The ongoing Phase 2 clinical study AdeLE (”Adenoviral gene therapy for the treatment of LymphEdema”) is multi-center, randomized, double-blind, placebo-controlled study in patients with secondary lymphedema associated with the treatment of breast cancer. The study is planned to enroll 40 patients in Finland and Sweden and will assess the efficacy, safety, and tolerability of Lymfactin® in patients undergoing lymph node transfer surgery. Half of the patients will receive one dose of Lymfactin® and half will receive placebo. All patients will undergo a lymph node transplantation surgery, which can be of benefit for the patients regardless of being in the Lymfactin® group or placebo group.
The AdeLE study intends to assess the safety and efficacy of Lymfactin® in the treatment of breast cancer associated lymphedema when combined with a conventional lymph node transplantation surgery. The impact of the treatment on the lymphedema, quality of life of the patient, and possible adverse reactions are monitored in the study. In addition, the clinical study will investigate the distribution of the drug substance in the body and compare different methods of assessing the symptoms of lymphedema.
The study is a randomized and double-blinded study, which means that the patients are randomized to receive either the placebo or Lymfactin®. During the study neither the patient, nor the responsible physician, nor anyone else knows which patient is assigned in which group. This will ensure an unbiased assessment of the results.
In total about 40 patients will participate in the AdeLE study in Finland and Sweden.
The combination of Lymfactin® and lymph node transplantation surgery has been assessed previously in 15 patients in a Phase 1 clinical study in Finland. Based on the results Lymfactin® is safe and well tolerated.
Patients with breast cancer associated lymphedema, aged between 18 and 70, may enrol in the AdeLE study.
The study investigator, who is a plastic surgeon, will carefully assess each patient’s eligibility to participate in the study in a screening process. Patients who do not fulfill the criteria to participate will be informed of the reasons for their exclusion from the study. Such patients will continue to receive the same health care they would normally receive.
Some of the most important criteria for inclusion in the clinical study are:
- Aged between 18 and 70 (inclusive), non-smoking, woman or man with breast cancer associated lymphedema and otherwise of normal health; body mass index (BMI) between 18 and 32
- At least 2 years from breast cancer surgery and other active breast cancer treatments (such as radiotherapy or chemotherapy, excluding hormonal therapy), during which period there has been no observed relapse of the breast cancer
- Lymph node metastasis were observed in at most 9 axillary lymph nodes in sentinel lymph node biopsies and/or lymph node resection of the breast cancer
- Requires garment use as a compression treatment for the lymphedema in the affected arm.
- Volume of the affected arm is at least 10% greater than of the unaffected arm following 7 days without compression garment.
- Has the presence of pitting edema in the affected arm without compression garment.
- Has had lymphedema for less than 5 years
The patient can decide to not participate in the clinical study, discontinue participation, or withdraw consent, without providing any reason to such a decision, at any time during the study without such a decision having any impact on the rights of the patient to receive the appropriate treatment.
If a patient decides to discontinue participation in the study, any information collected on that patient until the discontinuation can be used to assess the results of the study if necessary when assessing the safety of the investigational medicinal product or the quality of the clinical study.
There are no curative treatments or approved medicinal products for the treatment of lymphedema. Known treatments such as wearing a compression garment, lymphatherapy and exercise may alleviate the symptoms but there are no curative therapies. It is also possible use surgical procedures, such as lymph node transfer, to treat lymphedema.
The sponsor of this clinical study is a drug development company based in Finland, Herantis Pharma Plc.
The national coordinating investigator in Finland (“tutkimuksesta vastaava henkilö”) is plastic surgeon, adjunct professor Anne Saarikko. The participating study sites in Finland and their clinical investigators are:
- Plastic surgeon Sinikka Suominen (Töölö hospital, Helsinki)
- Plastic surgeon Pauliina Hartiala (Tyks, Turku)
- Plastic surgeon Juha Kiiski (Tays, Tampere)
The national coordinating investigator in Sweden is plastic surgeon, associate professor Maria Mani. The participating study sites in Sweden and their clinical investigators are:
- Plastic surgeon Maria Mani (Uppsala University Hospital)
- Plastic surgeon Martin Halle (Karolinska Institutet, Stockholm)
Participation in the clinical study takes for approximately two years during which there are a total 14 study visits to the hospital in addition to the lymph node transfer surgery. The health of the participating patients will be followed for up to five years. The study subject may also be contacted by telephone.
The study is implemented as a placebo-controlled and double-blinded study. Half of the participating patients will receive Lymfactin® as an adjunct to the surgery and half will receive a placebo (saline solution). During the study neither the patient, nor the responsible physician, nor anyone else knows who receives Lymfactin® and who receives placebo. The participant or the investigator cannot influence the randomization in either group.
Comparison to a placebo is necessary for an unbiased assessment of the efficacy of Lymfactin® for the treatment of lymphedema. Double-blinding is necessary in order to avoid any knowledge of having received Lymfactin® impacting the assessment.
In the clinical study, the dosing of Lymfactin® is always associated with a surgical procedure, lymph node transplantation. In the surgery the patient’s own soft tissue, which contains lymph nodes, is transplanted from the donor site (usually the abdominal wall or groin) to the axilla of the affected arm. The investigational medicinal product Lymfactin®, or placebo, is injected in the tissue flap during the procedure. In some patients this procedure may be combined with a breast reconstruction surgery. The patients will remain hospitalized for approximately 5-7 days after the surgery. Each patient receives only a single dose of Lymfactin® or placebo as an adjunct to the lymph node transplantation surgery.
More information about the study visits and the related procedures such as imaging and biological samples to be taken can be found in the patient information package.
If the patient is frequently taking any medicines, their use should not be changed from 14 days prior to surgery until 30 days after the surgery. However, the use of a specific group of anti-inflammatory drugs, so-called COX-2 inhibitors, shall be discontinued two weeks prior to the surgery and continued again after at least four weeks after the surgery. Common anti-inflammatory drugs such as ibuprofen, naproxen, or diclofenac, are not COX-2 inhibitors.
Any changes in medication during the study participation such as starting to take new medicines or changing the doses of previously taken medicines must be discussed with the study investigator prior to the changes. The patient shall also inform any other treating physicians about the participation in the clinical study. Simultaneous participation in other clinical studies is not permitted.
Study patients who are in a fertile age must use reliable contraception for six months after the surgery.
It is possible that there are no benefits from participating in the clinical study. The possible efficacy of Lymfactin® is not yet known because the AdeLE study is only its second clinical study. The study will however help assess the safety and efficacy of the combination of Lymfactin® and lymph node transplantation surgery, which may help develop a better treatment for lymphedema and thereby benefit future lymphedema patients.
The patient may benefit from the transplantation of his or her own lymph nodes in the axilla of the affected arm, and of the possibly generated new lymphatic vessels, which may reduce the swelling associated with lymphedema and thus improve the health of the patient.
The patient will receive information on his or her personal health based on the physical examinations and scans during the study.
Possible adverse reactions associated with the lymph node transplantation surgery are infections or slow healing of the surgical wounds or their bleeding, or necrosis or partial necrosis of the transplanted tissue. Also, the accumulation of lymph in the axilla, numbness, and pain are possible. The risk of developing lymphedema in the lower limb as a consequent of the surgery is considered theoretical and highly unlikely.
Adverse reactions associated with the investigational medicinal product Lymfactin® are also possible. Since Lymfactin® is still in its development phase all possible adverse reactions are not known. Possible adverse reactions include fever and flu-like symptoms, and a temporary elevation of liver enzymes.
The surgical wounds in the axilla may still secrete fluids after the patient is discharged from the hospital. Since those fluids may contain the therapeutic virus, which is associated with a theoretical risk of infection, the study patients and anyone living in the same household must maintain a high hygiene of their hands. When the study patient is discharged from hospital, he or she will receive detailed instructions regarding hygiene and wound care. The wound secretions are not expected to cause any infection or other harm to the study patients or their family members, because the therapeutic virus is unable to replicate and more susceptible to the human immune system than a corresponding natural virus. In the worst case an infection would be comparable to a common cold.
A theoretical risk exists for VEGF-C, the natural human growth factor specific for lymphatic vessels, to contribute to the formation of malignant tumors. This risk is, however, considered very small because the amount of VEGF-C in the study is small and its expression is temporary (at most some weeks) and local. Also, Lymfactin® is not injected directly in the damaged area but in the tissue flap harvested from another anatomical region where the presence of any malignant cells is highly unlikely.
Unexpected adverse reactions are also possible.
The safety of Lymfactin® has been assessed by the regulatory authorities of both Finland and Sweden independently and both have authorized the ongoing clinical study.
If any new relevant information regarding the safety of the clinical study emerges during the study, the clinical investigator will immediately contact the study patients. The clinical investigator or the study sponsor may be forced to prematurely discontinue the study or participation in the study.
Participation in the clinical study and the related visits to the study site are free of charge to the study patient. The associated reasonable travel expenses are also reimbursed to the patient. However, the lymph node transplantation surgery, which is a standard treatment for lymphedema patients, involves normal patient fees according to the national practice for such a standard treatment.
The first visit where the patient’s eligibility for lymph node transplantation surgery is assessed is charged to the patient according to the national practice for outpatient visits.
The study center (hospital) is paid by the study sponsor for implementing the study. The clinical investigators and study nurses are paid for their involvement in the study.
The study is financed by its sponsor Herantis Pharma Plc, a drug development company based in Finland.
Before the end of the clinical study, the clinical investigator will discuss with the study patient any other necessary therapies. The study patient will be provided information regarding the available therapies that appear most appropriate for the treatment of his or her disease.
All study results are confidential information and they are only handled using anonymous codes.
The personal identity of the study patient is only known by the personnel of the study center (hospital) who are bound by strict confidentiality obligations. The study sponsor, Herantis Pharma Plc, will not receive information about the personal identity of the study patients.
The results of the study may be published in scientific medical journals and presented in scientific conferences, meetings, and seminars. The results of the study may also be provided to regulatory authorities or collaborators of the sponsor for well-defined purposes. Such reports or publications shall never reveal the identity of study patients. The identity of the study patients shall never be revealed to any other parties such as insurance companies.
A description of the clinical study is publicly available in the ClinicalTrials.gov database and after the completion of the study a summary on results will be provided at the same site. No such information will be published that might help identify individual study patients.
Certain authorized persons will have access to the medical records of the study patients in order for them to be able to verify that the clinical study is conducted and the information is collected appropriately. In addition, a regulatory authority or an Ethical Review Board may request permission for their representative to access medical records of study patients to ensure that the clinical study is conducted appropriately.
The registry holder for the clinical study is Herantis Pharma Plc for any coded information (i.e., information that does not contain names, birthdays or other such information that might reveal the identity of the patients), and the participating study centers (hospitals) for any non-coded information. The registry holders are responsible for confidentiality of the collected information and for its processing in compliance with applicable laws.
The study sponsor has obtained a clinical study insurance, which covers any damages or incidents associated with the clinical study. Any study patient who believes he or she has suffered from an adverse reaction or damage associated with the clinical study should contact the clinical investigator.
Finnish Medicines Agency Fimea of Finland, and Swedish Medical Products Agency MPA of Sweden, as well as the relevant ethical review boards in both Finland and Sweden, have approved this clinical study to be conducted at the University hospitals of Helsinki, Turku, and Tampere in Finland; and Karolinska (Stockholm) and Uppsala in Sweden.