ALXN-1210-TMA-314
Research type
Research Study
Full title
A Phase 3, Open-label, Single Arm, Multicenter Study of Ravulizumab in Addition to Best Supportive Care in Pediatric Participants (from 1 month to < 18 years of age) with Thrombotic Microangiopathy (TMA) after Hematopoietic Stem Cell Transplantation (HSCT)
IRAS ID
288227
Contact name
Sarah Lawson
Contact email
Sponsor organisation
Alexion Pharmaceuticals, Inc.
Eudract number
2020-000761-16
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 5 months, 24 days
Research summary
Research Summary
This study will look at an investigational drug called ravulizumab which is being developed to treat Thrombotic Microangiopathy (TMA) after Haematopoietic Stem Cell Transplant (HSCT)[HSCT-TMA] when received in addition to the standard treatment. TMA is a potentially fatal, post-transplant complication of HSCT in which small blood vessels inside vital organs do not function normally. Ravulizumab functions by blocking complement activity. The complement system is part of the immune system which fights against infections. In patients with HSCT-TMA, abnormal complement activity is present which may cause destruction of the red blood cells and platelets in the blood stream and can damage some organs such as the kidney, heart, lung and brain.
This is a phase 3 open-label study with one treatment group. Ravulizumab will be given in addition to the standard treatment (also known as Best Supportive Care (BSC)) for HSCT-TMA to approximately 40 participants. The expected duration of participation for each participant will be up to 53 weeks divided into 3 different periods:
• Screening period (up to 1 week)
• Treatment period (26 weeks)
• Follow up period (26 weeks)Key Inclusion and Exclusion criteria
Inclusion:
- Participants must be 1 month of age up to <18 years of age
- Paediatric participants who received HSCT within the past 6 months at time of screening
- A TMA diagnosis
- Participants must have HSCT-TMA that persists for at least 72 hours after initial management of any triggering agent/condition
Exclusion
- Pregnancy or breastfeeding
- Known familial or acquired ‘a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13’ (ADAMTS13) deficiency
- Known Shiga toxin-related hemolytic uremic syndrome
- Positive direct Coombs test
- Known bone marrow/graft failure
- Human immunodeficiency virus
- Unresolved meningococcal diseas
- Presence or suspicion of sepsisSummary of Results
STUDY IDENTIFICATION INFORMATION TREATMENTS STUDIED:
STUDY TITLE:
STUDY NUMBERS:
"Ravulizumab, also known as ALXN1210 (trade name: Ultomiris®)"
"A Phase 3, Open-label, Single Arm, Multicenter Study of Ravulizumab in Addition to Best Supportive Care in Pediatric Participants With Thrombotic Microangiopathy (TMA) After Hematopoietic Stem Cell Transplantation (HSCT)"What was the purpose of this study?
This study tested a drug called ravulizumab. The researchers wanted to know how effective and safe ravulizumab was in the treatment of children with Thrombotic Microangiopathy (also known as TMA) after Hematopoietic Stem Cell Transplantation (HSCT). Researchers measured the efficacy of ravulizumab by quantifying how many participants’ TMA got better during the 26 weeks of treatment."Clinical studies 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 typically look at the overall risks and benefits of a treatment. This was a Phase 3 “single-arm” study, which means that all participants received ravulizumab."
What is TMA?
"TMA is a serious medical condition that can happen after a person has a stem cell transplant. In this condition, tiny blood clots form in small blood vessels throughout the body. These clots can damage and cause inflammation in small blood vessels, making the kidneys and other organs stop working properly. After HSCT, a part of the immune system (the body’s natural defense), known as the complement system, can become overactive and trigger TMA."
What are the symptoms of TMA?
"People who develop TMA may experience a range of signs and symptoms. These include trouble breathing, high blood pressure, bruising, tiredness, confusion, anemia (a lack of healthy red blood cells), and a low number of platelets (which help stop bleeding). TMA can also cause blood clots. The most serious complications are damage to the kidneys, brain, or heart. If the kidneys stop working well, the person may need dialysis (a way to clean the blood when the kidneys do not work properly)."
What treatments are available for TMA?
"Currently, there are no approved treatments for TMA that develops after HSCT. The main treatment approach is to avoid certain drugs and treat or stop underlying triggers, such as infections. However, for many patients, these steps alone are not enough to resolve TMA."
"Blocking the complement system has shown promise. The complement system is composed of more than 40 proteins, including a protein called C5. Eculizumab is a drug that blocks C5. Although it is not approved specifically for TMA after HSCT, some studies have shown that eculizumab can help improve this medical condition."What were the treatments researched in this study?
"Ravulizumab is a protein made in the laboratory. Ravulizumab is a research drug that also sticks to C5, like eculizumab and stops it from working. Ravulizumab remains in the body for a longer period and inhibits the complement system more effectively than eculizumab."
"In this study participants received ravulizumab given intravenously (IV; administered through a vein into the bloodstream). During the Treatment Period (up to 26 weeks), participants received “open-label” ravulizumab. This means that participants, their caregivers, and study doctors knew what drug and what dose was given.""At the start, participants received the first doses of ravulizumab (loading doses) based on their weight on Days 1, 5, and 10. These first doses ranged from 300 milligrams (mg) to 3,000 mg, based on the participants’ weight. After Day 15, participants started to receive maintenance doses. Participants under 20 kilograms (kg) received from 400 mg to 800 mg every 4 weeks."
"Participants weighing 20 kg or more received from 2,100 mg to 3,600 mg every 8 weeks. All participants received the best supportive care (BSC) provided in their respective countries and study sites. This means participants received treatments and support to help manage"
"symptoms, prevent problems, and keep them as comfortable as possible during the Treatment Period, even if the main disease could not be cured.""After the Treatment Period, participants entered the Follow-up Period and continued to receive BSC for another 26 weeks. The study doctors continued to check their health and symptoms."
Screening
Up to 7 days
Treatment Period
(26 Weeks)
Follow-up Period
(26 Weeks)
41 Participants
divided into groups according
Ravulizumab
Off ravulizumab
to their body
weight
Day 1 Day 5 Day 10 Day 15 End
of the study
Loading
Doses
Maintenance
"Every 4 or 8 weeks, depending on"
the participant’s
body weight
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
children
Confirmed diagnosis
of TMA after HSCT
Between 28 days
and 18 years of age
Individuals were unable to take part if study doctors determined they did not produce enough "of an enzyme called ADAMTS13. This enzyme helps prevent blood clots from forming in small blood vessels. Individuals were also excluded if they had other medical conditions that could make it hard to test if the study drug is safe or could make the results hard to understand. Also, those who had already taken a medicine that blocks the complement system could not take part in the study.""A parent or guardian provided consent for participants under 18 years of age. Where applicable, children and young adults under 18 years of age could also provide their assent to participate in this study."
How many participants took part in this study?
21 girls + 20 boys = 41 participantsParticipants were between 28 days and 17 years of age at the start of ravulizumab administration.
The study started in December 2020 and ended in May 2025.
"WHERE WAS THIS STUDY DONE?
The study took place in 26 study centers in 7 countries across Israel, Italy, Japan, South Korea, Spain, United Kingdom, and USA."
WHAT WERE THE RESULTS OF THIS STUDY?
The researchers wanted to see how effective and safe ravulizumab was in the treatment of participants with TMA after HSCT. Study doctors considered TMA fully resolved if participants met all the three conditions listed below:
"• The count of platelets, which are tiny pieces of cells in the blood that help stop bleeding,"
was within the normal range.
"• The blood levels of a marker of tissue and organ damage, known as lactate dehydrogenase (LDH), were within the normal range."
• The amount of protein in the urine (a sign of kidney stress or damage) had dropped by at least 50% from the start of the study.How many participants had their TMA fully resolved after 26 weeks of treatment with ravulizumab?
"After 26 weeks of treatment, TMA was fully resolved in 7 out of 41 participants (17.1%)."
"Study doctors also checked for improvements in the individual signs of TMA, even if the condition was not completely resolved. After 26 weeks of treatment with ravulizumab:"
• 24 out of 41 participants (58.5%) had a healthier platelet count.
• 15 of 41 participants (36.6%) had better levels of a marker of tissue and organ damage (LDH).
• 22 out of 41 participants (53.7%) had less protein in their urine.The researchers wanted to answer another important question during the study.
How many participants remained alive during the 26 weeks of treatment and the 26 weeks of the follow-up period?Most children in the study survived through treatment with ravulizumab and follow-up.
"• After the first 100 days, 38 out of 41 participants (92.6%) were alive."
"• After 26 weeks of treatment, 36 out of 41 participants (87.2%) were alive."
"• By the end of the study, 31 out of 41 participants (73.4%) were alive."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 researchers to 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?
"Overall, 30 out of 41 participants (73.2%) had serious side effects during the Treatment Period, the majority of which were thought by study doctors to be complications not related to ravulizumab"
A total of 3 out of 41 participants (7.3%) experienced related serious side effects of:
• Serious damage to soft tissue (muscles, fat, blood vessels, and nerves, but not bones)
• Seizure affecting the whole brain or seizures affecting only parts of the brain
• Infection that spreads through the body and causes organs to not work well
• Blockage of the tiny blood vessels in the liver causing the liver to not work well
Six out of 41 participants (14.6%) died during the Treatment Period due to several organs not "working well, severe infection along with low blood pressure and organs not working well, virus infection, heart not pumping enough blood and oxygen, and serious fungal infection. All cases of death were considered not related to ravulizumab."What side effects did participants have in this study?
"Overall, all 41 participants (100%) had side effects during the study, the majority of which were thought by the study doctors to be not related to ravulizumab. A total of 8 out of 41 participants (19.5%) had a side effect during the Treatment Period that was thought by study doctors to be related to ravulizumab."
"The most common related side effects during the Treatment Period, which happened in 1 or more participants in the study, are shown below:"
"During the Follow-up Period, the side effects were similar to those observed during the Treatment Period.
Were there any other important safety findings in this study?
"Seven out of 41 participants (17.1%) stopped taking ravulizumab because of side effects. These side effects included uneven heartbeat, fluid around the heart, several organs not working well, viral infection, serious fungal infection, making less urine, serious damage to soft tissue (muscles, fat, blood vessels, and nerves, but not bones), and dry skin."
26-Week Treatment Period
Ravulizumab
(41 participants)
Related side effects in 1 or more participants in the study Fluid around the heart 1 (2.4%)
Blockage of the tiny blood vessels in the liver causing the liver 1 (2.4%)
to not work well
Allergic reaction 1 (2.4%)
Norovirus infection (stomach flu) 1 (2.4%)
Infection that spreads through the body and causes organs to 1 (2.4%)
not work well
Making less urine 1 (2.4%)
"Serious damage to soft tissue (muscles, fat, blood vessels, and" 1 (2.4%)
"nerves, but not bones)"
Small red or brown-red soft bump on the skin 1 (2.4%)
Seizures affecting only part of the brain 1 (2.4%)
Seizure 1 (2.4%)
Dry skin 1 (2.4%)OUTCOME OF THE STUDY
How has this study helped participants and researchers?
"The information collected in this study showed that ravulizumab was effective in blocking the complement system protein C5. This resulted in TMA after HSCT in children fully resolving in some participants included in the study, improving their chances of survival. The majority of side effects were thought by study doctors to be due to a combination of causes not related to ravulizumab, including complications of HSCT and other medical problems."
"Before a treatment can be approved for patients to use, researchers look at the results of many studies to decide which treatments work best and are safe. If you have any questions about ravulizumab or your treatment of TMA after HSCT, please talk to your doctor. You should not change your treatment based on the results of this study without talking to a doctor first. Ravulizumab is under research for the treatment of TMA after HSCT and has not yet received approval from the regulatory authorities for prescribed treatment.
Useful clinical study websitesThis 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 register(s):
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7C8179455ad4884313255108de543d2bba%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639040818869849278%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=8G636OjuBgRYeQzg879WuUIbaVW97XiCTB6nDMoBo%2BA%3D&reserved=0
Use the study number NCT04557735 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%7C8179455ad4884313255108de543d2bba%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639040818869883944%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=eINo%2FF9aDYmwnniWMn%2BFlQOOM3lD0aPDY5mLV8Vqon0%3D&reserved=0Use the study number 2020-000761-16 to search for more information on this website.
REC name
West Midlands - Edgbaston Research Ethics Committee
REC reference
20/WM/0297
Date of REC Opinion
6 Jan 2021
REC opinion
Further Information Favourable Opinion