HALT Progression of Polycystic Kidney Disease Study B

Study Overview
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Brief Summary
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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
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* 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).

Official Title
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HALT Progression of Polycystic Kidney Disease Study B

Conditions
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Kidney, Polycystic

Intervention / Treatment
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* Drug: Lisinopril
* Drug: Telmisartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: ACE-I + placebo<br>Monotherapy of lisinopril and placebo. Standard blood pressure control of 110-130/80 mm Hg | Drug: Lisinopril<br>* Lisinopril titrated to 5mg, 10mg, 20mg, 40mg as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.<br>* Other names: Ace-Inhibitor;Drug: Placebo<br>* Placebo titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.<br>* Other names: Control;|
| Active Comparator: ACE-I + ARB<br>Dual therapy of lisinopril and telmisartan treatments. Standard blood pressure control of 110-130/80 mm Hg. | Drug: Lisinopril<br>* Lisinopril titrated to 5mg, 10mg, 20mg, 40mg as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.<br>* Other names: Ace-Inhibitor;Drug: Telmisartan<br>* Telmisartan titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.<br>* Other names: ARB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 8 years (annually assessed) | 
| 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. | up at 8 years (annually assessed) | 
| Hospitalizations | Hospitalization for any cause | up to 8 years | 
| Cardiovascular Hospitalizations | Cause-specific hospitalizations (cardiovascular) | up to 8 years | 
| 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. | up to 8 years (annually assessed) | 
| 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. | up to 8 years (annually assessed) | 
| Back or Flank Pain | Report of back or flank pain since the last visit (yes or no) | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pkd, polycystic kidney disease, polycystic, kidney, disease, adpkd, halt, blood pressure, bp, hypertension, renal, renin-angiotensin-aldosterone-system, RAAS