Hyperphosphatemia
Conditions
Brief summary
This Phase 3, 26-week, open label study with a 12-week, placebo-controlled, randomized withdrawal period followed by an open label long term safety extension will evaluate the safety and efficacy of tenapanor to treat hyperphosphatemia in end-stage renal disease (ESRD) on hemodialysis and peritoneal dialysis.
Detailed description
The study consists of a screening visit, a phosphate binder-free washout period of up to 4 weeks, a 26-week treatment period, an up to 12-week placebo-controlled, randomized withdrawal period, during which patients are randomized 1:1 to either remain on their tenapanor treatment or placebo, followed by an open label safety extension period for a total treatment period of up to 52 weeks. An active control group, for safety analysis only, will receive sevelamer carbonate, open label, for the entire 52-week study period Depending on increase in serum phosphate (s-P) levels, subjects can be randomized 2 or 3 weeks after being taken off their phosphate lowering medication. Subjects who qualify to enroll in the study will be randomized 3:1 to either receive tenapanor at a dose of 30 mg bid or sevelamer carbonate.
Interventions
Sponsors
Ardelyx
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Females must be non-pregnant, non-lactating, and either be post-menopausal for at least 12 months, have documentation of irreversible surgical sterilization, or confirm the use of one of the acceptable contraceptive methods * Males must agree to avoid fathering a child and agree to use an appropriate method of contraception * Chronic maintenance hemodialysis 3x a week for at least 3 months * Chronic maintenance peritoneal dialysis for a minimum of 6 months * Kt/V ≥ 1.2 at most recent measurement prior to screening * Prescribed and taking at least 3 doses of phosphate binder per day * Serum phosphorus levels should be between 4.0 and 8.0 mg/dL at screening * Unchanged dose of vitamin D or calcimimetics for the last 4 weeks prior to screening * For enrollment in the study after at least 2 weeks of wash-out, subjects must have serum phosphorus levels of at least 6.0 mg/dL but not more than 10.0 mg/dL and have had an increase of at least 1.5 mg/dL versus pre-wash out value after 2 or 3 weeks wash-out of phosphate binders
Exclusion criteria
* Severe hyperphosphatemia defined as serum phosphorus greater than 10.0 mg/dL on phosphate-binders at any time point during clinical routine monitoring for the 3 preceding months before screening visit * Serum/plasma parathyroid hormone \>1200 pg/mL * Clinical signs of hypovolemia at enrollment * History of IBD or IBS-D * Scheduled for living donor kidney transplant, change to peritoneal dialysis, home HD or plans to relocate to another center during the study period * Positive serology with evidence of significant hepatic impairment or WBC elevation according to the Investigator * Life expectancy \<6 months * Previous exposure to tenapanor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the Responder Population | 12 weeks (randomized withdrawal period) | Patients with at least a 1.2 mg/dL decrease in serum phosphorus during the first 26 weeks of the study were defined as the responder population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the ITT Population | 12 weeks (randomized withdrawal period) | Placebo Adjusted Change in Serum Phosphorus from the beginning to the end of the Randomized Withdrawal Period in all patients |
| Serum Phosphorus From Baseline | 26 weeks (open label treatment period) | Serum Phosphorus from baseline (post washout) to end of 26 week period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tenapanor 10 mg, 20 mg, 30 mg BID During the 26-week open label part, all enrolled subjects will receive 30 mg BID doses of tenapanor. Investigators may decrease or increase the dose in 10 mg increments to a minimum of 10 g BIDor a maximum of 30 mg BID
Tenapanor: Active Drug | 419 |
| Placebo Placebo
Placebo: Inactive Drug | 0 |
| Sevelamer Carbonate Subjects randomized into the active control group, for safety analysis, will receive sevelamer carbonate, open label, for the entire 52-week study period. Sevelamer carbonate will be dosed based on package insert instructions (standard of care)
Sevelamer Carbonate: Active control | 137 |
| Total | 556 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 2 to 4 Week Washout Period | Screen failure (did not meet study entry requirements) | 0 | 995 | 0 |
Baseline characteristics
| Characteristic | Sevelamer Carbonate | Tenapanor 10 mg, 20 mg, 30 mg BID | Total |
|---|---|---|---|
| Age, Continuous | 59.00 years STANDARD_DEVIATION 12.638 | 57.74 years STANDARD_DEVIATION 12.639 | 58.05 years STANDARD_DEVIATION 12.639 |
| BMI | 31.41 kg/m^2 STANDARD_DEVIATION 9.918 | 31.30 kg/m^2 STANDARD_DEVIATION 7.505 | 31.33 kg/m^2 STANDARD_DEVIATION 8.159 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants | 115 Participants | 156 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants | 302 Participants | 398 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 11 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 21 Participants | 28 Participants |
| Race (NIH/OMB) Black or African American | 60 Participants | 195 Participants | 255 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 | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 70 Participants | 189 Participants | 259 Participants |
| Sex: Female, Male Female | 46 Participants | 154 Participants | 200 Participants |
| Sex: Female, Male Male | 91 Participants | 265 Participants | 356 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 419 | 1 / 126 | 5 / 137 |
| other Total, other adverse events | 222 / 419 | 2 / 126 | 10 / 137 |
| serious Total, serious adverse events | 47 / 419 | 4 / 126 | 39 / 137 |
Outcome results
Primary
Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the Responder Population
Patients with at least a 1.2 mg/dL decrease in serum phosphorus during the first 26 weeks of the study were defined as the responder population.
Time frame: 12 weeks (randomized withdrawal period)
Population: The sevalmer arm was not included in the randomized withdrawal period. They were treated as an active safety comparator.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tenapanor 10 mg, 20 mg, 30 mg BID | Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the Responder Population | 0.43 mg/dL | Standard Deviation 0.199 |
| Placebo | Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the Responder Population | 1.80 mg/dL | Standard Deviation 0.196 |
p-value: <0.0001ANCOVA
Secondary
Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the ITT Population
Placebo Adjusted Change in Serum Phosphorus from the beginning to the end of the Randomized Withdrawal Period in all patients
Time frame: 12 weeks (randomized withdrawal period)
Population: The sevelamer group did not participate in the randomized withdrawal period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tenapanor 10 mg, 20 mg, 30 mg BID | Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the ITT Population | 0.22 mg/dL | Standard Deviation 0.149 |
| Placebo | Change in Serum Phosphorus Levels During Placebo Controlled Randomized Withdrawal Period in the ITT Population | 0.88 mg/dL | Standard Deviation 0.15 |
p-value: 0.002ANCOVA
Secondary
Serum Phosphorus From Baseline
Serum Phosphorus from baseline (post washout) to end of 26 week period
Time frame: 26 weeks (open label treatment period)
Population: There were no placebo during this period and the sevelamer arm was a safety comparator only
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tenapanor 10 mg, 20 mg, 30 mg BID | Serum Phosphorus From Baseline | Baseline Serum Phosphorus | 7.44 mg/dL | Standard Deviation 1.439 |
| Tenapanor 10 mg, 20 mg, 30 mg BID | Serum Phosphorus From Baseline | End of Period serum Phosphorus | 5.88 mg/dL | — |