HALT Progression of Polycystic Kidney Disease (HALT PKD) Study A

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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.

Condition or disease	Intervention/treatment	Phase
Kidney, Polycystic	Drug: Lisinopril; Drug: Telmisartan; Drug: Placebo; Other: Standard Blood Pressure Control; Other: Low Blood Pressure Control	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	558 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Polycystic Kidney Disease-Treatment Network
Study Start Date :	January 2006
Actual Primary Completion Date :	June 2014
Actual Study Completion Date :	June 2014

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Study A, Arm 1; Lisinopril + Telmisartan (ACE-I + ARB) and standard blood pressure control of 120-130/70-80 mm Hg	Drug: Lisinopril; Lisinopril titrated to 5mg, 10mg, 20mg, 40mg; Other Names: ACE-I; ACE; Ace-Inhibitor Drug: Telmisartan; Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants; Other Name: ARB Other: Standard 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; Other Name: blood pressure control
Active Comparator: Study A, Arm 2; Lisinopril + Telmisartan (ACE-I + ARB) and low blood pressure control of 95-110/60-75 mm Hg	Drug: Lisinopril; Lisinopril titrated to 5mg, 10mg, 20mg, 40mg; Other Names: ACE-I; ACE; Ace-Inhibitor Drug: Telmisartan; Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants; Other Name: ARB Other: Low 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; Other Name: blood pressure control
Placebo Comparator: Study A, Arm 3; Lisinopril + Placebo (ACE-I + Placebo) and standard blood pressure control of 120-130/70-80 mm Hg	Drug: Lisinopril; Lisinopril titrated to 5mg, 10mg, 20mg, 40mg; Other Names: ACE-I; ACE; Ace-Inhibitor Drug: Placebo; Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants Other: Standard 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; Other Name: blood pressure control
Placebo Comparator: Study A, Arm 4; Lisinopril + Placebo (ACE-I + Placebo) and low blood pressure control of 95-110/60-75 mm Hg	Drug: Lisinopril; Lisinopril titrated to 5mg, 10mg, 20mg, 40mg; Other Names: ACE-I; ACE; Ace-Inhibitor Drug: Placebo; Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants Other: Low 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; Other Name: blood pressure control

Outcome Measures

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Primary Outcome Measures :

1. Study A: Percent Annual Change in Total Kidney Volume [ Time Frame: 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 Outcome Measures :

1. Kidney Function (eGFR) [ Time Frame: 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.
2. Albuminuria [ Time Frame: Up to 96 months (assessed annually) ]
   Urine albumin excretion, centrally processed from 24 hour urine collection
3. Aldosterone [ Time Frame: Up to 96 months (assessed annually) ]
   Urinary aldosterone excretion, centrally processed, 24 hour urine collection
4. Left Ventricular Mass Index [ Time Frame: 0, 24 months, 48 months, 60 months ]
   Left ventricular mass index (g/m^2) measured by MRI, centrally reviewed and measured
5. Renal Blood Flow [ Time Frame: 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).
6. All-Cause Hospitalizations [ Time Frame: Up to 96 months ]
7. Quality of Life Physical Component Summary [ Time Frame: 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)
8. Quality of Life Mental Component Summary [ Time Frame: 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)

Eligibility Criteria

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Ages Eligible for Study:	15 Years to 64 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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).

Contacts and Locations

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Locations

United States, Colorado
University of Colorado Health Sciences Center
Denver (Aurora), Colorado, United States, 800045
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Tufts University-New England Medical Center
Boston, Massachusetts, United States, 02111
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Ohio
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Boehringer Ingelheim

Merck Sharp & Dohme Corp.

Polycystic Kidney Disease Foundation

Investigators

Study Chair:	Robert Schrier, M.D.	University of Colorado, Denver
Principal Investigator:	Arlene Chapman, M.D.	Emory University
Principal Investigator:	Ronald Perrone, M.D.	Tufts University-New England Medical Center
Principal Investigator:	Vicente Torres, M.D.	Mayo Clinic
Study Director:	Marva Moxey-Mims, M.D.	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator:	Charity G Moore, MS,PhD	University of Pittsburgh

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Polycystic Kidney Disease Foundation Website 

National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Bae KT, Moore CG, Chapman AB; HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2255-66. doi: 10.1056/NEJMoa1402685. Epub 2014 Nov 15.

Hogan MC, Abebe K, Torres VE, Chapman AB, Bae KT, Tao C, Sun H, Perrone RD, Steinman TI, Braun W, Winklhofer FT, Miskulin DC, Rahbari-Oskoui F, Brosnahan G, Masoumi A, Karpov IO, Spillane S, Flessner M, Moore CG, Schrier RW. Liver involvement in early autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol. 2015 Jan;13(1):155-64.e6. doi: 10.1016/j.cgh.2014.07.051. Epub 2014 Aug 9.

Torres VE, Chapman AB, Perrone RD, Bae KT, Abebe KZ, Bost JE, Miskulin DC, Steinman TI, Braun WE, Winklhofer FT, Hogan MC, Oskoui FR, Kelleher C, Masoumi A, Glockner J, Halin NJ, Martin DR, Remer E, Patel N, Pedrosa I, Wetzel LH, Thompson PA, Miller JP, Meyers CM, Schrier RW; HALT PKD Study Group. Analysis of baseline parameters in the HALT polycystic kidney disease trials. Kidney Int. 2012 Mar;81(6):577-85. doi: 10.1038/ki.2011.411. Epub 2011 Dec 28.

Responsible Party:	Charity G Moore, PhD, Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier:	NCT00283686 History of Changes
Other Study ID Numbers:	DK62401-PKD-TN (IND)
First Posted:	January 30, 2006
Results First Posted:	February 27, 2015
Last Update Posted:	March 19, 2015
Last Verified:	March 2015

Keywords provided by Charity G Moore, PhD, University of Pittsburgh:

pkd; polycystic kidney disease; polycystic; kidney; disease; adpkd; halt	blood pressure; bp; hypertension; renal; renin-angiotensin-aldosterone-system; RAAS

Additional relevant MeSH terms:

Kidney Diseases; Polycystic Kidney Diseases; Urologic Diseases; Kidney Diseases, Cystic; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn; Telmisartan; Hydrochlorothiazide; Lisinopril; Calcium Channel Blockers; Antihypertensive Agents; Diuretics	Natriuretic Agents; Physiological Effects of Drugs; Sodium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Cardiotonic Agents; Protective Agents