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