Study to Evaluate the Efficacy of Tenapanor as Adjunctive Therapy to Phosphate Binder Therapy

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo-controlled study to evaluate the effect of tenapanor on change in s-P levels when tenapanor is administered orally, twice daily for 28 days as adjunctive therapy to ESRD subjects with hyperphosphatemia on stable phosphate binder therapy.

Detailed Description
-----------------
The study consists of a Screening visit; a Run-in Period of at least 2 weeks and up to 4 weeks, where existing phosphate binder treatment is maintained; and a 4-week Double-Blind Treatment Period. At Screening, a subject must be on thrice daily phosphate binder therapy and have a serum phosphate (s-P) level ≥5.5 and ≤10.0 mg/dL to qualify for entering the study. s-P will be measured at each visit during the run-in period to enable the evaluation of the s-P randomization criteria. Subjects who qualify to enroll in the study will be randomized in a 1:1 ratio to receive tenapanor or placebo while continuing their existing phosphate binder treatment. During the Double-Blind Treatment Period, subjects will receive tenapanor or placebo starting at a dose of 30 mg bid

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Tenapanor as Adjunctive Therapy to Phosphate Binder Therapy in End-Stage Renal Disease (ESRD) Subjects With Hyperphosphatemia

Conditions
-----------------
Hyperphosphatemia

Intervention / Treatment
-----------------
* Drug: Tenapanor
* Drug: Placebo
* Drug: Phosphate Binder Agents


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed and dated informed consent prior to any study specific procedures. Males or females aged 18 to 80 years, inclusive, at Screening Females must be non-pregnant, non-lactating and either be post-menopausal for at least -2 months, have documentation of irreversible surgical sterilization, use of acceptable -contraceptive method, or sexual abstinence, or a sterile sexual partner from Screening -until 30 days after the last subject visit. Males must agree to avoid fathering a child (or donating sperm), and therefore be either sterile (documented) or agree to use approved methods of contraception, from the time of enrollment until 30 days after end of study. Chronic maintenance hemodialysis (HD) 3x/week for at least 3 months or chronic maintenance peritoneal dialysis (PD) for a minimum of 6 months. If receiving active vitamin D or calcimimetics, the dose should have been unchanged for the last 4 weeks prior to Screening. Kt/V ≥1.2 at most recent measurement prior to Screening. Prescribed and taking phosphate binder medication at least 3 times per day, and the prescribed dose should have been unchanged during the last 4 weeks prior to Screening. Serum phosphorus levels must be ≥5.5 and ≤10.0 mg/dL at Screening and the end of the run-in period, analyzed at the central laboratory used in the study. Exclusion Criteria: Severe hyperphosphatemia defined as having an s-P level >10.0 mg/dL on phosphate-binders at any time point during routine clinical monitoring for the 3 preceding months before Screening. Serum/plasma parathyroid hormone >1200 pg/mL. Clinical signs of hypovolemia at Screening as judged by the Investigator. History of inflammatory bowel disease (IBD) or irritable bowel syndrome with diarrhea (IBS-D). Scheduled for living donor kidney transplant or plans to relocate to another center during the study period. Use of an investigational agent within 30 days prior to Screening. Involvement in the planning and/or conduct of the study (applies to both Ardelyx/Contract Research Organization (CRO) staff and/or staff at the study site). If, in the opinion of the Investigator, the subject is unable or unwilling to fulfill the requirements of the protocol or has a condition which would render the results uninterpretable.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenapanor 30 mg BID<br>During the Double-Blind Treatment Period, subjects will receive tenapanor starting at a dose of 30 mg bid (three 10 mg tablets each time). Investigators may decrease or increase the dose of study medication based on s-P levels and/or gastrointestinal (GI) tolerability in 10 mg increments to a minimum of 10 mg bid or a maximum of 30 mg bid at any time during the Double-Blind Treatment Period. | Drug: Tenapanor<br>* Active Drug<br>Drug: Phosphate Binder Agents<br>* standard of care phosphate binder use at study entry was maintained throughout the entire study<br>* Other names: sucroferric oxyhydroxide;|
| Placebo Comparator: Placebo<br>same size, weight and appearance of experimental drug | Drug: Placebo<br>* Inactive Drug<br>Drug: Phosphate Binder Agents<br>* standard of care phosphate binder use at study entry was maintained throughout the entire study<br>* Other names: sucroferric oxyhydroxide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Phosphorus (s-P) Level From Baseline to Week 4. | Difference in mean change from baseline in s-P level at Week 4 between the tenapanor and placebo groups. | 4 Weeks (28 days randomization period; from baseline to week 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| s-P Response at Week 4 | Achieving an s-P level <5.5 mg/dL | 4 Weeks (28 days randomization period) | 
| Relative Change From Baseline in iFGF23 at Week 4 | iFGF23 at Week 4/baseline iFGF23 - 1 | 4 Weeks (28 days randomization period) | 
| Relative Change From Baseline in cFGF23 at Week 4 | cFGF23 at Week 4/baseline cFGF23 - 1 | 4 Weeks (28 days randomization period) |