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Effects of Topical Diclofenac on Tumor Metabolism

Primary Purpose

Actinic Keratoses

Status

Completed

Phase

Phase 4

Locations

Germany

Study Type

Interventional

Intervention

3% diclofenac in 2.5% hyaluronic acid gel

About this trial

This is an interventional basic science trial for Actinic Keratoses focused on measuring actinic keratoses, tumor metabolism, glycolysis, diclofenac, warburg effect

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Written informed consent has been signed prior to or at Screening Visit
Caucasian male and female patients
Age > 18 years
Negative pregnancy test in women of childbearing age
Clinical diagnosis of actinic keratosis (AK)
A minimum of three AK lesions

Exclusion Criteria in immunocompromised patients :

Concomitant UV-phototherapy
Pregnancy or lactation
Women in child-bearing age who do not use highly efficient contraceptive methods (<1% failure rate per year)
Skin diseases that might interfere with response evaluation of study treatment
Topical pretreatment of the AK study lesions with photodynamic therapy, Solaraze® 3% gel, Aldara®, 5-FU, or polyphenon E during the 8 weeks preceding study treatment
Radiation therapy performed in the treatment area during the 3 months preceding study therapy
Systemic treatment with diclofenac
Known intolerance to diclofenac or to any other ingredient of Solaraze® 3% gel
Conditions that might interfere with the ability to understand the study and thus give written informed consent
Simultaneous participation in another clinical study or participation in another clinical study in the 30 days directly preceding inclusion
Suspected lack of compliance

Exclusion criteria in immunocompetent patients:

Concomitant UV-phototherapy
Pregnancy or lactation
Women in child-bearing age who do not use highly efficient contraceptive methods (<1% failure rate per year)
Patients with clinically relevant suppression of the immune system (e.g. drug induced, infection)
Skin diseases that might interfere with response evaluation of study treatment
Topical pretreatment of the AK study lesions with photodynamic therapy, Aldara®, Solaraze® 3% gel , 5-FU, or polyphenon E during the 8 weeks preceding study treatment
Systemic treatment with cytostatic drugs or radiation therapy performed in the treatment area during the 3 months preceding study therapy
Systemic treatment with diclofenac
Known intolerance to diclofenac or to any other ingredient of Solaraze® 3% gel
Conditions that might interfere with the ability to understand the study and thus give written informed consent
Simultaneous participation in another clinical study or participation in another clinical study in participation in another clinical study in the 30 days directly preceding inclusion
Suspected lack of compliance

Sites / Locations

University hospital Regensburg

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Diclofenac

Arm Description

3 % diclofenac in 2.5% hyaluronic acid gel (Solaraze® 3% gel) is applied twice daily in the treatment area. 3 % diclofenac in 2.5% hyaluronic acid gel (Solaraze® 3% gel) is to be applied 1cm beyond the single AK.

Outcomes

Primary Outcome Measures

Lactate level in skin biopsies of actinic keratoses

Assessment of the effects of topical 3% diclofenac in 2.5% hyaluronic acid gel on lactate level in skin biopsies of actinic keratoses. Skin biopsies of actinic keratoses are obtained prior to treatment and 4 weeks after the treatment.

Secondary Outcome Measures

Lactate level in skin biopsies of healthy skin in a subpopulation

Assessment of the effects of topical 3% diclofenac in 2.5% hyaluronic acid gel on lactate level in skin biopsies of actinic keratoses compared to untreated sun damaged, healthy skin in a subpopulation

Glycolysis-relevant proteins evaluated using PCR and Westernblot techniques

Metabolic changes (e.g. glucose, amino acids)

Metabolic changes (e.g. glucose, amino acids) evaluated by NMR methods and bioluminescence imaging techniques

Full Information

NCT ID

NCT01935531

First Posted

August 30, 2013

Last Updated

March 30, 2016

Sponsor

University Hospital Regensburg

Collaborators

German Research Foundation

1. Study Identification

Unique Protocol Identification Number

NCT01935531

Brief Title

Effects of Topical Diclofenac on Tumor Metabolism

Official Title

Prospective, Controlled and Monocentric Study to Evaluate the Effects of Topical 3% Diclofenac in 2.5% Hyaluronic Acid Gel on Tumor Metabolism in the Treatment of Actinic Keratoses in Immunocompetent and Immunocompromised Patients

Study Type

Interventional

2. Study Status

Record Verification Date

March 2016

Overall Recruitment Status

Completed

Study Start Date

June 2013 (undefined)

Primary Completion Date

January 2016 (Actual)

Study Completion Date

March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Hospital Regensburg

Collaborators

German Research Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The rationale of this study is to investigate the effects of topical diclofenac on tumor metabolism in the treatment of actinic keratoses in immunocompetent and immunocompromised patients. Study hypothesis is that topical diclofenac lowers lactate level in skin biopsies of actinic keratoses. Planned number of patients is 38. This study is a monocenter study investigating the effects of 3% diclofenac in 2.5% hyaluronic acid gel on tumor metabolism in the treatment of actinic keratoses. Treatment duration is 3 months. Skin biopsies will be obtained before treatment, at the end of the treatment and four weeks after the treatment. Control biopsies at visit 1 and 3 are performed in healthy, sun damaged and untreated skin. Evaluation of efficacy will be performed at the end of the treatment and four weeks after the treatment. Duration of treatment is 3 months (±4 weeks). Approximately 0,5g Solaraze® 3% gel is applied on a 5cm x 5cm lesion. Solaraze® 3% gel is applied twice daily on the study lesions.

Detailed Description

Neoplastic cells show an increased glucose metabolism and glycolysis which is associated with high lactate concentrations. There is also data for several tumor entities that high levels of lactate in the tumor are associated with tumor progression, metastasis and poor clinical outcome. Kreutz et al. demonstrated that diclofenac inhibits tumor cell proliferation in vitro and tumor growth in vivo via COX-independent effects on glucose metabolism. Diclofenac is taken up by tumor cells and inhibits tumor cell proliferation through inhibition of the oncogene MYC and subsequently glycolysis and block of lactate transport. MYC regulates genes involved in glycolysis and is upregulated in neoplastic cells, which is in line with the metabolic switch to glycolysis, the so called "Warburg effect", that cancer cells show. Although these results were found in vitro using human melanoma cells and in vivo in a mouse model, a similar mechanism of action is assumed to be relevant for the treatment of actinic keratoses with topical diclofenac. However tumor metabolism in diclofenac-treated actinic keratoses has never been investigated. To investigate the mechanism of action of diclofenac in the treatment of actinic keratoses, a clinical study analyzing particularly lactate levels, glycolysis and inflammatory infiltrate is needed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Actinic Keratoses

Keywords

actinic keratoses, tumor metabolism, glycolysis, diclofenac, warburg effect

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

38 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Diclofenac

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

3% diclofenac in 2.5% hyaluronic acid gel

Other Intervention Name(s)

Solaraze Gel

Primary Outcome Measure Information:

Title

Lactate level in skin biopsies of actinic keratoses

Description

Time Frame

4 weeks after the treatment

Secondary Outcome Measure Information:

Title

Lactate level in skin biopsies of healthy skin in a subpopulation

Description

Time Frame

Before treatment and 4 weeks after the treatment

Title

Glycolysis-relevant proteins evaluated using PCR and Westernblot techniques

Description

Glycolysis-relevant proteins evaluated using PCR and Westernblot techniques

Time Frame

at the end of the treatment and 4 weeks after the treatment

Title

Metabolic changes (e.g. glucose, amino acids)

Description

Metabolic changes (e.g. glucose, amino acids) evaluated by NMR methods and bioluminescence imaging techniques

Time Frame

at the end of the tretment and 4 weeks after the treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Written informed consent has been signed prior to or at Screening Visit Caucasian male and female patients Age > 18 years Negative pregnancy test in women of childbearing age Clinical diagnosis of actinic keratosis (AK) A minimum of three AK lesions Exclusion Criteria in immunocompromised patients : Concomitant UV-phototherapy Pregnancy or lactation Women in child-bearing age who do not use highly efficient contraceptive methods (<1% failure rate per year) Skin diseases that might interfere with response evaluation of study treatment Topical pretreatment of the AK study lesions with photodynamic therapy, Solaraze® 3% gel, Aldara®, 5-FU, or polyphenon E during the 8 weeks preceding study treatment Radiation therapy performed in the treatment area during the 3 months preceding study therapy Systemic treatment with diclofenac Known intolerance to diclofenac or to any other ingredient of Solaraze® 3% gel Conditions that might interfere with the ability to understand the study and thus give written informed consent Simultaneous participation in another clinical study or participation in another clinical study in the 30 days directly preceding inclusion Suspected lack of compliance Exclusion criteria in immunocompetent patients: Concomitant UV-phototherapy Pregnancy or lactation Women in child-bearing age who do not use highly efficient contraceptive methods (<1% failure rate per year) Patients with clinically relevant suppression of the immune system (e.g. drug induced, infection) Skin diseases that might interfere with response evaluation of study treatment Topical pretreatment of the AK study lesions with photodynamic therapy, Aldara®, Solaraze® 3% gel , 5-FU, or polyphenon E during the 8 weeks preceding study treatment Systemic treatment with cytostatic drugs or radiation therapy performed in the treatment area during the 3 months preceding study therapy Systemic treatment with diclofenac Known intolerance to diclofenac or to any other ingredient of Solaraze® 3% gel Conditions that might interfere with the ability to understand the study and thus give written informed consent Simultaneous participation in another clinical study or participation in another clinical study in participation in another clinical study in the 30 days directly preceding inclusion Suspected lack of compliance

Facility Information:

Facility Name

University hospital Regensburg

City

Regensburg

State/Province

Bavaria

ZIP/Postal Code

93053

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

31334125

Citation

Singer K, Dettmer K, Unger P, Schonhammer G, Renner K, Peter K, Siska PJ, Berneburg M, Herr W, Oefner PJ, Karrer S, Kreutz M, Datz E. Topical Diclofenac Reprograms Metabolism and Immune Cell Infiltration in Actinic Keratosis. Front Oncol. 2019 Jul 3;9:605. doi: 10.3389/fonc.2019.00605. eCollection 2019.

Results Reference

derived

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Effects of Topical Diclofenac on Tumor Metabolism

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