Holocore

• Research type

  Research Study

• Full title

  Multinational, multicentre, prospective, open-label, uncontrolled clinical trial to assess the efficacy and safety of Autologous Cultivated Limbal Stem Cells Transplantation (ACLSCT) for restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns (HOLOCORE)

• IRAS ID

  186764

• Contact name

  Sajjad Ahmad

• Contact email

  Sajjad.Ahmad@moorfields.nhs.uk

• Sponsor organisation

  CHIESI FARMACEUTICI S.p.A

• Eudract number

  2014-002845-23

• Duration of Study in the UK

  4 years, 8 months, 0 days

• Research summary

  Summary of Research
  This is phase IV multinational, multicentre, prospective, open label, uncontrolled clinical trial. The Study population includes patients suffering from moderate to severe (at least two corneal quadrants, central corneal involvement resulting in severe visual impairment) Limbal Stem Cell Deficiency (LSCD) secondary to physical or chemical ocular burns. These patients will undergo to an Autologous Cultured Limbal Stem Cells Transplantation (ACLSCT) with the aim to restore their cornea. Approximately 10% of patients resulting positive at the infectious assessments will be included. Approximately 12-18 sites in 8 countries in Europe is planned to be open (3 Sites in the

  Summary of Results
  A clinical trial to provide further insights into the benefits and risks of Holoclar, a fast-track approved tissue engineered stem cell product for the treatment of adult patients with moderate to severe limbal stem-cell deficiency caused by burns

  Company: Holostem Terapie Avanzate s.r.l. (Via G. Gottardi 100, 41125 Modena, Italy)

  General information on the HOLOCORE trial

  The HOLOCORE clinical trial was conducted in eight countries between 28 October 2015 – 11 March 2022 to collect further information on the benefits and risks of Holoclar, used for the treatment of patients with moderate to severe limbal stem-cell deficiency caused by burns. (EudraCT number: 2014 002845 23)

  General information on Holoclar

  Holoclar is a stem-cell treatment, that received conditional approval, through the Centralised Procedure, in the European Union in 2015. The period of validity of the Conditional Marketing Authorisation is one year. Since the Conditional Marketing Authorisation has been granted, seven renewal applications have been submitted (the last on 29 July 2022).
  In addition, due to the BREXIT requirements, a marketing authorisation approval was obtained on 14 June 2021 in the United Kingdom. No other Marketing Authorisation Applications have been requested in any other countries.

  Holoclar is used in the eye to replace damaged cells on surface (epithelium) of the cornea, the transparent layer covering the iris (the coloured part). It is used in adult patients with moderate and severe limbal stem-cell deficiency caused by burns, including chemical burns, to the eyes. Patients with this condition do not have enough limbal stem cells which normally act as a regeneration system, replenishing the outer corneal cells when they get damaged and when they age which can lead to sever reduction or complete loss of vision. Because the number of patients with limbal stem-cell deficiency due to burns to the eyes is low, the disease is considered ‘rare’. Therefore, Holoclar is a medical product to treat a rare medical condition and officially received the orphan drug status in the EU in 2008 (EU/3/08/579).

  The Holoclar transplant and treatment procedure

  During the trial, aappropriately trained and qualified eye surgeons in a hospital setting transplant ed Holoclar to each patient whose limbal cells were used to manufacture the medicine.

  Biopsy
  • Initially, a small part of healthy limbal tissue (1 − 2 mm2 of tissue from the edge of the cornea, called “limbus”) was taken from the healthy eye for each patient involved in the study in hospital and sent to the manufacturer on the same day. Antibiotics to prevent eye infection were given to patients after limbal tissue had been taken from them.
  Holoclar transplant procedure
  • Cells from the biopsy tissue were grown in a laboratory and frozen until the date of surgery was confirmed.
  • Thawed cells were used to make Holoclar by growing them on a membrane made of a protein called fibrin.
  • Holoclar, comprising the cells and the membrane, was then sent back to the hospital, where it was immediately surgically implanted in the patient’s eye.
  Holoclar treatment
  • Once implanted in the eye, the corneal cells of Holoclar help to replace the corneal surface, while the limbal stem cells serve as a reservoir of new cells that continuously replenish the cornea. Following the surgery, the patient received antibiotics and an appropriate anti-inflammatory medicine.
  • Holoclar is intended for a single treatment, although treatment can be repeated if the doctor considers it necessary.

  Information on the HOLOCORE trial participants

  Overall, 80 patients (76 adults and 4 paediatric patients) with moderate to severe forms of limbal stem-cell deficiency caused by burns agreed to participate in the HOLOCORE trial and underwent to a biopsy for the product manufacturing (Holoclar). The inclusion of the paediatric population in the HOLOCORE trial was part of the Paediatric Investigation Plan agreed with the European Medicines Agency.

  Among them, 73 patients (69 adults and 4 paediatric patients) received Holoclar transplant. Upon the Investigator’s evaluation, seven patients (6 adult and 1 paediatric patient) agreed to repeat the procedure. Sixty-eight patients (64 adults and 4 paediatric patients) ended the 12-month follow-up period after the first transplant.

  Identified benefits associated with Holoclar

  Holoclar was shown to be associated with an acceptable rate of success of transplantation in patients with moderate or severe limbal stem-cell deficiency caused by burns. One year after the initial Holoclar implantation, 25 out of 61 adult patients (41.0%) were judged to have had successful implants based on the presence of stable corneal surface with no surface epithelial defects (82.0%). Moreover, 37 patients (57.8%) experienced a lowering in ingrown blood vessel (a common feature of limbal stem-cell deficiency) in the same period. There were also reductions in patients’ symptoms, 75.4% of patients had no burning presence, and 78.7% reported no presence of pain one year after the Holoclar procedure. Furthermore, no signs of increase limbal blood was observes in 49.2% of the patients and normal corneal sensitivity was reported from 37.7% of patients. Overall, one year after the initial Holoclar implantation, the general vision had improved, while general health was maintained. However, patients that repeated the Holoclar implantation did not achieve successful transplantation.

  Identified risks associated with Holoclar

  Adult patients

  Out of the 76 adult patients that agreed to participate in the HOLOCORE trial, 31 patients (40.8%) experienced side effect prior to the Holoclar treatment, with 6.6 % of all side effects being possibly attributed to the biopsy procedure. Holoclar treatment-related side effects were reported in 27 patients (35.5%), however, the majority (26.3%) were thought to be possibly related to the surgical procedure before transplant performed to prepare the eye to receive Holoclar. Serious Holoclar treatment-related side effects were reported in 6 patients (7.9%). The most common side effect with Holoclar (seen in 11 out of 76 patients [ 14.5%]) was eye pain followed by corneal epithelium defect (seen in 8 out of 76 patients [ 14.5%]). Corneal epithelium defects and corneal thinning, defined as side effect that emerged during the Holoclar treatment and that should be intended as lack of efficacy of the treatment, led to the discontinuation of 3 patients (3.9%) from the HOLOCORE trial.

  Paediatric patients

  Out of the 4 paediatric patients that agreed to participate in the HOLOCORE trial, 1 patient (25.0%) experienced side effect prior to the Holoclar treatment. Holoclar treatment-related side effects were reported in 2 patients (50.0%) which were possibly related to the transplant surgical procedures. In detail, a severe increase in lacrimation and mild conjunctival hyperaemia, a conjunctival reaction that appears as dilation and redness of the conjunctival vessels, were resolved in Holoclar treated paediatric patients. No serious Holoclar treatment related side effects were reported and none of the paediatric patients discontinued from the HOLOCORE trial.

  Comments on the outcome of the clinical trial

  Holoclar treatment was effective in restoring healthy corneal surfaces in patients with moderate or severe limbal stem-cell deficiency caused by burns as well as in improving their symptoms and vision. Side effects of Holoclar treatment were generally manageable.

  Indication if follow-up clinical trials are foreseen

  All patients transplanted with Holoclar in the HOLOCORE trial had the opportunity to enroll in the long-term extension HOLOCORE-FU trial (EudraCT number: 2015 001344 11).

  Additional information about Holoclar

  For more information about treatment with Holoclar, please read the package leaflet or contact your doctor: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRV-2FG90vnhLN7JRXvODTOQrrNsHxuF1dCp5tINBwz4WrYx-2FXtyZiGnV5fiJu3ZTeGQ-3D-3Dukjn_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIiHs7h398Q11zIP9Ij99UimvVt-2BDAcshTriFoVREMqHrXq-2FQneCMIzWBZ8nIiP1aeY7kD15Hz5fxrv9mtBf2W3fYdXESysXKTsPoN39VS-2Fd35Q-2FAzld6KSOe-2BlJOm86ZjAfSv5w4HuLV8pDNSVTeDHzJbNGORf0qzPZK2ZVr5dlw-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C0dab97fe4ffc4e3966bb08db2c7ea292%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638152694627673734%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=XTeqFcD%2BglFDul2ztegu7eH2aM6AabHJtmHqjydDLYU%3D&reserved=0

  For detailed information on the long-term extension HOLOCORE-FU trial, please visit the EU Clinical Trials Register: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfatiYvtk1-2B2gi1K6vKImual9G6VG4-2FeFhNKGHEnJKTVSurIx-2Fh0tDbps2qtKTTC3ZmR-2FVhEFf2CFpVd7VWzv11Rf7Uq_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIiHs7h398Q11zIP9Ij99UicHAAQi6bfyD5aa4OKONAmSHScObv1gQKorLNjfJM9SnusZDSootQRq3WuF-2BwAL-2BUYhCOPCWxIDbUrYP-2BDNeJEIedJ7e4S2olwS2lmn6Jura3oRUzXgb22iSCiw7pIeNkBSFdfAj-2F7ObvvF3r-2FJCniA-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C0dab97fe4ffc4e3966bb08db2c7ea292%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638152694627673734%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=i%2BF2TcQ5rWb1uwBNYLkTMF2yb2wQVWUvs9gXZBWLBnw%3D&reserved=0

  Detailed information on this medicine is available on the European Medicines Agency web site:
  https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbYukaTAVjiWcF8oJh4V0XaKl5xbHvnYEsw5Wev2FdNtIfvi8e2wohAFwhkkYACEq1T8lyQqISl9YCjS-2Be15aHJGsxlfm1xGbnUyRgG2AW4jgDUX5FwBqAqYezpH-2BAsB50Q-3D-3DKavz_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIiHs7h398Q11zIP9Ij99Ui3zr5hK8Ua1VPAMf1cr3M42MdmPg5d-2Fp28CKw7CUGkHKjc7JxPA-2F9jtd4JrLLf-2FvMkWiiSFxkKIMtvEHPDos2mZmafrSUTArS5adIyHr2sC03y-2FznPWo0C4wY-2FuX0fQr6koedHSs6w7HEq2rO5DBf-2Fw-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C0dab97fe4ffc4e3966bb08db2c7ea292%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638152694627673734%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Mukku7k3%2Bgwm5fwbJgeeFuhE2sjEWq9BTmmWSeX0blM%3D&reserved=0

  For information on how to report side effects, please see the package leaflet, stating:

  “If you get any side effects, talk to your surgeon. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V (attached to this document). By reporting side effects, you can help provide more information on the safety of this medicine.”

  UK).

• REC name

  London - West London & GTAC Research Ethics Committee

• REC reference

  15/LO/1480

• Date of REC Opinion

  30 Oct 2015

• REC opinion

  Further Information Favourable Opinion