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

Study Overview
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Brief Summary
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The purpose of this study is to characterize and compare the pharmacokinetics of hPTH(1 34) after treatment with a modified oral formulation (EBP11 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.

Official Title
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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

Conditions
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Hypoparathyroidism

Intervention / Treatment
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* Drug: EBP05
* Drug: Forteo 20 mg
* Drug: EBP11
* Drug: EBP22


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A EBP05 2.5 mg<br>Single dose of oral EBP05 2.5 mg | Drug: EBP05<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment B EBP05 1.5 mg<br>Single dose of oral EBP05 1.5 mg | Drug: EBP05<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment C Forteo 20 mg<br>Single SC injection of Forteo 0.02 mg | Drug: Forteo 20 mg<br>* Subcutaneous injection<br>* Other names: hPTH(1-34);|
| Experimental: Treatment D EBP11 1.5 mg<br>Single dose of oral EBP11 1.5 mg | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment E EBP11 BID (dose determined after IA)<br>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. | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment F EBP11 BID (dose determined after IA)<br>BID administration of oral EBP11 tablets 1.5 mg tablets (3 x 0.5 mg tablets) as first dose and 2.5 mg (5 x 0.5 mg tablets) as second dose. | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment G EBP11 1.5 mg<br>Single dose of oral EBP11 1.5 mg | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment I EBP22 1.5 mg<br>Single dose of oral EBP22 1.5 mg | Drug: EBP22<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment J EBP22 1.5 mg<br>Single dose of oral EBP22 1.5 mg | Drug: EBP22<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment K oral EBP formulation determined based on IA results<br>Single dose of oral 1.5 mg of the selected oral formulation (EBP11 or EBP22) based on the results of all Cohort 1 and 2 Interim Analyses | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);Drug: EBP22<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment L BID of oral EBP formulation determined based on IA results<br>BID dose of oral 1.5 mg of the selected oral formulation (EBP11 or EBP22) based on the results of all Cohort 1 and 2 Interim Analyses | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);Drug: EBP22<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment M BID of EBP05 2.5 mg<br>BID dose of oral EBP05 2.5 mg | Drug: EBP05<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment N single dose of Treatment K<br>Single dose of Treatment K | Drug: EBP11<br>* Oral tablets<br>* Other names: hPTH(1-34);Drug: EBP22<br>* Oral tablets<br>* Other names: hPTH(1-34);|
| Experimental: Treatment H EBP22 2.5 mg (5 x 0.5 mg).<br>Singe dose of oral EBP22 2.5 mg (5 x 0.5 mg). | Drug: EBP22<br>* Oral tablets<br>* Other names: hPTH(1-34);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 6 hours | 
| 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 | 6 hours | 
| 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 | 6-14 hours | 
| Calculation of plasma levels of hPTH(1-34) AUC%extrap for each treatment regimen | Pharmacokinetic parameter - Percent of AUC0-inf extrapolated to confirm reliability | 6-14 hours | 
| Calculation of plasma levels of hPTH(1-34) Cmax for each treatment regimen | Pharmacokinetic parameter - hPTH (1-34) maximal concentration in pg/mL (Cmax) | 6-14 hours | 
| 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) | 6-14 hours | 
| 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 | 6 hours | 
| 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 | 6-14 hours | 
| 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 | 6-14 hours | 
| Assessment of inter-subject variability of hPTH(1-34) for each treatment regimen | Pharmacokinetic parameter - Coefficient of Variance (CV%) of hPTH (1-34) | 6-14 hours | 
| Calculation of dose proportionality for hPTH(1-34) for relevant treatment regimen | Pharmacokinetic parameter | 6 hours | 
| Assessment of the duration of exposure to hPTH(1-34) in minutes | Pharmacokinetic parameter - up to 360 min. post dose | 6 hours | 
| Vital Signs - body temperature (Celsius) | Safety parameter (group mean at each time point up to 360 min. post dose) | 6 hours | 
| Vital Signs - respiratory rate (breaths per minute) | Safety parameter (group mean at each time point up to 360 min. post dose) | 6 hours | 
| Vital Signs - blood pressure (systolic/diastolic mmHg) | Safety parameter (group mean at each time point up to 360 min. post dose) | 6 hours | 
| Vital Signs - heart rate (beats per minute) | Safety parameter (group mean at each time point up to 360 min. post dose) | 6 hours | 
| Incidence of Treatment-Emergent Adverse Events as assessed by the Principle Investigator | Safety parameter - AEs observed over duration of study participation | 6-14 hours | 
| Incidence of Serious Adverse Events (SAEs) as assessed by the Principle Investigator | Safety parameter - SAEs observed over duration of study participation | 6-14 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoparathyroidism, PTH(1-34), Parathyroid Hormone, Teriparatide