Official Title: “Polycystic Kidney Disease-Treatment Network”

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). 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 a total of four years, while those enrolled in Study B will be followed for four-to-six years, with the average length of follow-up being five years. The two concurrent randomized clinical trials differ by eligibility criteria, interventions and outcomes to be studied.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Efficacy Study

Study Primary Completion Date: December 2012

* Specific Aims of Study A

To study the efficacy of ACE-I/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. * 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 eGFR, 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).

Intervention(s) in this Clinical Trial

• Drug: Lisinopril and Placebo
  • Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and placebo titrated to 40mg and 80mg, as tolerated by participants, to achieve low blood pressure control of 95-110/60-75 mm Hg.
• Drug: Lisinopril and Telmisartan
  • Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and telmisartan titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 120-130/70-80 mm Hg.
• Drug: Lisinopril and Telmisartan
  • Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and telmisartan titrated to 40mg and 80mg, as tolerated by participants, to achieve low blood pressure control of 95-110/60-75 mm Hg.
• Drug: Lisinopril and Placebo
  • Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and placebo titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 120-130/70-80 mm Hg.
• Drug: Lisinopril and Telmisartan
  • Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and telmisartan titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.
• Drug: Lisinopril and Placebo
  • Lisinopril titrated to 5mg, 10mg, 20mg, 40mg and placebo titrated to 40mg and 80mg, as tolerated by participants, to achieve standard blood pressure control of 110-130/80 mm Hg.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Study A, Arm 1
  • ACE-I + ARB and standard blood pressure control of 120-130/70-80 mm Hg
• Active Comparator: Study A, Arm 2
  • ACE-I + ARB and low blood pressure control of 95-110/60-75 mm Hg
• Placebo Comparator: Study A, Arm 3
  • ACE-I + Placebo and standard blood pressure control of 120-130/70-80 mm Hg
• Placebo Comparator: Study A, Arm 4
  • ACE-I + Placebo and low blood pressure control of 95-110/60-75 mm Hg
• Active Comparator: Study B, Arm 1
  • ACE-I + ARB and standard blood pressure control of 110-130/80 mm Hg
• Placebo Comparator: Study B, Arm 2
  • ACE-I + placebo and standard blood pressure control of 110-130/80 mm Hg

Primary Measures

• Study A: Change in total kidney volume, as assessed by abdominal MR at baseline, 2 years, and 4 years follow-up.
  • Time Frame: Baseline and 2- and 4-year follow-up
    Safety Issue?: No
• Study B: Time to the 50% reduction of baseline eGFR, ESRD (initiation of dialysis or preemptive transplant), or death.
  • Time Frame: As noted above
    Safety Issue?: No

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 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 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 MR imaging (Study A).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 15 Years

Maximum Age for this Clinical Trial: 64 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Overall Clinical Trial Officials and Contacts

Robert Schrier, M.D. Study Chair University of Colorado at Denver and Health Sciences Center  

Overall Contact: Robin Woltman, B.S. 314-362-1318 robinw@wubios.wustl.edu

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00283686

Study ID Number: DK62401-PKD-TN

ClinicalTrials.gov Identifier: NCT00283686

Health Authority: United States: Food and Drug Administration

HALT PKD Home Page

Polycystic Kidney Disease Foundation Website

National Institute of Diabetes & Digestive & Kidney Diseases Website

HALT PKD Study Brochure

HALT PKD Information for Physicians Brochure