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 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; NCT01885559). Participants will be recruited and enrolled, either to Study A or B, over the first three years. Participants enrolled in Study A will be followed for at least 5 years, while those 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. The two concurrent randomized clinical trials differ by eligibility criteria, interventions and outcomes to be studied.
Detailed description
\* Specific Aims of Study A To study the efficacy of angiotensin-converting-enzyme inhibitor (ACE-I) and angiotensin-receptor blockade (ARB) combination therapy as compared to ACE-I monotherapy and usual vs. low blood pressure targets on the percent change in kidney volume in participants with preserved renal function (GFR \>60 mL/min/1.73m2)and high-normal blood pressure or hypertension (\>130/80 mm Hg). \* Hypotheses to be tested in Study A In ADPKD individuals with hypertension or high-normal blood pressure and relatively preserved renal function (GFR \>60 mL/min/1.73 m2), multi-level blockade of the RAAS using ACE-I/ARB combination therapy will delay progression of cystic disease as compared to ACE-I monotherapy, and a low blood pressure goal will delay progression as compared with standard control.
Interventions
DRUGTelmisartan
Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants
DRUGLisinopril
Lisinopril titrated to 5mg, 10mg, 20mg, 40mg
DRUGPlacebo
Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants
OTHERStandard Blood Pressure Control
Achieve standard blood pressure control of 120-130/70-80 mm Hg using step dosing specified in protocol of lisinopril, study drug, hydrochlorothiazide, metoprolol, or non-dihydropyridine and dihydropyridine calcium channel blockers (diltiazem), clonidine, minoxidil, hydralazine at the discretion of the investigator
OTHERLow Blood Pressure Control
Achieve low blood pressure control of 95-110/60-75 mm Hg using step dosing specified in protocol of lisinopril, study drug, hydrochlorothiazide, metoprolol, or non-dihydropyridine and dihydropyridine calcium channel blockers (diltiazem), clonidine, minoxidil, hydralazine at the discretion of the investigator
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
FACTORIAL
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 per liter (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 imaging (Study A).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Study A: Percent Annual Change in Total Kidney Volume | Baseline and 2-, 4- and 5-year follow-up | Annual percentage change in total kidney volume as assessed by abdominal magnetic resonance imaging (MRI) at baseline, 2 years, 4 years, and 5 years follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kidney Function (eGFR) | Up to 96 months (6 month assessments) | The estimated GFR was calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation with the use of central serum creatinine measurements. |
| Albuminuria | Up to 96 months (assessed annually) | Urine albumin excretion, centrally processed from 24 hour urine collection |
| Aldosterone | Up to 96 months (assessed annually) | Urinary aldosterone excretion, centrally processed, 24 hour urine collection |
| Left Ventricular Mass Index | 0, 24 months, 48 months, 60 months | Left ventricular mass index (g/m\^2) measured by MRI, centrally reviewed and measured |
| Renal Blood Flow | 0, 24 months, 48 months, 60 months | renal blood flow (mL/min/1.73 m\^2) from MRI, centrally reviewed and measured. This outcome was more difficult to measure resulting in more missing data than other MRI outcomes such as total kidney volume (TKV) and left ventricular mass index (LVMI). |
| All-Cause Hospitalizations | Up to 96 months | — |
| Quality of Life Physical Component Summary | baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually) | Short Form-36 Quality of Life Physical Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome) |
| Quality of Life Mental Component Summary | baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually) | Short Form-36 Quality of LIfe Mental Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome) |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at seven clinical sites between February 2006 and June 2009.
Participants by arm
| Arm | Count |
|---|---|
| ACE-I/ARB and Standard BP ACE-I + ARB and standard blood pressure control of 120-130/70-80 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 120-130/70-80 mm Hg. | 140 |
| ACE-I/ARB and Low BP ACE-I + ARB and low blood pressure control of 95-110/60-75 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 low blood pressure control of 95-110/60-75 mm Hg. | 133 |
| ACE-I/Placebo and Standard BP ACE-I + Placebo and standard blood pressure control of 120-130/70-80 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 120-130/70-80 mm Hg. | 144 |
| ACE-I/Placebo and Low BP ACE-I + Placebo and low blood pressure control of 95-110/60-75 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 low blood pressure control of 95-110/60-75 mm Hg. | 141 |
| Total | 558 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 | 0 |
| Overall Study | Less than full participation | 7 | 9 | 6 | 12 |
| Overall Study | Lost to Follow-up | 21 | 31 | 26 | 20 |
Baseline characteristics
| Characteristic | ACE-I/ARB and Standard BP | Total | ACE-I/Placebo and Low BP | ACE-I/Placebo and Standard BP | ACE-I/ARB and Low BP |
|---|---|---|---|---|---|
| Age at Diagnosis of autosomal dominant polycystic kidney disease (ADPKD) | 27.2 years STANDARD_DEVIATION 10 | 27.6 years STANDARD_DEVIATION 10 | 27.6 years STANDARD_DEVIATION 10.4 | 27.0 years STANDARD_DEVIATION 9.5 | 28.5 years STANDARD_DEVIATION 10 |
| Age, Continuous | 37.0 years STANDARD_DEVIATION 8.3 | 36.7 years STANDARD_DEVIATION 8.3 | 36.8 years STANDARD_DEVIATION 8 | 35.8 years STANDARD_DEVIATION 8.6 | 37.1 years STANDARD_DEVIATION 8.4 |
| Body Mass Index (kg/m2) | 27.4 kg/m2 STANDARD_DEVIATION 5.4 | 27.2 kg/m2 STANDARD_DEVIATION 5.2 | 26.8 kg/m2 STANDARD_DEVIATION 4.8 | 27.3 kg/m2 STANDARD_DEVIATION 5.5 | 27.4 kg/m2 STANDARD_DEVIATION 5.1 |
| Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) eGFR (ml/min/m2) | 88.5 ml/min/m2 STANDARD_DEVIATION 18.8 | 88.9 ml/min/m2 STANDARD_DEVIATION 18.5 | 87.6 ml/min/m2 STANDARD_DEVIATION 17.2 | 92.9 ml/min/m2 STANDARD_DEVIATION 18.5 | 86.5 ml/min/m2 STANDARD_DEVIATION 19.3 |
| PKD Genotype No information | 12 participants | 46 participants | 13 participants | 12 participants | 9 participants |
| PKD Genotype No Mutation Detected | 10 participants | 46 participants | 14 participants | 12 participants | 10 participants |
| PKD Genotype PKD1 | 103 participants | 382 participants | 91 participants | 101 participants | 87 participants |
| PKD Genotype PKD2 | 15 participants | 84 participants | 23 participants | 19 participants | 27 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 5 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 14 Participants | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 15 Participants | 2 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 127 Participants | 517 Participants | 131 Participants | 131 Participants | 128 Participants |
| Serum Creatinine (mg/dl) | 1.0 mg/dl STANDARD_DEVIATION 0.3 | 1.0 mg/dl STANDARD_DEVIATION 0.2 | 1.0 mg/dl STANDARD_DEVIATION 0.2 | 0.9 mg/dl STANDARD_DEVIATION 0.2 | 1.0 mg/dl STANDARD_DEVIATION 0.2 |
| Sex: Female, Male Female | 68 Participants | 275 Participants | 70 Participants | 73 Participants | 64 Participants |
| Sex: Female, Male Male | 72 Participants | 283 Participants | 71 Participants | 71 Participants | 69 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 273 | 21 / 285 | 23 / 274 | 21 / 284 |
| serious Total, serious adverse events | 58 / 273 | 90 / 285 | 69 / 274 | 79 / 284 |
Outcome results
Primary
Study A: Percent Annual Change in Total Kidney Volume
Annual percentage change in total kidney volume as assessed by abdominal magnetic resonance imaging (MRI) at baseline, 2 years, 4 years, and 5 years follow-up.
Time frame: Baseline and 2-, 4- and 5-year follow-up
Population: Analyses were conducted on all participants who had at least one total kidney volume measurement using intention to treat.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Study A: Percent Annual Change in Total Kidney Volume | 6.0 percentage of Total Kidney Volume |
| ACE-I Alone | Study A: Percent Annual Change in Total Kidney Volume | 6.2 percentage of Total Kidney Volume |
| Low Blood Pressure Group | Study A: Percent Annual Change in Total Kidney Volume | 5.6 percentage of Total Kidney Volume |
| Standard Blood Pressure Group | Study A: Percent Annual Change in Total Kidney Volume | 6.6 percentage of Total Kidney Volume |
p-value: 0.5295% CI: [-0.8, 5]Mixed Models Analysis
p-value: 0.00695% CI: [-1.6, -0.2]Mixed Models Analysis
Secondary
Albuminuria
Urine albumin excretion, centrally processed from 24 hour urine collection
Time frame: Up to 96 months (assessed annually)
Population: Analysis by intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Albuminuria | -1.1 annual percent change in mg/24 hr |
| ACE-I Alone | Albuminuria | -0.4 annual percent change in mg/24 hr |
| Low Blood Pressure Group | Albuminuria | -3.8 annual percent change in mg/24 hr |
| Standard Blood Pressure Group | Albuminuria | 2.4 annual percent change in mg/24 hr |
p-value: 0.5795% CI: [-3.3, 1.9]Mixed Models Analysis
p-value: <0.000195% CI: [-8.5, -3.4]Mixed Models Analysis
Secondary
Aldosterone
Urinary aldosterone excretion, centrally processed, 24 hour urine collection
Time frame: Up to 96 months (assessed annually)
Population: Analysis using intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Aldosterone | -8.5 annual % change micrograms per 24 hr |
| ACE-I Alone | Aldosterone | -7.3 annual % change micrograms per 24 hr |
| Low Blood Pressure Group | Aldosterone | -8.5 annual % change micrograms per 24 hr |
| Standard Blood Pressure Group | Aldosterone | -7.3 annual % change micrograms per 24 hr |
p-value: 0.1895% CI: [-3.1, 0.6]Mixed Models Analysis
p-value: 0.1995% CI: [-3.1, 0.6]Mixed Models Analysis
Secondary
All-Cause Hospitalizations
Time frame: Up to 96 months
Population: Intention to treat analysis: All participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-I + ARB | All-Cause Hospitalizations | 85 events |
| ACE-I Alone | All-Cause Hospitalizations | 128 events |
| Low Blood Pressure Group | All-Cause Hospitalizations | 93 events |
| Standard Blood Pressure Group | All-Cause Hospitalizations | 120 events |
p-value: 0.022895% CI: [0.53, 0.95]Regression, Cox
p-value: 0.5995% CI: [0.7, 1.22]Regression, Cox
Secondary
Kidney Function (eGFR)
The estimated GFR was calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation with the use of central serum creatinine measurements.
Time frame: Up to 96 months (6 month assessments)
Population: Analyses were intention to treat: All participants who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Kidney Function (eGFR) | -3.0 ml/min/1.73/m2/yr |
| ACE-I Alone | Kidney Function (eGFR) | -2.9 ml/min/1.73/m2/yr |
| Low Blood Pressure Group | Kidney Function (eGFR) | -2.9 ml/min/1.73/m2/yr |
| Standard Blood Pressure Group | Kidney Function (eGFR) | -3.0 ml/min/1.73/m2/yr |
p-value: 0.5295% CI: [-0.6, 0.3]Mixed Models Analysis
p-value: 0.5595% CI: [-0.3, 0.6]Mixed Models Analysis
Secondary
Left Ventricular Mass Index
Left ventricular mass index (g/m\^2) measured by MRI, centrally reviewed and measured
Time frame: 0, 24 months, 48 months, 60 months
Population: Analyses were conducted using intention to treat for participants with at least one left ventricular mass index measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Left Ventricular Mass Index | -0.91 annual change in g/m^2 |
| ACE-I Alone | Left Ventricular Mass Index | -0.83 annual change in g/m^2 |
| Low Blood Pressure Group | Left Ventricular Mass Index | -1.17 annual change in g/m^2 |
| Standard Blood Pressure Group | Left Ventricular Mass Index | -0.57 annual change in g/m^2 |
p-value: 0.5895% CI: [-0.4, 0.22]Mixed Models Analysis
p-value: 0.000295% CI: [-0.91, -0.29]Mixed Models Analysis
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)
Time frame: baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually)
Population: Analysis using intention to treat.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Quality of Life Mental Component Summary | 0.19 annual change in units on a scale |
| ACE-I Alone | Quality of Life Mental Component Summary | -0.06 annual change in units on a scale |
| Low Blood Pressure Group | Quality of Life Mental Component Summary | -0.05 annual change in units on a scale |
| Standard Blood Pressure Group | Quality of Life Mental Component Summary | 0.18 annual change in units on a scale |
p-value: 0.022195% CI: [0.036, 0.46]Mixed Models Analysis
p-value: 0.033995% CI: [-0.44, -0.018]Mixed Models Analysis
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)
Time frame: baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually)
Population: Analysis using intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Quality of Life Physical Component Summary | -0.24 annual change in units on a scale |
| ACE-I Alone | Quality of Life Physical Component Summary | -.23 annual change in units on a scale |
| Low Blood Pressure Group | Quality of Life Physical Component Summary | -0.17 annual change in units on a scale |
| Standard Blood Pressure Group | Quality of Life Physical Component Summary | -0.30 annual change in units on a scale |
p-value: 0.8795% CI: [-0.19, 0.17]Mixed Models Analysis
p-value: 0.1495% CI: [-0.046, 0.31]Mixed Models Analysis
Secondary
Renal Blood Flow
renal blood flow (mL/min/1.73 m\^2) from MRI, centrally reviewed and measured. This outcome was more difficult to measure resulting in more missing data than other MRI outcomes such as total kidney volume (TKV) and left ventricular mass index (LVMI).
Time frame: 0, 24 months, 48 months, 60 months
Population: Analyses were conducted using intention to treat analyses for participants with at least one valid renal blood flow measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ACE-I + ARB | Renal Blood Flow | -6.6 annual change in mL/min/1.73 m^2 |
| ACE-I Alone | Renal Blood Flow | -9.5 annual change in mL/min/1.73 m^2 |
| Low Blood Pressure Group | Renal Blood Flow | -7.6 annual change in mL/min/1.73 m^2 |
| Standard Blood Pressure Group | Renal Blood Flow | -8.5 annual change in mL/min/1.73 m^2 |
p-value: 0.2995% CI: [-2.55, 8.5]Mixed Models Analysis
p-value: 0.7395% CI: [-4.54, 6.5]Mixed Models Analysis