Clinical trial NCT02781844: Study to Assess the Blood Concentrations and Actions of Recombinant Human Parathyroid Hormone (rhPTH [1-84]) When Given Once and Twice Daily to Participants With Hypoparathyroidism
Official title: An Open-Label, Randomized, Crossover Study to Assess the Pharmacokinetic and Pharmacodynamic Profiles of Once Daily and Twice Daily Dose Regimens of Recombinant Human Parathyroid Hormone (rhPTH[1-84]) Administered Subcutaneously to Subjects With Hypoparathyroidism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypoparathyroidism
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-05-25
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84)
timeFrame: 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
measure: Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84)
timeFrame: 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
measure: Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84)
timeFrame: 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
measure: Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84)
timeFrame: 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
measure: Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84)
timeFrame: 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
measure: Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84)
timeFrame: BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours post-dose
measure: 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)
timeFrame: 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
measure: Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84)
timeFrame: 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
measure: 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
timeFrame: Day -1
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
timeFrame: Day -1
measure: Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1
timeFrame: Day -1
measure: Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1
timeFrame: Day -1
measure: 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
timeFrame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
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 2
timeFrame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
measure: Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2
timeFrame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
measure: Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2
timeFrame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose
measure: Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day -1
timeFrame: Day -1
measure: Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2
timeFrame: Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose
measure: Total Urinary Excretion of Calcium Over 24 Hours by Day -1
timeFrame: Day -1
measure: Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2
timeFrame: Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose
Secondary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE's)
timeFrame: From signing of informed consent up to follow up (up to Day 182)
Other outcomes:
Locations:
city: North Hollywood
country: United States
facility: Providence Clinical Research
state: California
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Lexington
country: United States
facility: University Of Kentucky School of Medicine
state: Kentucky
city: Metairie
country: United States
facility: Crescent City Clinical Research Center, LLC
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - PPDS
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Knoxville
country: United States
facility: New Orleans Center for Clinical Research (NOCCR) - Knoxville
state: Tennessee
city: Quebec
country: Canada
facility: CHU de Quebec-Universite Laval
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital
state: Central Jutland
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
state: Csongrád
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Pécs
country: Hungary
facility: Pécsi Tudományegyetem
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: