An 8-Week Study to Evaluate Tenapanor in the Treatment of Hyperphosphatemia in End-Stage Renal Disease Patients on Hemodialysis (ESRD-HD)

• Sponsor: Ardelyx (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02675998
• Collaborator: (none)
• Enrollment: 219
• Locations: 32
• Arms: 4
• Duration (Months): 24.5
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hyperphosphatemia	Drug: Tenapanor; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 219 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: An 8-week, Multicenter, Randomized, Double-Blind, Parallel Group Study With a 4-week, Placebo-Controlled, Randomized Withdrawal Period to Evaluate the Efficacy, Safety, and Tolerability of Tenapanor to Treat Hyperphosphatemia in End-Stage Renal Disease Patients on Hemodialysis (ESRD-HD)
• Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Jan 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 3mg BID Tenapanor, 3mg BID (6mg total)	Drug: Tenapanor; Other Names: RDX5791, AZD1722
Experimental: 10mg BID Tenapanor, 10mg BID (20mg total)	Drug: Tenapanor; Other Names: RDX5791, AZD1722
Experimental: 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	Drug: Tenapanor; Other Names: RDX5791, AZD1722
Placebo Comparator: Placebo Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ardelyx Investigative Site 429	Huntsville	Alabama	United States	35805
2	Ardelyx Investigative Site 425	Riverside	California	United States	92505
3	Ardelyx Clinical Site 403	Denver	Colorado	United States	80230
4	Ardelyx Investigative Site 410	Lauderdale Lakes	Florida	United States	33313
5	Ardelyx Investigative Site 430	Miami	Florida	United States	33173
6	Ardelyx Investigative Site 427	Meridian	Idaho	United States	83642
7	Ardelyx Investigative Site 432	Shreveport	Louisiana	United States	71101
8	Ardelyx Investigative Site 415	Bethesda	Maryland	United States	20814
9	Ardelyx Investigative Site 402	Kalamazoo	Michigan	United States	49008
10	Ardelyx Investigative Site 424	Roseville	Michigan	United States	48066
11	Ardelyx Investigative Site 409	Brookhaven	Mississippi	United States	39601
12	Ardelyx Investigative Site 417	Columbus	Mississippi	United States	39705
13	Ardelyx Investigative Site 431	Tupelo	Mississippi	United States	38801
14	Ardelyx Investigative Site 423	Saint Louis	Missouri	United States	63136
15	Ardelyx Investigative Site 416	Albuquerque	New Mexico	United States	87109
16	Ardelyx Investigative Site 419	Bronx	New York	United States	10803
17	Ardelyx Investigative Site 408	Asheville	North Carolina	United States	28805
18	Ardelyx Investigative Site 411	Charlotte	North Carolina	United States	28204
19	Ardelyx Investigative Site 420	New Bern	North Carolina	United States	28562
20	Ardelyx Investigative Site 426	Raleigh	North Carolina	United States	27609
21	Ardelyx Investigative Site 412	Wilmington	North Carolina	United States	28403
22	Ardelyx Investigative Site 414	Bethlehem	Pennsylvania	United States	18017
23	Ardelyx Investigative Site 404	Columbia	South Carolina	United States	29203
24	Ardelyx Investigative Site 421	Orangeburg	South Carolina	United States	29118
25	Ardelyx Investigative Site 428	Sumter	South Carolina	United States	29150
26	Ardelyx Investigative Site 413	Knoxville	Tennessee	United States	37923
27	Ardelyx Investigative Site 418	Nashville	Tennessee	United States	37205
28	Ardelyx Investigative Site 406	Austin	Texas	United States	78758
29	Ardelyx Investigative Site 405	Bellville	Texas	United States	77418
30	Ardelyx Investigative Site 422	San Antonio	Texas	United States	78215
31	Ardelyx Investigative Site 407	San Antonio	Texas	United States	78229
32	Ardelyx Investigative Site 401	Saint George	Utah	United States	84790

Sponsors and Collaborators

• Ardelyx

Investigators

• Study Chair: David P Rosenbaum, Ph.D., Ardelyx, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ardelyx
• ClinicalTrials.gov Identifier: NCT02675998
• Other Study ID Numbers: TEN-02-201
• First Posted: Feb 5, 2016
• Last Update Posted: Aug 10, 2020
• Last Verified: Aug 1, 2020

• Additional relevant MeSH terms: Kidney Failure, Chronic; Hyperphosphatemia

Study Results

Participant Flow

Arm/Group Title	3mg BID	10mg BID	30 mg Dose Titration	Randomized Withdrawal Period Placebo
Arm/Group Description	Tenapanor, 3mg BID (6mg total) Tenapanor	Tenapanor, 10mg BID (20mg total) Tenapanor	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 Tenapanor	These were participants re-randomized to placebo during the 4-week withdrawal period.
Period Title: 8-Week Treatment Period
STARTED	74	73	72	0
COMPLETED	57	54	53	0
NOT COMPLETED	17	19	19	0
Period Title: 8-Week Treatment Period
STARTED	25	23	34	82
COMPLETED	24	22	32	74
NOT COMPLETED	1	1	2	8

Baseline Characteristics

Arm/Group Title	3mg BID	10mg BID	Dose Titration	Placebo	Total
Arm/Group Description	Tenapanor, 3mg BID (6mg total)	Tenapanor, 10mg BID (20mg total)	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	Placebo Placebo	Total of all reporting groups
Overall Participants	74	73	72	0	219
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.7 (11.49)	57.4 (10.81)	54.2 (10.87)	55.8 (11.09)
Sex: Female, Male (Count of Participants)
Female	28 37.8%	39 53.4%	24 33.3%	91 Infinity
Male	46 62.2%	34 46.6%	48 66.7%	128 Infinity
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	13 17.6%	8 11%	19 26.4%	40 Infinity
Not Hispanic or Latino	61 82.4%	65 89%	53 73.6%	179 Infinity
Unknown or Not Reported	0 0%	0 0%	0 0%	0 NaN
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.4%	1 1.4%	0 0%	2 Infinity
Asian	2 2.7%	0 0%	0 0%	2 Infinity
Native Hawaiian or Other Pacific Islander	1 1.4%	2 2.7%	1 1.4%	4 Infinity
Black or African American	40 54.1%	45 61.6%	40 55.6%	125 Infinity
White	30 40.5%	25 34.2%	31 43.1%	86 Infinity
More than one race	0 0%	0 0%	0 0%	0 NaN
Unknown or Not Reported	0 0%	0 0%	0 0%	0 NaN
Body Mass Index (m/kg^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m/kg^2]	32.5 (8.52)	33.6 (8.50)	33.4 (8.15)	33.1 (8.37)

Outcome Measures

1. Primary Outcome

Title	Placebo Adjusted Change in Serum Phosphate During Randomized Withdrawal Period From Pooled Tenapanor Arms
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	3mg BID	10mg BID	30 mg Dose Titration	Placebo
Arm/Group Description	Tenapanor, 3mg BID (6mg total) Tenapanor	Tenapanor, 10mg BID (20mg total) Tenapanor	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 Tenapanor	Placebo Placebo
Measure Participants	0	0	43	37
Least Squares Mean (Standard Error) [mg/dL]	1.4 (0.23)	0.6 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	30 mg Dose Titration, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change in Serum Phosphate During 8-Week Treatment Period
Description	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

Outcome Measure Data

Analysis Population Description

There was no placebo group during the 8-week treatment period.

Arm/Group Title	3mg BID	10mg BID	30 mg Dose Titration	Placebo
Arm/Group Description	Tenapanor, 3mg BID (6mg total) Tenapanor	Tenapanor, 10mg BID (20mg total) Tenapanor	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 Tenapanor	Placebo Placebo
Measure Participants	74	73	72	0
Least Squares Mean (Standard Error) [mg/dL]	-1.1 (0.17)	-1.1 (0.17)	-1.1 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	30 mg Dose Titration
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	12 weeks. The first 8 weeks were tenapanor only and during the last 4 weeks half of the tenapanor-treated patients from the first 8 weeks were randomized to receive placebo
Adverse Event Reporting Description	There was no placebo during the first 8-weeks
Arm/Group Title	3mg BID		10mg BID		30 mg Dose Titration		Randomized Withdrawal Period Placebo
Arm/Group Description	Tenapanor, 3mg BID (6mg total)		Tenapanor, 10mg BID (20mg total)		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		The 164 patients that ended the 8 week treatment period were re-randomized 1:1 to stay on tenapanor or receive placebo. The patients in this group were re-randomized to receive placebo for the last 4 weeks of the study
All Cause Mortality
	3mg BID		10mg BID		30 mg Dose Titration		Randomized Withdrawal Period Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/74 (1.4%)		0/73 (0%)		0/72 (0%)		0/82 (0%)
Serious Adverse Events
	3mg BID		10mg BID		30 mg Dose Titration		Randomized Withdrawal Period Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/74 (1.4%)		0/73 (0%)		0/72 (0%)		0/82 (0%)
Gastrointestinal disorders
Diarrhea	1/74 (1.4%)	1	0/73 (0%)	1	0/72 (0%)	1	0/82 (0%)	1
Other (Not Including Serious) Adverse Events
	3mg BID		10mg BID		30 mg Dose Titration		Randomized Withdrawal Period Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/74 (29.7%)		30/73 (41.1%)		34/72 (47.2%)		7/82 (8.5%)
Gastrointestinal disorders
Diarrhea	22/74 (29.7%)	22	30/73 (41.1%)	30	34/72 (47.2%)	34	7/82 (8.5%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.