The ACTION Study
Research type
Research Study
Full title
A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-Label Phase: The ACTION Study
IRAS ID
303032
Contact name
Albert Ong
Contact email
Sponsor organisation
Palladio Biosciences Inc.
Eudract number
2021-003062-12
Clinicaltrials.gov Identifier
136,419, IND
Duration of Study in the UK
2 years, 10 months, 3 days
Research summary
Research Summary
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic condition that causes cysts (small fluid-filled sacs) to develop in the kidneys. It causes a wide range of problems including high blood pressure, stomach/back pain, and kidney stones. ADPKD is the most common inherited cause of end-stage kidney failure.
While tolvaptan has been approved in many countries to slow the progression of kidney function deterioration in patients with ADPKD, drug-induced liver injury occurs in some patients, therefore patients on tolvaptan require frequent liver tests in order to prevent serious outcomes.
Lixivaptan is currently being developed for the treatment of ADPKD. Early analyses have demonstrated that lixivaptan improves polycystic disease symptoms and does not have the same potential for liver injury as tolvaptan. Thus, lixivaptan may be a safer alternative to tolvaptan with similar effectiveness.
The aim of this study is to demonstrate the effectiveness and safety of lixivaptan compared with placebo (dummy drug with no active ingredient) in patients with ADPKD.
Participants will be allocated randomly to take either lixivaptan or placebo capsules orally twice a day for 52 weeks (Part 1). The participant will not know if they are taking lixivaptan or placebo. Participants will then continue into an 'open-label' treatment phase where all participants will take lixivaptan for 52 weeks (Part 2).
Approximately 1200 patients with ADPKD worldwide will take part in this study.
Summary of Results
The ACTION Study: A Study to Test Whether Lixivaptan is Effective and Safe in People with Autosomal Dominant Polycystic Kidney Disease (ADPKD) Full Study Title: A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-Label Phase: The ACTION Study
1 STUDY INTRODUCTION
Research is a way to learn new things. Clinical research studies use human volunteers to learn more about new medicines, such as how well they work and how safe they are. All new medicines being made must undergo clinical research studies.
This document is a summary of a clinical research study, also called a “clinical trial”. It has been written for a general audience and for people who took part in or cared for a person in the study.
Researchers look at the results of many studies to decide which drugs work best and are safest for patients. It takes many participants and many studies all around the world to advance medical science.
This summary only shows the results from this study, The ACTION Study. Other studies using the same medicine may show different results. Do not use this summary to make decisions about changes to your medicines without discussing it with your doctor.
The ACTION Study was a phase 3 study, which is a study of a new treatment in a large number of patients. In this study, researchers looked at how well a medicine called lixivaptan works in a group of people with ADPKD, and how safe it is.
2 WHO SPONSORED THIS STUDY?
Palladio Biosciences, Inc.
1 Federal Street
Floor 38
Boston, MA 02110
United States
3 GENERAL INFORMATION ABOUT THE CLINICAL STUDY
3.1 Where Was the Study Done?
This study took place in the following countries:
European Union (EU):
Bulgaria
Rest of World (ROW):
United States
3.2 When Was the Study Done?
This study started in November 2021 and ended in August 2022. The sponsor decided to stop the study early for business reasons. These reasons were not related to how well lixivaptan works, or how safe it is.
3.3 What Happened in this Study?
In this study, researchers compared a new study drug, lixivaptan, to placebo. Placebo is a treatment that looks and tastes exactly like the study drug but does not contain any active ingredient. This comparison was done to see whether any improvements in ADPKD or side effects were caused by the study drug or were a “placebo effect”. A placebo effect is where some people believe they experience an effect after receiving a treatment that has no known medical effect. This also allowed researchers to see whether any benefit of the study drug outweighed any possible side effects.
The study design is described below. There were 2 parts planned for this study, and each part was made up of different periods. During the course of the study, patients had various meetings with their study doctor so the doctor could take measurements and samples from the patients, to check how they were doing.
Part 1
Period 1: After joining the study, all patients were given placebo for a period of 1 week. This period was “single-blinded”, which means the patients did not know which treatment they were given (lixivaptan or placebo), but the study doctor did know. Patients took 4 capsules of placebo twice a day in Period 1.
Period 2: All patients were given a combination of lixivaptan and placebo capsules for up to 6 weeks. The dose of lixivaptan was gradually increased during this period, as long as the patients did not experience any side effects. If they did, their dose was reduced again. This period of the study was also single-blinded; the patients did not know which treatment they were given (but the study doctor did know).
Period 3: Patients were assigned, or put into, 1 of 2 groups by chance; this means this part of the study was “randomized”. Putting the study patients into 2 groups was done by a computer program, in a similar way to tossing a coin. Two out of every 3 patients were given lixivaptan, and 1 out of every 3 patients was given placebo. As well as being randomized, this period of the study was “double-blinded”. This means that neither patients nor doctors knew who was given which treatment. This was done to make sure that the study results were not influenced in any way.
Period 4: In this period of the study (up to 4 weeks), patients did not take any lixivaptan or placebo capsules. Patients still had visits with their study doctor, so the doctor could check how they were doing.
Part 2
Part 2 of the study was planned as follows, and was “open label”. This means that both the patients and doctors knew what treatment was being given. However, because the study was stopped early, none of the patients reached Part 2.
Period 1: This period of the study lasted for 2 to 4 weeks. Patients were given increasing doses of lixivaptan until:
o They reached the same dose they were taking at the end of Part 1, Period 3 (for patients who took lixivaptan in Part 1, Period 3),
or
o They reached the equivalent lixivaptan dose based on the final dose level they were taking at the end of Part 1, Period 3 (for patients who took placebo in Part 1, Period 3).
Period 2: During this period, all patients continued taking lixivaptan for up to 1 year, at the dose reached at the end of Period 1.
Period 3: In the final period of the study (up to 4 weeks), patients did not take any lixivaptan capsules. Patients still had visits with their study doctor, so the doctor could check how they were doing.
3.4 What Were the Main Objectives of this Study?
Patients who have ADPKD experience a gradual decline in how well their kidneys work. The main purpose of this study was to see if lixivaptan can slow down that deterioration. The study was designed to compare what happens to kidney function when some patients take lixivaptan and some patients take placebo. In addition, researchers wanted to study how safe lixivaptan is when taken by patients who have ADPKD, and to see if it can be taken without patients experiencing major side effects to the liver.
4 WHO WAS INCLUDED IN THIS STUDY?
4.1 The Number of Patients Included in the Study
A total of 2250 patients with ADPKD were planned to take part in this study. As the study ended early, only 12 patients, 2 in the EU (Bulgaria) and 10 in the ROW (United States), took part.
Part 1, Period 1: 12 patients started and completed this period of the study, where patients were given placebo.
Part 1, Period 2: 8 patients started this period of the study, where patients were given increasing doses of lixivaptan. 5 patients completed this period.
Part 1, Period 3: 5 patients started this period of the study (4 patients were randomized to lixivaptan and 1 was randomized to placebo). The study was stopped before these patients could complete this period.
Part 1, Period 4: This period was planned to check the safety of the patients taking part in the study and how well the drug was working. Even though the study had been stopped, 4 patients started and completed this period.
Part 2: None of the patients started this period of the study.
4.2 Age Group and Sex Breakdown
The youngest patient in this study was aged 29 years and the oldest was aged 60 years. The average age of patients in this study was 45 years.
Of the 12 patients who took part in the study, 7 patients (58%) were females, and 5 patients (42%) were males.) and 5 (71%) were in the United States. Of the 5 male patients, 0 (0%) were in Bulgaria and 5 (100%) were in the United States.
4.3 Inclusion and Exclusion Criteria
To take part in this study, patients must have been diagnosed with ADPKD.
Patients aged between 18 years and 60 years of age could be recruited into this study.
Both male and female patients could take part in the study. In patients who could have children, effective birth control methods had to be used throughout the study and for 30 days after the last dose of study drug. Pregnant or breastfeeding patients were not allowed to take part in the study.
Study doctors also looked at other factors when deciding if someone could take part in the study:
Patients had to be at risk of their ADPKD getting worse (according to the study doctor) How well the patient’s kidneys worked If the patient had high blood pressure, it had to be under control The patient’s weight had to be within a certain range The patient had to agree, and be willing, to take part in the study.
Patients could not take part in the study if they:
Had advanced diabetes, or significant issues with their kidneys not due to ADPKD or liver Had problems with urinating (peeing) Had limitations to their physical activity due to heart failure, or any heart findings that would mean taking part in the study could be dangerous for them Had to take medicines which were not allowed during the study, or that they had taken within 2 months of their first study visit Positive test results, or a history of positive test results, for specific conditions.
5 WHICH MEDICINES WERE USED?
Patients were given capsules of both lixivaptan and placebo during the study. The lixivaptan and placebo capsules looked identical and were to be swallowed whole with water. The capsules could be taken with or without food. Patients took four capsules twice a day, once in the morning and then approximately 10 hours later. Lixivaptan capsules each contained 50 mg of lixivaptan plus some inactive ingredients (these ingredients produce no effect when they are taken). Placebo capsules did not contain any lixivaptan but contained the same inactive ingredients as the lixivaptan capsules. The type of capsules (lixivaptan or placebo) taken by patients depended on the part and period of the study, and which group they were in.
Part 1, Period 1: Patients took 4 capsules of placebo twice a day during this period.
Part 1, Period 2: Patients took a total of 4 capsules twice a day, in one of the following combinations:
o 1 lixivaptan/3 placebo
o 2 lixivaptan/2 placebo
o 3 lixivaptan/1 placebo
o 4 lixivaptan/0 placebo
Patients started this period taking 1 lixivaptan/3 placebo capsules, and then gradually increased the number of lixivaptan capsules and reduced the number of placebo capsules, as long as they had no side effects.
Part 1, Period 3: Patients who were randomized to take lixivaptan continued to take the same dose they were taking at the end of Period 2, but always as 4 capsules twice a day. Patients who were randomized to take placebo took 4 capsules of placebo, twice a day.
Part 1, Period 4: Patients did not take any lixivaptan or placebo capsules.
No patients reached Part 2 of the study.
6 WHAT WERE THE SIDE EFFECTS?
Side effects are unwanted medical events (e.g., headache) that the study doctor/sponsor thinks could be related to the study drug. Not all of the patients in this study had side effects.
No deaths or serious side effects were reported during this study. A serious side effect is one that was life threatening or required the patient to go to hospital. No patients had to stop doing the study because of a side effect. The side effects were mild or moderate in how intense they were; there were no severe side effects reported during the study. All side effects went away during the monitoring period of the study.
Of the 8 patients who received treatment with lixivaptan, 3 of them (38%) experienced side effects. The 3 patients experienced 5 side effects, 2 of which were in one patient, 2 of which were in a second patient, and 1 of which was in the third patient. These were:
Thirstiness
Urinating (peeing) more than usual
Kidneys were not working properly (acute kidney injury) Low blood pressure Unwanted increase in a type of enzyme made by the liver The researchers were particularly interested to know if any of the people in this study had any side effects involving the liver after taking lixivaptan. The only side effect affecting the liver was the one mentioned above: the increase in a type of enzyme made by the liver in one patient randomized to the placebo group and who had taken lixivaptan during Part 1, Period 2. No other patients experienced any side effects involving their liver during the study.
7 WHAT WERE THE OVERALL RESULTS OF THE STUDY?
The main purpose of this study was to see if lixivaptan is effective at slowing down the deterioration in kidney function experienced by patients with ADPKD. Because the study was stopped early, it was not possible to find this out. However, another purpose of the study was to find out if lixivaptan was safe to take and if patients taking it had any side effects. Three of the 8 patients (38%) taking part in the study experienced a side effect. One patient had a side effect which involved their liver, which the sponsor was particularly interested in. However, because the study was stopped early, and not as many patients took lixivaptan as expected, more research should be done before lixivaptan is considered safe to take. To learn more about this study, including where to find the complete outcomes of this study, see Section 10.
8 HOW DID THIS STUDY HELP PATIENTS AND RESEARCHERS?
As this study was stopped early because of business reasons, the results of this study should be interpreted with caution.
9 ARE THERE PLANS FOR FURTHER STUDIES? No further clinical studies with lixivaptan are planned at the current time.
10 WHERE CAN I FIND OUT MORE INFORMATION ABOUT THIS STUDY?
To learn more about this study, including where to find the complete outcomes of this study, go to:
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C0b0966308ded45c1a5fd08daf578e901%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638092196893732776%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Emr5pPW4UcfobQXWcbuQsctFAqUa4oAId1HTJV3GU7Y%3D&reserved=0 and search for “NCT04064346” (the ClinicalTrials.gov identifier) or “PA ADPKD 301” (the study protocol number)
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REC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
21/EM/0255
Date of REC Opinion
2 Dec 2021
REC opinion
Further Information Favourable Opinion