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

Hypoparathyroidism Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04209179
• Other study ID #: PCO104UG
• Status: Terminated
• Phase: Phase 1
• Start date: July 23, 2020
• Est. completion date: May 25, 2021

Study information

• Verified date: June 2021
• Source: Chugai Pharmaceutical
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: May 25, 2021
• Est. primary completion date: December 28, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hypoparathyroidism

Intervention

Drug:
• PCO371
PCO371 capsule
• Placebo
Placebo capsule

Locations

Country	Name	City	State
Canada	McMaster University Bone Research & Education Centre	Oakville	ONT
Canada	Endocrinologie et néphrologie Centre de recherche du CHU de Québec	Québec	CAN
Hungary	Semmelweis Egyetem, Általános Orvostudományi Kar, Belgyógyászati és Onkológiai Klinika	Budapest	HU
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago	Chicago	Illinois
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	University of Kentucky	Lexington	Kentucky
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	The Lundquist Institute	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Chugai Pharmaceutical

Countries where clinical trial is conducted

United States,  Canada,  Hungary, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment-emergent adverse events	Treatment-emergent adverse events (TEAEs) will be assessed including the number and rate of TEAEs.	13 weeks
Primary	Selected adverse events	Hypercalcemia and hypocalcemia will be assessed including the number and rate of these.	13 weeks
Primary	Clinically significant change in the safety parameters; vital signs	Abnormal change in vital signs.	13 weeks
Primary	Clinically significant change in the safety parameters; body weight	Abnormal change in body weight.	13 weeks
Primary	Clinically significant change in the safety parameters; physical examination findings	Abnormal change in physical examination findings.	13 weeks
Primary	Clinically significant change in the safety parameters; laboratory test value	Abnormal change in laboratory test value including hematology, biochemistry, coagulation, urinalysis.	13 weeks
Primary	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	Pharmacokinetic data of PCO371; Plasma concentrations of PCO371	Plasma concentrations versus time data	13 weeks
Secondary	Pharmacokinetic data of PCO371; AUC0-last	AUC0-last of PCO371	13 weeks
Secondary	Pharmacokinetic data of PCO371; Cmax of PCO371	Cmax of PCO371	13 weeks
Secondary	Pharmacokinetic data of PCO371; Tmax of PCO371	Tmax of PCO371	13 weeks
Secondary	Pharmacokinetic data of PCO371; T1/2 of PCO371	T1/2 of PCO371	13 weeks
Secondary	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
Secondary	Pharmacodynamic data in urine	Urinary excretion of Ca, phosphate, magnesium, protein, sodium, potassium, chloride, and cAMP (via 24-hour urine collection)	13 weeks
Secondary	Pharmacodynamic data; nephrogenous cAMP concentration	Time profile of nephrogenous cAMP concentration	13 weeks
Secondary	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