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

• Register: ClinicalTrials.gov
• Last refreshed on: 7 June 2021
• Main ID: NCT02781844
• Date of registration: 19/04/2016
• Prospective Registration: Yes
• Primary sponsor: Shire
• Public title: 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 PARALLAX
• Scientific 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
• Date of first enrolment: April 3, 2017
• Target sample size: 34
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02781844
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Crossover Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

Canada, Denmark, Hungary, United States

Contacts

• Name: Study Director
• Affiliation: Takeda

Key inclusion & exclusion 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 select


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Hypoparathyroidism

Intervention(s)

Drug: 25mcg rhPTH(1-84)

Drug: 50mcg rhPTH(1-84)

Drug: 100mcg rhPTH(1-84)

Primary Outcome(s)

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 [Time Frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose]

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 [Time Frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose]

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) [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]

Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 [Time Frame: Day -1]

Terminal Half-Life (t1/2) of Baseline Adjusted rhPTH(1-84) [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]

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 [Time Frame: Day -1]

Maximum Plasma Concentration (Cmax) of Baseline Adjusted rhPTH(1-84) [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]

Time of Maximum Observed Concentration (Cmax) During a Dosing Interval (Tmax) of Baseline Adjusted rhPTH(1-84) [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]

Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day -1 [Time Frame: Day -1]

Area Under the Concentration Curve From Time Zero to 12 Hours Post the First Dose (AUC0-12) of Baseline Adjusted rhPTH(1-84) [Time Frame: BID: Pre-dose,10,20,30 minutes,1,1.5,2,4,8,12 hours post-dose]

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 [Time Frame: Day -1]

Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Baseline Adjusted rhPTH(1-84) [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]

Area Under the Curve Extrapolated to Infinity (AUCinf) of Baseline Adjusted rhPTH(1-84) [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]

Time to Maximum Effect (TEmax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 [Time Frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose]

Area Under the Concentration Curve From Time Zero to 24 Hours Post the First Dose (AUC0-24) of Baseline Adjusted rhPTH(1-84) [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]

Maximum Effect (Emax) of Baseline-Adjusted Serum Calcium Concentrations on Day 1/Day 2 [Time Frame: Day1- QD: Pre-dose up to 24 hours post dose, Day2- BID: Pre-dose up to 36 hours post dose]

Total Amount of Urinary Calcium Excretion to Total Relative Amount of Creatinine Over 24 Hours by Day 1/ Day 2 [Time Frame: 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 [Time Frame: Day -1]

Total Urinary Excretion of Calcium Over 24 Hours by Day -1 [Time Frame: Day -1]

Total Urinary Excretion of Calcium Over 24 Hours by Day 1/ Day 2 [Time Frame: Day 1- QD: Pre-dose up to 24 hours post dose, Day 2- BID: Pre-dose up to 24 hours post dose]

Secondary Outcome(s)

Number of Participants With Treatment Emergent Adverse Events (TEAE's) [Time Frame: From signing of informed consent up to follow up (up to Day 182)]

Secondary ID(s)

SHP634-101

2015-004757-40

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 09/04/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02781844