A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia (OPAL)

• Sponsor: Relypsa, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01810939
• Collaborator: (none)
• Enrollment: 243
• Locations: 58
• Arms: 2
• Duration (Months): 5.9
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy and safety of patiromer (investigational drug) in the treatment of hyperkalemia (high serum potassium). The study also evaluated the effect of withdrawing patiromer treatment and assessed whether chronic treatment with patiromer prevented the recurrence of hyperkalemia. The safety of patiromer treatment was also evaluated.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease (CKD); Hyperkalemia (HK)	Drug: Patiromer; Drug: Placebo	Phase 3

Detailed Description

There were two parts in the study, Part A and Part B.

Part A was an assessment of 4 weeks of dosing with patiromer in the treatment of hyperkalemia; Part B was a randomized, placebo-controlled, 8-week assessment of the withdrawal of patiromer in participants with a baseline serum potassium at the beginning of Part A ≥ 5.5 mEq/L who responded to the 4 weeks of treatment with patiromer during Part A.

All participants received patiromer during Part A; Part B participants were randomized to continue patiromer or switch to placebo. Total study participation was up to 14 weeks (including up to 2 weeks of follow up).

The dose of patiromer could be titrated based on participant's serum potassium response.

Study Design

• Study Type: Interventional
• Actual Enrollment: 243 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Patiromer Patiromer was administered twice a day as a powder mixed with water.	Drug: Patiromer; Other Names: RLY5016 for Oral Suspension Veltassa
Placebo Comparator: Placebo Placebo was administered twice a day as a powder mixed with water.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change in Serum Potassium From Part A Baseline to Part A Week 4 [Part A Baseline to Part A Week 4]

   The primary analysis endpoint is the change from Baseline at Week 4. The estimate of the change at Week 4 is from a repeated measures model, which includes data from Weeks 1, 2, 3 and 4. The analysis includes all intent to treat participants who had a serum potassium result at baseline and at least one weekly post-baseline visit (i.e. Part A Week 1 or later) and excludes six participants who had no result collected after Day 3).

2. Change in Serum Potassium From Part B Baseline [Part B Baseline to Part B Week 4 or first local laboratory serum potassium < 3.8 mEq/L or ≥ 5.5 mEq/L]

   Change in Serum Potassium from Part B Baseline to either: Part B Week 4 visit, if the participant's serum potassium remained ≥ 3.8 mEq/L and < 5.5 mEq/L up to the Part B Week 4 visit or the earliest Part B visit at which the participant's serum potassium was < 3.8 mEq/L or ≥ 5.5 mEq/L.

Secondary Outcome Measures

1. Proportion of Participants With Serum Potassium Levels in the Target Range of 3.8 to < 5.1 mEq/L at Part A Week 4 [Week 4]

2. Proportion of Participants With Serum Potassium That Was ≥ 5.5 mEq/L in Part B [Part B Baseline to Part B Week 8]

3. Proportion of Participants With Serum Potassium ≥ 5.1 mEq/L in Part B [Part B Baseline to Part B Week 8]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males and females ages 18 - 80

• Chronic kidney disease (CKD) - eGFR 15 to < 60 mL/min/1.73m2 at screening

• Hyperkalemia, defined as a serum potassium value of 5.1 to < 6.5 mEq/L at screening

• Taking either an Angiotensin-Converting Enzyme (ACE) Inhibitor, an Angiotensin II receptor blocker (ARB), or an aldosterone antagonist (AA) medication

• Informed consent given

Exclusion Criteria:

• Participants with auto-immune related chronic kidney disease such as lupus nephritis or renal scleroderma/scleroderma renal crisis, or mixed connective tissue disease with renal involvement

• Participants with uncontrolled Type 1 diabetes, defined as or a HbA1c > 10.0 %, or hospitalization to treat hyper- or hypo-glycemia in the past 3 months within the previous 6 months in participants with Type 2 diabetes

• Participants with severe heart failure, defined as NYHA (New York Heart Association) class IV

• Participants with major surgery including thoracic and cardiac, in the past 3 months, or participants with heart or kidney transplant

• Participants with significant cardiovascular or cerebrovascular events in the past 2 months, such as cardiac arrest, myocardial infarction, or stroke

• Participants with BMI ≥ 40 kg/m2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigator Site 3121	Azusa	California	United States	91702
2	Investigator Site 3133	Los Angeles	California	United States	90025
3	Investigator Site 3103	Sacramento	California	United States	95825
4	Investigator Site 3129	Santa Barbara	California	United States	93110
5	Investigator Site 3130	Ventura	California	United States	93003
6	Investigator Site 3105	Edgewater	Florida	United States	32132
7	Investigator Site 3113	Hollywood	Florida	United States	33021
8	Investigator Site 3106	Port Charlotte	Florida	United States	33952
9	Investigator Site 3120	Augusta	Georgia	United States	30909
10	Investigator Site 3102	Farmington	Missouri	United States	63640
11	Investigator Site 3104	Kansas City	Missouri	United States	64111
12	Investigator Site 3134	Flushing	New York	United States	11355
13	Investigator Site 3107	Bethlehem	Pennsylvania	United States	18017
14	Investigator Site 3110	San Antonio	Texas	United States	78229
15	Investigator Site 1103	Karlovac		Croatia	47000
16	Investigator Site 1102	Osijek		Croatia	31000
17	Investigator Site 1104	Zagreb		Croatia	10000
18	Investigator Site 1105	Zagreb		Croatia	10000
19	Investigator Site 1106	Zagreb		Croatia	10000
20	Investigator Site 1205	Znojmo		Czechia	66 902
21	Investigator Site 2103	Aarhus N		Denmark	8200
22	Investigator Site 2107	Fredericia		Denmark	7000
23	Investigator Site 2101	Roskilde		Denmark	4000
24	Investigator Site 2105	Viborg		Denmark	8800
25	Investigator Site 1308	Tbilisi		Georgia	0102
26	Investigator Site 1312	Tbilisi		Georgia	0144
27	Investigator Site 1301	Tbilisi		Georgia	0159
28	Investigator Site 1302	Tbilisi		Georgia	0159
29	Investigator Site 1304	Tbilisi		Georgia	0159
30	Investigator Site 1305	Tbilisi		Georgia	0159
31	Investigator Site 1306	Tbilisi		Georgia	0159
32	Investigator Site 1307	Tbilisi		Georgia	0159
33	Investigator Site 1309	Tbilisi		Georgia	0159
34	Investigator Site 1310	Tbilisi		Georgia	0159
35	Investigator Site 1311	Tbilisi		Georgia	0159
36	Investigator Site 1303	Tbilisi		Georgia	0186
37	Investigator Site 1410	Balatonfured		Hungary	H-8230
38	Investigator Site 1415	Budapest		Hungary	H-1133
39	Investigator Site 1401	Gyor		Hungary	H-9024
40	Investigator Site 1406	Hatvan		Hungary	H-3000
41	Investigator Site 1405	Jaszbereny		Hungary	H-5100
42	Investigator Site 1411	Kistarcsa		Hungary	H-2143
43	Investigator Site 1407	Veszprem		Hungary	H-8200
44	Investigator Site 2201	Pavia		Italy	27100
45	Investigator Site 1703	Belgrade		Serbia	11000
46	Investigator Site 1710	Vrsac		Serbia	26300
47	Investigator Site 1707	Zrenjanin		Serbia	23000
48	Investigator Site 1802	Celje		Slovenia	3000
49	Investigator Site 1803	Jesenice		Slovenia	4270
50	Investigator Site 1915	Ivano-Frankivsk		Ukraine	76018
51	Investigator Site 1904	Kharkiv		Ukraine	61007
52	Investigator Site 1903	Kharkiv		Ukraine	61018
53	Investigator Site 1908	Kharkiv		Ukraine	61039
54	Investigator Site 1909	Kyiv		Ukraine	04114
55	Investigator Site 1911	Kyiv		Ukraine	3680
56	Investigator Site 1914	Lugansk		Ukraine	91045
57	Investigator Site 1907	Zaporizhzhia		Ukraine	69001
58	Investigator Site 1906	Zaporizhzhia		Ukraine	69118

Sponsors and Collaborators

• Relypsa, Inc.

Investigators

• Study Director: Director Clinical Operations, Relypsa, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Relypsa company website

Publications

• Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-Schmidt H, Berman L, Pitt B; OPAL-HK Investigators. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015 Jan 15;372(3):211-21. doi: 10.1056/NEJMoa1410853. Epub 2014 Nov 21.

• Responsible Party: Relypsa, Inc.
• ClinicalTrials.gov Identifier: NCT01810939
• Other Study ID Numbers: RLY5016-301; 2012-001956-20
• First Posted: Mar 14, 2013
• Last Update Posted: Jun 3, 2021
• Last Verified: May 1, 2021

• Keywords provided by Relypsa, Inc.: Chronic Kidney Disease; Treatment of Hyperkalemia; Hyperkalemia
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hyperkalemia

Study Results

Participant Flow

Arm/Group Title	Part A Patiromer	Part B Patiromer	Part B Placebo
Arm/Group Description	Participants were administered patiromer starting dose of 8.4 g or 16.8 g daily as a divided dose twice a day, orally, for 4 weeks.	Participants continued on the same daily patiromer dose as administered at the time of the Part A Week 4 Visit for 8 weeks.	Participants were administered placebo orally twice a day for 8 weeks.
Period Title: Part A Treatment Period
STARTED	243	0	0
COMPLETED	219	0	0
NOT COMPLETED	24	0	0
Period Title: Part A Treatment Period
STARTED	0	55	52
COMPLETED	0	45	30
NOT COMPLETED	0	10	22

Baseline Characteristics

Arm/Group Title	Part A Patiromer
Arm/Group Description	Participants were administered patiromer starting dose of 8.4 g or 16.8 g daily as a divided dose twice a day, orally, for 4 weeks.
Overall Participants	243
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	112 46.1%
>=65 years	131 53.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64.2
Sex: Female, Male (Count of Participants)
Female	103 42.4%
Male	140 57.6%

Outcome Measures

1. Secondary Outcome

Title	Proportion of Participants With Serum Potassium Levels in the Target Range of 3.8 to < 5.1 mEq/L at Part A Week 4
Time Frame	Week 4

Outcome Measure Data

Analysis Population Description

Proportion of participants with serum potassium level in the target range at Part A Week 4

Arm/Group Title	Part A Patiromer
Arm/Group Description	Participants were administered patiromer starting dose of 8.4 g or 16.8 g daily as a divided dose twice a day, orally, for 4 weeks.
Measure Participants	243
Number (95% Confidence Interval) [percentage of participants]	76 31.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A Patiromer
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.7 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Participants With Serum Potassium That Was ≥ 5.5 mEq/L in Part B
Time Frame	Part B Baseline to Part B Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part B Placebo	Part B Patiromer
Arm/Group Description	Participants were administered placebo orally twice a day for 8 weeks.	Participants continued on the same daily patiromer dose as administered at the time of the Part A Week 4 Visit for 8 weeks.
Measure Participants	52	55
Number [percentage of participants]	60 24.7%	15 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A Patiromer, Part B Patiromer
	Comments	Test for difference between treatment groups in proportion with serum potassium ≥ 5.5 mEq/L
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mantel Haenszel
	Comments

3. Secondary Outcome

Title	Proportion of Participants With Serum Potassium ≥ 5.1 mEq/L in Part B
Time Frame	Part B Baseline to Part B Week 8

Outcome Measure Data

Analysis Population Description

Percentages were estimated not as simple ratios, but by using a stratified method, in order to account for differences between the patiromer and placebo groups in terms of whether participants had type 2 diabetes mellitus and whether they entered the study with serum potassium < 5.8 mEq/L or serum potassium ≥ 5.8 mEq/L.

Arm/Group Title	Part B Placebo	Part B Patiromer
Arm/Group Description	Participants were administered placebo orally twice a day for 8 weeks.	Participants continued on the same daily patiromer dose as administered at the time of the Part A Week 4 Visit for 8 weeks.
Measure Participants	52	55
Number [percentage of participants]	91 37.4%	43 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A Patiromer, Part B Patiromer
	Comments	Test for difference between treatment groups in proportion with serum potassium ≥ 5.1 mEq/L
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mantel Haenszel
	Comments

4. Primary Outcome

Title	Change in Serum Potassium From Part A Baseline to Part A Week 4
Description	The primary analysis endpoint is the change from Baseline at Week 4. The estimate of the change at Week 4 is from a repeated measures model, which includes data from Weeks 1, 2, 3 and 4. The analysis includes all intent to treat participants who had a serum potassium result at baseline and at least one weekly post-baseline visit (i.e. Part A Week 1 or later) and excludes six participants who had no result collected after Day 3).
Time Frame	Part A Baseline to Part A Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part A Patiromer
Arm/Group Description	Participants were administered patiromer starting dose of 8.4 g or 16.8 g daily as a divided dose twice a day, orally, for 4 weeks. The dose of patiromer could be titrated based on participant's serum potassium response.
Measure Participants	237
Least Squares Mean (Standard Error) [mEq/L]	-1.01 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A Patiromer
	Comments	Estimation of mean change in serum potassium from Part A Baseline to Part A Week 4 and test mean change different from zero.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Longitudinal mixed models
	Comments	Test that the mean change is significantly different from zero.

5. Primary Outcome

Title	Change in Serum Potassium From Part B Baseline
Description	Change in Serum Potassium from Part B Baseline to either: Part B Week 4 visit, if the participant's serum potassium remained ≥ 3.8 mEq/L and < 5.5 mEq/L up to the Part B Week 4 visit or the earliest Part B visit at which the participant's serum potassium was < 3.8 mEq/L or ≥ 5.5 mEq/L.
Time Frame	Part B Baseline to Part B Week 4 or first local laboratory serum potassium < 3.8 mEq/L or ≥ 5.5 mEq/L

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part B Placebo	Part B Patiromer
Arm/Group Description	Participants were administered placebo orally twice a day for 8 weeks.	Participants continued on the same daily patiromer dose as administered at the time of the Part A Week 4 Visit for 8 weeks.
Measure Participants	52	55
Median (Inter-Quartile Range) [mEq/L]	0.72	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A Patiromer, Part B Patiromer
	Comments	Test for difference between treatment groups in serum potassium change in Part B
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	2 weeks after Week 4 for Part A subjects who did not continue in Part B and 2 weeks after Week 12 for Part B.
Adverse Event Reporting Description	Participants who received at least one dose of trial medication
Arm/Group Title	Part A Patiromer		Part B Patiromer		Part B Placebo
Arm/Group Description	Participants were administered patiromer starting dose of 8.4 g or 16.8 g daily as a divided dose twice a day, orally, for 4 weeks.		Participants continued on the same daily patiromer dose as administered at the time of the Part A Week 4 Visit for 8 weeks.		Participants were administered placebo orally twice a day for 8 weeks.
All Cause Mortality
	Part A Patiromer		Part B Patiromer		Part B Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part A Patiromer		Part B Patiromer		Part B Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/243 (1.2%)		0/55 (0%)		1/52 (1.9%)
Cardiac disorders
Atrial fibrillation	1/243 (0.4%)		0/55 (0%)		0/52 (0%)
Gastrointestinal disorders
Thrombosis mesenteric vessel	0/243 (0%)		0/55 (0%)		1/52 (1.9%)
Infections and infestations
Escherichia bacteraemia	1/243 (0.4%)		0/55 (0%)		0/52 (0%)
Urinary tract infection	1/243 (0.4%)		0/55 (0%)		0/52 (0%)
Endocarditis enterococcal	1/243 (0.4%)		0/55 (0%)		0/52 (0%)
Investigations
Anticoagulation drug level below therapeutic	1/243 (0.4%)		0/55 (0%)		0/52 (0%)
Renal and urinary disorders
Renal failure chronic	1/243 (0.4%)		0/55 (0%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	Part A Patiromer		Part B Patiromer		Part B Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/243 (13.6%)		5/55 (9.1%)		8/52 (15.4%)
Gastrointestinal disorders
Constipation	26/243 (10.7%)		2/55 (3.6%)		0/52 (0%)
Infections and infestations
Influenza	1/243 (0.4%)		1/55 (1.8%)		3/52 (5.8%)
Nervous system disorders
Headache	2/243 (0.8%)		2/55 (3.6%)		4/52 (7.7%)
Vascular disorders
Hypertension	4/243 (1.6%)		0/55 (0%)		3/52 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Our agreements generally provide that PI cannot publish single site data before publication of the multi-site publication, unless 1 year has elapsed since completion of the study at all sites. Thereafter, PI may publish provided that PI shall: provide a copy of the publication to sponsor at least 60 days in advance of submission for publication; delete sponsor's confidential information as requested; and delay publication up to an additional 90 days to permit protection of intellectual property.