Condition category
Urological and Genital Diseases
Date applied
11/12/2013
Date assigned
20/01/2014
Last edited
05/05/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Chronic kidney disease affects about 1 in 10 adults. The illness can worsen over time. This means that some people eventually need to have dialysis or a kidney transplant. There are treatments that can slow the rate of decline of kidney function . However, despite such treatment some people still need transplantation or dialysis. The aim of the study is to investigate whether a new drug (LCZ696) has the potential to protect the kidneys better than the current standard treatment.

Who can participate?
Men and women aged 18 and over with chronic kidney disease who have increased levels of protein in their urine.

What does the study involve?
You will need to participate in the study for about 13 months. You will be asked to attend about seven hospital appointments, some of which may coincide with your routine renal outpatient appointments. In addition, we will measure your kidney function very precisely on two occasions during the study. At your first visit to the clinic a trained researcher (usually a nurse) will ask you about your medical history. The researcher will take your blood pressure and a sample of blood and urine. You will then be provided with a supply of the study tablets and asked to take two a day. This visit will take about 45 minutes. You may be asked to stop some of your current blood pressure treatment (because the study treatment will replace them). Over the course of the next few weeks you will have the chance to try out the study tablets. This will allow you and the study doctors and nurses to be sure the routine of taking these particular tablets agrees with you. Towards the end of this period you may be asked to collect your urine for 24 hours, but this is optional and you can still participate even if you don’t want to do this. After at least 4 weeks of taking the study tablets you will be asked to attend a second appointment to see if you would like to continue. We will measure your kidney function and your blood pressure and we will ask for another blood and urine sample. Your height and weight will also be recorded at this visit. If you have had no problems with the study treatments during the first few weeks and are happy to continue, you will be asked to commit to the study for another 12 months. This visit will take about 30 minutes. Following this appointment you will take two different tablets once daily: an active tablet and a placebo (dummy) tablet. You will be randomly allocated to take either active LCZ696 and placebo irbesartan, or placebo LCZ696 and active irbesartan. Irbesartan is an angiotensin receptor blocker and is commonly used to treat kidney disease. At further visits you will be asked to have a blood test after about two weeks to check your potassium level. This can be done at your GP surgery or your kidney clinic. The dose of your study treatment will then increase to the full dose (two tablets of active treatment and two tablets of placebo once daily).You will be asked to attend five further appointments (about 1, 3, 6, 9 and 12 months later) to see how you are getting on. Your blood pressure will be checked and a blood and urine sample will be taken at each visit. At the final visit you will have a second measurement of your kidney function. Each visit will last about 30 minutes.

What are the possible benefits and risks of participating?
You may be helping yourself, but you will most certainly be helping doctors and scientists improve treatment for people who have chronic kidney disease and who may be at risk of needing dialysis or a transplant. If successful, results from this study will help to design a larger trial of LCZ696 which could reliably show whether LCZ696 is better than current treatment in slowing the progression of chronic kidney disease. Most treatments have side effects which some people may experience and others do not. If you do experience any side effects while on the study they will be noted, so that scientists can learn from you. You can withdraw from the study if you wish. Irbesartan is generally very well-tolerated. It has been tested in thousands of people and is taken by hundreds of thousands of people worldwide. It lowers blood pressure so it can cause dizziness. Other side effects include nausea, muscle pain and fatigue. It can raise potassium levels in the blood and you will be monitored for this. Over 8,000 people have taken LCZ696 in other clinical trials and it is generally well-tolerated. It also lowers blood pressure so can cause dizziness and fatigue. Rarely it may cause swelling of the mouth and face. The treatment can raise potassium levels in the blood and you will be monitored for this. One patient who received LCZ696 had an allergic reaction which included abnormal liver function tests. At this stage, scientists cannot rule out the possibility of there being side effects (such as diarrhoea or muscle pains), or effects on other blood tests. Throughout the study you will be carefully monitored by our nursing team for possible side effects. At every visit, the study staff would discuss any new information about the drug with you. The study includes two measurements of your kidney function which involve an injection of a small amount of radioactive material. The dose of radioactivity is small (equivalent to one day of natural background radiation in the UK) and poses a negligible risk to health.

Where is the study run from?
The study is coordinated by the Clinical Trial Service Unit at the University of Oxford. There will be about 20 centres taking part around the UK.

When is the study starting and how long is it expected to run for?
The study will start in early 2014 and last for about one year. Participants will be recruited during the first 6 months and follow-up in the study is for 12 months.

Who is funding the study?
Novartis AG Pharma (UK)

Who is the main contact?
Dr Richard Haynes

Trial website

http://www.harp3trial.org/

Contact information

Type

Scientific

Primary contact

Dr Richard Haynes

ORCID ID

Contact details

Clinical Trial Service Unit
Richard Doll Building
Old Road Campus
Headington
Oxford
OX3 7LF
United Kingdom

Additional identifiers

EudraCT number

2013-004205-89

ClinicalTrials.gov number

Protocol/serial number

CTSUHARP3

Study information

Scientific title

Randomized multicentre pilot study of LCZ696 versus irbesartan in patients with chronic kidney disease: UK Heart And Renal Protection (HARP)-III

Acronym

UK HARP-III

Study hypothesis

Current hypothesis as of 03/05/2016:
The primary aim is to assess the difference in the change in measured glomerular filtration rate from baseline to 12 months between participants allocated LCZ696 versus those allocated irbesartan control.

Previous hypothesis:
The primary aim is to assess the difference in the change in measured glomerular filtration rate from baseline to 6 months between participants allocated LCZ696 versus those allocated irbesartan control.

Ethics approval

Nottinghamshire 2 REC, Conditional approval received 05/12/2013, ref: 13/EM/0434

Study design

Multicentre double-blind randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details below to request a patient information sheet

Condition

Chronic kidney disease

Intervention

Current interventions as of 03/05/2016:
LCZ696: 200 mg orally once daily for 2 weeks then increased to 400 mg orally once daily for total duration 12 months.
Irbesartan: 150 mg orally once daily for 2 weeks then increased to 300 mg orally once daily for total duration 12 months.

Previous interventions:
LCZ696: 200 mg orally once daily for 2 weeks then increased to 400 mg orally once daily for total duration 6 months.
Irbesartan: 150 mg orally once daily for 2 weeks then increased to 300 mg orally once daily for total duration 6 months.

Intervention type

Drug

Phase

Not Applicable

Drug names

LCZ696, irbesartan

Primary outcome measures

Current primary outcome measures as of 03/05/2016:
Change in measured glomerular filtration rate from baseline to 12 months

Previous primary outcome measures:
Change in measured glomerular filtration rate from baseline to 6 months

Secondary outcome measures

Current secondary outcome measures as of 03/05/2016:
1. Urine albumin:creatinine ratio will be measured from baseline to 12 months
2. Pharmacokinetics will be measured at 3 months

Previous secondary outcome measures:
1. Urine albumin:creatinine ratio will be measured from baseline to 6 months
2. Pharmacokinetics will be measured at 3 months

Overall trial start date

01/11/2014

Overall trial end date

01/03/2017

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 03/05/2016:
1. Men or women aged ≥18 years (at screening)
2. Established proteinuric chronic kidney disease i.e. on measurements in the last 3 months:
2.1. An estimated glomerular filtration rate ≥20 <45 mL/min/1.73m2 (estimated with Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) OR
2.2. An estimated glomerular filtration rate ≥45 <60 mL/min/1.73m2 and albumin:creatinine ratio >20 mg/mmol (or protein:creatinine ratio >30 mg/mmol)

Previous inclusion criteria:
1. Men or women aged ≥18 years (at screening)
2. Established proteinuric chronic kidney disease i.e. on measurements in the last 3 months:
2.1. Estimated glomerular filtration rate (eGFR) ≥20 <60 mL/min/1.73m2 (estimated with Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology
Collaboration [CKD-EPI] formula) AND
2.2. Urine albumin:creatinine ratio ≥30 mg/mmol

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

400

Participant exclusion criteria

1. Angiotensin receptor blocker (ARB) therapy contraindicated e.g. bilateral renal artery stenosis
2. Known intolerance of ARB
3. Current treatment with aliskiren
4. Mean systolic blood pressure >180 mmHg at screening visit (or investigator unwilling to withdraw angiotensin-converting enzyme inhibitors [ACEi], ARB or DRI for another reason)
5. Serum potassium >5.5 mmol/L (updated 03/05/2016; previously >5.2 mmol/L)
6. Presence of nephrotic syndrome (i.e. urine protein:creatinine ratio >350 mg/mmol [or albumin:creatinine ratio >300 mg/mmol] AND serum albumin <30 g/L) or currently receiving immunosuppression for nephrotic syndrome
7. Functioning renal transplant
8. Acute coronary syndrome, stroke or transient ischaemic attack in 3 months prior to Screening
9. Known chronic liver disease or alanine aminotransferase/aspartate aminotransferase (ALT/AST) >2x upper limit normal (ULN) at screening
10. History of angioedema (drug-related or otherwise)
11. Use of unlicensed investigational medicinal product in previous month
12. Pregnancy or women with child-bearing potential (refusing a reliable method of contraception3)
13. Medical history that might limit the patient’s ability to take study treatments for the duration of the study (e.g. severe respiratory disease, or recent history of alcohol or substance misuse or history of cancer or evidence of spread in last 5 years other than non-melanoma skin cancer)

Recruitment start date

01/11/2014

Recruitment end date

31/01/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Oxford University Hospitals
-

Trial participating centre

Royal Free London
-

Trial participating centre

Royal Derby Hospital
-

Trial participating centre

Queen Elizabeth Hospital, Birmingham
-

Trial participating centre

Salford Royal Hospital
-

Trial participating centre

Royal Berkshire Hospital
-

Trial participating centre

Royal Devon and Exeter Hospital
-

Trial participating centre

Manchester Royal Infirmary
-

Trial participating centre

Dorset County Hospital, Dorchester
-

Trial participating centre

Sheffield Teaching Hospitals
-

Trial participating centre

University Hospital of North Staffordshire
-

Trial participating centre

Leicester General Hospital
-

Trial participating centre

Southmead Hospital, Bristol
-

Trial participating centre

Plymouth Hospitals
-

Trial participating centre

Nottingham University Hospitals
-

Trial participating centre

Royal Wolverhampton
-

Trial participating centre

Portsmouth Hospitals
-

Trial participating centre

The Princess Royal Hospital, Telford
-

Trial participating centre

York Teaching Hospitals
-

Trial participating centre

University Hospital of Wales
-

Trial participating centre

University Hospitals Coventry and Warwickshire
-

Trial participating centre

The James Cook University Hospital
-

Trial participating centre

Morriston Hospital
-

Trial participating centre

Aberdeen Royal Infirmary
-

Sponsor information

Organisation

University of Oxford (UK)

Sponsor details

University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom
+44 (0)1865 270000
harp3@ctsu.ox.ac.uk

Sponsor type

University/education

Website

http://www.ox.ac.uk

Funders

Funder type

Industry

Funder name

Novartis Pharmaceuticals UK Limited

Alternative name(s)

Novartis UK

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Results and Publications

Publication and dissemination plan

To be confirmed at a later date

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

03/05/2016: the following changes were made to the trial record: 1. The overall trial start date was changed from 01/02/2014 to 01/11/2014. 2. The overall trial end date was changed from 31/01/2015 to 01/03/2017. 3. The target number of participants was changed from 360 to 400.