Clinical trial NCT02204579: 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
Official title: Open-label Dose Escalation Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous NPSP795 in Autosomal Dominant Hypocalcemia Due to Mutations in the Calcium-sensing Receptor Gene: A Drug Repurposing Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autosomal Dominant Hypocalcemia (ADH)
Keywords: Autosomal Dominant Hypocalcemia
Hypocalcemia
ADH
Hypoparathyroidism
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
First posted: 2014-07-30
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label study looking at the effects of NPSP795 (a selective calcium receptor antagonist) on activating mutations of the Calcium-sensing receptor in patients with Autosomal Dominant Hypocalcemia. Patients with ADH have low blood calcium levels and an inappropriately increased renal calcium excretion, decreased renal phosphate excretion, and hyperphosphatemia. PTH and blood calcium levels will be tested during and after the IV infusion of NPSP795. Concentrations of NPSP795 and length of time of IV infusion will vary depending on measured levels of ionized calcium.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)
measure: Number of Participants With Clinically Significant Vital Signs and Electrocardiogram (ECG) Abnormalities
timeFrame: From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)
measure: Number of Participants With Potentially Clinically Important Laboratory Abnormalities
timeFrame: From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)
measure: Number of Participants With Clinically Significant Abnormalities Related to Physical Examination
timeFrame: From Day 1 up to safety follow-up assessment (upto Day 17 after discharge)
measure: Change From Baseline in Ionised Calcium
timeFrame: 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
measure: Change From Baseline in Serum Calcium
timeFrame: 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.
measure: Change From Baseline in Urinary Calcium
timeFrame: 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.
measure: Change From Baseline in Serum Parathyroid Hormone (PTH)
timeFrame: 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:
measure: Area Under the Plasma Concentration Versus Time Curve (AUC[0-t]) of NPSP795
timeFrame: 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
measure: Area Under the Concentration Time Curve Extrapolated to Infinity (AUC0-infinity) of NPSP795
timeFrame: 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
measure: Maximum Observed Drug Concentration (Cmax) of NPSP795 in Plasma
timeFrame: 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
measure: Elimination Half-life (t1/2) of NPSP795 in Plasma
timeFrame: 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
measure: Change From Baseline in Fractional Excretion of Calcium (FECa)
timeFrame: 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.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institute of Health (NIH)
state: Maryland
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: