Hyperphosphatemia
Conditions
Brief summary
This phase 3, 8-week, randomized, double-blind, parallel group, multi-center study with a 4-week, placebo-controlled, randomized withdrawal period will evaluate the efficacy, safety and tolerability of Tenapanor to treat hyperphosphatemia in end-stage renal disease patients on hemodialysis (ESRD-HD). Subjects who qualify are randomized into the study will either receive 3 mg BID, 10 mg BID, or a titration regimen of tenapanor.
Detailed description
The study consists of a screening visit, a wash out period of up to 3 weeks, when existing phosphate lowering medication is withheld, an 8-week treatment period, in which all groups receive tenapanor, and a 4-week placebo-controlled, randomized withdrawal period, during which patients are re-randomized 1:1 to either remain on their current tenapanor treatment or placebo. Depending on the increase in serum phosphate levels, subjects can be randomized 1,2, or 3 weeks after being taken off their phosphate lowering medication.
Interventions
DRUGTenapanor
DRUGPlacebo
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
* 18 to 80 years old * 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/week for at least 3 months * Kt/V ≥ 1.3 at most recent measurement prior to screening * Prescribed and taking at least 3 doses of phosphate binder per day * Serum phosphate levels should be between 4.0 and 7.0 mg/dL (inclusive) at screening * For randomization in the study, after 1 week wash-out of phosphate binders, subjects must have serum phosphate level of at least 9 mg/dL but below 10 mg/dL and have had an increase of at least 1.5 mg/dL versus pre-wash out value * For randomization in the study, after 2 or 3 weeks wash-out of phosphate binders, subjects must have serum phosphate level of at least 6 mg/dL but below 10 mg/dL and have had an increase of at least 1.5 mg/dL versus pre-wash out value
Exclusion criteria
* Severe hyperphosphatemia defined as \>10 mg/dL on Phosphate-binders at any time point during clinical routine monitoring for the 3 preceding months before screening * Serum parathyroid hormone \>1200 pg/mL * Persistent metabolic acidosis defined as serum carbon dioxide \<18 mmol/L from two consecutive measurements during screening and washout periods * Clinical signs of hypovolemia at randomization * History of inflammatory bowel disease (IBD) or diarrhea predominant irritable bowel syndrome (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 * Diarrhea or loose stools during the week before randomization defined as BSFS ≥ 6 and frequency ≥ 3 for 2 or more days * Any evidence of or treatment of malignancy within one year, excluding non-melanomatous malignancies of the skin * Positive serology with evidence of significant hepatic impairment or WBC elevation according to the Investigator * Life expectancy \< 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Placebo Adjusted Change in Serum Phosphate During Randomized Withdrawal Period From Pooled Tenapanor Arms | 4 weeks | Serum phosphorus difference between placebo and tenapanor in the change from the end of the 8 week treatment period to the end of the randomized withdrawal period in Efficacy Analysis Set. The efficacy analysis was pre-defined to be a pooled analysis of all tenapanor treated patients with a minimum of a 1.2 mg/dL decrease in serum phosphorus during the 8-week treatment period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Phosphate During 8-Week Treatment Period | Baseline and 8 weeks | Serum phosphorus difference between baseline (end of washout period) to the end of the 8 week treatment period in ITT analysis set |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3mg BID Tenapanor, 3mg BID (6mg total) | 74 |
| 10mg BID Tenapanor, 10mg BID (20mg total) | 73 |
| Dose Titration Tenapanor, patients start at 30mg BID and can down titrate weekly to 20, 15, 10, and 3mg BID, sequentially based on a GI tolerability question | 72 |
| Placebo Placebo
Placebo | 0 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 4-Week Randomized Withdrawal Period | Adverse Event | 0 | 0 | 1 | 3 |
| 4-Week Randomized Withdrawal Period | Lack of Efficacy | 0 | 1 | 1 | 3 |
| 4-Week Randomized Withdrawal Period | Physician Decision | 1 | 0 | 0 | 0 |
| 4-Week Randomized Withdrawal Period | Protocol Violation | 0 | 0 | 0 | 1 |
| 4-Week Randomized Withdrawal Period | Withdrawal by Subject | 0 | 0 | 0 | 1 |
| 8-Week Treatment Period | Adverse Event | 6 | 5 | 6 | 0 |
| 8-Week Treatment Period | GI side Effects | 1 | 4 | 2 | 0 |
| 8-Week Treatment Period | Lack of Efficacy | 2 | 5 | 3 | 0 |
| 8-Week Treatment Period | Other | 3 | 1 | 2 | 0 |
| 8-Week Treatment Period | Physician Decision | 1 | 0 | 2 | 0 |
| 8-Week Treatment Period | Protocol Violation | 1 | 1 | 1 | 0 |
| 8-Week Treatment Period | Withdrawal by Subject | 3 | 3 | 3 | 0 |
Baseline characteristics
| Characteristic | 3mg BID | 10mg BID | Dose Titration | Total |
|---|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 11.49 | 57.4 years STANDARD_DEVIATION 10.81 | 54.2 years STANDARD_DEVIATION 10.87 | 55.8 years STANDARD_DEVIATION 11.09 |
| Body Mass Index | 32.5 m/kg^2 STANDARD_DEVIATION 8.52 | 33.6 m/kg^2 STANDARD_DEVIATION 8.5 | 33.4 m/kg^2 STANDARD_DEVIATION 8.15 | 33.1 m/kg^2 STANDARD_DEVIATION 8.37 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 8 Participants | 19 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 65 Participants | 53 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 40 Participants | 45 Participants | 40 Participants | 125 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 25 Participants | 31 Participants | 86 Participants |
| Sex: Female, Male Female | 28 Participants | 39 Participants | 24 Participants | 91 Participants |
| Sex: Female, Male Male | 46 Participants | 34 Participants | 48 Participants | 128 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 74 | 0 / 73 | 0 / 72 | 0 / 82 |
| other Total, other adverse events | 22 / 74 | 30 / 73 | 34 / 72 | 7 / 82 |
| serious Total, serious adverse events | 1 / 74 | 0 / 73 | 0 / 72 | 0 / 82 |
Outcome results
Primary
Placebo Adjusted Change in Serum Phosphate During Randomized Withdrawal Period From Pooled Tenapanor Arms
Serum phosphorus difference between placebo and tenapanor in the change from the end of the 8 week treatment period to the end of the randomized withdrawal period in Efficacy Analysis Set. The efficacy analysis was pre-defined to be a pooled analysis of all tenapanor treated patients with a minimum of a 1.2 mg/dL decrease in serum phosphorus during the 8-week treatment period
Time frame: 4 weeks
Population: Patients who completed the first 8-weeks and had a minimum of a 1.2 mg/dL decrease in serum phosphorus were included in the analysis. Also, it was a pre-specificied pooled analysis where all the tenapanor treated patients were combined thus all patients are included in the 30 mg dose titration group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 30 mg Dose Titration | Placebo Adjusted Change in Serum Phosphate During Randomized Withdrawal Period From Pooled Tenapanor Arms | 1.4 mg/dL | Standard Error 0.23 |
| Placebo | Placebo Adjusted Change in Serum Phosphate During Randomized Withdrawal Period From Pooled Tenapanor Arms | 0.6 mg/dL | Standard Error 0.21 |
p-value: 0.01ANCOVA
Secondary
Change in Serum Phosphate During 8-Week Treatment Period
Serum phosphorus difference between baseline (end of washout period) to the end of the 8 week treatment period in ITT analysis set
Time frame: Baseline and 8 weeks
Population: There was no placebo group during the 8-week treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 3mg BID | Change in Serum Phosphate During 8-Week Treatment Period | -1.1 mg/dL | Standard Error 0.17 |
| 10mg BID | Change in Serum Phosphate During 8-Week Treatment Period | -1.1 mg/dL | Standard Error 0.17 |
| 30 mg Dose Titration | Change in Serum Phosphate During 8-Week Treatment Period | -1.1 mg/dL | Standard Error 0.18 |
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA