HALT Progression of Polycystic Kidney Disease Study A

Study Overview
=================
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.

Official Title
-----------------
HALT Progression of Polycystic Kidney Disease Study A

Conditions
-----------------
Kidney, Polycystic

Intervention / Treatment
-----------------
* Drug: Lisinopril
* Drug: Telmisartan
* Drug: Placebo
* Other: Standard Blood Pressure Control
* Other: Low Blood Pressure Control


Participation Criteria
=================
Eligibility Criteria
-----------------
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).

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study A, Arm 1<br>Lisinopril + Telmisartan (ACE-I + ARB) and standard blood pressure control of 120-130/70-80 mm Hg | Drug: Lisinopril<br>* Lisinopril titrated to 5mg, 10mg, 20mg, 40mg<br>* Other names: Ace-Inhibitor;Drug: Telmisartan<br>* Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants<br>* Other names: ARB;Other: Standard Blood Pressure Control<br>* 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<br>* Other names: blood pressure control;|
| Active Comparator: Study A, Arm 2<br>Lisinopril + Telmisartan (ACE-I + ARB) and low blood pressure control of 95-110/60-75 mm Hg | Drug: Lisinopril<br>* Lisinopril titrated to 5mg, 10mg, 20mg, 40mg<br>* Other names: Ace-Inhibitor;Drug: Telmisartan<br>* Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants<br>* Other names: ARB;Other: Low Blood Pressure Control<br>* 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<br>* Other names: blood pressure control;|
| Placebo Comparator: Study A, Arm 3<br>Lisinopril + Placebo (ACE-I + Placebo) and standard blood pressure control of 120-130/70-80 mm Hg | Drug: Lisinopril<br>* Lisinopril titrated to 5mg, 10mg, 20mg, 40mg<br>* Other names: Ace-Inhibitor;Drug: Placebo<br>* Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants<br>Other: Standard Blood Pressure Control<br>* 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<br>* Other names: blood pressure control;|
| Placebo Comparator: Study A, Arm 4<br>Lisinopril + Placebo (ACE-I + Placebo) and low blood pressure control of 95-110/60-75 mm Hg | Drug: Lisinopril<br>* Lisinopril titrated to 5mg, 10mg, 20mg, 40mg<br>* Other names: Ace-Inhibitor;Drug: Placebo<br>* Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants<br>Other: Low Blood Pressure Control<br>* 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<br>* Other names: blood pressure control;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 2-, 4- and 5-year follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 96 months (6 month assessments) | 
| Albuminuria | Urine albumin excretion, centrally processed from 24 hour urine collection | Up to 96 months (assessed annually) | 
| Aldosterone | Urinary aldosterone excretion, centrally processed, 24 hour urine collection | Up to 96 months (assessed annually) | 
| Left Ventricular Mass Index | Left ventricular mass index (g/m^2) measured by MRI, centrally reviewed and measured | 0, 24 months, 48 months, 60 months | 
| 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). | 0, 24 months, 48 months, 60 months | 
| All-Cause Hospitalizations |  | Up to 96 months | 
| 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) | baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually) | 
| 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) | baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually) | 

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