Autosomal Dominant Hypocalcemia (ADH), Autosomal Dominant Hypocalcemia Type 1 (ADH1)
Conditions
Brief summary
The primary purpose of this study is to evaluate the safety, tolerability and effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1).
Interventions
DRUGEncaleret
Tablets administered orally
Sponsors
Calcilytix Therapeutics, Inc., a BridgeBio company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Day 1 up to 16 months | 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Periods 1 and 2: Day 5; Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3) | — |
| Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) | Period 2: Baseline, Day 5 (Period was 5 days), Period 3: Baseline, Week 24 (Period was 24 weeks) | Data values presented are for the change from baseline for the average values at the specified timepoints/visits. |
| Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion | Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks) | 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. |
| Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion | Periods 1 and 2: Day 5; Period 3, Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3) | — |
| Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | 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) | 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. |
| Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D | 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) | — |
| Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood | 15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days) | Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay. |
| Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | 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) | — |
| Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations | 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) | — |
| Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | 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) | — |
| Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations | 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) | — |
| Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) | 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) | Blood samples were taken for analysis of bone resorption markers (CTx). |
| Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) | 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) | Blood samples were taken for analysis of bone formation markers (P1NP). |
| Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | 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) | — |
| Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret | Periods 1 and 2: Day 5 (Periods were 5 days) | — |
| Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Periods 1 and 2: Day 5, Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3) | — |
Countries
United States
Participant flow
Pre-assignment details
A total of 13 participants were enrolled. Participants were enrolled in 3 periods sequentially to receive encaleret, Period 1(inpatient), Period 2(inpatient), and Period 3(outpatient). 6 participants were enrolled into Period 1. Participants who completed Period 1 enrolled into Period 2, and 7 additional participants enrolled into Period 2. 13 participants who completed Period 2 enrolled into Period 3. As pre-specified, data were collected and reported pooled for Period 1, 2 and 3 respectively.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Encaleret |
|---|---|
| Age, Continuous Period 1 | 40.0 years STANDARD_DEVIATION 17.65 |
| Age, Continuous Periods 2 and 3 | 38.9 years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Period 1 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Period 1 Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Period 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Periods 2 and 3 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Periods 2 and 3 Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Periods 2 and 3 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Period 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Period 1 Asian | 0 Participants |
| Race (NIH/OMB) Period 1 Black or African American | 0 Participants |
| Race (NIH/OMB) Period 1 More than one race | 0 Participants |
| Race (NIH/OMB) Period 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Period 1 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Period 1 White | 6 Participants |
| Race (NIH/OMB) Periods 2 and 3 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Periods 2 and 3 Asian | 0 Participants |
| Race (NIH/OMB) Periods 2 and 3 Black or African American | 0 Participants |
| Race (NIH/OMB) Periods 2 and 3 More than one race | 0 Participants |
| Race (NIH/OMB) Periods 2 and 3 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Periods 2 and 3 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Periods 2 and 3 White | 13 Participants |
| Sex: Female, Male Period 1 Female | 3 Participants |
| Sex: Female, Male Period 1 Male | 3 Participants |
| Sex: Female, Male Periods 2 and 3 Female | 8 Participants |
| Sex: Female, Male Periods 2 and 3 Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 13 |
| other Total, other adverse events | 5 / 6 | 13 / 13 |
| serious Total, serious adverse events | 0 / 6 | 0 / 13 |
Outcome results
Primary
Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa)
Time frame: Baseline, Week 24
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Encaleret | Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa) | 1.9 milligrams (mg)/deciliter (dL) | Standard Deviation 0.48 |
Primary
Period 3: Rate of Urinary Calcium Excretion
Time frame: Week 24
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Encaleret | Period 3: Rate of Urinary Calcium Excretion | 202 mg/24hour (hr) | Standard Deviation 83 |
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.
Time frame: Day 1 up to 16 months
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 5 Participants |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 13 Participants |
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.
Time frame: Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Encaleret | Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion | 0.016 percentage | Standard Deviation 0.004 |
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).
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) | Period 1: Day 5 AM 180 mg | 27.33 Micrograms per liter (mcg/L) | Standard Deviation 5.007 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) | Period 2: Day 5 AM | 26.8 Micrograms per liter (mcg/L) | Standard Deviation 12.25 |
| Period 3: Encaleret | Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) | Period 3: Week 24 | 103.7 Micrograms per liter (mcg/L) | Standard Deviation 87.2 |
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).
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) | Period 1: Day 5 AM 180 mg | 386 Picograms per milliliter (pg/mL) | Standard Deviation 165 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) | Period 2: Day 5 AM | 266 Picograms per milliliter (pg/mL) | Standard Deviation 161 |
| Period 3: Encaleret | Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) | Period 3: Week 24 | 744 Picograms per milliliter (pg/mL) | Standard Deviation 565 |
Secondary
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Creatinine - Period 1: Day 5 AM 180 mg, PM 180 mg | 1454 mg/24hr | Standard Deviation 248 |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Creatinine - Period 1: Day 5 AM 180 mg, PM 120 mg | 1190 mg/24hr | — |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Phosphorus - Period 1: Day 5 AM 180 mg, PM 180 mg | 877 mg/24hr | Standard Deviation 353 |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Phosphorus - Period 1: Day 5 AM 180 mg, PM 120 mg | 1100 mg/24hr | — |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Magnesium - Period 1: Day 5 AM 180 mg, PM 180 mg | 104 mg/24hr | Standard Deviation 5 |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Magnesium - Period 1: Day 5 AM 180 mg, PM 120 mg | 110 mg/24hr | — |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Citrate - Period 1: Day 5 AM 180 mg, PM 180 mg | 662 mg/24hr | Standard Deviation 77 |
| Period 1: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Citrate - Period 1: Day 5 AM 180 mg, PM 120 mg | 778 mg/24hr | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Citrate - Period 2: Day 5 | 381 mg/24hr | Standard Deviation 203 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Creatinine - Period 2: Day 5 | 1408 mg/24hr | Standard Deviation 367 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Magnesium - Period 2: Day 5 | 161 mg/24hr | Standard Deviation 66 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Phosphorus - Period 2: Day 5 | 962 mg/24hr | Standard Deviation 226 |
| Period 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Phosphorus - Period 3: Week 24 | 754 mg/24hr | Standard Deviation 240 |
| Period 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Citrate - Period 3: Week 24 | 439 mg/24hr | Standard Deviation 224 |
| Period 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Magnesium - Period 3: Week 24 | 121 mg/24hr | Standard Deviation 38 |
| Period 3: Encaleret | Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations | Creatinine - Period 3: Week 24 | 1345 mg/24hr | Standard Deviation 373 |
Secondary
Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations | Period 1: Day 5 AM, 180 mg, PM 180 mg, 0-4 hours post-dose | 2.98 nanomoles per deciliter (nmol/dL) | Standard Deviation 0.795 |
| Period 1: Encaleret | Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations | Period 1: Day 5, AM 180 mg, PM 120 mg 0-4 hours post-dose | 2.90 nanomoles per deciliter (nmol/dL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations | Period 2: Day 5 0-4 hours post-dose | 2.79 nanomoles per deciliter (nmol/dL) | Standard Deviation 0.762 |
| Period 3: Encaleret | Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations | Period 3: Week 24 0-4 hours post-dose | 2.68 nanomoles per deciliter (nmol/dL) | Standard Deviation 0.704 |
Secondary
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | ⦁ Phosphorus - Period 1: Day 5 AM (180 mg) | 2.9 mg/dL | Standard Deviation 0.39 |
| Period 1: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | ⦁ Magnesium - Period 1: Day 5 AM (180 mg) | 2.2 mg/dL | Standard Deviation 0.36 |
| Period 1: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | ⦁ Creatinine - Period 1: Day 5 AM (180 mg) | 0.93 mg/dL | Standard Deviation 0.188 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | Phosphorus - Period 2: Day 5 AM | 3.1 mg/dL | Standard Deviation 0.75 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | Magnesium - Period 2: Day 5 AM | 1.9 mg/dL | Standard Deviation 0.28 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | Creatinine - Period 2: Day 5 AM | 0.94 mg/dL | Standard Deviation 0.229 |
| Period 3: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | Magnesium - Period 3: Week 24 | 2.0 mg/dL | Standard Deviation 0.2 |
| Period 3: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | Creatinine - Period 3: Week 24 | 1.01 mg/dL | Standard Deviation 0.212 |
| Period 3: Encaleret | Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations | Phosphorus - Period 3: Week 24 | 3.7 mg/dL | Standard Deviation 0.52 |
Secondary
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret
Time frame: Periods 1 and 2: Day 5, Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 1: Day 5 AM 180mg | 2593.3 nanograms (ng)/milliliter (mL) | Standard Deviation 655.89 |
| Period 1: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 1: Day 5 PM 180 mg | 1834.0 nanograms (ng)/milliliter (mL) | Standard Deviation 470.46 |
| Period 1: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 1: Day 5 PM 120 mg | 1890.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 10 mg | 102.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 30 mg | 223.6 nanograms (ng)/milliliter (mL) | Standard Deviation 169.94 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 60 mg | 496.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 90 mg | 1041.0 nanograms (ng)/milliliter (mL) | Standard Deviation 303.4 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 120 mg | 1720.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 150 mg | 1560.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5AM 180 mg | 1956.7 nanograms (ng)/milliliter (mL) | Standard Deviation 748.09 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 10 mg | 134.3 nanograms (ng)/milliliter (mL) | Standard Deviation 34.53 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 30 mg | 226.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 60 mg | 373.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 90 mg | 822.3 nanograms (ng)/milliliter (mL) | Standard Deviation 73.93 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 120 mg | 1670.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 150 mg | 1590.0 nanograms (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 2: Day 5PM 180 mg | 2203.3 nanograms (ng)/milliliter (mL) | Standard Deviation 254.23 |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 5 mg | 44.4 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 10 mg | 58.6 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 20 mg | 200.5 nanograms (ng)/milliliter (mL) | Standard Deviation 50.2 |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 30 mg | 466.0 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 60 mg | 403.0 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 70 mg | 472.0 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 80 mg | 872.0 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 120 mg | 1090.0 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 150 mg | 1110.0 nanograms (ng)/milliliter (mL) | — |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 180 mg | 2125.0 nanograms (ng)/milliliter (mL) | Standard Deviation 21.21 |
| Period 3: Encaleret | Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret | Period 3: Week 24 190 mg | 2080.0 nanograms (ng)/milliliter (mL) | — |
Secondary
Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations | Period 1: Day 5 AM 180 mg; PM 180 mg 0-24 hours post-dose | 6.2 pH | Standard Deviation 2.02 |
| Period 1: Encaleret | Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations | Period 1: Day 5 AM 180 mg; PM 120 mg 0-24 hours post-dose | 5.0 pH | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations | Period 2: Day 5 0-24 hours post-dose | 6.1 pH | Standard Deviation 0.68 |
| Period 3: Encaleret | Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations | Period 3: Week 24 0-24 hours post-dose | 6.5 pH | Standard Deviation 0.69 |
Secondary
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Potassium Period 1: Day 5 AM 180 mg, PM 180 mg | 79.00 Milliequivalents (meq)/24hr | Standard Deviation 48.662 |
| Period 1: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Potassium Period 1: Day 5 AM 180 mg, PM 120 mg | 82.00 Milliequivalents (meq)/24hr | — |
| Period 1: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Sodium Period 1: Day 5 AM 180 mg, PM 180 mg | 186.33 Milliequivalents (meq)/24hr | Standard Deviation 84.831 |
| Period 1: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Sodium Period 1: Day 5 AM 180 mg, PM 120 mg | 192.00 Milliequivalents (meq)/24hr | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Sodium Period 2: Day 5 | 184.77 Milliequivalents (meq)/24hr | Standard Deviation 51.038 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Potassium Period 2: Day 5 | 69.38 Milliequivalents (meq)/24hr | Standard Deviation 24.476 |
| Period 3: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Sodium Period 3: Week 24 | 182.23 Milliequivalents (meq)/24hr | Standard Deviation 95.407 |
| Period 3: Encaleret | Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations | Potassium Period 3: Week 24 | 61.46 Milliequivalents (meq)/24hr | Standard Deviation 32.196 |
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | Period 1: Day 5 AM (180 mg) | 91.1 mL/min/1.73m^2 | Standard Deviation 18.73 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | Period 2: Day 5 AM | 90.6 mL/min/1.73m^2 | Standard Deviation 25.3 |
| Period 3: Encaleret | Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | Period 3: Week 24 | 82.0 mL/min/1.73m^2 | Standard Deviation 21.1 |
Secondary
Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D | Period 1: Day 5 AM (180 mg) | 25.8 picograms per milliliter (pg/mL) | Standard Deviation 12.24 |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D | Period 2: Day 5 AM | 30.5 picograms per milliliter (pg/mL) | Standard Deviation 16.4 |
| Period 3: Encaleret | Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D | Period 3: Week 24 | 31.2 picograms per milliliter (pg/mL) | Standard Deviation 16.19 |
Secondary
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret
Time frame: Periods 1 and 2: Day 5; Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 1: Day 5 PM 120 mg | 2.0 hour |
| Period 1: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 1: Day 5 AM 180mg | 1.1 hour |
| Period 1: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 1: Day 5 PM 180 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 60 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 90 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 120 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 150 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 180 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 10 mg | 1.4 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 30 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 60 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 90 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 120 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 150 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5PM 180 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 10 mg | 1.5 hour |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 2: Day 5AM 30 mg | 4.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 20 mg | 2.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 30 mg | 0.5 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 60 mg | 2.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 70 mg | 4.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 80 mg | 0.5 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 120 mg | 2.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 150 mg | 4.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 180 mg | 2.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 190 mg | 2.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 5 mg | 2.0 hour |
| Period 3: Encaleret | Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret | Period 3: Week 24 10 mg | 2.0 hour |
Secondary
Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion
Time frame: Periods 1 and 2: Day 5; Period 3, Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion | Period 1: Day 5 AM 180 mg; PM 180 mg | 84 mg/24hr | Standard Deviation 146 |
| Period 1: Encaleret | Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion | Period 1: Day 5 AM 180 mg; PM 120 mg | 0 mg/24hr | — |
| Periods 2 and 3: Encaleret | Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion | Period 2: Day 5 | 179 mg/24hr | Standard Deviation 108 |
| Period 3: Encaleret | Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion | Period 3: Week 24 | 202 mg/24hr | Standard Deviation 83 |
Secondary
Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret
Time frame: Periods 1 and 2: Day 5 (Periods were 5 days)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret | Period 1: Day 5 AM 180mg | 11283.7 hour (hr)*nanogram (ng)/milliliter (mL) | Standard Deviation 3556.12 |
| Period 1: Encaleret | Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret | Period 1: Day 5 PM 180 mg | 13127.7 hour (hr)*nanogram (ng)/milliliter (mL) | Standard Deviation 2992.61 |
| Period 1: Encaleret | Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret | Period 1: Day 5 PM 120 mg | 12417.0 hour (hr)*nanogram (ng)/milliliter (mL) | — |
| Periods 2 and 3: Encaleret | Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret | Period 2: Day 5 PM 10mg | 623.7 hour (hr)*nanogram (ng)/milliliter (mL) | — |
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.
Time frame: 15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood | Period 1: Day 5 (180 mg) | 43.8 Picograms (pg)/milliliter (mL) | Standard Deviation 34.06 |
| Periods 2 and 3: Encaleret | Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood | Period 2: Day 5 | 20.6 Picograms (pg)/milliliter (mL) | Standard Deviation 15.87 |
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.
Time frame: Period 2: Baseline, Day 5 (Period was 5 days), Period 3: Baseline, Week 24 (Period was 24 weeks)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Encaleret | Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) | Period 2: Day 5 | 1.5 milligram (mg)/ deciliter (dL) | Standard Deviation 0.6 |
| Periods 2 and 3: Encaleret | Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) | Period 3: Week 24 | 1.9 milligram (mg)/ deciliter (dL) | Standard Deviation 0.48 |