A Study to Determine the Effects of NPSP795 on the Calcium-sensing Receptor in Subjects With Autosomal Dominant Hypocalcemia as Measured by PTH Levels and Blood Calcium Concentrations

• NPSP795 (Drug)

Primary outcomes

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)]
• Number of Participants With Clinically Significant Vital Signs and Electrocardiogram (ECG) Abnormalities [From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)]
• Number of Participants With Potentially Clinically Important Laboratory Abnormalities [From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)]
• Number of Participants With Clinically Significant Abnormalities Related to Physical Examination [From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)]
• Change From Baseline in Ionised Calcium [10 Minute (min) Infusion Time: within 5 min pre-dose; & post-dose 15, 30, 45, 60, 75, 90, 105 min, and 2, 2.5, 3, 3.5, & 4 hour (hr) 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 15, 30, 45, 60, 75, 90, 105 min, & 2, 2.5, 3, 3.5, 4, 5, and 8 hr]
• Change From Baseline in Serum Calcium [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 1, 2, 3, 4, 8 12 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 1, 2, 3, 4, 8 12 hr.]
• Change From Baseline in Urinary Calcium [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 1, 2, 3, 4, 8 12 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 1, 2, 3, 4, 8 12 hr.]
• Change From Baseline in Serum Parathyroid Hormone (PTH) [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 5, 10, 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 8 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 5.5 hr]

Secondary outcomes

• Area Under the Plasma Concentration Versus Time Curve (AUC[0-t]) of NPSP795 [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 5, 10, 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 8 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 5.5 hr]
• Area Under the Concentration Time Curve Extrapolated to Infinity (AUC0-infinity) of NPSP795 [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 5, 10, 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 8 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 5.5 hr]
• Maximum Observed Drug Concentration (Cmax) of NPSP795 in Plasma [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 5, 10, 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 8 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 5.5 hr]
• Elimination Half-life (t1/2) of NPSP795 in Plasma [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 5, 10, 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 8 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 15, 30 min, & 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 5.5 hr]
• Change From Baseline in Fractional Excretion of Calcium (FECa) [10 Minutes (min) Infusion Time: within 5 min pre-dose; & post-dose 1, 2, 3, 4, 8, 12 hours (hr). 3.5 hr Infusion Time: within 5 min pre-dose; & post-dose 1, 2, 3, 4, 8, 12 hr.]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Subjects with a heterozygous activating mutation of the CaSR gene (ADH); if not previously confirmed, genetic testing will be performed at the screening visit
* At least 18 years of age
* Body mass index (BMI) ≥ 18.5 to < 39 kg/m2

Exclusion Criteria:

* Diseases or conditions that might compromise any major body system or interfere with the pharmacokinetics of NPSP795
* History of treatment with PTH 1-84 or 1-34 within the previous 6 months
* History of hypocalcemia requiring frequent IV calcium infusions
* History of hypocalcemic seizure within the past 3 months
* Blood 25-hydroxy vitamin D level < 25 ng/mL. If subjects have a blood 25-hydroxy vitamin D level < 25 ng/mL at the outpatient screening visit, they will be prescribed vitamin D replacement. Once the 25-hydroxy vitamin D level is > 25 ng/mL, the subject will be eligible to continue on to the treatment phase of the study
* Estimated glomerular filtration rate (GFR) < 25 mL/minute, and/or abnormal hepatic, hematologic, and/or clotting function
* 12 lead resting electrocardiogram (ECG) with clinically significant abnormalities
* Concomitant medications with the potential to interfere with NPSP795 metabolism
* History of thyroid or parathyroid surgery

Participant flow

Outcome results

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) (Primary), Number, participants: NPSP795 3
• Number of Participants With Clinically Significant Vital Signs and Electrocardiogram (ECG) Abnormalities (Primary), Number, participants: NPSP795 0
• Number of Participants With Potentially Clinically Important Laboratory Abnormalities (Primary), Number, participants: NPSP795 1
• Number of Participants With Clinically Significant Abnormalities Related to Physical Examination (Primary), Number, participants: NPSP795 1
• Change From Baseline in Ionised Calcium (Primary), Mean, millimole/liter (mmol/L): NPSP795 on Day 1 (5 mg/10 Minutes) 0.972 +/- 0.058; NPSP795 on Day 2 (15 mg/3.5 Hours) 0.950 +/- 0.054; NPSP795 on Day 3 (30 mg/3.5 Hours) 0.986 +/- 0.045; NPSP795 on Day 4 (30 mg/3.5 Hours) 0.933 +/- 0.055; NPSP795 on Day 4 (50 mg/3.5 Hours) 1.025 +/- 0.078
• Change From Baseline in Serum Calcium (Primary), Mean, millimole/liter (mmol/L): NPSP795 on Day 1 (5 mg/10 Minutes) 1.914 +/- 0.157; NPSP795 on Day 2 (15 mg/3.5 Hours) 1.790 +/- 0.125; NPSP795 on Day 3 (30 mg/3.5 Hours) 1.852 +/- 0.132; NPSP795 on Day 4 (30 mg/3.5 Hours) 1.677 +/- 0.135; NPSP795 on Day 4 (50 mg/3.5 Hours) 1.980 +/- 0.184
• Change From Baseline in Urinary Calcium (Primary), Mean, millimole/liter (mmol/L): NPSP795 on Day 1 (5 mg/10 Minutes) 3.302 +/- 2.283; NPSP795 on Day 2 (15 mg/3.5 Hours) 3.912 +/- 3.299; NPSP795 on Day 3 (30 mg/3.5 Hours) 2.936 +/- 1.750; NPSP795 on Day 4 (30 mg/3.5 Hours) 2.537 +/- 1.968; NPSP795 on Day 4 (50 mg/3.5 Hours) 2.065 +/- 1.916
• Change From Baseline in Serum Parathyroid Hormone (PTH) (Primary), Mean, nanogram/liter (ng/L): NPSP795 on Day 1 (5 mg/10 Minutes) 7.32 +/- 2.93; NPSP795 on Day 2 (15 mg/3.5 Hours) 9.14 +/- 3.29; NPSP795 on Day 3 (30 mg/3.5 Hours) 9.58 +/- 5.32; NPSP795 on Day 4 (30 mg/3.5 Hours) 12.80 +/- 8.68; NPSP795 on Day 4 (50 mg/3.5 Hours) 7.40 +/- 3.54
• Area Under the Plasma Concentration Versus Time Curve (AUC[0-t]) of NPSP795 (Secondary), Mean, nanogram*hour per millilitre (ng·h/mL): NPSP795 on Day 1 (5 mg/10 Minutes) 309.512 +/- 122.601; NPSP795 on Day 2 (15 mg/3.5 Hours) 795.766 +/- 294.345; NPSP795 on Day 3 (30 mg/3.5 Hours) 1561.746 +/- 546.479; NPSP795 on Day 4 (30 mg/3.5 Hours) 1657.057 +/- 650.156; NPSP795 on Day 4 (50 mg/3.5 Hours) 2251.818 +/- 568.782
• Area Under the Concentration Time Curve Extrapolated to Infinity (AUC0-infinity) of NPSP795 (Secondary), Mean, nanogram*hour per milliliter(ng·h/mL): NPSP795 on Day 1 (5 mg/10 Minutes) 2.672 +/- 1.775; NPSP795 on Day 2 (15 mg/3.5 Hours) 5.572 +/- 2.724; NPSP795 on Day 3 (30 mg/3.5 Hours) 5.437 +/- 2.587; NPSP795 on Day 4 (30 mg/3.5 Hours) 7.648 +/- 3.607; NPSP795 on Day 4 (50 mg/3.5 Hours) 4.521 +/- 2.991
• Maximum Observed Drug Concentration (Cmax) of NPSP795 in Plasma (Secondary), Mean, nanogram/milliliter (ng/mL): NPSP795 on Day 1 (5 mg/10 Minutes) 301.900 +/- 120.664; NPSP795 on Day 2 (15 mg/3.5 Hours) 745.335 +/- 254.205; NPSP795 on Day 3 (30 mg/3.5 Hours) 1467.102 +/- 475.343; NPSP795 on Day 4 (30 mg/3.5 Hours) 1515.086 +/- 548.056; NPSP795 on Day 4 (50 mg/3.5 Hours) 2141.500 +/- 475.706
• Elimination Half-life (t1/2) of NPSP795 in Plasma (Secondary), Mean, hour: NPSP795 on Day 1 (5 mg/10 Minutes) 3.013 +/- 0.612; NPSP795 on Day 2 (15 mg/3.5 Hours) 3.913 +/- 0.222; NPSP795 on Day 3 (30 mg/3.5 Hours) 4.213 +/- 0.449; NPSP795 on Day 4 (30 mg/3.5 Hours) 3.839 +/- 0.294; NPSP795 on Day 4 (50 mg/3.5 Hours) 4.000 +/- 0.000
• Change From Baseline in Fractional Excretion of Calcium (FECa) (Secondary), Mean, Fraction of excretion: NPSP795 on Day 1 (5 mg/10 Minutes) 0.030 +/- 0.023; NPSP795 on Day 2 (15 mg/3.5 Hours) 0.031 +/- 0.017; NPSP795 on Day 3 (30 mg/3.5 Hours) 0.027 +/- 0.014; NPSP795 on Day 4 (30 mg/3.5 Hours) 0.030 +/- 0.011; NPSP795 on Day 4 (50 mg/3.5 Hours) 0.026 +/- 0.032

Adverse events

Time frame: From the sign of informed consent form (Day -93) up to safety follow-up assessment (upto Day 17 after discharge)

Serious adverse events by term

Other adverse events by term

• Study Director, Study director, Takeda