HALT Progression of Polycystic Kidney Disease Study A

NCT ID: NCT00283686

Last Updated: 2020-04-21

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

558 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-01-31

Study Completion Date

2014-06-30

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 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

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\* 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.

Conditions

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Kidney, Polycystic

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Study A, Arm 1

Lisinopril + Telmisartan (ACE-I + ARB) and standard blood pressure control of 120-130/70-80 mm Hg

Group Type ACTIVE_COMPARATOR

Lisinopril

Intervention Type DRUG

Lisinopril titrated to 5mg, 10mg, 20mg, 40mg

Telmisartan

Intervention Type DRUG

Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

Standard Blood Pressure Control

Intervention Type OTHER

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

Study A, Arm 2

Lisinopril + Telmisartan (ACE-I + ARB) and low blood pressure control of 95-110/60-75 mm Hg

Group Type ACTIVE_COMPARATOR

Lisinopril

Intervention Type DRUG

Lisinopril titrated to 5mg, 10mg, 20mg, 40mg

Telmisartan

Intervention Type DRUG

Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

Low Blood Pressure Control

Intervention Type OTHER

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

Study A, Arm 3

Lisinopril + Placebo (ACE-I + Placebo) and standard blood pressure control of 120-130/70-80 mm Hg

Group Type PLACEBO_COMPARATOR

Lisinopril

Intervention Type DRUG

Lisinopril titrated to 5mg, 10mg, 20mg, 40mg

Placebo

Intervention Type DRUG

Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

Standard Blood Pressure Control

Intervention Type OTHER

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

Study A, Arm 4

Lisinopril + Placebo (ACE-I + Placebo) and low blood pressure control of 95-110/60-75 mm Hg

Group Type PLACEBO_COMPARATOR

Lisinopril

Intervention Type DRUG

Lisinopril titrated to 5mg, 10mg, 20mg, 40mg

Placebo

Intervention Type DRUG

Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

Low Blood Pressure Control

Intervention Type OTHER

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

Interventions

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Lisinopril

Lisinopril titrated to 5mg, 10mg, 20mg, 40mg

Intervention Type DRUG

Telmisartan

Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

Intervention Type DRUG

Placebo

Telmisartan/Placebo titrated to 40mg and 80mg, as tolerated by participants

Intervention Type DRUG

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

Intervention Type 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

Intervention Type OTHER

Other Intervention Names

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ACE-I ACE Ace-Inhibitor ARB blood pressure control blood pressure control

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 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).
Minimum Eligible Age

15 Years

Maximum Eligible Age

64 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Boehringer Ingelheim

INDUSTRY

Sponsor Role collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role collaborator

Polycystic Kidney Disease Foundation

OTHER

Sponsor Role collaborator

University of Pittsburgh

OTHER

Sponsor Role collaborator

Washington University School of Medicine

OTHER

Sponsor Role collaborator

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

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Robert Schrier, M.D.

Role: STUDY_CHAIR

University of Colorado, Denver

Arlene Chapman, M.D.

Role: PRINCIPAL_INVESTIGATOR

Emory University

Ronald Perrone, M.D.

Role: PRINCIPAL_INVESTIGATOR

Tufts University-New England Medical Center

Vicente Torres, M.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Marva Moxey-Mims, M.D.

Role: STUDY_DIRECTOR

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

Charity G Moore, MS,PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

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University of Colorado Health Sciences Center

Aurora, Colorado, United States

Site Status

Emory University School of Medicine

Atlanta, Georgia, United States

Site Status

University of Kansas Medical Center

Kansas City, Kansas, United States

Site Status

Tufts University-New England Medical Center

Boston, Massachusetts, United States

Site Status

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Site Status

Mayo Clinic

Rochester, Minnesota, United States

Site Status

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Site Status

Countries

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United States

References

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St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.

Reference Type DERIVED
PMID: 39356039 (View on PubMed)

Heerspink HJL, Inker LA, Tighiouart H, Collier WH, Haaland B, Luo J, Appel GB, Chan TM, Estacio RO, Fervenza F, Floege J, Imai E, Jafar TH, Lewis JB, Kam-Tao Li P, Locatelli F, Maes BD, Perna A, Perrone RD, Praga M, Schena FP, Wanner C, Xie D, Greene T; on behalf of CKD-EPI CT. Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD. J Am Soc Nephrol. 2023 Jun 1;34(6):955-968. doi: 10.1681/ASN.0000000000000117. Epub 2023 Mar 15.

Reference Type DERIVED
PMID: 36918388 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30803434 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25399733 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25111236 (View on PubMed)

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.

Reference Type DERIVED
PMID: 22205355 (View on PubMed)

Related Links

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http://www.pkdcure.org

Polycystic Kidney Disease Foundation Website

Other Identifiers

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U01DK062401

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01DK082230

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HALT PKD A

Identifier Type: -

Identifier Source: org_study_id

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