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Assess Safety and Compare PK of New Oral hPTH(1-34) Tablet Formulations vs. EBP05 Tablets and Subcutaneous Forteo

Primary Purpose

Hypoparathyroidism

Status
Recruiting
Phase
Phase 1
Locations
Israel
Study Type
Interventional
Intervention
EBP05
Forteo 20 mg
EBP11
EBP22
EBP11-M
Sponsored by
Entera Bio Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoparathyroidism focused on measuring Hypoparathyroidism, PTH(1-34), Parathyroid Hormone, Teriparatide

Eligibility Criteria

18 Years - 35 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria: Healthy male subjects, 18 - 35 years of age, inclusive, at screening. Continuous nonsmoker who has not used nicotine containing products (including e-cigarettes, vapors, etc.) for at least 12 months prior to first dosing and throughout the study, based on subject self-reporting. Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kg/m2 at screening. Medically healthy with no clinically significant medical condition, physical examination, laboratory profiles, vital signs, orthostatic vital sign measurements, or ECGs, as deemed by the PI or designee to be relevant to the study and does not pose an additional risk to the subject by their participation in the study. Understands the study procedures described in the Informed Consent Form (ICF), be willing and able to comply with the protocol, and provides written consent. Exclusion Criteria: History or current condition of mental instability or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures. Active gastrointestinal inflammatory disorder, gastrointestinal motility disorders, and chronic gastritis, including but not limited to: ulcerative colitis, Crohn's disease, irritable bowel syndrome, short bowel syndrome, celiac disease, gastroparesis, that may affect drug bioavailability. Any conditions or factors that, in the judgment of the PI or designee, somehow may impact gastrointestinal absorption, distribution or metabolism of parathyroid hormone analogues, or known to potentiate or predispose to undesired effects. History of significant gastrointestinal, liver or kidney disease, or gastrointestinal surgery (including bariatric surgery, or any other interventional procedures with stomach and intestinal tract) that may affect either drug bioavailability, or hPTH(1-34) or SNAC metabolism. History or presence of alcohol or drug abuse or positive urine drug or blood alcohol results at screening. Known allergies or sensitivities to components of the Study Medication (e.g. soy) or known hypersensitivity to PTH or hPTH(1-34). History or presence of clinically significant: Urolithiasis; Angina at Screening, in the opinion of the PI; Hypocalcemia or hypercalcemia at screening; Personal or family history of congenital long QT syndrome or known family history of sudden death. Subjects with ECG findings deemed abnormal with clinical significance by the PI or designee at screening for the following: QTcF interval > 470 msec; PR > 220 msec; QRS > 120 msec. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). Seated blood pressure is less than 90 systolic or 40 diastolic mmHg or greater than 140 systolic or 90 diastolic mmHg at screening; Orthostatic vital sign results with a decrease in systolic > 20 mmHg or decrease in diastolic > 10 mm Hg, and/or increase in heart rate of > 20 beats per minute at screening or Day 1 check-in. Seated heart rate is lower than 50 bpm or higher than 99 bpm at screening (when clinically significant as determined by PI). Estimated creatinine clearance < 80 mL/min at screening Unable to refrain from or anticipates the use of: Any drug, including prescription and nonprescription medications, herbal remedies, or vitamin supplements that should be taken on the treatment visit day before the dosing of Study Medication and 2 hours after the dosing of Study Medication. H2 blocker or PPI or antacid (including prescription and nonprescription) three days before the dosing of the Study Medication and 2 hours after the dosing of Study Medication. Donation of blood or significant blood loss within 56 days prior to first dosing. Hemoglobin levels below 13 g/dL at screening or at in screening test done during the study. Plasma donation within 7 days prior to first dosing. Participation in another interventional clinical study within 30 days prior to screening visit.

Sites / Locations

  • Clinical Research Center Hadassah Ein Kerem Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Treatment A EBP05 2.5 mg

Treatment B EBP05 1.5 mg

Treatment C Forteo 20 mg

Treatment D EBP11 1.5 mg

Treatment E EBP11 BID (dose determined after IA)

Treatment F EBP11 BID (dose determined after IA)

Treatment G EBP11 1.5 mg

Treatment H EBP11-M 1.5 mg

Treatment I EBP22 1.5 mg

Treatment J EBP22 1.5 mg

Treatment K oral EBP formulation determined based on IA results

Treatment L BID of oral EBP formulation determined based on IA results

Treatment M BID of EBP05 2.5 mg

Treatment N single dose of Treatment K

Arm Description

Single dose of oral EBP05 2.5 mg

Single dose of oral EBP05 1.5 mg

Single SC injection of Forteo 0.02 mg

Single dose of oral EBP11 1.5 mg

Based on PK data from 1st Interim Analysis BID administration of oral EBP11. The selected BID dose to be administered will be either 1.5, 2.0 or 2.5 mg.

BID administration of oral EBP11 tablets. The selected EBP11 dose will be either 1.5, 2.0 or 2.5 mg based on hPTH(1-34) PK data from the 1st and 2nd Interim Analyses.

Single dose of oral EBP11 1.5 mg

Single dose of oral EBP11-M 1.5 mg

Single dose of oral EBP22 1.5 mg

Single dose of oral EBP22 1.5 mg

Single dose of oral 1.5 mg of the selected oral formulation (EBP11, EBP11-M, or EBP22) based on the results of all Cohort 1 and 2 Interim Analyses

BID dose of oral 1.5 mg of the selected oral formulation (EBP11, EBP11-M, or EBP22) based on the results of all Cohort 1 and 2 Interim Analyses

BID dose of oral EBP05 2.5 mg

Single dose of Treatment K

Outcomes

Primary Outcome Measures

Assessment of the pharmacokinetic profile of plasma hPTH(1-34) after single or twice daily oral administration for treatment regimen as listed under Arms and Interventions at 5, 10, 15, 20, 40, 50, 60, 75, 90, 105, 120, 180, 240, 360 min. post dose
Pharmacokinetic parameter - plasma hPTH(1-34) in pg/mL
Calculation of plasma levels of hPTH(1-34) AUC0-t for each treatment regimen
Pharmacokinetic parameter - total drug exposure at different time points up to 360 min. post dose
Calculation of plasma levels of hPTH(1-34) AUC0-inf for each treatment regimen
Pharmacokinetic parameter - total drug exposure in pg/mL over time from 0 extrapolated to infinity
Calculation of plasma levels of hPTH(1-34) AUC%extrap for each treatment regimen
Pharmacokinetic parameter - Percent of AUC0-inf extrapolated to confirm reliability
Calculation of plasma levels of hPTH(1-34) Cmax for each treatment regimen
Pharmacokinetic parameter - hPTH (1-34) maximal concentration in pg/mL (Cmax)
Calculation of plasma levels of hPTH(1-34) Tmax for each treatment regimen
Pharmacokinetic parameter - time in minutes to reach max. concentration of hPTH(1-34)
Calculation of plasma levels of hPTH(1-34) Kel for each treatment regimen
Pharmacokinetic parameter - elimination rate constant in pg/mL, fraction of drug eliminated per time-point up to 360 min. post dose
Calculation of plasma levels of hPTH(1-34) t½ for each treatment regimen
Pharmacokinetic parameter - terminal elimination half life of hPTH(1-34) in minutes
Calculation of plasma levels of hPTH(1-34) Tlast for each treatment regimen
Pharmacokinetic parameter - time of the last measurable concentration of hPTH(1-34) in minutes
Assessment of inter-subject variability of hPTH(1-34) for each treatment regimen
Pharmacokinetic parameter - Coefficient of Variance (CV%) of hPTH (1-34)
Calculation of dose proportionality for hPTH(1-34) for relevant treatment regimen
Pharmacokinetic parameter
Assessment of the duration of exposure to hPTH(1-34) in minutes
Pharmacokinetic parameter - up to 360 min. post dose
Vital Signs - body temperature (Celsius)
Safety parameter (group mean at each time point up to 360 min. post dose)
Vital Signs - respiratory rate (breaths per minute)
Safety parameter (group mean at each time point up to 360 min. post dose)
Vital Signs - blood pressure (systolic/diastolic mmHg)
Safety parameter (group mean at each time point up to 360 min. post dose)
Vital Signs - heart rate (beats per minute)
Safety parameter (group mean at each time point up to 360 min. post dose)
Incidence of Treatment-Emergent Adverse Events as assessed by the Principle Investigator
Safety parameter - AEs observed over duration of study participation
Incidence of Serious Adverse Events (SAEs) as assessed by the Principle Investigator
Safety parameter - SAEs observed over duration of study participation

Secondary Outcome Measures

Full Information

First Posted
June 8, 2023
Last Updated
July 27, 2023
Sponsor
Entera Bio Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT05965167
Brief Title
Assess Safety and Compare PK of New Oral hPTH(1-34) Tablet Formulations vs. EBP05 Tablets and Subcutaneous Forteo
Official Title
A Phase 1b, Open-label, Partially Randomised Study to Assess Safety and Compare Pharmacokinetics of New Oral hPTH(1-34) Tablet Formulations vs. Oral EBP05 Tablets and Subcutaneous Forteo® Injection in Healthy Male Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 11, 2023 (Actual)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Entera Bio Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to characterize and compare the pharmacokinetics of hPTH(1 34) after treatment with a modified oral formulation (EBP11, EBP11-M, and EBP22) versus two dose levels of Entera Bio's extensively studied oral EBP05 1.5 mg and 2.5 mg as well as the commercial Forteo 0.02 mg subcutaneous injection.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoparathyroidism
Keywords
Hypoparathyroidism, PTH(1-34), Parathyroid Hormone, Teriparatide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment A EBP05 2.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP05 2.5 mg
Arm Title
Treatment B EBP05 1.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP05 1.5 mg
Arm Title
Treatment C Forteo 20 mg
Arm Type
Experimental
Arm Description
Single SC injection of Forteo 0.02 mg
Arm Title
Treatment D EBP11 1.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP11 1.5 mg
Arm Title
Treatment E EBP11 BID (dose determined after IA)
Arm Type
Experimental
Arm Description
Based on PK data from 1st Interim Analysis BID administration of oral EBP11. The selected BID dose to be administered will be either 1.5, 2.0 or 2.5 mg.
Arm Title
Treatment F EBP11 BID (dose determined after IA)
Arm Type
Experimental
Arm Description
BID administration of oral EBP11 tablets. The selected EBP11 dose will be either 1.5, 2.0 or 2.5 mg based on hPTH(1-34) PK data from the 1st and 2nd Interim Analyses.
Arm Title
Treatment G EBP11 1.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP11 1.5 mg
Arm Title
Treatment H EBP11-M 1.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP11-M 1.5 mg
Arm Title
Treatment I EBP22 1.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP22 1.5 mg
Arm Title
Treatment J EBP22 1.5 mg
Arm Type
Experimental
Arm Description
Single dose of oral EBP22 1.5 mg
Arm Title
Treatment K oral EBP formulation determined based on IA results
Arm Type
Experimental
Arm Description
Single dose of oral 1.5 mg of the selected oral formulation (EBP11, EBP11-M, or EBP22) based on the results of all Cohort 1 and 2 Interim Analyses
Arm Title
Treatment L BID of oral EBP formulation determined based on IA results
Arm Type
Experimental
Arm Description
BID dose of oral 1.5 mg of the selected oral formulation (EBP11, EBP11-M, or EBP22) based on the results of all Cohort 1 and 2 Interim Analyses
Arm Title
Treatment M BID of EBP05 2.5 mg
Arm Type
Experimental
Arm Description
BID dose of oral EBP05 2.5 mg
Arm Title
Treatment N single dose of Treatment K
Arm Type
Experimental
Arm Description
Single dose of Treatment K
Intervention Type
Drug
Intervention Name(s)
EBP05
Other Intervention Name(s)
hPTH(1-34)
Intervention Description
Oral tablets
Intervention Type
Drug
Intervention Name(s)
Forteo 20 mg
Other Intervention Name(s)
hPTH(1-34)
Intervention Description
Subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
EBP11
Other Intervention Name(s)
hPTH(1-34)
Intervention Description
Oral tablets
Intervention Type
Drug
Intervention Name(s)
EBP22
Other Intervention Name(s)
hPTH(1-34)
Intervention Description
Oral tablets
Intervention Type
Drug
Intervention Name(s)
EBP11-M
Other Intervention Name(s)
hPTH(1-34)
Intervention Description
Oral tablets
Primary Outcome Measure Information:
Title
Assessment of the pharmacokinetic profile of plasma hPTH(1-34) after single or twice daily oral administration for treatment regimen as listed under Arms and Interventions at 5, 10, 15, 20, 40, 50, 60, 75, 90, 105, 120, 180, 240, 360 min. post dose
Description
Pharmacokinetic parameter - plasma hPTH(1-34) in pg/mL
Time Frame
6 hours
Title
Calculation of plasma levels of hPTH(1-34) AUC0-t for each treatment regimen
Description
Pharmacokinetic parameter - total drug exposure at different time points up to 360 min. post dose
Time Frame
6 hours
Title
Calculation of plasma levels of hPTH(1-34) AUC0-inf for each treatment regimen
Description
Pharmacokinetic parameter - total drug exposure in pg/mL over time from 0 extrapolated to infinity
Time Frame
6-14 hours
Title
Calculation of plasma levels of hPTH(1-34) AUC%extrap for each treatment regimen
Description
Pharmacokinetic parameter - Percent of AUC0-inf extrapolated to confirm reliability
Time Frame
6-14 hours
Title
Calculation of plasma levels of hPTH(1-34) Cmax for each treatment regimen
Description
Pharmacokinetic parameter - hPTH (1-34) maximal concentration in pg/mL (Cmax)
Time Frame
6-14 hours
Title
Calculation of plasma levels of hPTH(1-34) Tmax for each treatment regimen
Description
Pharmacokinetic parameter - time in minutes to reach max. concentration of hPTH(1-34)
Time Frame
6-14 hours
Title
Calculation of plasma levels of hPTH(1-34) Kel for each treatment regimen
Description
Pharmacokinetic parameter - elimination rate constant in pg/mL, fraction of drug eliminated per time-point up to 360 min. post dose
Time Frame
6 hours
Title
Calculation of plasma levels of hPTH(1-34) t½ for each treatment regimen
Description
Pharmacokinetic parameter - terminal elimination half life of hPTH(1-34) in minutes
Time Frame
6-14 hours
Title
Calculation of plasma levels of hPTH(1-34) Tlast for each treatment regimen
Description
Pharmacokinetic parameter - time of the last measurable concentration of hPTH(1-34) in minutes
Time Frame
6-14 hours
Title
Assessment of inter-subject variability of hPTH(1-34) for each treatment regimen
Description
Pharmacokinetic parameter - Coefficient of Variance (CV%) of hPTH (1-34)
Time Frame
6-14 hours
Title
Calculation of dose proportionality for hPTH(1-34) for relevant treatment regimen
Description
Pharmacokinetic parameter
Time Frame
6 hours
Title
Assessment of the duration of exposure to hPTH(1-34) in minutes
Description
Pharmacokinetic parameter - up to 360 min. post dose
Time Frame
6 hours
Title
Vital Signs - body temperature (Celsius)
Description
Safety parameter (group mean at each time point up to 360 min. post dose)
Time Frame
6 hours
Title
Vital Signs - respiratory rate (breaths per minute)
Description
Safety parameter (group mean at each time point up to 360 min. post dose)
Time Frame
6 hours
Title
Vital Signs - blood pressure (systolic/diastolic mmHg)
Description
Safety parameter (group mean at each time point up to 360 min. post dose)
Time Frame
6 hours
Title
Vital Signs - heart rate (beats per minute)
Description
Safety parameter (group mean at each time point up to 360 min. post dose)
Time Frame
6 hours
Title
Incidence of Treatment-Emergent Adverse Events as assessed by the Principle Investigator
Description
Safety parameter - AEs observed over duration of study participation
Time Frame
6-14 hours
Title
Incidence of Serious Adverse Events (SAEs) as assessed by the Principle Investigator
Description
Safety parameter - SAEs observed over duration of study participation
Time Frame
6-14 hours
Other Pre-specified Outcome Measures:
Title
Measurement of plasma soybean trypsin inhibitor, Kunitz type (SBTI) levels (EBP05 only)
Description
Pharmacokinetic parameter in ng/mL
Time Frame
6 hours
Title
Measurement of plasma salcaprozate sodium (SNAC) levels (EBP05 only)
Description
Pharmacokinetic parameter in μg/mL
Time Frame
6 hours
Title
Measurement of serum calcium (albumin-corrected total calcium) for all treatment regimen
Description
Pharmacodynamic parameter in mg/dL at 120, 240, 360 min post dose
Time Frame
6 hours
Title
Measurement of serum phosphate for all treatment regimen
Description
Pharmacodynamic parameter in mg/dL at 120, 240, 360 min post dose
Time Frame
6 hours
Title
Measurement of serum intact hPTH(1-84) for all treatment regimen
Description
Pharmacodynamic parameter in pg/mL at 120, 240, 360 min post dose
Time Frame
6 hours
Title
Measurement of serum 1,25-(OH)2D for all treatment regimen (optional)
Description
Pharmacodynamic parameter in ng/mL at 120, 240, 360 min post dose
Time Frame
6 hours

10. Eligibility

Sex
Male
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy male subjects, 18 - 35 years of age, inclusive, at screening. Continuous nonsmoker who has not used nicotine containing products (including e-cigarettes, vapors, etc.) for at least 12 months prior to first dosing and throughout the study, based on subject self-reporting. Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kg/m2 at screening. Medically healthy with no clinically significant medical condition, physical examination, laboratory profiles, vital signs, orthostatic vital sign measurements, or ECGs, as deemed by the PI or designee to be relevant to the study and does not pose an additional risk to the subject by their participation in the study. Understands the study procedures described in the Informed Consent Form (ICF), be willing and able to comply with the protocol, and provides written consent. Exclusion Criteria: History or current condition of mental instability or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures. Active gastrointestinal inflammatory disorder, gastrointestinal motility disorders, and chronic gastritis, including but not limited to: ulcerative colitis, Crohn's disease, irritable bowel syndrome, short bowel syndrome, celiac disease, gastroparesis, that may affect drug bioavailability. Any conditions or factors that, in the judgment of the PI or designee, somehow may impact gastrointestinal absorption, distribution or metabolism of parathyroid hormone analogues, or known to potentiate or predispose to undesired effects. History of significant gastrointestinal, liver or kidney disease, or gastrointestinal surgery (including bariatric surgery, or any other interventional procedures with stomach and intestinal tract) that may affect either drug bioavailability, or hPTH(1-34) or SNAC metabolism. History or presence of alcohol or drug abuse or positive urine drug or blood alcohol results at screening. Known allergies or sensitivities to components of the Study Medication (e.g. soy) or known hypersensitivity to PTH or hPTH(1-34). History or presence of clinically significant: Urolithiasis; Angina at Screening, in the opinion of the PI; Hypocalcemia or hypercalcemia at screening; Personal or family history of congenital long QT syndrome or known family history of sudden death. Subjects with ECG findings deemed abnormal with clinical significance by the PI or designee at screening for the following: QTcF interval > 470 msec; PR > 220 msec; QRS > 120 msec. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). Seated blood pressure is less than 90 systolic or 40 diastolic mmHg or greater than 140 systolic or 90 diastolic mmHg at screening; Orthostatic vital sign results with a decrease in systolic > 20 mmHg or decrease in diastolic > 10 mm Hg, and/or increase in heart rate of > 20 beats per minute at screening or Day 1 check-in. Seated heart rate is lower than 50 bpm or higher than 99 bpm at screening (when clinically significant as determined by PI). Estimated creatinine clearance < 80 mL/min at screening Unable to refrain from or anticipates the use of: Any drug, including prescription and nonprescription medications, herbal remedies, or vitamin supplements that should be taken on the treatment visit day before the dosing of Study Medication and 2 hours after the dosing of Study Medication. H2 blocker or PPI or antacid (including prescription and nonprescription) three days before the dosing of the Study Medication and 2 hours after the dosing of Study Medication. Donation of blood or significant blood loss within 56 days prior to first dosing. Hemoglobin levels below 13 g/dL at screening or at in screening test done during the study. Plasma donation within 7 days prior to first dosing. Participation in another interventional clinical study within 30 days prior to screening visit.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arthur C Santora, MD
Organizational Affiliation
Entera Bio Chief Medical Officer
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Research Center Hadassah Ein Kerem Medical Center
City
Jerusalem
ZIP/Postal Code
91120,
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yosef Caraco, MD
Phone
02-677-8584
Email
caraco@hadassah.org.il
First Name & Middle Initial & Last Name & Degree
Yosef Caraco, MD

12. IPD Sharing Statement

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Assess Safety and Compare PK of New Oral hPTH(1-34) Tablet Formulations vs. EBP05 Tablets and Subcutaneous Forteo

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