Safety, Tolerability, and Efficacy of Encaleret in Partic... | NCT04581629

NCT04581629

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1: Ascending + Steady-State Dose	Experimental	Period 1: Participants will receive an ascending dose of encaleret once daily for the first 3 days. Participants will then receive an individualized dose of encaleret twice daily for 2 days. Period 2: Participants will receive encaleret twice daily for 5 days at a single dose level based on responses from Period 1. Period 3: After completion of Period 2, participants will be eligible to receive encaleret for an additional 24 weeks. Long-Term Extension (LTE): At the end of the study, participants will also have an option to receive encaleret for up to an additional 2 years.	Drug: Encaleret
Cohort 2: Steady-State Dose	Experimental	Participants will directly be enrolled into Period 2, and receive encaleret twice daily at a dose based on data and responses from Cohort 1 Period 1. Period 2: Participants will receive encaleret twice daily for 5 days. Period 3: After completion of Period 2, participants will be eligible to receive encaleret for an additional 24 weeks. LTE: At the end of the study, participants will also have an option to receive encaleret for up to an additional 2 years.	Drug: Encaleret

Name	Type	Description	Arm Group Labels	Other Names
Encaleret	Drug	Tablets administered orally	Cohort 1: Ascending + Steady-State Dose Cohort 2: Steady-State Dose

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Adverse events (AEs) were defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. Treatment-emergence was defined as any AE(s) regardless of relationship to investigational medicinal product (IMP), that had an onset or worsened in severity on or after the first dose of IMP.	Day 1 up to 16 months
Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa)		Baseline, Week 24
Period 3: Rate of Urinary Calcium Excretion		Week 24

Secondary Outcomes

Measure	Description	Time Frame
Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood	Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay.	15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days)
Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret

Eligibility Module

Eligibility Criteria

Key Inclusion Criteria:

Be able to understand and sign a written informed consent or assent form, which must be obtained prior to initiation of study procedures.
Postmenopausal women are allowed to participate in this study
Body mass index (BMI) ≥ 18.5 to < 39 kilograms (kg)/square meter (m^2)
Have an activating mutation of the Calcium-sensing receptor (CASR) gene
Participants being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides
Participants being treated with strong Cytochrome P3A4 (CYP3A4) inhibitors should ideally, if clinically appropriate, discontinue these medications during the screening period
Participants being treated with magnesium or potassium citrate supplements should discontinue such treatment starting on Day -1 during Period 1 and Period 2 and may be asked to discontinue treatment during Period 3

Key Exclusion Criteria:

History of treatment with parathyroid hormone (PTH) 1-84 or 1-34 within the previous 3 months
History of hypocalcemic seizure within the past 3 months
Blood 25-OH Vitamin D level < 25 nanograms (ng)/milliliter (mL)
Participants with hemoglobin (Hgb) < 13 grams (g)/deciliter (dL) for men and < 12 g/dL for women
Estimated glomerular filtration rate (eGFR) < 25 mL/minute/1.73 m^2 using Chronic Kidney Disease Epidemiology Collaboration (for participants <18 years old the Schwartz equation will be calculated)
12-lead resting electrocardiogram (ECG) with clinically significant abnormalities
Participants with positive hepatitis B surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test results at the Screening Visit
Pregnant or nursing (lactating) women
History of drug or alcohol dependency within 12 months preceding the Screening Visit
History of thyroid or parathyroid surgery
Current participation in other investigational drug studies
Unwillingness to refrain from blood donation within 12 weeks prior to Screening Visit from the start of the study enrollment through one year after the last dose of the study drug

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts/Locations Module

Name	Affiliation	Role
Calcilytix Medical Director	Calcilytix Therapeutics, Inc., a BridgeBio company	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
National Institutes of Health (NIH) Clinical Center		Bethesda	Maryland	20892	United States

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	May 18, 2023	Sep 4, 2024

Derived Section

Miscellaneous Info Module

Submission Tracking

Condition Browse Module

Intervention Browse Module

No data available

No data is available for this block.

Masking Info

FG0010 subjectsThis group did not enroll participants for Period 1.

FG0020 subjectsThis group did not enroll participants for Period 1.

Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified, data were collected and are reported pooled for Period 1 and for Periods 2 and 3 combined.

Arm/Group Information

ID	Title	Description
BG000	Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID). In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.

Units	Counts
Participants	BG00013

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.

Mean

Standard Deviation

years

Title

Denominators

Categories

Period 1

- ParticipantsBG0006

Title	Measurements
	BG00040.0± 17.65

Periods 2 and 3

- ParticipantsBG000

Sex: Female, Male

Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.

Count of Participants

Participants

Title

Denominators

Categories

Period 1

- ParticipantsBG0006

Title	Measurements
Female	BG000

Ethnicity (NIH/OMB)

Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.

Count of Participants

Participants

Title

Denominators

Categories

Period 1

- ParticipantsBG0006

Title	Measurements
Hispanic or Latino	BG000

Race (NIH/OMB)

Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.

Count of Participants

Participants

Title

Denominators

Categories

Period 1

- ParticipantsBG0006

Title	Measurements
American Indian or Alaska Native	BG000

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Adverse events (AEs) were defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. Treatment-emergence was defined as any AE(s) regardless of relationship to investigational medicinal product (IMP), that had an onset or worsened in severity on or after the first dose of IMP.

Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data were collected and are presented pooled for Periods 2 and 3.

Posted

Count of Participants

Participants

Day 1 up to 16 months

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Periods 2 and 3: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.

Units	Counts
Participants	OG0006 OG00113

Title

Denominators

Categories

Title	Measurements
	OG0005 OG00113

Primary

Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa)

Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Period 3 only. As pre-specified, data were collected and are reported pooled for all dose levels in Period 3 and are presented at the specified timepoint.

Posted

Mean

Standard Deviation

milligrams (mg)/deciliter (dL)

Baseline, Week 24

ID	Title	Description
OG000	Period 3: Encaleret	In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.

Units	Counts
Participants	OG000

Primary

Period 3: Rate of Urinary Calcium Excretion

Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Period 3 only. Number analyzed = number of participants evaluable at the specified timepoint. As pre-specified, data were collected and are reported pooled for all dose levels in Period 3 and are presented at the specified timepoint.

Posted

Mean

Standard Deviation

mg/24hour (hr)

Week 24

ID	Title	Description
OG000	Period 3: Encaleret	In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.

Units	Counts
Participants	OG000

Secondary

Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood

Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay.

Safety Analysis Set, all participants who received at least 1 dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Periods 1 and 2 only. Overall number of participants analyzed=those evaluable for this endpoint. Number analyzed=those evaluable at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 at the specified timepoint and per dose at the specified timepoint in Period 1.

Posted

Mean

Standard Deviation

Picograms (pg)/milliliter (mL)

15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret

Pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of study drug and who had at least one non-missing PK concentration result. Overall number of participants analyzed = participants evaluable for this endpoint. Number analyzed = participants evaluable for this endpoint at the specified timepoints. As pre-specified in the protocol, data are presented for Periods 1 and 2 only.

Posted

Mean

Standard Deviation

hour (hr)*nanogram (ng)/milliliter (mL)

Periods 1 and 2: Day 5 (Periods were 5 days)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret

Pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of study drug and who had at least one non-missing PK concentration result. Overall number of participants analyzed = participants evaluable for the endpoint. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified in the protocol, data for Periods 2 and 3 are reported per dose received.

Posted

Mean

Standard Deviation

nanograms (ng)/milliliter (mL)

Periods 1 and 2: Day 5, Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.
OG002	Period 3: Encaleret

Secondary

Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret

Pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of study drug and who had at least one non-missing PK concentration result. Overall number of participants analyzed = participants evaluable for the endpoint. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified in the protocol, data for Periods 2 and 3 are reported per dose received.

Posted

Median

Full Range

hour

Periods 1 and 2: Day 5; Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.
OG002	Period 3: Encaleret

Secondary

Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa)

Data values presented are for the change from baseline for the average values at the specified timepoints/visits.

Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Periods 2 and 3 only. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and are reported pooled for all dose levels in Period 2 and Period 3 and are presented at the specified timepoints.

Posted

Mean

Standard Deviation

milligram (mg)/ deciliter (dL)

Period 2: Baseline, Day 5 (Period was 5 days), Period 3: Baseline, Week 24 (Period was 24 weeks)

ID	Title	Description
OG000	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.
OG001	Period 3: Encaleret	In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2

Secondary

Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion

Fractional Excretion of Calcium was derived as (Urine Calcium at the interval considered * Serum Creatinine at the end of the interval considered)/(Serum Calcium at the end of the interval considered * Urine Creatinine at the interval considered) and is presented as percentage.

Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and are reported pooled for all dose levels in Period 3 and are presented at the specified timepoint.

Posted

Mean

Standard Deviation

percentage

Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks)

ID	Title	Description
OG000	Period 3: Encaleret	In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.

Units	Counts
Participants	OG000

Secondary

Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion

Safety Analysis Set, which included all participants who received at least one dose of study drug in the considered period. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and are reported pooled for all dose levels in Period 2 and Period 3 at the specified timepoints. As pre-specified, data were collected and are presented per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

mg/24hr

Periods 1 and 2: Day 5; Period 3, Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.
OG002	Period 3: Encaleret

Secondary

Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR)

eGFR was calculated using Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) formula (mL/min/1.73m^2) = 141 x min (SCr/K, 1)^α x max(SCR /K,1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black], where SCr is the serum creatinine (mg/dL), K = 0.7 for female and 0.9 for males, α is -0.329 for female and -0.411 for males.

Posted

Mean

Standard Deviation

mL/min/1.73m^2

Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose) (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret

Secondary

Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D

Safety Analysis Set, all participants who received at least 1 dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at the specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

picograms per milliliter (pg/mL)

Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are presented per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

mg/dL

Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

mg/24hr

Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

Periods 1 and 2: Day 5 (0-24 hours post-dose), Period 3: Week 24: (0-24 hours post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.
OG002

Secondary

Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

Milliequivalents (meq)/24hr

Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for periods 1 and 2; 24 weeks for period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

nanomoles per deciliter (nmol/dL)

Periods 1 and 2: Day 5 (0-4h post-dose), Period 3: Week 24 (0-4h post dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx)

Blood samples were taken for analysis of bone resorption markers (CTx).

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

Picograms per milliliter (pg/mL)

Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Secondary

Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP)

Blood samples were taken for analysis of bone formation markers (P1NP).

Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Posted

Mean

Standard Deviation

Micrograms per liter (mcg/L)

Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

ID	Title	Description
OG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).
OG001	Period 2: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Period 1: Encaleret	In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	0	6	0	6	5	6
EG001	Periods 2 and 3: Encaleret	In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2	0	13	0	13	13	13

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0014 affected13 at risk
Vulvovaginal mycotic infection	Infections and infestations	MedDRA v24.1	Systematic Assessment	Number at risk adjusted as this is a sex-specific event.	EG0000 affected3 at risk EG0013 affected8 at risk
Pharyngitis	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0001 affected6 at risk EG0011 affected13 at risk
Bacterial vaginosis	Infections and infestations	MedDRA v24.1	Systematic Assessment	Number at risk adjusted as this is a sex-specific event.	EG0000 affected3 at risk EG0011 affected8 at risk
Chronic sinusitis	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Green nail syndrome	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Sinusitis	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Viral infection	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA v24.1	Systematic Assessment		EG0002 affected6 at risk EG0019 affected13 at risk
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0016 affected13 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA v24.1	Systematic Assessment		EG0001 affected6 at risk EG0015 affected13 at risk
Iron deficiency	Metabolism and nutrition disorders	MedDRA v24.1	Systematic Assessment		EG0001 affected6 at risk EG0010 affected13 at risk
Arthropod bite	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Heat exhaustion	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Ligament sprain	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Muscle strain	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Skin abrasion	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Wrist fracture	Injury, poisoning and procedural complications	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Nausea	Gastrointestinal disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0014 affected13 at risk
Constipation	Gastrointestinal disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0013 affected13 at risk
Dizziness	Nervous system disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0013 affected13 at risk
Headache	Nervous system disorders	MedDRA v24.1	Systematic Assessment		EG0001 affected6 at risk EG0012 affected13 at risk
Paraesthesia	Nervous system disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Pyrexia	General disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0012 affected13 at risk
Injection site reaction	General disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Oedema peripheral	General disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Blood pressure decreased	Investigations	MedDRA v24.1	Systematic Assessment		EG0001 affected6 at risk EG0011 affected13 at risk
Weight decreased	Investigations	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0012 affected13 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0012 affected13 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Hypertension	Vascular disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0012 affected13 at risk
Superficial vein thrombosis	Vascular disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Anxiety	Psychiatric disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Depression	Psychiatric disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Dermatitis contact	Skin and subcutaneous tissue disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0012 affected13 at risk
Sinus tachycardia	Cardiac disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Tinnitus	Ear and labyrinth disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Seasonal allergy	Immune system disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Skin papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk
Hypocitraturia	Renal and urinary disorders	MedDRA v24.1	Systematic Assessment		EG0000 affected6 at risk EG0011 affected13 at risk

First MCP Posted Date

ID	Term
C562783	Hypercalciuric Hypocalcemia, Familial

Units	Counts
Participants	OG00013 OG00113

In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.

Standard deviation could not be calculated as there was only 1 participant with evaluable data.

Standard deviation could not be calculated as there was only one participant with evaluable data.