Clinical trial NCT00283686: HALT Progression of Polycystic Kidney Disease Study A
Official title: HALT Progression of Polycystic Kidney Disease Study A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kidney, Polycystic
Keywords: polycystic kidney disease
polycystic
kidney
disease
adpkd
halt
pkd
blood pressure
bp
hypertension
renal
renin-angiotensin-aldosterone-system
RAAS
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: Boehringer Ingelheim
name: Merck Sharp & Dohme LLC
name: Polycystic Kidney Disease Foundation
name: University of Pittsburgh
name: Washington University School of Medicine
First posted: 2006-01-30
Enrollment: 558
Sex: ALL
Minimum age (years): 15
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Study A: Percent Annual Change in Total Kidney Volume
timeFrame: Baseline and 2-, 4- and 5-year follow-up
Secondary outcomes:
measure: Kidney Function (eGFR)
timeFrame: Up to 96 months (6 month assessments)
measure: Albuminuria
timeFrame: Up to 96 months (assessed annually)
measure: Aldosterone
timeFrame: Up to 96 months (assessed annually)
measure: Left Ventricular Mass Index
timeFrame: 0, 24 months, 48 months, 60 months
measure: Renal Blood Flow
timeFrame: 0, 24 months, 48 months, 60 months
measure: All-Cause Hospitalizations
timeFrame: Up to 96 months
measure: Quality of Life Physical Component Summary
timeFrame: baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually)
measure: Quality of Life Mental Component Summary
timeFrame: baseline, 12, 24, 36, 48, 60, 72, 84, and 96 months (assessed annually)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Tufts University-New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
Study officials:
affiliation: University of Colorado, Denver
name: Robert Schrier, M.D.
role: STUDY_CHAIR
affiliation: Emory University
name: Arlene Chapman, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts University-New England Medical Center
name: Ronald Perrone, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Vicente Torres, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Marva Moxey-Mims, M.D.
role: STUDY_DIRECTOR
affiliation: University of Pittsburgh
name: Charity G Moore, MS,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.