The ongoing Phase 2 clinical study AdeLE (”Adenoviral gene therapy for the treatment of LymphEdema”) is a randomized, double-blind, placebo-controlled study in which Lymfactin® is studied in the treatment in combination with lymph node transfer surgery fof breast cancer treatment associated lymphedema. The study will assess the efficacy, safety, and tolerability of Lymfactin®. Half of the study participants will receive one dose of Lymfactin® and half will receive placebo. All study participants will undergo a lymph node transplantation surgery, which can be of benefit for the study participants regardless of being in the Lymfactin® group or placebo group.
The AdeLE study intends to assess the safety, tolerability and efficacy of Lymfactin® investigational product that is developed for the treatment of secondary lymphedema, which is associated with breast cancer treatment associated lymphedema when combined with a conventional lymph node transplantation surgery. The impact of the treatment on the lymphedema, quality of life of the study participants, 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 study participants are randomized to receive either the placebo or Lymfactin®. During the study neither the study participant, nor the responsible physician, nor anyone else knows which participant is assigned in which group. This will ensure an unbiased assessment of the results.
In total about 40 study participants 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 study participants in a Phase 1 clinical study in Finland. No one of the participants had severe side effects.
Persons with breast cancer associated lymphedema, aged between 18 and 70, may participate in the study. In total about 40 study participants will participate in the study in Finland and Sweden at university hospitals departments of plastic surgery.
The study investigator, who is a plastic surgeon, will carefully assess each study participant’s eligibility to participate in the study in a screening process. Study participants 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
Participation to the clinical study is voluntary. The study participant 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 study participant to receive the appropriate treatment.
If a study participant decides to discontinue participation in the study, any information collected on that participant 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.
In Sweden the study is conducted by specialists in plastic surgery.
- Plastic surgeon Maria Mani (Uppsala University Hospital), the responsible physician of the study in Sweden
- Plastic surgeon Martin Halle (Karolinska Institutet, Stockholm)
The national coordinating investigator in Finland (“tutkimuksesta vastaava henkilö”) is plastic surgeon, docent Anne Saarikko. The other specialists in plastic surgery who conducts the study are:
- Plastic surgeon Sinikka Suominen (Töölö hospital, Helsinki)
- Plastic surgeon Pauliina Hartiala (Tyks, Turku)
- Plastic surgeon Juha Kiiski (Tays, Tampere)
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 study participants will be followed for up to five years. The study participant may also be contacted by telephone.
The study is implemented as a placebo-controlled and double-blinded study. Half of the participating study participants will receive Lymfactin® as an adjunct to the surgery and half will receive a placebo (saline solution which corresponds to human blood composition). During the study neither the study participant, 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 study participant’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 study participants this procedure may be combined with a breast reconstruction surgery. The participants will remain hospitalized for approximately 5-7 days after the surgery. Each participant receives only a single dose of Lymfactin® or placebo as an adjunct to the lymph node transplantation surgery as described above.
More information about the study visits and the related procedures such as imaging and biological samples to be taken can be found in the study participants information package including the visit schedule (in Swedish).
If the study participant 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. The reason for this limitation is that previous studies have showed that COX-2 promotes the formation of lymph vessels and, thus, there is a theoretic possibility that COX-2 inhibitors inhibit the growth of new lymphatic vessels. 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 study participant shall also inform any other treating physicians about the participation in the clinical study. Simultaneous participation in other clinical studies is not permitted.
Study participants 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 study participant 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 study participant.
The study participant 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 participant and anyone living in the same household must maintain a high hygiene of their hands. When the study participant 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 participant 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 participant. 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 participant. The associated reasonable travel expenses are also reimbursed to the study participant. The first visit where the study participant’s eligibility for lymph node transplantation surgery is assessed is charged to the patient according to the local practice for outpatient visits. The lymph node transplantation surgery, which is a standard treatment for lymphedema patients, involves normal patient fees according to the local practice for such treatment.
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 participant any other necessary therapies. The study participant 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.
Only the personnel of the study center (hospital) who are bound by strict confidentiality obligations have the access to the code and know the identity of the study participants. The study sponsor, Herantis Pharma Plc, will not receive information about the personal identity of the study participants.
All collected personal data, study participant’s answers and all the results are treated so that unauthorized persons will not be able to access them. During the data processing, the study participant’s data will be encoded. Only encoded study data will be transferred to the sponsor, Herantis Pharma Plc, or its collaborators in such a way that the study participant cannot be identified.
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 participants. The identity of the study participants 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 to identify individual study participants.
Certain authorized persons will have access to the medical records of the study participants 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 participants 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 ensuring that unauthorized persons cannot access the collected information and its processing is 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 participant 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.