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Breast Cancer LymphedemaPhase 1/2NCT04541290

Tacrolimus as Treatment of Breast Cancer-Related Lymphedema

A Phase 1/2 study testing Protopic 0.1 % Topical Ointment in people with Breast Cancer Lymphedema, run by Odense University Hospital at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

BACKGROUND Breast cancer-related lymphedema is a severe and life-long side-effect to breast cancer treatment. The condition increases the risk of infections and decreases health-related quality of life (HR-QOL) in patients. No prophylactic or curative treatment is currently available for this condition. Read more about this study

Who is it for?
Ages 30 to 65 years, women only
Conditions the study is for
Breast Cancer Lymphedema
What is being tested?
Protopic 0.1 % Topical Ointment
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteDenmark
Study dates
22 Sep 2020to 6 Jan 2022
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 to 65 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age between 30-65 years
  • Female
  • Lymphedema diagnosis as a result of breast cancer treatment
  • Active Lymphedema (excessive fluid)
  • Significant lymphedema
  • Grade I-II lymphedema
Show all 10Show fewer
  • Postmenopausal (Absence/lack of menstruation in at least 12 consecutive months) or continuously usage of contraceptive drugs (Spiral, birth-control pills, implant, transdermal patches, vaginal ring or depot injection). Contraceptive drugs must be used throughout the project and at least three weeks subsequent to the ending of the project (last application of the ointment).
  • Clinically good general condition No lymphedema in the opposite arm (normal arm)
  • Understands the purpose og the study and gives written consent to participate
  • Can read and understand the danish language

Who cannot join

  • Pregnant, breast-feeding or with wish of pregnancy within the next year
  • Bilateral breast cancer
  • Grade 0, III or IV lymphedema
  • Known allergies for Tacrolimus or and other macrolide
  • Removal of lymph nodes in the opposite armpit
  • Suffers from psychiatric disorders that may affect the participation in the project
Show all 9Show fewer
  • Reduced kidney or liver function
  • Defect skin-barrier
  • Diagnosed immunodeficiency

Trial locations and contacts

1 site in 1 country.

Denmark1 site

  • Department of Plastic Surgery, Odense University Hospital

    Odense, 5000

Other trials in Denmark

About this study

BACKGROUND Breast cancer-related lymphedema is a severe and life-long side-effect to breast cancer treatment. The condition increases the risk of infections and decreases health-related quality of life (HR-QOL) in patients. No prophylactic or curative treatment is currently available for this condition.

CD4+-cells plays a critical role in the development of lymphedema. The cells facilitate inflammation and fibrosis formation in the subcutaneous tissue which inhibits lymphatic regeneration. Tacrolimus is an immunosuppressive and anti-inflammatory macrolide that targets the CD4+-cells. Tacrolimus as treatment of lymphedema has already shown promising results in animal studies. Tacrolimus has the potential to cure an otherwise uncurable and life-long side-effect of BC and will therefore benefit a large number of patients who suffers from BCRL.

Read more

AIM To assess the effect of Tacrolimus treatment on breast cancer-related lymphedema METHOD Study design A pilot study with a planned inclusion of 20 patients with a 12 month follow-up period. The purpose of this study is to assess the effect of tacrolimus treatment on lymphedema and HR-QOL. Results are attained from objective measures and questionnaires.

The patients will be seen at a consultation prior to the treatment start and then 3 times hereafter (at 3, 6 and 12 months) as follow up consultations where effect of treatment is evaluated.

Primary endpoint:

  • Arm volume measured with water displacement test.

Secondary endpoints:

  • Arm volume measured with measuring tape and calculated with volume of a cone formula
  • Patient-reported outcome measured through the Danish versions of , LYMPH-ICF, DASH and SF-36 questionnaires
  • Bioimpedance
  • Lymphangiography Primary- and secondary endpoint data will be collected at each of the 3 consultations (prior to treatment and 3 and 6 months after the treatment start).

CLINICAL IMPACT This will be the first clinical pharmacological study on regarding treatment of lymphedema with Tacrolimus. This study will test the feasibility and efficacy of Tacrolimus ointment in a population of breast cancer patients who have developed lymphedema. The study may lead to a routine clinical implementation of tacrolimus ointment to patients diagnosed with Lymphedema. Regardless of the outcome, the study will benefit the patients and future research in the field of lymphedema.

Being tested
Protopic 0.1 % Topical Ointment
Medical subject headings
Breast Cancer Lymphedema

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Protopic 0.1 % Topical OintmentDrug

    Applied in a thin layer covering all of the arm including the armpit and hand once a day for six months

Study groups in NCT04541290
Study groupRoleWhat they receive
TreatmentExperimentalWomen with stage 1-2 lymphedema due to breast cancer treatment
Receives: Drug: Protopic 0.1 % Topical Ointment

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Arm volume from Baseline

    measured with water displacement test. The patient lowers her arm in a basin of water (Bravometer, Novuqare BV, PJ Horst, NL) and arm volume is hereafter read in mL prior to and after the lowering of the arm. This method is established at the department we use for this project. Arm volume of both arms are measured at each consultation.

    Measured: Baseline + change in arm volume at 3, 6 and 12 months from baseline

Secondary outcomes (6)

  1. Bioimpedance

    Bioimpedance measuring is a tool in estimating the excess liquid in the body. The test is non-invasive and is done by placing electrodes on the skin of the hands and feet similarly to the procedure of an ECG. Signals run through the electrodes connected to a machine that sends electric impulses trough the body and estimates the excess liquid in the extremities.

    The test is done at every consultation and has a duration of a couple of minutes. There is no side-effects or discomfort associated to the test.

    Measured: Baseline + at 3, 6 and 12 month follow-up

  2. Lymphangiography

    An imaging-tool to quantify the lymph-flow and -vessels. ICG is a fluorescent that is absorbed in the lymphatic system and metabolized in the liver with a half-life at 3-4 minutes. The florescent ICG is detectable by cameras at specific wavelengths and is thereby possible to visualize. The outcome of this test is classified into groups: linear pattern and dermal backflow patterns. Dermal backflow patterns can then be subdivided into "splash", "stardust" and "diffuse patterns" via pattern-recognition.

    The procedure is done by injecting 0.02 mL ICG subcutaneously in the web space between each finger. Fluorescent imaging of the lymph-vessels and -flow is then obtained by using an infrared camera. There is no exposition of radiation associated with this test.

    The ICG lymphangiography is done on both arms. Outcome is measured as the pattern of the lymph-flow.

    Measured: Baseline + at 6 and 12 month follow-up

  3. Questionnaire: Lymphedema Functioning, Disability and Health questionnaire (Lymph-ICF) LYMPH-ICF

    A Danish validated questionnaire developed specifically for lymphedema-patients. The questionnaire contains 5 domains: lymphedema symptoms, mental function, household activities, mobility activities movement and life and social activities.

    29 questions regarding the 5 domains are answered on a scale ranging from 0-10. Raw scores will be transformed into scores ranging from 0 (Worst) to 100 (best) using the original scoring key

    Measured: Baseline + at 3, 6 and 12 month follow-up

  4. Questionnaire: The disabilities of the arm, shoulder and hand (DASH) questionnaire

    A Danish validated questionnaire developed for patients with disabilities of the arms, shoulders and hands. It includes 38 questions about the patient's ability to perform different actions/movements. The questions are answered on a 5-step scale from not difficult to impossible.

    Raw scores will be transformed into scores ranging from 0 (Worst) to 100 (best) using the original scoring key

    Measured: Baseline + at 3, 6 and 12 month follow-up

  5. Questionnaire: 36-Item Short-Form Health Survey questionnaire (SF-36)

    A Danish validated generic quality of life-questionnaire. The questionnaire includes 36 questions regarding the patient's the general quality of life. The questions are answered on a 3-, 5- and 6-step scale and binary (Yes/No) depending on the question.

    Raw scores will be transformed into scores ranging from 0 (Worst) to 100 (best) using the original scoring key

    Measured: Baseline + at 3, 6 and 12 month follow-up

  6. Arm volume measured with measuring tape

    Manual measuring with measuring tape and then calculated with through volume of a cone formula

    Measured: Baseline + at 3, 6 and 12 month follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Sep 2020
  2. Study start22 Sep 2020
  3. Primary completion6 Jan 2022
  4. Study completion6 Jan 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04541290
Sponsor's protocol ID
Tacrolimus_2020
Status last verified
Feb 2022
First submitted
28 Aug 2020
Last updated
9 Feb 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Zou L, Liu FH, Shen PP, Hu Y, Liu XQ, Xu YY, Pen QL, Wang B, Zhu YQ, Tian Y. The incidence and risk factors of related lymphedema for breast cancer survivors post-operation: a 2-year follow-up prospective cohort study. Breast Cancer. 2018 May;25(3):309-314. doi: 10.1007/s12282-018-0830-3. Epub 2018 Feb 3.

    PubMed 29397555

  • Ribeiro Pereira ACP, Koifman RJ, Bergmann A. Incidence and risk factors of lymphedema after breast cancer treatment: 10 years of follow-up. Breast. 2017 Dec;36:67-73. doi: 10.1016/j.breast.2017.09.006. Epub 2017 Oct 6.

    PubMed 28992556

  • Grada AA, Phillips TJ. Lymphedema: Pathophysiology and clinical manifestations. J Am Acad Dermatol. 2017 Dec;77(6):1009-1020. doi: 10.1016/j.jaad.2017.03.022.

    PubMed 29132848

  • Taghian NR, Miller CL, Jammallo LS, O'Toole J, Skolny MN. Lymphedema following breast cancer treatment and impact on quality of life: a review. Crit Rev Oncol Hematol. 2014 Dec;92(3):227-34. doi: 10.1016/j.critrevonc.2014.06.004. Epub 2014 Jul 2.

    PubMed 25085806

  • Pusic AL, Cemal Y, Albornoz C, Klassen A, Cano S, Sulimanoff I, Hernandez M, Massey M, Cordeiro P, Morrow M, Mehrara B. Quality of life among breast cancer patients with lymphedema: a systematic review of patient-reported outcome instruments and outcomes. J Cancer Surviv. 2013 Mar;7(1):83-92. doi: 10.1007/s11764-012-0247-5. Epub 2012 Dec 5.

    PubMed 23212603

  • Terada M, Yoshimura A, Sawaki M, Hattori M, Naomi G, Kotani H, Adachi Y, Iwase M, Kataoka A, Sugino K, Mori M, Horisawa N, Ozaki Y, Iwata H. Patient-reported outcomes and objective assessments with arm measurement and bioimpedance analysis for lymphedema among breast cancer survivors. Breast Cancer Res Treat. 2020 Jan;179(1):91-100. doi: 10.1007/s10549-019-05443-1. Epub 2019 Sep 18.

    PubMed 31535321

  • Sackey H, Johansson H, Sandelin K, Liljegren G, MacLean G, Frisell J, Brandberg Y. Self-perceived, but not objective lymphoedema is associated with decreased long-term health-related quality of life after breast cancer surgery. Eur J Surg Oncol. 2015 Apr;41(4):577-84. doi: 10.1016/j.ejso.2014.12.006. Epub 2015 Jan 13.

    PubMed 25659877

  • Ghanta S, Cuzzone DA, Torrisi JS, Albano NJ, Joseph WJ, Savetsky IL, Gardenier JC, Chang D, Zampell JC, Mehrara BJ. Regulation of inflammation and fibrosis by macrophages in lymphedema. Am J Physiol Heart Circ Physiol. 2015 May 1;308(9):H1065-77. doi: 10.1152/ajpheart.00598.2014. Epub 2015 Feb 27.

    PubMed 25724493

  • Ogata F, Fujiu K, Matsumoto S, Nakayama Y, Shibata M, Oike Y, Koshima I, Watabe T, Nagai R, Manabe I. Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema. J Invest Dermatol. 2016 Mar;136(3):706-714. doi: 10.1016/j.jid.2015.12.001. Epub 2015 Dec 10.

    PubMed 27015456

  • Muller GG, Jose NK, de Castro RS, de Holanda EC. Long-term use of topical tacrolimus ointment: a safe and effective option for the treatment of vernal keratoconjunctivitis. Arq Bras Oftalmol. 2019 Mar-Apr;82(2):119-123. doi: 10.5935/0004-2749.20190026. Epub 2019 Jan 24.

    PubMed 30698232

  • Remitz A, Harper J, Rustin M, Goldschmidt WF, Palatsi R, van der Valk PG, Sharpe G, Smith CH, Dobozy A, Turjanmaa K; European Tacrolimus Ointment Study Group. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. Acta Derm Venereol. 2007;87(1):54-61. doi: 10.2340/00015555-0167.

    PubMed 17225017

  • Gardenier JC, Kataru RP, Hespe GE, Savetsky IL, Torrisi JS, Nores GD, Jowhar DK, Nitti MD, Schofield RC, Carlow DC, Mehrara BJ. Topical tacrolimus for the treatment of secondary lymphedema. Nat Commun. 2017 Feb 10;8:14345. doi: 10.1038/ncomms14345.

    PubMed 28186091

  • Harvey LA. REDCap: web-based software for all types of data storage and collection. Spinal Cord. 2018 Jul;56(7):625. doi: 10.1038/s41393-018-0169-9. No abstract available.

    PubMed 29977003

  • Lasinski BB, McKillip Thrift K, Squire D, Austin MK, Smith KM, Wanchai A, Green JM, Stewart BR, Cormier JN, Armer JM. A systematic review of the evidence for complete decongestive therapy in the treatment of lymphedema from 2004 to 2011. PM R. 2012 Aug;4(8):580-601. doi: 10.1016/j.pmrj.2012.05.003.

    PubMed 22920313

  • Damstra RJ, Glazenburg EJ, Hop WC. Validation of the inverse water volumetry method: A new gold standard for arm volume measurements. Breast Cancer Res Treat. 2006 Oct;99(3):267-73. doi: 10.1007/s10549-006-9213-0. Epub 2006 Jun 3.

    PubMed 16752072

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Protopic 0.1 % Topical Ointment in people with Breast Cancer Lymphedema, run by Odense University Hospital at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Arm volume from Baseline (time frame: Baseline + change in arm volume at 3, 6 and 12 months from baseline). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04541290, which also lists 20 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2022.

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