II: Treatment C | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 18.000 hours |
| Cohort II: Treatment C | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 10.000 hours |
| Cohort I+II: Treatment B | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 8.017 hours |
| Cohort I+II: Treatment B | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 9.917 hours |
| Cohort III: Treatment D | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 18.000 hours |
| Cohort III: Treatment D | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 13.508 hours |
| Cohort IV: Treatment F | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 17.000 hours |
| Cohort IV: Treatment F | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 16.000 hours |
| Cohort III + IV: Treatment E | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Calcium (albumin-corrected) | 9.075 hours |
| Cohort III + IV: Treatment E | Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 | Total Calcium | 8.092 hours |
Primary
Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1
Total amount of urinary calcium excretion to total relative amount of creatinine over 24 hours by Day -1 was reported.
Time frame: Day -1
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | 0.806 mmol/mmol | Standard Deviation 0.2284 |
| Cohort II: Treatment C | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | 0.836 mmol/mmol | Standard Deviation 0.302 |
| Cohort I+II: Treatment B | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | 0.727 mmol/mmol | Standard Deviation 0.2859 |
| Cohort III: Treatment D | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | 0.874 mmol/mmol | Standard Deviation 0.267 |
| Cohort IV: Treatment F | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | 0.855 mmol/mmol | Standard Deviation 0.2858 |
| Cohort III + IV: Treatment E | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1 | 0.807 mmol/mmol | Standard Deviation 0.2764 |
Primary
Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2
Total amount of urinary calcium excretion to total relative amount of creatinine over 24 hours by Day 1/ Day 2 was reported.
Time frame: Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | 0.401 millimoles Per millimoles (mmol/mmol) | Standard Deviation 0.1665 |
| Cohort II: Treatment C | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | 0.394 millimoles Per millimoles (mmol/mmol) | Standard Deviation 0.1278 |
| Cohort I+II: Treatment B | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | 0.475 millimoles Per millimoles (mmol/mmol) | Standard Deviation 0.1725 |
| Cohort III: Treatment D | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | 0.678 millimoles Per millimoles (mmol/mmol) | Standard Deviation 0.2123 |
| Cohort IV: Treatment F | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | 0.673 millimoles Per millimoles (mmol/mmol) | Standard Deviation 0.2377 |
| Cohort III + IV: Treatment E | Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 | 0.691 millimoles Per millimoles (mmol/mmol) | Standard Deviation 0.2364 |
Primary
Total Urinary Excretion of Calcium Over 24 Hours by Day -1
Total urinary excretion of calcium over 24 Hours by Day -1 was reported.
Time frame: Day -1
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | 9.348 mmol | Standard Deviation 3.9559 |
| Cohort II: Treatment C | Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | 10.239 mmol | Standard Deviation 3.713 |
| Cohort I+II: Treatment B | Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | 8.880 mmol | Standard Deviation 3.7407 |
| Cohort III: Treatment D | Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | 10.831 mmol | Standard Deviation 2.8306 |
| Cohort IV: Treatment F | Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | 10.735 mmol | Standard Deviation 2.9224 |
| Cohort III + IV: Treatment E | Total Urinary Excretion of Calcium Over 24 Hours by Day -1 | 9.717 mmol | Standard Deviation 2.9354 |
Primary
Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2
Total urinary excretion of calcium over 24 hours by Day1/Day 2 was reported.
Time frame: Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose
Population: PD analysis set. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment A | Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | 4.904 mmol | Standard Deviation 1.9684 |
| Cohort II: Treatment C | Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | 5.137 mmol | Standard Deviation 1.98 |
| Cohort I+II: Treatment B | Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | 6.037 mmol | Standard Deviation 2.5353 |
| Cohort III: Treatment D | Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | 7.440 mmol | Standard Deviation 2.5379 |
| Cohort IV: Treatment F | Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | 8.813 mmol | Standard Deviation 2.8213 |
| Cohort III + IV: Treatment E | Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 | 7.928 mmol | Standard Deviation 2.3159 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAE's)
An AE that occured during the study was considered a TEAE if it had a start date/time on or after the first dose of investigational product or if it had a start date before the date of the first dose of investigational product, but increased in severity on or after the date/time of the first dose of investigational product. Number of participants with TEAE's were reported.
Time frame: From signing of informed consent up to follow up (up to Day 182)
Population: Safety analysis set included enrolled participants who received at least 1 dose of rhPTH(1 84).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I: Treatment A | Number of Participants With Treatment Emergent Adverse Events (TEAE's) | 3 Participants |
| Cohort II: Treatment C | Number of Participants With Treatment Emergent Adverse Events (TEAE's) | 1 Participants |
| Cohort I+II: Treatment B | Number of Participants With Treatment Emergent Adverse Events (TEAE's) | 4 Participants |
| Cohort III: Treatment D | Number of Participants With Treatment Emergent Adverse Events (TEAE's) | 5 Participants |
| Cohort IV: Treatment F | Number of Participants With Treatment Emergent Adverse Events (TEAE's) | 3 Participants |
| Cohort III + IV: Treatment E | Number of Participants With Treatment Emergent Adverse Events (TEAE's) | 7 Participants |