HALT-PKD study final results

Some of you (or your relatives or friends) may have been participants in the HALT-PKD study – the first prospective, randomized clinical interventional study for adults with autosomal dominant polycystic disease (ADPKD).

The HALT-PKD study was completed in June, 2014. To receive email notification when final results are published, sign up to receive our ACT alerts.

The HALT-PKD clinical trials were developed to evaluate certain FDA-approved drugs for effectiveness in slowing kidney growth and kidney function in people with ADPKD. Two clinical trials were conducted in seven centers in the United States. Financial support of the study was provided by the NIH-National Institute of Diabetes & Digestive & Kidney Diseases and the PKD Foundation. Study medications were provided by Boehringer Ingleheim and Merck.

The HALT study is important to the PKD community because neither the optimal blood pressure target levels, nor the best medications for control of blood pressure in ADPKD, were known when the study was started in 2006. Currently, the complications of hypertension, including stroke and heart attack, affect many more individuals with ADPKD than ADPKD-specific complications such as liver cysts or brain aneurysms.

HALT Study – Key Publications (Please note that all of the already published papers reflect only analysis of the baseline data, prior to any treatment).

The HALT Polycystic Kidney Disease Trials: Design and Implementation (Chapman, et. al., 2010)

This publication reports on the design and implementation of the HALT-PKD trials (Study A and Study B) where 1,018 hypertensive ADPKD patients were planned to be studied over four to eight years of follow-up. These trials will evaluate potential benefits of rigorous BP control and inhibition of hypertension-causing agents on kidney disease progression in ADPKD. Having two studies, early vs. late PKD, the potential benefits of positive outcomes for either study could translate into years of life gained without dialysis for PKD patients.

HALT-PKD is the first (and largest) multicenter, interventional clinical trial of ADPKD to look at both early disease (Study A) and late disease (Study B), using the same drug intervention. The design using two studies addressed issues unique to ADPKD and will influence the design of future ADPKD trials.

Study A:

  • Looked at early PKD defined by GFR greater than 60 mL/min/1.73 m2
  • Patients were randomized into the following interventions:
    • Combination of two drug therapies: angiotensin converting enzyme inhibitor (ACEi) AND angiotensin receptor blockers (ARB) versus ACEi plus placebo
    • Two levels of blood pressure control
  • Primary outcome measure was change in total kidney volume (TKV) as assessed by abdominal MRI at baseline, 2, 4, and 5 years follow-up
  • Secondary outcome measures included
    • Rate of change in GFR
    • Renal blood flow
    • Left ventricular mass (measured by MRI)
    • Rate of change of albuminuria and 24 hour urinary excretion of aldosterone
    • Frequency of hospitalizations (all causes; cardiovascular events causing hospitalization were specifically tracked)
    • Quality of life
    • Pain
    • Frequency of PKD-related symptoms
    • Adverse effects of study medications

Study B:

  • Looked at moderately advanced PKD defined by GFR 25-60 mL/min/1.73 m2
  • Participants were randomized into the following interventions:
    • ACEi and ARB versus ACEi and placebo drug therapy
    • BP control of 120 – 130/70 -80 mmHg.
  • Primary outcome measure was time to the 50% reduction of baseline eGFR, ESRD (initiation of dialysis or preemptive transplant, or death.
  • Secondary outcome measures included:
    • Rate of change of albuminuria and 24 hour urinary excretion of aldosterone
    • Frequency of hospitalizations (all causes; cardiovascular events causing hospitalization were specifically tracked)
    • Quality of life
    • Pain
    • Frequency of PKD-related symptoms
    • Adverse effects of study medications

Inclusion and exclusion criteria for enrollment into HALT study A and B

Inclusion criteria

  • Age 15 to 49 yr for study A; age 18 to 64 yr for study B
  • GFR  60 ml/min per 1.73 m2, equated from serum creatinine using the four-variable MDRD equation(study A), GFR 25 to 60 ml/min per 1.73 m2, equated from serum creatinine using the four-variableMDRD equation (study B)
  • Hypertension or high–normal blood pressure
  • Informed consent

Exclusion criteria

  • Documented renal vascular disease
  • Spot urine albumin-to-creatinine ratio of0.5 (study A) or 1.0 (study B), and/or findings suggestiveof kidney disease other than ADPKD
  • Diabetes requiring insulin or oral hypoglycemic agents or a fasting serum glucose of 126 mg/dl ora random nonfasting glucose of 200 mg/dl (in accordance with ADA recommendations fordiagnosis of diabetes)
  • Currently pregnant or intention of becoming pregnant throughout the duration of study
  • Serum potassium 5.5 mEq/L for participants currently on ACEi or ARB therapy; 5.0 mEq/L forparticipants not currently on ACEi or ARB therapy
  • History of angioneurotic edema or other absolute contraindication with ACEi or ARB. Intolerablecough associated with ACEi has been defined as cough that developed within 6 mo of initiation ofACEi in the absence of other causes and resolved on discontinuation of the ACEi
  • Indication (other than hypertension) for -blocker or calcium channel blocker therapy (e.g., angina,past myocardial infarction, arrhythmia), unless approved by the site principal investigator
  • Systemic illness necessitating NSAIDs, immunosupressant, or immunomodulatory medications
  • Systemic illness with renal involvement
    Hospitalization for an acute illness in past 2 mo (not including elective admissions)
  • Life expectancy 2 yrs
  • History of noncompliance, drug, or alcohol dependence within the past year or other psychiatricdisturbance that would preclude successful completion of the study
  • Known presence of unclipped cerebral aneurysm 7 mm in diameter
  • Treatment within the past 30 days on an interventional study
  • Creatinine supplements within 3 mo before the screening visit
  • Congenital absence of a kidney or history of a total nephrectomy. A history of cyst reduction oraspiration procedures or partial nephrectomy will not preclude participation in study B10

Analysis of baseline parameters in the HALT polycystic kidney disease trials (Torres, et.al. 2011)

This publication reports on the analysis of the baseline characteristics of the HALT-PKD participant cohort. Its purpose was to identify factors that affect the development and progression of PKD.

The analysis found the following:

  1. Confirmed strong association between kidney volume and functional parameters
  2. Showed that gender and other factors affect the development of polycystic kidney and liver disease
  3. Suggested an association between human measures reflecting prenatal and/or postnatal growth and severity of PKD

Cardiac Magnetic Resonance Assessment of Left Ventricular Mass in Autosomal Dominant Polycystic Kidney Disease (Perrone, et. al. 2011)

This publication looked at baseline measurements (prior to any study intervention) of HALT-PKD Study A participants ONLY (it did not include Study B participants). The study represents the largest cardiac magnetic resonance (MR) assessment of left ventricular muscle mass (LVM) in ADPKD patients. It is also one of the largest cardiac MR studies in any hypertensive population.

The study found a low occurrence of left ventricular hypertrophy suggesting that that prior early treatment of blood pressure of ADPKD patients may have decreased the occurrence of left ventricular hypertrophy.  The impact of the blood pressure and medication interventions will be assessed in the final publication.

Health-Related Quality of Life in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 1-4: A Cross-sectional Study (Miskulin, et. al. 2013)

ADPKD patients show an average total kidney volume (TKV) that is roughly three times the norm, with an average of a 5% increase each year, despite a normal glomerular filtration rate (GFR). This study predicted that increased TKV would cause diminished quality of life (as determined by a survey completed by participants) in patients with advanced ADPKD.

This study is the largest comprehensive study of the daily living of ADPKD patients who have eGFR greater than 20 mL/min/1.73 m2, with comparisons across htTKV (height-corrected total kidney volume) and eGFR.

Although pain is common, even in early ADPKD, and affects a relatively high proportion of ADPKD patients, the study found that pain is not related to kidney size in early ADPKD (except in individuals with the largest kidneys at htTKV>1,000mL/m). The study did show that pain interferes with daily activities more in patients with eGFRs of less than 45 mL/min/1.73 m2 compared with patients at higher eGFRs. Additionally, symptoms relating to abdominal fullness are greater for lower eGFR patients vs. higher. One explanation (of several) put forth for these findings is that cyst size and location are more important than total number of cysts or TKV in causing pain.