SHP655-201: Pharmacokinetics, safety, and efficacy of SHP655 in aTTP
Research type
Research Study
Full title
A Phase 2, multicenter, randomized, placebo-controlled, doubleblind study in patients with acquired thrombotic thrombocytopenic purpura (aTTP) to evaluate the pharmacokinetics, safety, and efficacy of rADAMTS-13 (SHP655) administered in addition to standard of care (SoC) treatment
IRAS ID
262256
Contact name
Marie Scully
Contact email
Sponsor organisation
Shire
Eudract number
2018-003775-35
Duration of Study in the UK
1 years, 11 months, 18 days
Research summary
Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease. TTP causes problems with the blood system, including low platelet count, blood clots in small blood vessels and low iron levels caused by loss of red blood cells; these can damage multiple organs. TTP may occur in congenital (cTTP) or acquired (aTTP) forms. Patients with aTTP have low ADAMTS-13 levels.
Current aTTP treatment is daily plasma exchange (PEX) and immunosuppressive therapy. The medication being evaluated in this study, SHP655, is an artificially made ADAMTS-13. The study will assess ADAMTS-13 levels in aTTP subjects in response to PEX treatment with and without SHP655. The study will also assess how SHP655 is taken up, broken down, and removed by the body, SHP655’s side effects and evaluate the most effective dose of SHP655.
With current PEX treatment of aTTP, the mortality rate is 10-20%. PEX therapy can cause allergic reaction and carries a very small but not negligible risk of transmitting blood-borne viruses, SHP655 does not carry this risk. PEX infusions in patients undergoing long-term preventative treatment, can cause haemorrhage related to the insertion of a catheter, blood clots and infection. Furthermore, PEX is associated with high healthcare resource utilisation, is time consuming and can be stressful for patients. With SHP655 treatment it is expected that aTTP patients can receive adequate therapy, leading to a reduction in the severity of TTP episodes and time to resolution.
The study will compare SHP655 to a placebo (containing no active ingredient). Patients will be assigned to one of 3 groups by chance. Group 1: daily PEX + placebo immediately after PEX, and placebo 12 hours later, Group 2: daily PEX + SHP655 immediately after PEX, and placebo 12 hours later, Group 3: daily PEX + SHP655 immediately after PEX, and SHP655 12 hours later.
Summary of Results:
Thank you to the participants who took part in the clinical study, SHP655-201, called “Study of rADAMTS-13 (SHP655) in the Treatment of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) (SOAR-HI)”.
This study helped researchers find out if a medicine called SHP655 could help participants with aTTP.
Why was this study done?
Researchers wanted to see how well SHP655 worked as a treatment for acquired thrombotic thrombocytopenic purpura (aTTP).
aTTP is a rare autoimmune blood disease. Our normal immune system keeps us healthy by using white blood cells and antibodies to fight infections from foreign germs. An autoimmune disease is caused by the body’s immune system attacking itself.
Plasma
Plasma is the liquid part of the blood which contains nutrients, proteins, and antibodies. Patients with aTTP have antibodies in their plasma that attack ADAMTS13.
What is Plasma Exchange (PEX)?
Plasma exchange is a treatment in which plasma is separated from the blood and replaced with healthy plasma. Plasma exchange is usually done in aTTP patients to remove the antibodies that attack ADAMTS13 and restore its function.
In aTTP, the body develops antibodies that attack an enzyme called ADAMTS13. ADAMTS13 is responsible for breaking down clusters of a protein called von Willebrand factor (VWF). Without ADAMTS13, the clusters of VWF collect in small blood vessels and stick to platelets to form blood clots. Normally, blood clots are formed at the site of a cut or injury to stop bleeding. ADAMTS13 helps to break down VWF, which allows the blood clots to dissolve as the body heals.
But in patients with aTTP, ADAMTS13 protein is very low so the blood clots do not dissolve. These clots can interfere with the blood flow to vital organs such as the brain and heart, leading to serious problems. Common symptoms of aTTP are tiredness, fever, weakness, bleeding, and rashes or bruises around the body.
The current treatments for aTTP include plasma exchange (PEX) and medications that block the immune system. However, PEX has safety risks due to the procedures involved and the large amount of plasma needed. In up to half of patients, the signs of aTTP return even after PEX. Therefore, there is a need to develop better treatments.
The study medication, SHP655, is also called recombinant ADAMTS13. It is a form of ADAMTS13 enzyme that is prepared in a laboratory. It works in the same way that natural ADAMTS13 does. It is given as an injection into a vein.
Researchers wanted to know how giving SHP655 along with PEX treatment affected levels of ADAMTS13 in the blood. They also wanted to know how it affected levels of other signs of the disease. Researchers wanted to compare SHP655 given along with PEX to placebo and PEX. A placebo is a drug that looks like the study medication but does not have any medicine in it. Researchers used a placebo to make sure the effects of SHP655 they found in the study were caused by SHP655.
Researchers also wanted to know about any side effects that might be caused by the study treatments.
When was this study done?
This study started in October 2019 and ended in August 2021.
Lactate dehydrogenase (LDH)
LDH is an enzyme found in many cells in the body. In aTTP, blood clots cause red blood cells to break down and release LDH. LDH levels in the blood reflect the amount of blood clots.
cTTP
cTTP is also known as inherited TTP. It is a type of TTP where a defective copy of the gene that makes ADAMTS13 is passed from parents to children.
Who took part in this study?
Who was allowed to take part in this study?
Participants could take part if they:
• Were 18 to 75 years old
• Had aTTP
• Had low platelet counts and high levels
of LDH
Participants could not take part if they:
• Had congenital thrombotic thrombocytopenic purpura (cTTP)
For more information on who could take part in this study, please refer to the websites listed on the last page of this summary.
How many people took part in this study?
Altogether 28 participants took part in this study. There were 9 (32%) men and 19 (68%) women. Participants were between 24 and 73 years old.
The study took place at 12 clinics around the world. The list of countries where the study took place is shown below.
Countries where the study took place
Canada France
Germany Italy
Spain United Kingdom
United States
What happened during the study?
What did researchers want to know?
Researchers wanted to learn about the activity levels of ADAMTS13 in the body after participants were treated with SHP655 and PEX. Researchers also checked participants’ platelet counts and LDH levels.
Platelets are used to form blood clots, so platelet counts are usually low in the blood of patients with aTTP because all the blood clots use up the platelets. LDH is released into the blood after blood cells break down, so LDH levels are usually high in patients with aTTP. Measuring the levels of platelets and LDH helps researchers understand the amount of blood clots being formed. It also helps them find out if SHP655 can lower the number of blood clots.
To do this, researchers took blood samples from all participants before and multiple times after they took the study medications.
The main questions researchers wanted to answer were:
• What were the activity levels of ADAMTS13 before and after treatment?
• What were the platelet counts before and after treatment?
• What were the LDH levels before and after treatment?
Researchers also wanted to learn about any side effects participants experienced due to the study treatments.What medications were studied?
Researchers studied 2 medications. They were:
• SHP655: 36 to 44 International units per kilogram (IU/kg), dose calculated based on body weight, given once or twice daily as an injection into a vein
• Placebo: Given as an injection into a vein
All participants were also given a combination of methylprednisolone and rituximab as a standard treatment to reduce the immune system response.
How was the study done?
There are many types of clinical studies. This study was:
• Phase 2: In a Phase 2 study, a treatment is tested for safety and efficacy in a small number of participants.
• Randomized: Who got which study treatment was decided randomly by a computer program.
• Double-Blind: Neither researchers nor participants knew which treatment the participants received.
At first, participants who were having a sudden onset of aTTP symptoms went to a study center. There, they received PEX and were then screened to be sure they were a good fit for the study. The screening process included a physical exam, tests to measure brain function, and blood and urine tests.
After screening, a total of 28 participants were randomly put into 1 of the 3 study groups. The table below shows the study groups and the sequence of study medications given.
Treatment GroupsGroup Treatment Description
Placebo
(10 participants) PEX 1. Daily PEX.
2. Placebo right after PEX.
3. Placebo 12 hours after PEX.
Placebo
SHP655 once daily
(9 participants) PEX 1. Daily PEX.
2. SHP655 right after PEX.
3. Placebo 12 hours after PEX.
SHP655
Placebo
SHP655 twice daily
(9 participants) PEX 1. Daily PEX.
2. SHP655 right after PEX.
3. SHP655 12 hours after PEX.
SHP655Researchers continued to perform laboratory tests during treatment days. They also checked participants for side effects. Participants received treatment until they entered remission, which is when their platelet counts and LDH went back to normal.
After remission, participants had follow-up visits once every 3 days, then once a week, then once every 2 weeks for additional tests. They had a final visit 12 weeks after remission. The overall duration of the study was about 2 years.
What were the results?
Researchers collected blood samples from participants to measure the activity levels of ADAMTS13 and levels of platelets and LDH in their blood. The results below are based on the measurements from 28 participants who took at least 1 dose of the study medications. One participant was excluded from the results because tests showed they did not have aTTP.
What were the activity levels of ADAMTS13 before and after treatment?
Researchers found that:
• Higher activity levels of ADAMTS13 were found in the blood of participants who received SHP655. This included participants from both the SHP655 once daily and the SHP655 twice daily group.
What were the platelet counts before and after treatment?
Researchers recorded platelet counts before and after participants received the study treatments. The normal platelet count in blood is 150,000 to 450,000 platelets per microliter.
The table below shows the average platelet count before and after treatment.
Average platelet count Placebo
(10 participants) SHP655 once daily
(9 participants) SHP655 twice daily
(9 participants)Platelet count before treatment 36,000
28,000 15,000
Platelet count after treatment 279,000 267,000 286,000 Researchers found that platelet counts after treatment were similar across the 3 groups.What were the LDH levels before and after treatment?
Researchers recorded LDH levels before and after participants received the study treatments. The normal LDH levels in the blood are 140 to 280 units per liter.
The table below shows the LDH levels before and after treatment.
Average LDH levels Placebo
(10 participants) SHP655 once daily
(9 participants) SHP655 twice daily
(9 participants)LDH levels before treatment 635 616 788
LDH levels after treatment 197 209 220
Researchers found that LDH levels after treatment were similar across the 3 groups.
For more information on study results, please refer to the websites listed on the last page of this summary.
Were there any drug-related side effects?
Side effects are unwanted medical problems thought to be caused by a medicine or medical treatment. Not all of the participants in this study had side effects. Side effects results include all 28 participants who took at least 1 dose of study medication.
The table below shows how many participants in each group had side effects.
Drug-related side effects Placebo
(10 participants) SHP655 once daily
(9 participants) SHP655 twice daily
(9 participants) Number of participants (%)
Participants with any side effects 0 1 (11%) 0
Participants with serious side effects 0 0 0
Participants who left the study due to side effects 0 0 0
Deaths 0 0 0
A side effect is called ‘serious’ when it is life threatening, causes lasting problems, or needs hospital care. None of the participants had serious side effects.
Only 1 participant (11%) in the SHP655 once daily group had an allergic reaction to the infusion.
How has this study helped patients and researchers?
Researchers look at the results of many studies to decide which medicines work best and are safest for patients. This summary gives the results for 28 participants in a single study. Other studies may have more participants or may give different results.
Findings from this study may be used in other future studies to learn more about SHP655 in patients with aTTP.
Are there plans for further studies?
There are currently ongoing clinical studies with SHP655 for Thrombotic Thrombocytopenic Purpura.REC name
South Central - Hampshire B Research Ethics Committee
REC reference
19/SC/0208
Date of REC Opinion
3 Jul 2019
REC opinion
Further Information Favourable Opinion