Kidney, Polycystic
Conditions
Keywords
polycystic kidney disease, polycystic, kidney, disease, adpkd, halt, pkd, blood pressure, bp, hypertension, renal, renin-angiotensin-aldosterone-system, RAAS
Brief summary
The efficacy of interruption of the renin-angiotensin-aldosterone system (RAAS) on the progression of cystic disease and on the decline in renal function in autosomal dominant kidney disease (ADPKD) will be assessed in two simultaneous multicenter randomized clinical trials targeting different levels of kidney function: 1) early disease defined by GFR \>60 mL/min/1.73 m2 (Study A); and 2) moderately advanced disease defined by GFR 25-60 mL/min/1.73 m2 (Study B). Participants will be recruited and enrolled, either to Study A or B, over the first three years. Participants enrolled in Study B will be followed for five-to-eight years, with the average length of follow-up being six and a half years. Combination therapy will use angiotensin-converting-enzyme inhibitor (ACE-I) and an angiotensin-receptor blocker (ARB). Monotherapy will use ACE-I alone.
Detailed description
\* Specific Aim of Study B To study the effects of ACE-I/ARB combination therapy as compared to ACE-I monotherapy in the setting of standard blood pressure control (110-130/80 mm Hg) on the time to a 50% reduction of baseline estimated Glomerular Filtration Rate (eGFR), end-state renal disease (ESRD) or death, in hypertensive individuals with moderate renal insufficiency (GFR 25-60 mL/min/1.73m2). \* Hypothesis to be tested in Study B In hypertensive ADPKD individuals with moderate renal insufficiency (GFR 25-60 mL/min/1.73 m2), intensive blockade of the RAAS using combination ACE-I/ARB therapy will slow the decline in kidney function over ACE-I monotherapy, independent of standard blood pressure control (110-130/80 mm Hg).
Interventions
DRUGLisinopril
Lisinopril titrated to 5mg, 10mg, 20mg, 40mg as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.
DRUGTelmisartan
Telmisartan titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.
DRUGPlacebo
Placebo titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.
Sponsors
Boehringer Ingelheim
Merck Sharp & Dohme LLC
Polycystic Kidney Disease Foundation
University of Pittsburgh
Washington University School of Medicine
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
15 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of ADPKD. * Age 15-49 (Study A); Age 18-64 (Study B). * GFR \>60 mL/min/1.73 m2 (Study A); GFR 25-60 mL/min/1.73 m2 (Study B). * BP ≥130/80 or receiving treatment for hypertension. * Informed Consent.
Exclusion criteria
* Pregnant/intention to become pregnant in 4-6 yrs. * Documented renal vascular disease. * Spot urine albumin-to-creatinine ratio of \>0.5 (Study A) or ≥1.0 (Study B) and/or findings suggestive of kidney disease other than ADPKD. * Diabetes requiring insulin or oral hypoglycemic agents / fasting serum glucose of \>126 mg/dl / random non-fasting glucose of \>200 mg/dl. * Serum potassium \>5.5 milliequivalent (mEq) /L for participants currently on ACE-I or ARB; \>5.0 mEq/L for participants not currently on ACE-I or ARB. * History of angioneurotic edema or other absolute contraindication for ACE-I or ARB. Intolerable cough associated with ACE-I is defined as a cough developing within six months of initiation of ACE-I in the absence of other causes and resolving upon discontinuation of the ACE-I. * Indication (other than hypertension) for β-blocker or calcium channel blocker therapy (e.g. angina, past myocardial infarction, arrhythmia), unless approved by the site principal investigator. (PI may choose to accept an individual who is on only a small dose of one of these agents and would otherwise be eligible.) * Systemic illness necessitating nonsteroidal antiinflammatory drugs (NSAIDs), immunosuppressant or immunomodulatory medications. * Systemic illness with renal involvement. * Hospitalized for acute illness in past 2 months. * Life expectancy \<2 years. * History of non-compliance. * Unclipped cerebral aneurysm \>7mm diameter. * Creatine supplements within 3 months of screening visit. * Congenital absence of a kidney (also total nephrectomy for Study B). * Known allergy to sorbitol or sodium polystyrene sulfonate. * Exclusions specific to magnetic resonance (MR) imaging (Study A).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With 50% Reduction of Baseline eGFR, End Stage Renal Disease (ESRD, Initiation of Dialysis or Preemptive Transplant), or Death. | Patients followed for 5-8 years with average of 6.5 years follow up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Albuminuria | up to 8 years (annually assessed) | Annual percent change in 24 hour urine albumin, centrally processed. Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope of the model). The measure presented is the average annual percent change across the 8 years. |
| Aldosterone | up at 8 years (annually assessed) | Annual percent change in urinary aldosterone, centrally processed measure. Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope for time from the model). The measure presented is the average annual percent change across the 8 years. |
| Hospitalizations | up to 8 years | Hospitalization for any cause |
| Back or Flank Pain | 48 months | Report of back or flank pain since the last visit (yes or no) |
| Quality of Life Physical Component Summary | up to 8 years (annually assessed) | Short Form-36 Quality of Life Physical Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome). Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope for time from the model). The measure presented is the average annual change across the 8 years. |
| Quality of Life Mental Component Summary | up to 8 years (annually assessed) | Short Form-36 Quality of Life Mental Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome). Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope for time from the model). The measure presented is the average annual change across the 8 years. |
| Cardiovascular Hospitalizations | up to 8 years | Cause-specific hospitalizations (cardiovascular) |
Countries
United States
Participant flow
Recruitment details
Recruitment for HALT PKD Study B occurred at seven clinical sites between February 2006 and June 2009.
Participants by arm
| Arm | Count |
|---|---|
| ACE-I + Placebo ACE-I + placebo and standard blood pressure control of 110-130/80 mm Hg
Lisinopril and Placebo: Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and placebo titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg. | 242 |
| ACE-I + ARB ACE-I + ARB and standard blood pressure control of 110-130/80 mm Hg
Lisinopril and Telmisartan: Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and telmisartan titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg. | 244 |
| Total | 486 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Less than full participation | 9 | 19 |
| Overall Study | Lost to Follow-up | 15 | 16 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Total | ACE-I + ARB | ACE-I + Placebo |
|---|---|---|---|
| Age at Diagnosis of Autosomal Dominant Polycystic Kidney Disease (yrs) | 33.2 years STANDARD_DEVIATION 12.2 | 33.0 years STANDARD_DEVIATION 12 | 33.5 years STANDARD_DEVIATION 12.4 |
| Age, Continuous | 48.7 years STANDARD_DEVIATION 8.3 | 48.6 years STANDARD_DEVIATION 8.5 | 48.9 years STANDARD_DEVIATION 8.1 |
| Body Mass Index (kg/m2) | 28.0 kg/m2 STANDARD_DEVIATION 5.2 | 28.0 kg/m2 STANDARD_DEVIATION 4.9 | 28.0 kg/m2 STANDARD_DEVIATION 5.5 |
| Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) eGFR (ml/min/m^2) | 48.2 ml/min/m^2 STANDARD_DEVIATION 11.8 | 48.5 ml/min/m^2 STANDARD_DEVIATION 11.5 | 47.9 ml/min/m^2 STANDARD_DEVIATION 12.2 |
| PKD Genotype No data | 39 participants | 21 participants | 18 participants |
| PKD Genotype No Mutation Detected | 25 participants | 14 participants | 11 participants |
| PKD Genotype PKD1 | 362 participants | 179 participants | 183 participants |
| PKD Genotype PKD2 | 60 participants | 30 participants | 30 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 454 Participants | 230 Participants | 224 Participants |
| Serum Creatinine (mg/dl) | 1.6 mg/dl STANDARD_DEVIATION 0.4 | 1.5 mg/dl STANDARD_DEVIATION 0.4 | 1.6 mg/dl STANDARD_DEVIATION 0.4 |
| Sex: Female, Male Female | 251 Participants | 129 Participants | 122 Participants |
| Sex: Female, Male Male | 235 Participants | 115 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 66 / 242 | 60 / 244 |
| serious Total, serious adverse events | 88 / 242 | 88 / 244 |
Outcome results
Primary
Number of Participants With 50% Reduction of Baseline eGFR, End Stage Renal Disease (ESRD, Initiation of Dialysis or Preemptive Transplant), or Death.
Time frame: Patients followed for 5-8 years with average of 6.5 years follow up
Population: Intention to Treat analysis was used for the primary outcome
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-I + Placebo | Number of Participants With 50% Reduction of Baseline eGFR, End Stage Renal Disease (ESRD, Initiation of Dialysis or Preemptive Transplant), or Death. | 116 participants |
| ACE-I + ARB | Number of Participants With 50% Reduction of Baseline eGFR, End Stage Renal Disease (ESRD, Initiation of Dialysis or Preemptive Transplant), or Death. | 115 participants |
p-value: 0.5895% CI: [0.82, 1.42]Regression, Cox
Secondary
Albuminuria
Annual percent change in 24 hour urine albumin, centrally processed. Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope of the model). The measure presented is the average annual percent change across the 8 years.
Time frame: up to 8 years (annually assessed)
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + Placebo | Albuminuria | 7.5 annual percent change |
| ACE-I + ARB | Albuminuria | 7.3 annual percent change |
p-value: 0.8895% CI: [-3.2, 2.8]shared parameter model
Secondary
Aldosterone
Annual percent change in urinary aldosterone, centrally processed measure. Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope for time from the model). The measure presented is the average annual percent change across the 8 years.
Time frame: up at 8 years (annually assessed)
Population: Intention to treat analyses
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + Placebo | Aldosterone | -8.8 annual percent change |
| ACE-I + ARB | Aldosterone | -10.2 annual percent change |
p-value: 0.1795% CI: [-3.9, 0.7]Mixed Models Analysis
Secondary
Back or Flank Pain
Report of back or flank pain since the last visit (yes or no)
Time frame: 48 months
Population: Cross sectional analysis at 48 months is reported only for those participants responding at that time point. Intention to treat analysis was used for in the modeling over time to incorporate all repeated measures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-I + Placebo | Back or Flank Pain | 43 percentage of participants at 48 months |
| ACE-I + ARB | Back or Flank Pain | 46 percentage of participants at 48 months |
p-value: 0.6495% CI: [0.99, 1.01]Mixed Models Analysis
Secondary
Cardiovascular Hospitalizations
Cause-specific hospitalizations (cardiovascular)
Time frame: up to 8 years
Population: Intention to Treat analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-I + Placebo | Cardiovascular Hospitalizations | 29 events |
| ACE-I + ARB | Cardiovascular Hospitalizations | 16 events |
p-value: 0.5795% CI: [0.42, 1.6]Regression, Cox
Secondary
Hospitalizations
Hospitalization for any cause
Time frame: up to 8 years
Population: Intention to treat analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-I + Placebo | Hospitalizations | 173 events |
| ACE-I + ARB | Hospitalizations | 136 events |
p-value: 0.8595% CI: [0.8, 1.32]Regression, Cox
Secondary
Quality of Life Mental Component Summary
Short Form-36 Quality of Life Mental Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome). Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope for time from the model). The measure presented is the average annual change across the 8 years.
Time frame: up to 8 years (annually assessed)
Population: Intention to treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + Placebo | Quality of Life Mental Component Summary | -0.031 units on a scale per year |
| ACE-I + ARB | Quality of Life Mental Component Summary | -0.079 units on a scale per year |
p-value: 0.6695% CI: [-0.26, 0.16]shared parameter model
Secondary
Quality of Life Physical Component Summary
Short Form-36 Quality of Life Physical Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome). Data from multiple years were analyzed with the primary focus on the change over time for the measure (from the slope for time from the model). The measure presented is the average annual change across the 8 years.
Time frame: up to 8 years (annually assessed)
Population: Intention to Treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + Placebo | Quality of Life Physical Component Summary | -0.64 units on a scale per year |
| ACE-I + ARB | Quality of Life Physical Component Summary | -0.68 units on a scale per year |
p-value: 0.7595% CI: [-0.23, 0.16]shared parameter model