Ravulizumab administered SC vs IV in PNH patients
Research type
Research Study
Full title
A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With Eculizumab
IRAS ID
252938
Contact name
Austin Kulasekararaj
Contact email
Sponsor organisation
Alexion Pharmaceuticals Inc.
Eudract number
2017-002370-39
ISRCTN Number
ISRCTN00000000
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
128367, IND Number:
Duration of Study in the UK
2 years, 2 months, 1 days
Research summary
Research Summary
Paroxysmal nocturnal hemoglobinuria (PNH) is an very rare and dangerous disorder that destroys the red blood cells in the body. It is caused by uncontrolled activation of the terminal complement pathway. This study involves an investigational drug called ravulizumab (referred to as “study drug”). This drug is being developed to treat PNH by blocking complement activity. Complement activity is part of your immune system which fights against infections.
The purpose of this study is to compare the pharmacokinetics (PK; what the body does with the drug) of ravulizumab subcutaneous (SC; under the skin) to ravulizumab intravenous (IV; in the vein) in participants with PNH who have stable disease and have been treated with eculizumab (Soliris®) for at least 6 months prior to study entry.
The study will consist of an up to 4-week Screening Period, a 10-week randomised treatment Period, and a 42-week extension period. The duration of participation in the study is anticipated to be approximately 1 year. Participants will be randomised in a 2:1 ratio to receive either ravulizumab SC or ravulizumab IV.
Ravulizumab IV has been previously tested in PNH participants. However, this study will be the first to test ravulizumab SC in PNH participants. For ravulizumab SC dosing, participants will use an on-body delivery system (OBDS). The OBDS has been approved for use with another medicine in some countries, but has not been tested with ravulizumab.
The study will be global and is expected to enroll approximately 105 participants from 75 sites. A maximum of 144 participants may be enrolled if needed.
Summary of Results
CLINICAL STUDY RESULTS A Study to Learn if Ravulizumab Administered Under the Skin Works as Well as When Administered Into the Bloodstream in Participants with Paroxysmal Nocturnal Hemoglobinuria
THANK YOU!
Alexion would like to thank all of the participants, their families, and caregivers who took part in this clinical study. Taking part in studies like this one may contribute directly to the discovery of new treatments for people with paroxysmal nocturnal hemoglobinuria.STUDY IDENTIFICATION INFORMATION
TREATMENTS STUDIED: Ravulizumab, also known as ALXN1210 (trade name: ULTOMIRIS®) STUDY TITLE: A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With Eculizumab STUDY NUMBERS: United States, NCT03748823 | European Union, 2017-002370-39| Protocol, ALXN1210-PNH-303Why was this study conducted?
Clinical studies, also called clinical trials, aim to answer questions about specific diseases, or treatment procedures, and involve participants with medical conditions or healthy volunteers.Clinical studies to develop new treatments happen in four stages, from Phase 1 to Phase 4, each investigating specific questions about the treatment.
This was a Phase 3 study. Phase 3 studies look at the overall risks and benefits of a treatment compared to a placebo (a product similar in appearance to the treatment being tested but which contains no real medicine) or a control group (a group of participants who are not given the treatment in the study but serve as a reference).In this study, a drug called ravulizumab was tested in adults with paroxysmal nocturnal hemoglobinuria (also known as PNH). The researchers wanted to know if ravulizumab given subcutaneously (SC, administered as an injection under the skin) affects the body similarly as when given intravenously (IV, administered through a vein into the bloodstream). With SC administration, patients often self-administer the medicine. To see how the body handled ravulizumab SC as compared with ravulizumab IV, the researchers measured the amount of the drug in the participants’ blood.
In this study, ravulizumab SC was given using an on-body delivery system (OBDS). An OBDS is a small medical device that contains ravulizumab, a needle, and an activation button. It can be temporarily attached to the body (upper arm, abdomen, or thigh). Once the participants press the activation button, the OBDS automatically administers ravulizumab SC. The OBDS can be removed when the injection is completed.
Ravulizumab SC given through an OBDS is a drug-device product (a device used to deliver the drug). Ravulizumab IV is available for use in patients today. Ravulizumab SC administered through an OBDS is not commercially available and cannot be used outside this study.
What is PNH?
PNH is a very rare, life-threatening but treatable blood disorder in which some or all of the red blood cells (cells that carry oxygen around the body) are defective and lack important protective proteins that prevent the breakdown of the red blood cells. Without these protective proteins, the body’s natural defense system, also called the immune system, destroys the red blood cells. This process is known as hemolysis. For people living with PNH, hemolysis is constant and can result in serious health problems. During hemolysis, hemoglobin (the protein contained in red blood cells that carries oxygen around the body) is destroyed and the enzyme lactate dehydrogenase (also known as LDH) is released into the blood; the levels of LDH in the blood indicate how much hemolysis is taking place. High levels of LDH are a typical sign of PNH.What are the symptoms of PNH?
The most common symptoms of PNH include feeling tired, difficulty swallowing, trouble concentrating or thinking, shortness of breath, stomach pain, dark-colored urine, and erectile dysfunction (difficulty in getting and keeping an erection) in men. The lack of healthy red blood cells, known as anemia or being anemic, is a serious complication of PNH, which often results in patients needing blood transfusions. Life-threatening complications from PNH can include blood clots, kidney failure, and other organ damage.How do ravulizumab and eculizumab help treat PNH?
Ravulizumab IV and eculizumab are two of the approved treatments for PNH. Both drugs work by inhibiting (blocking the function of) the complement system, an important part of the immune system (the body’s natural defenses).Both eculizumab and ravulizumab are monoclonal antibodies, proteins of the immune system produced in laboratory cells and designed to recognize and attach to a specific target. Both are medicines that are used to inhibit the complement system. The complement system is composed of more than 40 proteins, including a protein called C5. When administered to people, ravulizumab works by sticking to, and blocking, the C5 protein within the complement system.
What were the treatments researched in this study?
In this study, participants received a medicine called ravulizumab. Ravulizumab was given either SC (administered through an OBDS) or IV. During the Treatment Period (up to 10 weeks), participants were given “open-label” ravulizumab SC or IV, which means that the participants, the participants’ caregivers, and the study doctors knew which treatment was received, including how the drug was given and how much was given. Before the start of the study, all the participants were treated with eculizumab for at least 3 months. When the study started, participants stopped receiving eculizumab and started receiving ravulizumab.During the Treatment Period, participants were randomized (assigned by chance) to either ravulizumab SC or ravulizumab IV through a process called “2:1 randomization”. This process ensured that twice the number of participants received ravulizumab SC than ravulizumab IV.
- On Day 1, all participants received an initial dose (loading dose) of ravulizumab IV of either 2400 milligrams (mg) or 2700 mg, based on their body weight.
- On Day 15, participants assigned to ravulizumab SC received a dose of 490 mg of ravulizumab SC. After Day 15, participants received the same dose every week during the Treatment Period.
- On Day 15, participants assigned to ravulizumab IV received a maintenance dose of either 3000 mg or 3300 mg of ravulizumab IV, based on their body weight. Participants received no further doses of ravulizumab IV during the Treatment Period.
At the end of the Treatment Period, participants could take part in the Extended Treatment Period (up to 3.5 years). In that period, participants assigned to ravulizumab SC continued to receive ravulizumab SC, and participants assigned to ravulizumab IV started to receive ravulizumab SC.
Who could take part in this study?
To be able to take part in the study, participants had to meet the following requirements:
- Male or female adults (18 years of age or older)
- Confirmed diagnosis of PNH
- Received eculizumab for at least 3 months before the start of the studyIndividuals were unable to take part if they had blood levels of LDH (an enzyme released in the blood during hemolysis) greater than 2 times the upper limit of the normal range (ULN) at least once during the 3 months before the start of the study. Individuals could not take part in the study if they had major adverse vascular events (MAVE), which include stroke (a sudden interruption of blood flow in the brain), thrombosis (blood clots), and other serious conditions affecting the blood vessels during the 6 months before the start of the study. Also, those who had a low platelet count (platelets are components that help the blood to clot) or neutrophils (a type of white blood cell) in the blood at the start of the study could not take part.
Complement inhibitors increase the risk of potentially life-threatening meningococcal infection, which is caused by a bacterium called Neisseria meningitidis. To help prevent it, all participants had to be adequately vaccinated with meningococcal vaccine before receiving ravulizumab.
Participants consented to be in the study.
How many participants took part in this study?
69 women + 60 men = 129 participantsParticipants were between 18 and 79 years of age at the start of the study. The study started in March 2019 and ended in August 2023.
WHERE WAS THIS STUDY DONE?
The study took place in 51 study centres in 14 countries. The 14 countries were Australia, Austria, Belgium, Brazil, Canada, Finland, France, Italy, the Netherlands, Russia, Spain, Sweden, Turkey and the United States.WHAT WERE THE RESULTS OF THIS STUDY?
The researchers wanted to see how levels of ravulizumab in the blood changed based on how the medicine was given to participants (through an OBDS as compared with IV). To answer this question, the researchers measured the blood levels of ravulizumab in participants receiving it SC or IV, just before the next doses were due (at the end of the Treatment Period, on Day 71).
These measurements helped researchers understand how much ravulizumab stays in the body when given SC as compared with IV, and whether the blood levels were considered sufficient for the drug to work properly.Were the blood levels of ravulizumab SC similar to ravulizumab IV at the end of the Treatment Period?
Overall, the results showed that participants receiving ravulizumab IV and SC showed similar blood levels of the drug at the end of the Treatment Period. The blood levels of ravulizumab IV and SC were considered sufficient for the drug to work as expected.The researchers wanted to answer other important questions throughout the entire study duration (Treatment Period + Extended Treatment Period). Participants received ravulizumab SC for most of the time (either during the entire study duration or after receiving ravulizumab IV for the first 10 weeks).
What was the change in LDH levels in participants receiving ravulizumab SC?
The researchers wanted to measure the change in the blood levels of LDH in participants receiving ravulizumab SC, either throughout the entire study duration (Treatment Period and Extended Treatment Period) or during the Extended Treatment Period only (after having received ravulizumab IV during the Treatment Period). If ravulizumab is blocking hemolysis, the blood levels of LDH should remain low (close to the normal range).
At the start of the study, all participants had blood levels of LDH only slightly above the normal limit (not higher than 1.5 times the upper limit of the normal range), indicating that the previous treatment with eculizumab stopped excessive hemolysis. Overall, the results showed that LDH levels remained stable in all participants until the end of the Extended Treatment Period. Ravulizumab SC kept levels of LDH in the participants’ blood at low levels, which indicates that it may be blocking hemolysis.How many participants receiving ravulizumab SC had breakthrough hemolysis episodes compared with participants receiving ravulizumab IV?
The researchers wanted to see if ravulizumab SC was effective in avoiding breakthrough hemolysis (serious episodes of hemolysis causing a worsening of PNH symptoms). To answer this question, researchers counted the number of participants having at least one breakthrough hemolysis episode among those who received ravulizumab SC throughout the entire study duration (Treatment Period and Extended Treatment Period) and among those who received ravulizumab SC during the Extended Treatment Period only (after having received ravulizumab IV during the Treatment Period).Overall, 3 out of 84 participants receiving ravulizumab SC throughout the entire study duration (3.6%) and 2 out of 44 participants receiving ravulizumab SC after having received ravulizumab IV (4.5%) had at least one episode of breakthrough hemolysis before the end of the study. The percentages of participants having episodes of breakthrough hemolysis were similar between the two groups; hence, ravulizumab SC was considered effective in avoiding breakthrough hemolysis when used as the first treatment as well as after switching from ravulizumab IV.
How many participants receiving ravulizumab SC did not need blood transfusions?
The researchers wanted to know if ravulizumab SC was effective in preventing the participants’
need for blood transfusion. To answer this question, researchers counted the number of participants who did not need any blood transfusion among those who received ravulizumab SC throughout the entire study duration (Treatment Period and Extended Treatment Period) and among those who received ravulizumab SC during the Extended Treatment Period only (after having received ravulizumab IV during the Treatment Period).Overall, the results showed that 62 out of 84 participants receiving ravulizumab SC throughout the entire study duration (73.8%) and 31 out of 44 participants receiving ravulizumab SC after having received ravulizumab IV (70.5%) did not need any blood transfusion and remained transfusion-free until the end of the study.
How many participants receiving ravulizumab SC had stable levels of hemoglobin?
The researchers also wanted to know if ravulizumab SC was effective in preserving the levels of hemoglobin, the protein contained in red blood cells that carries oxygen around the body.
To answer this question, researchers counted the number of participants who had stable levels of hemoglobin among those who received ravulizumab SC throughout the entire study duration (Treatment Period and Extended Treatment Period) and among those who received ravulizumab SC only during the Extended Treatment Period (after having received ravulizumab IV during the Treatment Period).Overall, 51 out of 79 participants receiving ravulizumab SC throughout the entire study duration (64.6%) and 26 out of 44 participants receiving ravulizumab SC after having received ravulizumab IV (59.1%) had stable levels of hemoglobin until the end of the study.
How many participants receiving ravulizumab SC had signs and symptoms of PNH?
The researchers wanted to see if ravulizumab SC was effective in reducing signs and symptoms typical of PNH. To answer this question, researchers counted the number of participants who had signs and symptoms of PNH among those who received ravulizumab SC throughout the entire study duration (Treatment Period and Extended Treatment Period) and among those who received ravulizumab SC only during the Extended Treatment Period (after having received ravulizumab IV during the Treatment Period).Overall, 53 out of 84 participants receiving ravulizumab SC throughout the entire study duration (63.1%) and 22 out of 44 participants receiving ravulizumab SC after having received ravulizumab IV (50.0%) had signs and symptoms of PNH occurring during the first year of the study.
What were the safety findings in this study?
A side effect is any symptom a participant has during the study which may or may not be related to the study treatment. Related side effects are unwanted medical events that happen during the study, and are considered to be related to study treatment. Side effects are classified as either “mild”, “moderate”, or “severe” in intensity.A serious side effect is thought to be an important medical event (e.g., requires a person to be admitted to the hospital, is life-threatening, causes disability, or causes death).
Side effects can vary from person to person. Researchers keep a record of all the side effects participants have when new treatments are studied. This helps determine which side effects occur as a result of the study treatment and which occur by chance or because of the participant’s underlying disease.
What serious side effects did participants have in this study?
Researchers evaluated the serious side effects during the treatment with ravulizumab SC given through the OBDS over the entire study period (Treatment Period + Extended Treatment Period). Specifically, researchers evaluated the serious side effects occurring from the start of the treatment with ravulizumab SC (either from Day 0 or the beginning of the Extended Treatment Period, at Week 11) up until the end of the Extended Treatment Period. The serious side effects occurring in participants receiving ravulizumab IV during the Treatment Period were excluded.Overall, 45 out of 128 participants (35.2%) had serious side effects while receiving ravulizumab SC, the majority of which were thought by study doctors to be not related to ravulizumab SC and/or the OBDS used to deliver it. Of those, 30 participants (35.7%) received ravulizumab SC during the entire study period (Treatment Period + Extended Treatment Period), and 15 participants (34.1%) received it only during the Extended Treatment Period.
A total of 1 out of 128 participants (0.8%) experienced hypotension (low blood pressure) considered to be related to the OBDS used to deliver ravulizumab SC.
A total of 4 out of 128 participants (3.1%) died during the study. None of the deaths were considered to be related to ravulizumab SC or the OBDS.
What side effects did participants have in this study?
Researchers evaluated the side effects during the treatment with ravulizumab SC given through the OBDS over the entire study period (Treatment Period + Extended Treatment Period). Specifically, researchers evaluated the side effects occurring from the start of the treatment with ravulizumab SC (either from Day 0 or the beginning of the Extended Treatment Period, at Week 11) up until the end of the Extended Treatment Period. The side effects that occurred in participants receiving ravulizumab IV during the Treatment Period were excluded.Overall, 128 out of 128 participants (100%) had side effects during the study, the majority of which were thought by study doctors to be not related to ravulizumab SC or the OBDS used to deliver it.
A total of 47 out of 128 participants (36.7%) had side effects that were thought by the study doctor to be related to SC or OBDS ravulizumab administration. Of those, 35 participants
(41.7%) received ravulizumab SC during the entire study period (Treatment Period + Extended Treatment Period), and 12 participants (27.3%) received it only during the Extended Treatment Period. The most common related side effects, which happened in 5 or more participants in the study, are shown below:Infusion site erythema (redness of the skin at the site of the infusion) Ravulizumab SC (84 participants) = 3 (3.6%) Ravulizumab SC (after ravulizumab IV) (44 participants) = 3 (6.8%) All (128 participants) = 6 (4.7%)
Injection site erythema (redness of the skin at the site of the injection) Ravulizumab SC (84 participants) = 5 (6.0%) Ravulizumab SC (after ravulizumab IV) (44 participants) = 1 (2.3%) All (128 participants) = 6 (4.7%)
Injection site reaction (allergic reaction at the site of the injection) Ravulizumab SC (84 participants) = 4 (4.8%) Ravulizumab SC (after ravulizumab IV) (44 participants) = 1 (2.3%) All (128 participants) =5 (3.9%)
Infusion-related reaction (an allergic reaction to the treatment administration) Ravulizumab SC (84 participants) = 3 (3.6%) Ravulizumab SC (after ravulizumab IV) (44 participants) = 2 (4.5%) All (128 participants) = 5 (3.9%)
Headache
Ravulizumab SC (84 participants) = 5 (6.0%) Ravulizumab SC (after ravulizumab IV) (44 participants) = 0 All (128 participants) = 5 (3.9%)Were there any other important safety findings in this study?
1 out of 128 participants (0.8%) stopped taking ravulizumab SC during the Extended Treatment Period because of a side effect considered not related to ravulizumab. No patients had meningococcal infections or developed anti-drug antibodies (proteins in the blood that interact with ravulizumab and inactivate it, which may result in loss of efficacy of ravulizumab).OUTCOME OF THE STUDY
How has this study helped participants and researchers?
The information collected in this study showed that ravulizumab SC given through an OBDS has the same pharmacology as ravulizumab IV in adults with PNH. Moreover, ravulizumab SC was as effective as ravulizumab IV in avoiding the worsening of hemolysis (measured as the change in blood levels of LDH, absence of breakthrough hemolysis, blood transfusion avoidance, and stabilization of hemoglobin levels) and reducing PNH signs and symptoms. The results show that participants can safely switch from ravulizumab IV to ravulizumab SC. The majority of side effects were thought by study doctors to be not related to ravulizumab SC or the OBDS used to deliver it.Despite the positive results obtained from this study, Alexion has made the difficult decision to discontinue plans to deliver ravulizumab SC through an OBDS in adults with PNH. The decision follows persistent efforts to reliably secure the availability of the OBDS.
The development of ravulizumab SC given through an OBDS will not be continued. Please talk to your doctor for any questions related to the treatment of your disease.
Useful clinical study websites
This document provides a summary of the main results of the study. It includes information about the side effects that happened to participants in the study and the results of the questions the researchers wanted to answer. This summary was reviewed for readability by a patient advocacy group.Complete study results are available to read at the following clinical study registers:
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7C500043696a4b48abbc8a08dcc83428e7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638605373556071006%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=EODwqfPJdSMGnZcfj%2FmmrKrnEeJJQkpFctkwj%2Fj27Po%3D&reserved=0
Use the study number NCT03748823 to search for more information on this website.
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7C500043696a4b48abbc8a08dcc83428e7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638605373556076827%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=cpqasCYPpyE486nFWLFeWEtuzbhC9YBvNuZ9LRrGtkQ%3D&reserved=0
Use the study number 2017-002370-39 to search for more information on this website.Further studies
Several studies investigating ravulizumab for the treatment of PNH are either completed or currently running. Also, a global registry continues to recruit patients with PNH. The PNH registry is a program that collects information on patients with PNH of any age, including minors, and those who are treated with ravulizumab. Please follow the links below to find out more information.
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.clinicaltrials.gov%252Fstudy%252FNCT01374360%2FNBTI%2F8qm3AQ%2FAQ%2F1bd027a8-a5ba-4003-a372-4deb999011c9%2F2%2FaD3i3RSGZb&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7C500043696a4b48abbc8a08dcc83428e7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638605373556081871%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=PDxT2WGQlvm%2BFrD5dbPCsX9EbADv9GAaEDOgi1%2BT2w0%3D&reserved=0REC name
West Midlands - Edgbaston Research Ethics Committee
REC reference
18/WM/0374
Date of REC Opinion
19 Feb 2019
REC opinion
Further Information Favourable Opinion