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Protocol Details

Phase 2 Study of the PTH-Independent Effects of Encaleret on Mineral Homeostasis in Subjects with Post-Surgical Hypoparathyroidism (PSH)

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

001085-D

Sponsoring Institute

National Institute of Dental And Craniofacial Research (NIDCR)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: 100 Years

Referral Letter Required

No

Population Exclusion(s)

Children;
Pregnant Women

Keywords

Hypoparathyroidism;
Hypocalcemia;
Post-Surgical Hypoparathyroidism;
Calcilytic;
Encaleret

Recruitment Keyword(s)

None

Condition(s)

Post-Surgical Hypoparathyroidism

Investigational Drug(s)

Encaleret

Investigational Device(s)

None

Intervention(s)

Drug: encaleret

Supporting Site

National Institute of Dental and Craniofacial Research

Background:

Parathyroid glands in the neck make a hormone that keeps blood calcium levels stable. Sometimes these glands are damaged or removed during neck surgery. This can lead to a condition called postsurgical hypoparathyroidism (PSH). People with PSH have low levels of calcium in their blood. Calcium and vitamin D pills can help them keep their blood calcium levels steady. But this can increase calcium in the urine and result in kidney problems. New treatments for PSH are needed.

Objective:

To test a drug (encaleret) in people with PSH.

Eligibility:

People aged 18 years and older who have PSH.

Design:

Participants will be in the study for 6 months. They will have a screening visit and a treatment visit.

Screening will take up to 2 days. Participants will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have an ultrasound of their kidneys; they will lie on a table for 15 to 30 minutes while a wand is moved over their back.

Treatment will require participants to stay in the clinic for 7 days and 6 nights. They will take the study drug (encaleret) by mouth twice a day for 5 days. They will have a small, flexible tube inserted into a vein; this will remain in place during the visit. Blood samples will be taken through the tube 4 to 9 times each day. Participants urine will be collected.

Participants will have follow-up blood tests 1 week after leaving the clinic. They will have 3 follow-up phone calls.

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Eligibility

INCLUSION CRITERIA:

Participants must meet the following criteria for inclusion during screening:

1. Be able to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.

2. Age >= 18 years

3. Postmenopausal women are allowed to participate in this study:

a. Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to start of the study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment, shall she be considered not of childbearing potential.

4. Body mass index (BMI) >= 18.5 to < 39 kg/m2

5. Have a diagnosis of PSH, either permanent PSH (Cohort 1, surgery >= 12 months ago) or recent PSH (Cohort 2, surgery < 12 months ago).

-Participants must have achieved a fasting albumin-corrected blood calcium level of 7.8-10.2 mg/dL on conventional therapy without significant symptoms of hypocalcemia or hypercalcemia at baseline.

6. Participants being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides for at least 5 half-lives prior to initiation of encaleret and remain off during the study

treatment period. (5 half-lives of hydrochlorothiazide = 75 hours; chlorothiazide = 10 hours; chlorthalidone = 12.5 days). If the thiazide is being used as an antihypertensive, as opposed to use as a urine calcium-lowering drug, alternative therapy will be offered.

7. Participants being treated with strong CYP3A4 inhibitors (including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) may be enrolled if they are willing and able to discontinue these medications for at least 5 half-lives prior to initiation of encaleret and remain off during the study treatment period.

8. Participants being treated with magnesium or potassium citrate supplements should discontinue such treatment starting on Day-2.

-Participants being treated with medications that have impacts on mineral metabolism which investigators believe may impact study endpoints may be enrolled if they are willing and safely able to discontinue the medication for at least 5 half-lives prior to initiation of encaleret and remain off during the study treatment period.

EXCLUSION CRITERIA:

Participants who meet any of the following criteria during Screening will not be eligible to

participate in the study:

1. History of treatment with any PTH analog (i.e., PTH 1-84, PTH 1-34, TransCon PTH, etc.) within the previous 3 months

2. History of prior treatment with encaleret

3. History of hypocalcemic seizure within the past 3 months

4. Blood 25-OH Vitamin D level <25 or >75 ng/mL

a. If subject has a blood 25-OH Vitamin D level < 25 ng/mL at the screening visit, they will be prescribed cholecalciferol or ergocalciferol supplementation. Once the 25-OH Vitamin D level is >= 25 ng/mL, the subject will be eligible to continue to the treatment phase of the study.

b. If a subject has a blood 25-OH Vitamin D level >75 ng/mL at the screening visit, their vitamin D supplementation will be adjusted. Once the 25-OH Vitamin D level is <=75 ng/mL, the subject will be eligible to continue to the treatment phase of the study.

5. Participants with hemoglobin (Hgb) < 13 g/dL for men and < 12 g/dL for women

a. If subject has a low Hgb at the screening visit due to iron, B12, or folate deficiency, they will be prescribed supplementation. Once the Hgb level is > 13 in men or > 12 in women, the subject will be eligible to continue to the treatment phase of the study.

6. Abnormal laboratory values which in the opinion of the investigator, would make the subject not suitable for participation in the study

7. Estimated glomerular filtration rate (eGFR) < 50 mL/minute/1.73 m2 using CKD-EPI.

8. Insufficient hepatic function defined as one of the following:

- Total Bilirubin > 1.5 x ULN OR

- Aspartate transaminase (AST) > 2x ULN OR

- Alanine transaminase (ALT) > 2x ULN

9. 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities. Participants with screening QTcF (using the Frederica equation) > 450 milliseconds (ms) will not be eligible for the treatment phase of the study.

- If a participant has a prolonged QTcF during screening due to a reversible cause of long QT (for example hypocalcemia or QT-prolonging medications), the subject may be eligible for the treatment phase of the study if the reversible cause can be addressed, and

repeat ECG shows QTcF <=450 milliseconds.

10. Clinically significant cardiac disease including any of the following:

- Congestive heart failure requiring treatment (NY Heart Association grade >= 2)

- History of clinically significant cardiac arrythmias including ventricular arrhythmias, atrial fibrillation, or conduction abnormalities

- History of unstable angina pectoris or acute myocardial infarction

11. Participants with positive hepatitis B surface antigen (HBsAg) or Hepatitis A immunoglobulin M (IgM) at the Screening Visit. Participants who are in complete remission from Hepatitis C as evidence by sensitive assay >=12 weeks after completion of HCV therapy are allowed to participate in the study. Participants with human immunodeficiency virus (HIV) infection on a stable dose of anti-retroviral therapy who have an undetectable viral load are allowed to participate in the study.

12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test

13. Abnormal thyroid function defined as one of the following:

- Thyroid Stimulating Hormone (TSH) >= 10 mIU/mL (hypothyroidism)

- TSH between upper limit of the normal range and 10 mIU/mL AND Free thyroxine < lower limit of normal (hypothyroidism)

- TSH < lower limit of normal, except in cases of intentional TSH-suppression for thyroid cancer.

- Participants with subclinical hypothyroidism, treated hypothyroidism, treated hyperthyroidism, and history of thyroid cancer are allowed to participate in this study. Participants with history of thyroid cancer requiring TSH-suppression therapy are allowed to participate in this study. If a participant does not meet the above criteria, the participant may be eligible for the treatment phase if their thyroid medications are adjusted, and subsequent thyroid function tests do not meet exclusion criteria.

14. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months following the discontinuation of study treatment. Highly effective contraception methods include:

-Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

-Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

-Male sterilization (at least 6 months prior to screening). For female participants on the study the vasectomized male partner should be the sole partner for that subject.

-Combination of the following (a+c or b+c):

a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception

b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

c. Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

15. Sexually active male participants who are unwilling to use a condom during vaginal intercourse while taking the encaleret (study drug) and for 3 months after the last dose of the study drug. Participants should not father a child during active participation in the study starting with the first encaleret dose. Condoms are not required if the subject is vasectomized or if the subject s partner is not a woman of child-bearing potential.

16. Hypersensitivity to any active substance or excipient of encaleret

17. History of drug or alcohol dependency within 12 months preceding the Screening Visit

18. Current participation in other investigational drug studies

19. Unwillingness to refrain from blood donation within 12 weeks prior to admission visit through one year after the last dose of the study drug. If subject donated blood within 12 weeks of the screening visit, they will need to wait until 12 weeks have passed since blood donation for the admission visit.

20. Participants who have a history of diseases of mineral metabolism other than hypoparathyroidism or hyperparathyroidism which investigators believe may impact study endpoints (for example, X-linked hypophosphatemia, rickets, etc).


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Citations:

Roberts MS, Gafni RI, Brillante B, Guthrie LC, Streit J, Gash D, Gelb J, Krusinska E, Brennan SC, Schepelmann M, Riccardi D, Bin Khayat ME, Ward DT, Nemeth EF, Rosskamp R, Collins MT. Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635). J Bone Miner Res. 2019 Sep;34(9):1609-1618. doi: 10.1002/jbmr.3747. Epub 2019 Jul 26. PMID: 31063613; PMCID: PMC6744344.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Michael T. Collins, M.D.
National Institute of Dental And Craniofacial Research (NIDCR)
NIHBC 30 BG RM 228
30 CONVENT DR
BETHESDA MD 20892
(301) 496-4913
mc247k@nih.gov

Karen A. Pozo, R.N.
National Institute of Dental And Craniofacial Research (NIDCR)
National Institutes of Health
Building 10
Room 1N103
10 Center Drive
Bethesda, Maryland 20892
(301) 827-1138
karen.pozo@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT05735015

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