A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism

A Randomized, Double-Blind, Multiple Ascending Oral Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PCO371 in Patients With Hypoparathyroidism

This is a multi-center, placebo-controlled, randomized, double-blind, multiple-ascending dose study in patients with hypoparathyroidism.

The total duration of study medication treatment will be 13 weeks and includes a Fixed-Dose Treatment period and a Dose Titration Treatment period. The Fixed-Dose Treatment period consists of multiple daily dosing at a fixed dose level. Once patients have completed the Fixed-Dose Treatment period, patients will enter the Dose Titration Treatment period where PCO371 (or placebo), oral calcium and oral active vitamin D can each be titrated according to the patient's albumin-corrected serum calcium level.

Study Overview

• Status: Terminated
• Conditions: Hypoparathyroidism
• Intervention / Treatment: Drug: Placebo; Drug: PCO371

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • CAN
    • Québec, CAN, Canada, G1V 4G2
      • Endocrinologie et néphrologie Centre de recherche du CHU de Québec
  • ONT
    • Oakville, ONT, Canada, L6M 1M1
      • McMaster University Bone Research & Education Centre
• Hungary
  • HU
    • Budapest, HU, Hungary, 1083
      • Semmelweis Egyetem, Általános Orvostudományi Kar, Belgyógyászati és Onkológiai Klinika
• United States
  • California
    • Torrance, California, United States, 90502
      • The Lundquist Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Able and willing to provide written informed consent, to use the device for PRO and electronic diary and to comply with the requirements of the protocol.
2. Adult males or females ≥18 years of age
3. History of hypoparathyroidism for more than 1-year post initial diagnosis
4. PTH level is inappropriately low
5. Dose of thyroid replacement therapy must have been stable for ≥3 months prior to first dose if receiving thyroid replacement therapy
6. Receiving treatment with active vitamin D therapy (calcitriol ≥0.25 μg/day or alfacalcidol ≥0.5 μg/day)
7. Receiving Oral calcium treatment (≥1000 mg/day)
8. No significant changes in the diet from 4 weeks prior to Screening and for the duration of the study.
9. Fasting albumin-corrected serum calcium concentration between 8.0 and 9.0 mg/dL at 2 consecutive visits during the Run-In period, and no more than 25% change in daily doses of oral Ca and active vitamin D between the 2 consecutive visits during the Run-In period.
10. On Day 1, fasting albumin-corrected serum calcium level between 7.5 and 9.0 mg/dL
11. Serum magnesium level ≥ lower limit of normal and ≤ 1.2 x laboratory upper limit of normal
12. Serum 25[OH] vitamin D level within the laboratory normal range
13. Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2
14. Women of childbearing potential must have a negative highly sensitive urine or serum pregnancy test result
15. For women of childbearing potential: agreement to use a highly effective contraceptive method during the treatment period and for 28 days after the last dose of study drug. Hormonal contraceptive methods must be supplemented by a barrier method (preferably male condom) and agreement to refrain from egg donation during the treatment period and for 28 days after the last dose of study drug.
16. For men: agreement to remain abstinent or use contraceptive measures. Men must refrain from donating sperm during this same period.
17. Ability to comply with the study protocol, in the investigator's judgment.
18. For Canadian sites only: Ferritin, as assessed by the local laboratory at screening, must be ≥ the lower limit of normal (LLN).

Exclusion Criteria:

1. Pregnant or breastfeeding or intending to become pregnant during the study or within 28 days after the last dose of PCO371
2. Known or suspected history of hypoparathyroidism resulting from an activating mutation in the Ca-sensing receptor gene or impaired responsiveness to PTH (pseudohypoparathyroidism)
3. Clinically significant hypomagnesemia. Adequately treated hypomagnesemia is permitted
4. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism
5. History of a major bone fracture within 3 months prior to Screening
6. Any history of clinically significant bleeding disorder or clinically significant abnormal clotting times
7. History of thyroid cancer unless documented to be disease free for ≥1 year
8. History of any other cancer in the past 3 years from Screening with the exception of thyroid cancer , completely removed nonmelanoma skin cancer, basal cell skin carcinoma, and cancer in situ of the cervix
9. Dependence on monthly or more frequent parenteral calcium infusions to maintain calcium homeostasis
10. Disease processes that may adversely affect gastrointestinal absorption
11. Use of oral bisphosphonates within 6 months of Screening and/or intravenous bisphosphonate preparations within 12 months of Screening. Any use of zoledronic acid prior to Screening.
12. Use of other drugs known to influence calcium and bone metabolism such as calcitonin, fluoride tablets or cinacalcet hydrochloride within 4 weeks prior to Screening.
13. Patients who have taken inducers of CYP3A4, Pgp,or BCRP within 1 month before IMP administration or taken inhibitors of CYP3A4, P-gp, or BCRP within 2 weeks before IMP administration (or either 6 times the t1/2 of the drugs mentioned above, whichever is longer).
14. Use of loop or thiazide diuretics within 14 days prior to first dose of IMP
15. Use of anti-coagulants, anti-platelet medications, and aspirin within 2 weeks (or within 6 times the t1/2 of the drug mentioned above, whichever is longer) prior to IMP administration
16. Use of proton pump inhibitors or H2 blockers within 48 hours prior to the first dose of IMP and antacids within 4 hours prior to the first dose of IMP.
17. History of radiotherapy to the skeleton within 5 years
18. Presence of open epiphyses at the distal radius and ulna as well as carpals, metacarpals, phalanges, and pelvis
19. ALT, AST, or ALP > 2.5 × ULN at Screening
20. Patients with documented active HBV, active HCV infection or any other known active virus infection considered to be clinically relevant by the investigator.
21. Evidence of active alcohol, drug, or other substance abuse or addiction
22. History of a seizure that is unrelated to hypocalcemia within 6 months prior to Screening
23. Insulin dependent diabetes mellitus or poorly controlled Type II diabetes mellitus (defined as hemoglobin A1c [HbA1c] >8%)
24. Chronic/severe cardiac disease
25. Active gout or history of active gout within 6 months prior to first dose of study medication
26. History of clinically significant cognitive deficit that would, at the discretion of the investigator, interfere with a patient's ability to participate in the trial.
27. Any disease or condition that, in the opinion of the investigator, has a high probability of precluding the patient from completing the study or where the patient could not or would not appropriately comply with study requirements
28. Participation in any clinical trials or has taken any IMP (including placebo) either within 2 months or 5 times the t1/2 of the IMP, whichever is longer, prior to first dose of IMP for this study
29. Previous treatment with PTH-like drugs, including PTH(1-84), PTH(1-34) or other Nterminal fragments or analogs of PTH or PTH-related proteins within 2 months or 5 times the t1/2 of the treatment (whichever is longer) prior to Screening.
30. Patients with hypersensitivity to PCO371 or to any component of this drug product

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PCO371 Low Dose and Low administration frequency; PCO371 low dose and low administration frequency by oral administration for the first period ( Fixed-Dose treatment period). PCO371 will be titrated in the following period (Dose Titration Treatment period).	Drug: PCO371; PCO371 capsule
Experimental: PCO371 High Dose and Low administration frequency; PCO371 high dose and low administration frequency by oral administration for the first period ( Fixed-Dose treatment period). PCO371 will be titrated in the following period (Dose Titration Treatment period).	Drug: PCO371; PCO371 capsule
Experimental: PCO371 High Dose and High administration frequency; PCO371 high dose and high administration frequency by oral administration for the first period ( Fixed-Dose treatment period). PCO371 will be titrated in the following period (Dose Titration Treatment period).	Drug: PCO371; PCO371 capsule
Placebo Comparator: Placebo; Placebo by oral administration.	Drug: Placebo; Placebo capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-emergent adverse events	Treatment-emergent adverse events (TEAEs) will be assessed including the number and rate of TEAEs.	13 weeks
Selected adverse events	Hypercalcemia and hypocalcemia will be assessed including the number and rate of these.	13 weeks
Clinically significant change in the safety parameters; vital signs	Abnormal change in vital signs.	13 weeks
Clinically significant change in the safety parameters; body weight	Abnormal change in body weight.	13 weeks
Clinically significant change in the safety parameters; physical examination findings	Abnormal change in physical examination findings.	13 weeks
Clinically significant change in the safety parameters; laboratory test value	Abnormal change in laboratory test value including hematology, biochemistry, coagulation, urinalysis.	13 weeks
Clinically significant change in the safety parameters; electrocardiogram results	Abnormal change in electrocardiogram results including PQ (PR), RR, QRS, QT, pulse, QTcB, QTcF and ECG abnormalities.	13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic data of PCO371; Plasma concentrations of PCO371	Plasma concentrations versus time data	13 weeks
Pharmacokinetic data of PCO371; AUC0-last	AUC0-last of PCO371	13 weeks
Pharmacokinetic data of PCO371; Cmax of PCO371	Cmax of PCO371	13 weeks
Pharmacokinetic data of PCO371; Tmax of PCO371	Tmax of PCO371	13 weeks
Pharmacokinetic data of PCO371; T1/2 of PCO371	T1/2 of PCO371	13 weeks
Pharmacodynamic data in serum or plasma	Time profile of serum/plasma concentrations in albumin corrected total calcium (Ca), 25 hydroxy vitamin D, 1,25-dihydroxy vitamin D, phosphate, magnesium, and cAMP	13 weeks
Pharmacodynamic data in urine	Urinary excretion of Ca, phosphate, magnesium, protein, sodium, potassium, chloride, and cAMP (via 24-hour urine collection)	13 weeks
Pharmacodynamic data; nephrogenous cAMP concentration	Time profile of nephrogenous cAMP concentration	13 weeks
Pharmacodynamic data; bone turnover markers in serum or plasma	Time profile of serum/plasma concentrations in bone turnover markers (i.e. bone-specific alkaline phosphatase, type 1 pro-collagen amino-terminal peptide, C-terminal telopeptide of type 1 collagen, and osteocalcin)	13 weeks

Collaborators and Investigators

• Sponsor: Chugai Pharmaceutical
• Investigators: Study Director: Sponsor Chugai Pharmaceutical Co. Ltd, clinical-trials@chugai-pharm.co.jp

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2020
• Primary Completion (Actual): December 28, 2020
• Study Completion (Actual): May 25, 2021

Study Registration Dates

• First Submitted: November 28, 2019
• First Submitted That Met QC Criteria: December 19, 2019
• First Posted (Actual): December 24, 2019

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 9, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Parathyroid Diseases; Hypoparathyroidism
• Other Study ID Numbers: PCO104UG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). For further details on Chugai's Data Sharing Policy and how to request access to related clinical study documents, see here (www.chugai-pharm.co.jp/english/profile/rd/ctds_request.html).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No