This study is currently recruiting participants.
Number
001521-D
Sponsoring Institute
National Institute of Dental And Craniofacial Research (NIDCR)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 16 Years Max Age: 99 Years
Referral Letter Required
No
Population Exclusion(s)
Pregnant Women;Adults who are or may become unable to consent
Keywords
Hypoparathyroidism
Recruitment Keyword(s)
None
Condition(s)
Investigational Drug(s)
Encaleret (CTLX-305)
Investigational Device(s)
Intervention(s)
Drug: Encaleret Drug: Calcium and calcitriol
Supporting Site
National Institute of Dental and Craniofacial Research
The CALIBRATE study is a clinical research study designed to find out whether a study medicine can balance calcium levels in people with autosomal dominant hypocalcemia type 1 (ADH1), a genetic condition that causes low blood calcium levels.
Who can join the CALIBRATE study?
Study participants may be able to join the study if they are 16 years of age or older and have a confirmed diagnosis of autosomal dominant hypocalcemia type 1 (ADH1). If you do not know whether you have ADH1, ask your doctor about a genetic test that can help to provide this information. Contact us to speak with a study doctor and learn more about what is required to participate in the study.
What is the study medicine?
The study medicine is an investigational drug called encaleret. Investigational means the drug has not been approved by any health or regulatory agency and can only be used in clinical studies.
This research study will check how safe and effective encaleret is in people with ADH1. Encaleret is a tablet taken by mouth. Some participants will receive standard of care supplements (calcium supplements and/or active vitamin D analogues) instead of encaleret during the first part of the study, but all participants will receive encaleret if they are eligible and choose to participate in the Long-term Extension.
What will happen during the CALIBRATE study?
Participation in the CALIBRATE study lasts about 1 year, followed by an optional extension of up to 4 years. Study participants can expect the following:
1. Informed Consent: The participant (or a parent or legal guardian if they are younger than 18 years old) is required to read and sign the Informed Consent Form (ICF) before the participant has any tests or procedures.
2. Screening and SoC Optimization (up to 5 months): Participants will take calcium supplements and/or active vitamin D (for example, calcitriol or alfacalcidol) which are considered to be current Standard of Care (SoC) for ADH1. Participants will receive study tests and procedures to determine if they qualify for the CALIBRATE Study.
3. SoC Maintenance (about 1 month): Participants will continue to take SoC supplements and attend two study visits for study tests and procedures.
4. Study Medication or SoC Adjustment (about 5 months): Participants will be assigned randomly to either a group that continues SoC supplements or to a group that takes the study medication (encaleret). There will be twice as many participants assigned to the study medication group. Participants will attend regular study visits for study tests and procedures.
5. Study Medication or SoC Maintenance (about 1 month): Participants continue taking encaleret or SoC supplements (as assigned) and attend 1 study visit for study tests and procedures.
6. Optional Long-Term Extension (4 years): All eligible participants who elect to take part in the long-term extension study will receive the study medicine (encaleret) and attend study visits regularly every 3 months (if you were previously assigned to SoC, you will have more frequent visits at first) for up to 4 years. About half of these visits may be able to be completed at home.
Participation in a clinical study is voluntary. You can ask any questions you have and may leave the study at any time, for any reason.
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INCLUSION CRITERIA: Participants must meet the following criteria for inclusion during Screening: Age 1. Participant must be at least 16 years of age, at the time of signing the informed consent or assent. Type of Participant and Disease Characteristics 2. Participants must have a documented pathogenic or likely pathogenic activating variant, or variant of uncertain significance, of the CASR gene associated with biochemical findings of hypoparathyroidism either present at Screening or a documented history of both: a) cCa < 8.6 mg/dL (2.2 mmol/L) in participants 16 to < 18 years, or < 8.5 mg/dL (2.1 mmol/L) in participants >= 18 years b) iPTH < 40 pg/mL (4.2 pmol/L) Note: A genetic analysis report for CASR will be acceptable. In the absence of any documentation for the CASR variant, participants must be willing to undergo CASR variant analysis. Participants who have undergone an allogeneic bone marrow transplant must provide CASR variant analysis report performed prior to the bone marrow transplant. Participants who have received a packed red blood cell transfusion must wait 2 weeks following the transfusion before undergoing CASR variant analysis, and participants who have received a whole blood transfusion must wait 4 weeks following the transfusion before undergoing CASR variant analysis. 3. Participants must have a documented history of symptoms or signs of ADH1. Symptoms of ADH1 include agitation, anxiety, back pain, brain fog, bronchospasm, blepharospasm, cardiac failure, cognitive impairment, difficulty focusing/concentration, esophageal spasm, facial spasm, headaches, hypoesthesia (including facial and oral), irritability, laryngospasm, muscle cramping, muscle fatigue, muscle spasms, muscle tightness, muscle twitching, musculoskeletal pain, musculoskeletal stiffness, myalgia, nephrolithiasis, nervousness, paresthesia (including oral), polydipsia, polyuria, seizure, tetany, throat tightness, or tremor. Signs of ADH1 include basal ganglia or other cerebral calcification, Chvostek sign, hypercalciuria, nephrocalcinosis, papilledema, premature cataracts, prolonged QT interval on ECG, pseudotumor cerebri, or Trousseau sign. 4. Participants 16 to < 18 years old must have closed growth plates on hand radiograph defined as a bone age of 15 years in females and 17 years in males. 5. Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to SoC Optimization Visit 1 through Week 24 (Period 3). When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed. 6. Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to SoC Optimization Visit 1. 7. Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret. 8. Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret. 9. Participants must meet SoC Optimization criteria Sex and Contraceptive Requirements 10. Male participants with women of childbearing potential (WOCBP) partners must use acceptable contraceptive methods. 11. Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception: a) Females are considered postmenopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause and must be confirmed with plasma FSH. b) Females are considered not of childbearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy. 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. 12. Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Informed Consent 13. Capable of giving signed informed consent or assent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. History of hypocalcemic seizure within the past 3 months preceding Screening. 2. History of thyroid or parathyroid surgery. 3. History of the following within 5 years of screening: cancer except thyroid cancer, basal cell skin cancer or squamous cell skin cancer, patients with skeletal malignancies or bone metastases or irradiation (radiotherapy) to the skeleton. 4. History of renal transplantation. 5. Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive beta-human chorionic gonadotropin (beta-hCG) laboratory test. Prior/Concomitant Therapy 6. History of treatment with PTH 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC doses exceeding >1.2 x their pre-PTH treatment total daily doses or bone turnover markers, CTx and P1NP, > upper limit of normal for sex, age (men only) and menopausal status (women only). Prior/Concurrent Clinical Study Experience 7. Received any investigational medicinal product other than encaleret within 30 days or 5 half-lives, whichever is longer, prior to the first day on study, or are in follow-up for another interventional clinical study during Screening. If the half-life of an investigational medicinal product is unknown, then 30 days prior to Screening. Diagnostic Assessments 8. Blood 25-OH Vitamin D level <25 ng/mL If participant has a blood 25-OH Vitamin D level <25 ng/mL at the Screening Visit, they will be prescribed cholecalciferol or ergocalciferol supplementation per the Investigator. Once the 25-OH Vitamin D level is >25 ng/mL, the participant will be eligible to proceed with SoC Optimization (if still within Screening window of up to 84 days total) or re-screen for the study. 9. Estimated glomerular filtration rate <30 mL/minute/1.73 m^2 using CKD-EPIcr_R (for participants < 18 years old the Bedside Schwartz equation should be used). 10. 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia. 11. Participants with positive Hepatitis B surface antigen (HbsAg), Hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test at the Screening Visit. Participants who are in complete remission from Hepatitis C virus (HCV) as evidenced by sensitive assay >= 12 weeks after completion of HCV therapy may participate in the study. Other Exclusions 12. Male or female participants planning to conceive a child prior to the LTE. 13. Hypersensitivity to any active substance or excipient of encaleret. 14. Any current disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism. 15. Current treatment with cardiac glycosides (because hypercalcemia of any cause may predispose to digitalis toxicity). 16. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency. 17. Presence or history of any disease or condition (eg, drug or alcohol dependency) that, in the view of the Investigator, would affect the participant s safety or places the participant at high risk of poor treatment compliance or of not completing the study.
Participants must meet the following criteria for inclusion during Screening:
Age
1. Participant must be at least 16 years of age, at the time of signing the informed consent or assent.
Type of Participant and Disease Characteristics
2. Participants must have a documented pathogenic or likely pathogenic activating variant, or variant of uncertain significance, of the CASR gene associated with biochemical findings of hypoparathyroidism either present at Screening or a documented history of both:
a) cCa < 8.6 mg/dL (2.2 mmol/L) in participants 16 to < 18 years, or < 8.5 mg/dL (2.1 mmol/L) in participants >= 18 years
b) iPTH < 40 pg/mL (4.2 pmol/L)
Note: A genetic analysis report for CASR will be acceptable. In the absence of any documentation for the CASR variant, participants must be willing to undergo CASR variant analysis. Participants who have undergone an allogeneic bone marrow transplant must provide CASR variant analysis report performed prior to the bone marrow transplant. Participants who have received a packed red blood cell transfusion must wait 2 weeks following the transfusion before undergoing CASR variant analysis, and participants who have received a whole blood transfusion must wait 4 weeks following the transfusion before undergoing CASR variant analysis.
3. Participants must have a documented history of symptoms or signs of ADH1.
Symptoms of ADH1 include agitation, anxiety, back pain, brain fog, bronchospasm, blepharospasm, cardiac failure, cognitive impairment, difficulty focusing/concentration, esophageal spasm, facial spasm, headaches, hypoesthesia (including facial and oral), irritability, laryngospasm, muscle cramping, muscle fatigue, muscle spasms, muscle tightness, muscle twitching, musculoskeletal pain, musculoskeletal stiffness, myalgia, nephrolithiasis, nervousness, paresthesia (including oral), polydipsia, polyuria, seizure, tetany, throat tightness, or tremor.
Signs of ADH1 include basal ganglia or other cerebral calcification, Chvostek sign, hypercalciuria, nephrocalcinosis, papilledema, premature cataracts, prolonged QT interval on ECG, pseudotumor cerebri, or Trousseau sign.
4. Participants 16 to < 18 years old must have closed growth plates on hand radiograph defined as a bone age of 15 years in females and 17 years in males.
5. Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to SoC Optimization Visit 1 through Week 24 (Period 3). When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed.
6. Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to SoC Optimization Visit 1.
7. Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret.
8. Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret.
9. Participants must meet SoC Optimization criteria
Sex and Contraceptive Requirements
10. Male participants with women of childbearing potential (WOCBP) partners must use acceptable contraceptive methods.
11. Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception:
a) Females are considered postmenopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause and must be confirmed with plasma FSH.
b) Females are considered not of childbearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy. 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.
12. Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret.
Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Informed Consent
13. Capable of giving signed informed consent or assent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of hypocalcemic seizure within the past 3 months preceding Screening.
2. History of thyroid or parathyroid surgery.
3. History of the following within 5 years of screening: cancer except thyroid cancer, basal cell skin cancer or squamous cell skin cancer, patients with skeletal malignancies or bone metastases or irradiation (radiotherapy) to the skeleton.
4. History of renal transplantation.
5. Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive beta-human chorionic gonadotropin (beta-hCG) laboratory test.
Prior/Concomitant Therapy
6. History of treatment with PTH 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC doses exceeding >1.2 x their pre-PTH treatment total daily doses or bone turnover markers, CTx and P1NP, > upper limit of normal for sex, age (men only) and menopausal status (women only).
Prior/Concurrent Clinical Study Experience
7. Received any investigational medicinal product other than encaleret within 30 days or 5 half-lives, whichever is longer, prior to the first day on study, or are in follow-up for another interventional clinical study during Screening. If the half-life of an investigational medicinal product is unknown, then 30 days prior to Screening.
Diagnostic Assessments
8. Blood 25-OH Vitamin D level <25 ng/mL
If participant has a blood 25-OH Vitamin D level <25 ng/mL at the Screening Visit, they will be prescribed cholecalciferol or ergocalciferol supplementation per the Investigator. Once the 25-OH Vitamin D level is >25 ng/mL, the participant will be eligible to proceed with SoC Optimization (if still within Screening window of up to 84 days total) or re-screen for the study.
9. Estimated glomerular filtration rate <30 mL/minute/1.73 m^2 using CKD-EPIcr_R (for participants < 18 years old the Bedside Schwartz equation should be used).
10. 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia.
11. Participants with positive Hepatitis B surface antigen (HbsAg), Hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test at the Screening Visit. Participants who are in complete remission from Hepatitis C virus (HCV) as evidenced by sensitive assay >= 12 weeks after completion of HCV therapy may participate in the study.
Other Exclusions
12. Male or female participants planning to conceive a child prior to the LTE.
13. Hypersensitivity to any active substance or excipient of encaleret.
14. Any current disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism.
15. Current treatment with cardiac glycosides (because hypercalcemia of any cause may predispose to digitalis toxicity).
16. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency.
17. Presence or history of any disease or condition (eg, drug or alcohol dependency) that, in the view of the Investigator, would affect the participant s safety or places the participant at high risk of poor treatment compliance or of not completing the study.
Principal Investigator
Referral Contact
For more information: