Chronic Kidney Diseases, Secondary Hyperparathyroidism Due to Renal Causes, Stage 5 Chronic Kidney Disease, Vitamin D Deficiency
Conditions
Brief summary
Safety, Efficacy, PK and PD of CTAP101 (calcifediol) ER Capsules for SHPT in HD Patients VDI
Detailed description
A Multi-Center, Randomized, Two-Cohort Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics (PK) and Pharmacodynamics (PD) of CTAP101 (calcifediol) Extended-Release Capsules to Treat Secondary Hyperparathyroidism (SHPT) in Subjects with Vitamin D Insufficiency (VDI) and Chronic Kidney Disease Requiring Regular Hemodialysis.
Interventions
Capsule, weekly
DRUGPlacebo oral capsule
Capsule, weekly
Sponsors
OPKO Health, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each subject must meet the following criteria to be enrolled in this study: 1. Be at least 18 years of age. 2. Be diagnosed with CKD requiring in-center HD tiw for the preceding 6 months, as confirmed by medical history. 3. Be without any disease state or physical condition that might impair evaluation of safety or which, in the investigator's opinion, would interfere with study participation, including: 1. Serum albumin ≤ 3.0 g/dL; and, 2. Serum transaminase (alanine transaminase \[ALT\], glutamic pyruvic transaminase \[SGPT\], aspartate aminotransferase \[AST\] or glutamic oxaloacetic transaminase \[SGOT\]) \> 2.5 times the upper limit of normal at screening. 4. Be receiving calcimimetic therapy (either etelcalcetide or cinacalcet) and/or calcitriol or other 1α-hydroxylated vitamin D analog (paricalcitol or doxercalciferol) for at least 1 month at the time of screening for enrollment. Approximately 50% of enrolled subjects will have been receiving calcimimetic therapy. 5. Exhibit during the initial screening visit: 1. Plasma iPTH ≥150 pg/mL and \<600 pg/mL if receiving etelcalcetide, cinacalcet, calcitriol or other 1α-hydroxylated vitamin D analog (paricalcitol or doxercalciferol); or 2. Plasma iPTH ≥300 pg/mL and \<900 pg/mL if not receiving etelcalcetide, cinacalcet, calcitriol or other 1α- hydroxylated vitamin D analog; and, 3. Serum total 25-hydroxyvitamin D \<30 ng/mL if not receiving vitamin D supplementation. 6. When otherwise confirmed eligible at Visit 1, must forgo any further treatment with etelcalcetide and cinacalcet for the duration of the study and undergo an 8-week washout period. 7. When otherwise confirmed eligible at Visit 1, must forgo any further treatment with calcitriol or other 1α-hydroxylated vitamin D analogs or vitamin D supplements for the duration of the study and undergo an 8-week washout period. 8. Exhibit after the 8-week washout period (if required due to prior use of etelcalcetide, cinacalcet, calcitriol or other 1α- hydroxylated vitamin D analogs, or vitamin D supplementation): 1. Plasma iPTH increased by at least 50%; 2. Plasma iPTH ≥300 pg/mL and \<1,200 pg/mL; 3. Corrected serum calcium \<9.8 mg/dL; 4. Serum total 25-hydroxyvitamin D \<50 ng/mL; and, 5. Serum phosphorus \<6.5 mg/dL. 9. When otherwise confirmed eligible at Visit 1, if taking more than 1,000 mg per day of elemental calcium, reduce calcium use (to ≤1,000 mg per day) and/or use non-calcium based phosphate binder therapies (as needed) for the duration of the study. 10. When otherwise confirmed eligible at Visit 1, if taking bone metabolism therapies that may interfere with study endpoints, must discontinue use of these agents for the duration of the study. 11. Willing and able to comply with study instructions and commit to all clinic visits for the duration of the study. 12. Female subjects of childbearing potential must be neither pregnant nor lactating and must have a negative serum betahuman chorionic gonadotropin (b-hCG) pregnancy test at the first screening visit and at other scheduled times. 13. All female subjects of childbearing potential and male subjects with female partners of childbearing potential must agree to use effective contraception (eg, implants, injectables, combined oral contraceptives, intrauterine device, sexual abstinence, vasectomy or vasectomized partner) for the duration of the study. 14. Be able to read, understand and sign the subject Informed Consent Form (ICF) or have a legal representative sign the ICF.
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from the study: 1. Scheduled kidney transplant or parathyroidectomy. 2. History (prior 2 months) of corrected serum calcium ≥9.8 mg/dL or serum phosphorus ≥6.5 mg/dL if not receiving calcitriol or other 1α-hydroxylated vitamin D analog. 3. Receipt of bisphosphonate therapy or other bone modifying treatment (eg, denosumab) within 6 months prior to enrollment. 4. Known previous or concomitant serious illness or medical condition, such as malignancy, human immunodeficiency virus, significant gastrointestinal or hepatic disease, intestinal malabsorption disorder, hepatitis or cardiovascular event that in the opinion of the investigator may worsen or reduce life expectancy, and/or interfere with participation in the study. 5. History of neurological/psychiatric disorder, including psychotic disorder or dementia, or any reason which, in the opinion of the investigator makes adherence to a treatment or follow-up schedule unlikely. 6. Known or suspected hypersensitivity to any of the constituents of the study drugs. 7. Currently participating in, or has participated in, an interventional/investigational study within 30 days prior to study screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response During Efficacy Assessment Period | 26 weeks | To evaluate the efficacy of repeated dosing with 900 mcg per week of CTAP101 extended release (ER) Capsules versus placebo in raising mean serum total 25-hydroxyvitamin D (25D) to ≥50 ng/mL and in reducing mean plasma intact parathyroid hormone (iPTH) by at least 30% from pre-treatment baseline. |
| Total 25-hydroxyvitamin D Response Analysis During Efficacy Period | 26 weeks | Summary of participants with mean serum total 25-hydroxyvitamin D ≥50 ng/mL at the end of treatment |
| Number of Participants With Intact Parathyroid Hormone (iPTH) Response During Efficacy Assessment Period | 26 weeks | Summary of participants who experienced a reduction in mean plasma iPTH by greater than 30% from the pre-treatment baseline |
| Pharmacokinetic (PK) Profile (Cmax) of Serum Calcifediol | 0, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours post-dose (single and repeat dose) | To assess Cmax of serum calcifediol after a single dose of 900 mcg at the start of the study (Single Dose PK Period), and a repeat dose of 300 mcg at the end of the study (Repeat Dose PK Period) |
| Pharmacokinetic (PK) Profile (Tmax) of Serum Calcifediol | 0, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours post-dose (single and repeat dose) | To assess Tmax of serum calcifediol after a single dose of 900 mcg at the start of the study (Single Dose PK Period), and a repeat dose of 300 mcg at the end of the study (Repeat Dose PK Period) |
| Pharmacokinetic (PK) Profile (AUC0-t) of Serum Calcifediol | 0, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours post-dose (single and repeat dose) | To assess AUC0-t of serum calcifediol after a single dose of 900 mcg at the start of the study (Single Dose PK Period), and a repeat dose of 300 mcg at the end of the study (Repeat Dose PK Period) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic Analysis of 1,25-dihydroxyvitamin D | 26 weeks | Effect of CTAP101 on 1,25-dihydroxyvitamin D |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CTAP101 Capsules 900mcg/Weekly CTAP101 Oral Capsules/Calcifediol, calcidiol, 25-hydroxyvitamin D3, 900mcg/weekly for 26 weeks
Calcifediol Oral Capsule: Capsule, weekly | 28 |
| Placebo Capsules Weekly Placebo Oral Capsules/weekly for 26 weeks
Placebo oral capsule: Capsule, weekly | 9 |
| Total | 37 |
Baseline characteristics
| Characteristic | CTAP101 Capsules 900mcg/Weekly | Placebo Capsules Weekly | Total |
|---|---|---|---|
| Age, Customized < 65 years old | 21 Participants | 7 Participants | 28 Participants |
| Age, Customized >= 65 years old | 7 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 5 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 5 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Female | 12 Participants | 5 Participants | 17 Participants |
| Sex: Female, Male Male | 16 Participants | 4 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 11 |
| other Total, other adverse events | 29 / 32 | 9 / 11 |
| serious Total, serious adverse events | 15 / 32 | 4 / 11 |
Outcome results
Primary
Number of Participants With Intact Parathyroid Hormone (iPTH) Response During Efficacy Assessment Period
Summary of participants who experienced a reduction in mean plasma iPTH by greater than 30% from the pre-treatment baseline
Time frame: 26 weeks
Population: mITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Number of Participants With Intact Parathyroid Hormone (iPTH) Response During Efficacy Assessment Period | 4 Participants |
| Placebo Capsules Weekly | Number of Participants With Intact Parathyroid Hormone (iPTH) Response During Efficacy Assessment Period | 0 Participants |
Primary
Number of Participants With Response During Efficacy Assessment Period
To evaluate the efficacy of repeated dosing with 900 mcg per week of CTAP101 extended release (ER) Capsules versus placebo in raising mean serum total 25-hydroxyvitamin D (25D) to ≥50 ng/mL and in reducing mean plasma intact parathyroid hormone (iPTH) by at least 30% from pre-treatment baseline.
Time frame: 26 weeks
Population: mITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Number of Participants With Response During Efficacy Assessment Period | 4 Participants |
| Placebo Capsules Weekly | Number of Participants With Response During Efficacy Assessment Period | 0 Participants |
p-value: 0.5536Fisher Exact
Primary
Pharmacokinetic (PK) Profile (AUC0-t) of Serum Calcifediol
To assess AUC0-t of serum calcifediol after a single dose of 900 mcg at the start of the study (Single Dose PK Period), and a repeat dose of 300 mcg at the end of the study (Repeat Dose PK Period)
Time frame: 0, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours post-dose (single and repeat dose)
Population: PK population. 6 subjects did not complete the repeat PK dosing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Pharmacokinetic (PK) Profile (AUC0-t) of Serum Calcifediol | AUC0-t (single PK) | 9118.4 hour x ng/mL | Standard Deviation 3557.65 |
| CTAP101 Capsules 900mcg/Weekly | Pharmacokinetic (PK) Profile (AUC0-t) of Serum Calcifediol | AUC0-t (repeat PK) | 95820.7 hour x ng/mL | Standard Deviation 44858.77 |
Primary
Pharmacokinetic (PK) Profile (Cmax) of Serum Calcifediol
To assess Cmax of serum calcifediol after a single dose of 900 mcg at the start of the study (Single Dose PK Period), and a repeat dose of 300 mcg at the end of the study (Repeat Dose PK Period)
Time frame: 0, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours post-dose (single and repeat dose)
Population: PK population. 6 subjects did not complete the repeat PK dosing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Pharmacokinetic (PK) Profile (Cmax) of Serum Calcifediol | Cmax (single PK) | 45.5 ng/mL | Standard Deviation 20.17 |
| CTAP101 Capsules 900mcg/Weekly | Pharmacokinetic (PK) Profile (Cmax) of Serum Calcifediol | Cmax (repeat PK) | 181.0 ng/mL | Standard Deviation 171.92 |
Primary
Pharmacokinetic (PK) Profile (Tmax) of Serum Calcifediol
To assess Tmax of serum calcifediol after a single dose of 900 mcg at the start of the study (Single Dose PK Period), and a repeat dose of 300 mcg at the end of the study (Repeat Dose PK Period)
Time frame: 0, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours post-dose (single and repeat dose)
Population: PK population. 6 subjects did not complete the repeat PK dosing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Pharmacokinetic (PK) Profile (Tmax) of Serum Calcifediol | Tmax (single PK) | 0.6 hours | Standard Deviation 0.41 |
| CTAP101 Capsules 900mcg/Weekly | Pharmacokinetic (PK) Profile (Tmax) of Serum Calcifediol | Tmax (repeat PK) | 2.5 hours | Standard Deviation 2.72 |
Primary
Total 25-hydroxyvitamin D Response Analysis During Efficacy Period
Summary of participants with mean serum total 25-hydroxyvitamin D ≥50 ng/mL at the end of treatment
Time frame: 26 weeks
Population: mITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Total 25-hydroxyvitamin D Response Analysis During Efficacy Period | 28 Participants |
| Placebo Capsules Weekly | Total 25-hydroxyvitamin D Response Analysis During Efficacy Period | 1 Participants |
Secondary
Pharmacodynamic Analysis of 1,25-dihydroxyvitamin D
Effect of CTAP101 on 1,25-dihydroxyvitamin D
Time frame: 26 weeks
Population: mITT population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CTAP101 Capsules 900mcg/Weekly | Pharmacodynamic Analysis of 1,25-dihydroxyvitamin D | Visit 24 | 50.7 pg/mL | Standard Error 7.8 |
| CTAP101 Capsules 900mcg/Weekly | Pharmacodynamic Analysis of 1,25-dihydroxyvitamin D | Baseline | 9.4 pg/mL | Standard Error 1.2 |
| Placebo Capsules Weekly | Pharmacodynamic Analysis of 1,25-dihydroxyvitamin D | Baseline | 12.6 pg/mL | Standard Error 2.7 |
| Placebo Capsules Weekly | Pharmacodynamic Analysis of 1,25-dihydroxyvitamin D | Visit 24 | 13.4 pg/mL | Standard Error 4.1 |