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

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.

Study Overview

• Status: Completed
• Conditions: Kidney, Polycystic
• Intervention / Treatment: Drug: Lisinopril; Drug: Placebo; Drug: Telmisartan

Detailed Description

* 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).

• Study Type: Interventional
• Enrollment (Actual): 486
• 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 (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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

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, PhD, University of Pittsburgh

Publications and helpful links

General Publications

• Torres VE, Abebe KZ, Chapman AB, Schrier RW, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Moore CG, Perrone RD; HALT-PKD Trial Investigators. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2267-76. doi: 10.1056/NEJMoa1402686. Epub 2014 Nov 15.

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: June 17, 2013
• First Submitted That Met QC Criteria: June 20, 2013
• First Posted (Estimate): June 25, 2013

Study Record Updates

• Last Update Posted (Actual): April 22, 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 B; 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