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

Overview

About this study

The purpose of this study is to test the safety of the drug PCO371 at different doses in patients with hypoparathyroidism, and to understand the way their bodies process PCO371 versus placebo.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

lusion 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.
  • Parathyroid Hormone (PTH) level is inappropriately low g (i.e., ≤ 20 pg/mL [2.4 pmol/L]).
  • 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 [625 nmol]/day or alfacalcidol ≥ 0.5 µg [1.25 µmol]/day) at time of Screening.
  • Receiving oral calcium (Ca) treatment (≥ 1000 mg [0.25 mmol]/day of elemental calcium) at time of screening.
  • No significant changes in the diet from 4 weeks prior to Screening and for the duration of the study. Dietary changes required per protocol (such as required fasting, Ca intake requirements, etc.) are permitted. 
  • Fasting albumin-corrected serum calcium concentration between 8.0 and 9.0 mg/dL (between 2.0 and 2.25 mmol/L) 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 (sCa) level between 7.5 and 9.0 mg/dL (between 1.87 and 2.25 mmol/L).
  • Serum magnesium level (with or without supplementation) ≥ lower limit of normal (LLN) and ≤ 1.2 x laboratory upper limit of normal (ULN) at Screening.
  • Serum 25-hydroxy-vitamin D (25[OH] vitamin D) level within the laboratory normal range at time of Screening. If the 25[OH] vitamin D value does not meet this value at the timing of screening, then the serum 25[OH] vitamin D level should be optimized during the Run-In period and re-evaluated prior to randomization to ensure that the value meets the criteria.
  • Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m^2 at Screening.
  • Women of childbearing potential must have a negative highly sensitive urine or serum pregnancy test result at Screening and on Day 4. The pregnancy test must have a minimum sensitivity of 25 mIU/ml.
  • For women of childbearing potential: agreement to use a highly effective contraceptive methods (excluding moderate and strong CYP3A4 inhibitors throughout the study, and weak CYP3A4 inhibitor until the morning of Day 8) with a failure rate of < 1% per year 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.
    • Note: A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
    • Note: Examples of highly effective contraceptive methods (excluding moderate and strong CYP3A4 inhibitors throughout the study, and weak CYP3A4 inhibitor until the morning of Day 8) with a failure rate of < 1% per year include bilateral tubal ligation, vasectomized partner (male sterilization), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine hormone-releasing system and copper-banded intrauterine devices, and sexual abstinence.
    • Note: Combined (estrogen and progestogen containing) hormonal contraceptives which are associated with inhibition of ovulation (oral, intravaginal, transdermal) are permitted from the morning of Day 8.
    • Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures. Men must refrain from donating sperm during this same period.
    • Note: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 28 days after the last dose of PCO371 to avoid exposing the embryo.
    • Note: The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • 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 (i.e., pseudohypoparathyroidism [PHP]).
  • Clinically significant hypomagnesemia. Adequately treated hypomagnesemia is permitted.
  • Any disease that might affect calcium metabolism or calciumphosphate homeostasis other than hypoparathyroidism, such as active hyperthyroidism, Paget's disease, severe and chronic cardiac, liver or renal disease, Cushing's syndrome, neuromuscular disease such as rheumatoid arthritis, myeloma, chronic pancreatitis, acute pancreatitis within last 2 years (from Screening), malnutrition, rickets, recent prolonged immobility, active malignancy, a history of parathyroid carcinoma, hypopituitarism, acromegaly, or multiple endocrine neoplasia types I and II.
  • History of a major bone fracture within 3 months prior to Screening that is deemed clinically significant by the investigator.
  • 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 (from Screening).
  • History of any other cancer in the past 3 years (from Screening) with the exception of thyroid cancer (as described in prior exclusion criterion), 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 including but not limited to short bowel syndrome, bowel resection, tropical sprue, celiac disease, ulcerative colitis, Crohn’s disease, previous gastric resection or active peptic ulcer disease requiring medical therapy.
  • Use of oral bisphosphonates within 6 months of Screening and/or intravenous (IV) 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 (other than oral calcium and oral active vitamin D) such as calcitonin, fluoride tablets or cinacalcet hydrochloride within 4 weeks prior to Screening.
  • Patients who have taken weak, moderate and strong inducers of CYP3A4, P-gp, or breast cancer resistance protein (BCRP) within 1 month before investigational medicinal product (IMP) administration or have taken weak, moderate or strong inhibitors of CYP3A4, P-gp, or BCRP (including herbal products, diets, and drinks) 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 (e.g., heparins, warfarin, and thrombolytic agents), anti-platelet medications (e.g., argatroban and ticlopidine), 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. All patients less than 20 years of age (at Screening) must have a radiograph of the left wrist at time of screening unless a radiograph of the left wrist performed within 6 months prior to screening demonstrates no open epiphysis of the distal radius.
  • Alanine transaminase, aspartate transaminase, or alkaline phosphatase > 2.5 × ULN at Screening.
  • Patients with documented active hepatitis B virus (HBV), active hepatitis C virus (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 including, but not limited to, clinically significant (as determined by the investigator) chronic heart failure, arrhythmias, symptomatic bradycardia, uncontrolled hypertension or hypotension.
  • Active gout or history of active gout within 6 months prior to first dose of study medication.
  • History of clinically significant cognitive deficit (including cerebrovascular accident) 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 N-terminal 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. Note: Hypersensitivity refers to immune-related reactions, and intolerances, such as lactose intolerance, which are not immune-related, do not meet this definition for exclusion.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Bart Clarke, M.D.

Contact us for the latest status

Contact information:

Tamera Roberson

(507) 255-8621

Roberson.Tamera@mayo.edu

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

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CLS-20484360

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