Oral PTH(1-34) PK and PD Study in Patients With Hypoparathyroidism

• ClinicalTrials.gov Identifier: NCT03516773
• Recruitment Status: Completed
• First Posted: May 4, 2018
• Last Update Posted: March 26, 2019
• Sponsor: Entera Bio Ltd.
• Information provided by (Responsible Party): Entera Bio Ltd.

Study Description

Brief Summary:

A Randomized, active comparator, two-part, partial crossover design. The study is designed to assess the pharmacokinetics and pharmacodynamics of EnteraBio's Oral PTH(1-34) [EB612 (EBP05)] in adult patients with hypoparathyroidism.

Condition or disease	Intervention/treatment	Phase
Hypoparathyroidism	Drug: EB612 (EBP05); Drug: NATPARA/NATPAR	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Randomized, active comparator, two-part, within-part, partial crossover design.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Evaluation of the Pharmacokinetics and Pharmacodynamics of Oral Parathyroid Hormone [PTH (1-34)] and NATPARA® in Patients With Hypoparathyroidism
• Actual Study Start Date: June 17, 2018
• Actual Primary Completion Date: December 5, 2018
• Actual Study Completion Date: February 24, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment A; Intervention: EB612 (EBP05) 2.25 mg orally (PO) four times a day (QID) (approximately 5 hours apart) for 4 doses, for a total dose of 9 mg per day	Drug: EB612 (EBP05); Entera Bio's proprietary drug for the administration of PTH(1-34) orally; Other Name: Oral PTH(1-34)
Experimental: Treatment B; Intervention: EB612 (EBP05) 2.25 mg PO twice a day (BID) (approximately 10 hours apart) for 2 doses, for a total dose of 4.5 mg per day	Drug: EB612 (EBP05); Entera Bio's proprietary drug for the administration of PTH(1-34) orally; Other Name: Oral PTH(1-34)
Active Comparator: Treatment C; Intervention: NATPARA/NATPAR PTH(1-84) 100 μg subcutaneous injection once daily (single dose)	Drug: NATPARA/NATPAR; A PTH replacement (PTH [1-84]; NATPARA (Shire-NPS Pharmaceuticals, Inc., Lexington, Massachusetts) was approved by the United States (US) Food and Drug Administration (FDA) in April 2015 / NATPAR (Shire Pharmaceuticals Ltd., Dublin, Ireland) was approved by the European Medicines Agency in April 2017 for use as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. Like many other hormonally active peptides, PTH (1 84); NATPARA is parenterally administered. In this protocol when a specific formulation is referenced (e.g. NATPARA) it may be read interchanged with the alternate formulation (e.g. NATPAR).; Other Name: PTH(1-84)
Experimental: Treatment D; Intervention: EB612 (EBP05) 2.25 mg PO TID (dose 1 and dose 2 approximately 10 hours apart; dose 2 and dose 3 approximately 5 hours apart- TID schedule option 2), for a total dose of 6.75 mg per day	Drug: EB612 (EBP05); Entera Bio's proprietary drug for the administration of PTH(1-34) orally; Other Name: Oral PTH(1-34)
Experimental: Treatment E - EB612 (EBP05); Intervention: EB612 (EBP05) 0.75 mg PO TID (dose 1 and dose 2 approximately 10 hours apart; dose 2 and dose 3 approximately 5 hours apart- TID schedule option 2), for a total dose of 2.25 mg per day	Drug: EB612 (EBP05); Entera Bio's proprietary drug for the administration of PTH(1-34) orally; Other Name: Oral PTH(1-34)

Outcome Measures

Primary Outcome Measures :

1. Plasma PTH(1-34) levels [ Time Frame: 18 weeks ]
   Pharmacokinetic Parameter
2. Serum albumin-adjusted total calcium levels [ Time Frame: 18 weeks ]
   Pharmacodynamic Parameter
3. urinary calcium levels [ Time Frame: 18 weeks ]
   Pharmacodynamic Parameter

Secondary Outcome Measures :

1. Adverse Events [ Time Frame: 60 days ]
   Safety Parameter
2. Rate of Adverse Events leading to discontinuation [ Time Frame: 60 days ]
   Tolerability Parameter

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

-Criteria for Inclusion:

1. Confirmed diagnosis of primary hypoparathyroidism, as defined by the European Society of Endocrinology as a patient with hypocalcemia and inappropriately low PTH levels. If the source of hypoparathyroidism is surgical or iatrogenic, diagnosis must be for more than 1 year. If the source of hypoparathyroidism is not surgical or iatrogenic, and confirmed by inappropriately low PTH levels and hypercalciuria, diagnosis does not have time limitations.
2. 1, 25(OH)2D levels ≥20 ng/mL.
3. Signed Informed Consent Form).
4. Age 18 to 80 years with body mass index of 19 to 35 kg/m2.
5. Patients able to adhere to the visit schedule and protocol requirements.

Criteria for Exclusion:

1. Known history of hypoparathyroidism resulting from an activating mutation in the calcium sensing receptor gene or impaired responsiveness to PTH (pseudohypoparathyroidism).
2. Hemoglobin <11.5 g/dL (females) / <12.5g/dL (males) [lower limit of reference range, 12 to 15 g/dL and 13 to 17 g/dL]
3. Acute or chronic renal failure (estimated glomerular filtration rate <60 mL/min/1.73 m²).
4. Significant liver function impairment (liver enzymes above ×2 the upper limit of normal range).
5. Patients with hypomagnesemia should be excluded unless serum magnesium is corrected prior to study initiation.
6. Active gastrointestinal inflammatory, gastrointestinal motility disorders, and chronic gastritis, such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, short bowel syndrome, celiac disease, gastroparesis, etc.
7. Active hepatitis or acquired immunodeficiency syndrome (AIDS)/AIDS-related syndrome
8. Any conditions or factors that, in the judgment of the Investigator, somehow may impact gastrointestinal absorption.
9. Concurrent therapy with the following medications: (1) 14 days: thiazide diuretics; loop diuretics (2) 30 days: lithium, systemic corticosteroid; (3) 1 month: calcitonin, cinacalcet hydrochloride, recombinant PTH(1-84) or N-terminal PTH or PTH-related peptide fragments or analogs; (4) females only; changes in hormone replacement therapy within 2 months; (5) 3 months: methotrexate, growth hormone, digoxin; raloxifene or similar selective estrogen receptor modulators; (7) chronic or concurrent use of gastrointestinal motility modulators (domperidone, loperamide, erythromycin metoclopramide etc.); and (8) other concurrent therapy that, in the Investigator's opinion, would interfere with the evaluation of the safety or efficacy of the study medication.
10. Significant drug or alcohol abuse as assessed by the PI.
11. Treatment with any investigational product within the last 30 days or 5 half-lives (if known) whichever is longer.
12. Has participated as a patient in any investigational drug study within the last 30 days preceding the screening visit or plans to participate in another investigational drug study at any time during the study or within 30 days of his/her completion of this study.
13. Presence of any other condition or circumstance that, in the judgment of the Investigator, might increase the risk to the patient or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
14. Historical documented allergy to soy bean products or known hypersensitivity to the PTH (1-34).
15. Patients at increased risk for osteosarcoma, such as those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, hereditary disorders predisposing to osteosarcoma, or with a prior history of external beam or implant radiation involving the skeleton.
16. Patients with skeletal malignancies or bone metastases.
17. Pregnancy or suspected pregnancy or lactating. Female patients of childbearing potential must have a negative pregnancy test at screening and be willing and able to use two medically acceptable methods of birth control (reliable use of oral contraceptive with physical barrier, non-hormonal intrauterine device with condom, diaphragm with condom, or condom with spermicide) from the screening visit through 90 days from last dose or declare that they are abstaining from sexual intercourse from the screening visit through the study termination visit or are surgically sterile (have undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or postmenopausal. True abstinence can only be in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and postovulation methods), declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of contraception.

Childbearing potential is defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal. Women will be defined as postmenopausal if they have been amenorrheic for 12 months (prior to signature of Informed Consent Form) without an alternative medical cause.

Contacts and Locations

Locations

Israel

Clinical Research Center Hadassah Ein Kerem Medical Center

Jerusalem, Israel, 91120,

Sponsors and Collaborators

Entera Bio Ltd.

Investigators

• Study Chair: Arthur Santora, MD; Entera Bio Ltd.

More Information

• Responsible Party: Entera Bio Ltd.
• ClinicalTrials.gov Identifier: NCT03516773
• Other Study ID Numbers: ENT-04-2018
• First Posted: May 4, 2018
• Last Update Posted: March 26, 2019
• Last Verified: March 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Entera Bio Ltd.:

Hypoparathyroidism, PTH(1-34), Parathyroid Hormone

Additional relevant MeSH terms:

Hypoparathyroidism; Parathyroid Diseases; Endocrine System Diseases; Parathyroid Hormone; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs