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

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.

Study Overview

• Status: Completed
• Conditions: Kidney, Polycystic
• Intervention / Treatment: Drug: Lisinopril; Drug: Telmisartan; Other: Standard Blood Pressure Control; Other: Low Blood Pressure Control; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 558
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 64 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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; 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 Names: blood pressure control; Drug: Placebo; Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants
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; 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 Names: blood pressure control; Drug: Placebo; Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

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)

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: Washington University School of Medicine; Merck Sharp & Dohme LLC; University of Pittsburgh; Boehringer Ingelheim; Polycystic Kidney Disease Foundation
• Investigators: Study Chair: Robert Schrier, M.D., University of Colorado, Denver; 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

Publications and helpful links

General Publications

• Kim K, Trott JF, Gao G, Chapman A, Weiss RH. Plasma metabolites and lipids associate with kidney function and kidney volume in hypertensive ADPKD patients early in the disease course. BMC Nephrol. 2019 Feb 25;20(1):66. doi: 10.1186/s12882-019-1249-6.
• 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.

Helpful Links

• Polycystic Kidney Disease Foundation Website

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2006
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: January 26, 2006
• First Submitted That Met QC Criteria: January 26, 2006
• First Posted (Estimate): January 30, 2006

Study Record Updates

• Last Update Posted (Actual): April 21, 2020
• Last Update Submitted That Met QC Criteria: April 13, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: renal; hypertension; blood pressure; kidney; disease; polycystic kidney disease; RAAS; polycystic; adpkd; halt; pkd; bp; renin-angiotensin-aldosterone-system
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Polycystic Kidney Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Telmisartan; Lisinopril; Angiotensin-Converting Enzyme Inhibitors
• Other Study ID Numbers: HALT PKD A; U01DK062401 (U.S. NIH Grant/Contract); U01DK082230 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data are available at the NIDDK Central Repository, https://repository.niddk.nih.gov/studies/halt-pkd/?query=halt%20pkd

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No