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

Sponsor

Chugai Pharmaceutical (Industry)

Overall Status

Terminated

CT.gov ID

NCT04209179

Collaborator

(none)

Enrollment

Locations

Arms

10.1

Actual Duration (Months)

0.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Hypoparathyroidism	Drug: PCO371 Drug: Placebo	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 23, 2020

Actual Primary Completion Date :

Dec 28, 2020

Actual Study Completion Date :

May 25, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Pharmacokinetic data of PCO371; Plasma concentrations of PCO371 [13 weeks]
Plasma concentrations versus time data
Pharmacokinetic data of PCO371; AUC0-last [13 weeks]
AUC0-last of PCO371
Pharmacokinetic data of PCO371; Cmax of PCO371 [13 weeks]
Cmax of PCO371
Pharmacokinetic data of PCO371; Tmax of PCO371 [13 weeks]
Tmax of PCO371
Pharmacokinetic data of PCO371; T1/2 of PCO371 [13 weeks]
T1/2 of PCO371
Pharmacodynamic data in serum or plasma [13 weeks]
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
Pharmacodynamic data in urine [13 weeks]
Urinary excretion of Ca, phosphate, magnesium, protein, sodium, potassium, chloride, and cAMP (via 24-hour urine collection)
Pharmacodynamic data; nephrogenous cAMP concentration [13 weeks]
Time profile of nephrogenous cAMP concentration
Pharmacodynamic data; bone turnover markers in serum or plasma [13 weeks]
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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Adult males or females ≥18 years of age
History of hypoparathyroidism for more than 1-year post initial diagnosis
PTH level is inappropriately low
Dose of thyroid replacement therapy must have been stable for ≥3 months prior to first dose if receiving thyroid replacement therapy
Receiving treatment with active vitamin D therapy (calcitriol ≥0.25 μg/day or alfacalcidol ≥0.5 μg/day)
Receiving Oral calcium treatment (≥1000 mg/day)
No significant changes in the diet from 4 weeks prior to Screening and for the duration of the study.
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.
On Day 1, fasting albumin-corrected serum calcium level between 7.5 and 9.0 mg/dL
Serum magnesium level ≥ lower limit of normal and ≤ 1.2 x laboratory upper limit of normal
Serum 25[OH] vitamin D level within the laboratory normal range
Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2
Women of childbearing potential must have a negative highly sensitive urine or serum pregnancy test result
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.
For men: agreement to remain abstinent or use contraceptive measures. Men must refrain from donating sperm during this same period.
Ability to comply with the study protocol, in the investigator's judgment.
For Canadian sites only: Ferritin, as assessed by the local laboratory at screening, must be ≥ the lower limit of normal (LLN).

Exclusion Criteria:

Pregnant or breastfeeding or intending to become pregnant during the study or within 28 days after the last dose of PCO371
Known or suspected history of hypoparathyroidism resulting from an activating mutation in the Ca-sensing receptor gene or impaired responsiveness to PTH (pseudohypoparathyroidism)
Clinically significant hypomagnesemia. Adequately treated hypomagnesemia is permitted
Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism
History of a major bone fracture within 3 months prior to Screening
Any history of clinically significant bleeding disorder or clinically significant abnormal clotting times
History of thyroid cancer unless documented to be disease free for ≥1 year
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
Dependence on monthly or more frequent parenteral calcium infusions to maintain calcium homeostasis
Disease processes that may adversely affect gastrointestinal absorption
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.
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.
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).
Use of loop or thiazide diuretics within 14 days prior to first dose of IMP
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
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.
History of radiotherapy to the skeleton within 5 years
Presence of open epiphyses at the distal radius and ulna as well as carpals, metacarpals, phalanges, and pelvis
ALT, AST, or ALP > 2.5 × ULN at Screening
Patients with documented active HBV, active HCV infection or any other known active virus infection considered to be clinically relevant by the investigator.
Evidence of active alcohol, drug, or other substance abuse or addiction
History of a seizure that is unrelated to hypocalcemia within 6 months prior to Screening
Insulin dependent diabetes mellitus or poorly controlled Type II diabetes mellitus (defined as hemoglobin A1c [HbA1c] >8%)
Chronic/severe cardiac disease
Active gout or history of active gout within 6 months prior to first dose of study medication
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.
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
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
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.
Patients with hypersensitivity to PCO371 or to any component of this drug product

Contacts and Locations

Locations

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

Sponsors and Collaborators

Chugai Pharmaceutical

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Chugai Pharmaceutical

ClinicalTrials.gov Identifier:

NCT04209179

Other Study ID Numbers:

PCO104UG

First Posted:

Dec 24, 2019

Last Update Posted:

Jun 11, 2021

Last Verified:

Jun 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Hypoparathyroidism

Study Results

No Results Posted as of Jun 11, 2021