EASE Study
Research type
Research Study
Full title
Double-blind, Randomised, Vehicle-controlled, Phase III, Efficacy and Safety Study with 24-month Open-label Follow-up of Oleogel-S10 in Patients with Inherited Epidermolysis Bullosa
IRAS ID
222493
Contact name
Anna Elizabeth Martinez
Contact email
Sponsor organisation
Amryt Research Limited
Eudract number
2016-002066-32
Duration of Study in the UK
3 years, 2 months, 30 days
Research summary
Summary of Research
This is a Phase III, Efficacy and Safety Study of Oleogel-S10 in Participants with Inherited Epidermolysis Bullosa (EB).EB is a rare group of genetic skin fragility disorders characterised by blistering of the skin in response to minor injury. In most cases, onset of EB is at birth or shortly after. All participants affected by any type of EB share the main characteristic of repeatedly developing painful wounds that take days to months to heal. Current treatment of EB is primarily preventative and supportive including protection from mechanical forces by avoiding rubbing, early treatment of wounds to prevent superinfections, and protection of the wound with adequate non adhesive dressings to enable healing.
Chronic, non healing wounds are a major source of complications in participants with EB. Both acute and chronic wounds impact the quality of life due to itching, pain, and the need for wound dressing changes. This clinical study of Oleogel-S10 in patients with inherited EB has been initiated to investigate whether Oleogel-S10 is effective and safe in the long term use.
Oleogel-S10 will be compared to a vehicle gel. A vehicle gel is an identical looking sunflower oil gel that does not contain any active substance. The participant will receive either Oleogel-S10 or vehicle gel. The probability that the participant will receive Oleogel-S10 is 50%, which means that they have a 1 in 2 chance of receiving Oleogel-S10. However, in the follow up of the study all participants will be treated with Oleogel S10 for a period of 24 months.
This clinical study will be performed in several countries including but not limited to Australia, Austria, France, Germany, Greece, Ireland, Israel, Italy, Spain, and United Kingdom; in total, about 164 participants are expected to participate.
Summary of Results
This clinical study was carried out to test a treatment for a rare condition called Epidermolysis Bullosa (EB). EB is a group of inherited diseases in which the skin is very fragile and forms severe blisters after even minor friction (rubbing) or injury. Children with EB are sometimes referred to as ‘butterfly children’ because their skin is as delicate as a butterfly’s wings. In most cases, symptoms of EB appear from birth or shortly after, but sometimes, symptoms may not occur until adulthood.
EB is caused by mutations (changes) in the genes responsible for the production of certain proteins that make the skin strong and elastic, such as collagen and keratins. EB patients develop so-called ‘partial thickness wounds’. Human skin is made up of several layers of different tissues (which can be seen under a microscope). A partial thickness wound is a wound that affects the upper part of the skin, but tissue layers beneath are not injured.
Doctors have been able to classify different types of EB, depending on the level within the skin (or the level of cleavage), where the wounds develop. The subtypes of EB that were permitted in this study were dystrophic EB (DEB), junctional EB (JEB), and Kindler EB (however, no patients with Kindler EB participated in the study).
Chronic, non-healing wounds are a major source of complications in patients with EB. Both acute and chronic wounds impact the quality of life due to itching, pain, and the need for wound dressing changes.
This study evaluated the effect of Oleogel-S10, a gel containing birch bark extract, on wound healing in patients with EB. Birch bark extract is the active ingredient of Oleogel-S10. Previous studies with this medicine led scientists to believe that it could speed up the wound healing process. Oleogel-S10 is now authorised in Europe under the name Filsuvez®.
The official BEB-13 study title is: “Double-blind, randomised, vehicle-controlled, phase III, efficacy and safety study with 24-month open-label follow-up of Oleogel-S10 in patients with inherited Epidermolysis Bullosa.” The study was registered with, and its results were published on the European clinical trials database (eudract.ema.europa.eu), with the EudraCT number 2016-002066-32. It was also registered on the ClinicalTrials.gov database, as NCT03068780. Further details about this study can be found on these databases.
Amryt Research Ltd., located at 45 Mespil Road, Dublin 4, Ireland, was the study Sponsor. Amryt Research Ltd. thanks everyone who took part in the study and the investigators and research staff who conducted it. The investigators had no competing financial interests, meaning there was no personal financial advantage associated with any particular study outcome.Summary of the research and key findings
Study title
The study title uses a number of technical terms to describe key features of the way this study was carried out, which are explained in short as:
• Double-blind: In a double-blind study each patient in the study receives one of two possible treatments. In this study they received either the test treatment (Oleogel-S10) or a control treatment (control gel, often referred to as placebo treatment or dummy treatment). The control gel was indistinguishable from the test treatment – it looked, felt, and smelled the same as Oleogel-S10, however, the control gel did not contain birch bark extract. The study was “double-blind” because neither the patients nor the doctors and nurses who were looking after them knew which of the two possible treatments were given to each patient.
• Randomised: There were two possible treatments available: the “test” treatment (Oleogel-S10) and the control (dummy) treatment. Whether a patient was given Oleogel-S10 or control gel during the double-blind phase of the study was down to chance. Putting people into groups by chance helps to make the two groups equal, and the comparison between the two groups is fairer.
• Vehicle-controlled: A clinical study is called “controlled” when a control group, also known as comparator group, is included. In the case of this study, “Vehicle-controlled” means the same as “Placebo-controlled”. “Vehicle” is a different word for “carrier” in topical treatments, where for instance the same cream is used, but without the active ingredient. For this study, vehicle, placebo and control have the same meaning. The results of the Oleogel-S10 (test) treatments were compared to the results of the control (dummy) treatments. This helped scientists to work out whether any difference seen between the Oleogel-S10 group of patients and the control gel group was due to treatment with Oleogel-S10.
• Phase III: In order for a medicine to be licensed for use, several clinical studies must be carried out, and the results of those studies need to show that the medicine is safe and effective. Studies start out with very few study participants who often only receive a single dose (“Phase I” trials). When results show the medicine is safe, and there is reason to believe that the test medicine works, further trials on increasing numbers of patients are carried out, over a longer time; these are Phase II and Phase III trials (Phase III typically being larger and longer than Phase II).
• Efficacy: Efficacy means that the effect of the medicine on a disease in patients is tested – does the test medicine do what the developers think it will do, and if so, how effectively does it do it?
• Safety: Safety means whether the medicine is safe to take, or if there are side effects that make patients unwell.
• 24-month open-label follow-up of Oleogel-S10: After the end of the 90-day double-blind phase of the study during which patients did not know what treatment they were receiving, all patients were then given the opportunity to knowingly take Oleogel-S10 for an additional 24 months, in the open-label phase of the study. It did not matter whether they had been given Oleogel-S10 or control gel during the double-blind phase. This helps doctors and scientists to collect more data on the safety of the medicine. If more patients take the medicine for longer, side effects that occur less often are more likely to be discovered.
• Patients with inherited Epidermolysis Bullosa: Most often Epidermolysis Bullosa is caused by mutated (changed) genes that were also present in the affected patient’s parents. Thus, the disease is ‘inherited’ from their parents, even though their parents might have no or only mild symptoms.How the study was carried out
The study was carried out in 26 countries in 49 study sites. Only people who met the following entry criteria were allowed to take part in the study:
1. Patients 4 years old or older with any type of inherited EB including DEB, JEB, and Kindler EB [Note: Children below 4 years of age were only included in the study (at interim safety review stage) when an independent committee had looked at available data and felt it was safe to do so.]
2. Patients with a target partial thickness wound (for explanation please see below - Key goal of the study) caused by EB - the target wound had to be of 10 cm2 to 50 cm2 in size and be between 21 days and less than 9 months old.
3. The patient and/or their parent/legal representative must have read and understood the patient information and informed consent form, and they must have given written informed consent.
4. The patient and/or their parent/legal representative must have been able and willing to follow study procedures and instructions.
Overall, 252 patients were seen by study investigators to determine if they met the entry criteria to take part in the study and be treated with Oleogel-S10 or control gel. 223 patients met the entry criteria; 109 patients were randomised to Oleogel-S10 and 114 patients were randomised to control gel. The patients were from the following age groups:
• 17 were younger than 4 years old;
• 85 were between 4-11 years old;
• 54 were adolescents, aged 12-17 years;
• 67 were adults, aged 18 years and older.
134 patients (60%) were male and 89 patients (40%) were female. Please find a summary of the patient numbers for age groups and sex in Table 1 below. Numbers of patients in the two treatment groups (Oleogel-S10 and Control Gel) are also shown.
Table 1 Demographic data of the patients who started the double-blind phase of the BEB-13 study
Oleogel-S10
(109 total) Control Gel
(114 total) All subjects
(223 total)
Age groups
0 to <4 years 7 10 17
4 to <12 years 42 43 85
12 to <18 years 25 29 54
≥18 years 35 32 67
Sex
Male 68 66 134
Female 41 48 89The trial was made up of patients with the following types of EB:
• 195 had DEB;
• 26 had JEB;
• 2 had EB simplex or EBS*
*After the study had started, it was decided that no further subjects with EBS should be included.These 223 patients entered the double-blind phase (DBP), which lasted for 90 days. Some patients did not finish the DBP; 9 in the Oleogel-S10 group and 15 in the control gel group. One hundred and ninety-nine (100 Oleogel-S10; 99 control gel) patients finished the DBP and entered the open-label phase (OLP), which is the 24-month phase of the study, where all patients receive Oleogel-S10. An additional 6 patients, who had not finished the DBP and had been in the control gel group, entered the OLP also, bringing the total number of patients who started the OLP to 205. The OLP was completed by 141 patients, 66 of whom had been in the Oleogel-S10 group in the DBP, and 75 who had been in the control gel group in the DBP.
Key goal of the study – Target wound closure within 45 days of treatment The main goal of this clinical study was to compare how treatment with Oleogel-S10 versus control gel treatment affected wound healing of partial-thickness wounds in EB patients with EB subtypes DEB, JEB and Kindler EB.
This study focussed on partial-thickness wounds which were of 10 cm2 to 50 cm2 in size and from 21 days to less than 9 months in age. For each patient the Investigator selected one wound that met these criteria (a target wound) and then started treatment with Oleogel-S10 or control gel. Doctors and hospital staff checked target wounds for closure at each visit. A wound was rated as “closed” at first appearance of complete re-epithelialization without drainage, meaning that newly formed skin covered the entire former wound area and no fluids were leaking from it. Target wound closure had to occur within 45 days of treatment; if it took longer, it was not counted as a wound closure in the final analysis.Key finding of the study – Oleogel-S10 helps with target wound closure within 45 days of treatment The key research question of this study was whether Oleogel-S10 can speed up target wound healing in patients with EB. One hundred and nine (109) patients received Oleogel-S10 and 114 received control gel as treatment for their EB wounds, for the 90-day-DBP. Forty-five (45) out of 109 patients (41%) in the Oleogel-S10 group achieved target wound closure within 45 days of treatment, compared to 33 out of 114 patients (29%) in the control gel group. In summary:
• Target wound closure within 45 days: 45/109 = 41% of the Oleogel-S10 group
• Target wound closure within 45 days: 33/114 = 29% of the control gel group
These numbers were then analysed using statistical tests, which showed that there was a significant difference between the two treatment groups and that Oleogel-S10 worked better than the control gel treatment. This significant difference was expressed as a so-called p-value of 0.013. This means that this study would have had to be repeated 77 times (1/ 0.013) for such a result being expected to occur by chance. Usually, results are viewed as being significant if the p-value is below 0.05.
Another way of summarising the results is that: “Patients in the Oleogel-S10 group were 44% more likely to achieve the first complete closure of the EB target wound within 45 days of treatment compared to subjects in the control gel group.”
Summary of Safety findingsNo significant differences regarding the safety of Oleogel-S10 were found in comparison with control gel. Any undesired effects or “Adverse Events” (AEs) that affected patients while taking part in the study were recorded by doctors and hospital staff. Some AEs are more serious than others. For instance, if an AE meets any of the below criteria, then it is considered a Serious Adverse Event (SAE):
• Is life-threatening;
• Requires inpatient hospitalisation or prolongation of existing hospitalisation;
• Leads to persistent or significant disability or permanent damage;
• Causes a congenital anomaly or birth defect;
• Or is otherwise serious (but does not necessarily require hospitalisation);Serious Adverse Events - SAEs
In the DBP, 10 SAEs were recorded in 7 out of the 109 patients (6%) in the Oleogel-S10 group, and 8 SAEs were recorded in 6 out of the 114 patients (5%) in the control gel group. This low overall occurrence of SAEs shows that both Oleogel-S10 and control gel was safe to take. More importantly, there was no difference in the occurrence of SAEs between the two groups, which shows that Oleogel-S10 was as safe as control gel to take.
In the DBP, the most common SAEs were anaemia (a condition where patients have low numbers of red blood cells, which carry oxygen through the body) and sepsis (potentially life-threatening condition that occurs when the body's response to an infection damages its own tissues). Three (3) patients in the Oleogel-S10 group had one event of anaemia each, which is a common and well-known complication affecting EB patients, and 2 patients in the control gel group had one event of sepsis each.
In the OLP a total of 116 SAEs occurred in 50 out of the 205 patients (24%). Two patients had SAEs that in the investigator’s opinion were related to Oleogel-S10. Nine patients (4.4%) died during the OLP; 7 (7.0%) in the former Oleogel-S10 group and 2 (1.9%) in the former control gel group. None of the 9 deaths were considered related to study treatment and were all assessed as anticipated with regards to the disease course.
Anaemia and oesophageal stenosis (narrowing of the food pipe, a common problem in EB patients) were the most often occurring SAEs in the OLP. For both anaemia and oesophageal stenosis, 15 occurrences were seen in 10 patients.Adverse Events - AEs
For AEs that were not serious the numbers were as follows: 282 AEs were recorded in 89 out of 109 patients (82%) in the Oleogel-S10 group, and 279 AEs were recorded in 92 out of 114 patients (81%) in the control gel group. Similar to the results for SAEs, the two study groups were almost equally affected by AEs. This suggests that using Oleogel-S10 was as safe as control gel in this study.
In the OLP, 833 AEs were recorded in 158 patients out of 205 total (77%). Sixty-two (62) AEs in 25 patients (12% of 205 total patients) were considered to be related to study treatment. 16 patients (8%) were taken out of the OLP part of the study because of AEs. These included 3 patients who had treatment-related AEs which were pain on the site of administration of treatment, staphylococcal (bacterial) wound infection and an SAE of rash.
One focus of safety data collection was directed on wound complications. Indeed, the most common AE was wound complication, which included the wound getting bigger from when the study started or from when it was last measured, wound reopening, wound injury, increase in wound burden, worsening of EB wound pain, wound odour, and wound worsening compared with the start of the study. In the DBP, 188 occurrences of wound complication were seen in 128 (57%) patients, and in the OLP, 107 occurrences of wound complication were seen in 84 (41%) patients. Most wound complication AEs were assessed as not related to treatment by the Investigator.
A patient’s age or sex did not affect the type of AE or how often the AE occurred.Conclusion
In conclusion, this Phase III study showed that Oleogel-S10 made EB partial-thickness wounds heal faster than control gel. The results also show that Oleogel-S10 gel is safe and well tolerated, with most of the AE’s associated with patients’ underlying disease.
REC name
London - City & East Research Ethics Committee
REC reference
17/LO/0374
Date of REC Opinion
24 May 2017
REC opinion
Further Information Favourable Opinion