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This study compares the effectiveness of a study drug versus placebo in the treatment of lymphedema.
Part 1 is feasibility, exploratory, open-label study of ketoprofen, to document effects.
Part 2, is open-label trial of ketoprofen to document histological response. Part 3 is double-blind randomized trial of receive placebo or ketoprofen to evaluate safety and efficacy.
We will try to determine how the study drug affects the body tissue by obtaining tissue biopsies (small pieces of skin from the arm or leg) before treatment and after treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1: Exploratory Group | Experimental | Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months |
|
| Part 2: Open-label Group | Experimental | Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months |
|
| Part 3: Placebo Group | Placebo Comparator | Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months |
|
| Part 3: Ketoprofen Group | Active Comparator | Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketoprofen | Drug |
| ||
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Count of Participants Able to Complete Ketoprofen Treatment | Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events. | Baseline to month 6 |
| Part 2: Change From Baseline in Cutaneous Histological Architecture | Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology. | Baseline; Month 4 |
| Part 3: Measurement of Skin Thickness | Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study. | Baseline and 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| Part 2: Measurement of Skin Thickness | Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed. | Baseline and 4 months |
| Part 3: Change From Baseline in Cutaneous Histological Architecture |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Stanley G Rockson, MD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30333315 | Derived | Rockson SG, Tian W, Jiang X, Kuznetsova T, Haddad F, Zampell J, Mehrara B, Sampson JP, Roche L, Kim J, Nicolls MR. Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI Insight. 2018 Oct 18;3(20):e123775. doi: 10.1172/jci.insight.123775. |
| Label | URL |
|---|---|
| Stanford Health Care: Center for Lymphatic and Venous Disorders | View source |
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Part 1 was feasibility, exploratory, open-label ketoprofen, to document effects. Part 2 was open-label trial of ketoprofen to document histological response. Part 3 was double-blind randomized to receive placebo or ketoprofen to evaluate safety and efficacy.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1: Exploratory Group | Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months |
| FG001 | Part 2: Open-label Group | Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months |
| FG002 | Part 3: Placebo Group | Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months |
| FG003 | Part 3: Ketoprofen Group | Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1 |
| |||||||||||||
| Part 2 |
| |||||||||||||
| Part 3 |
|
Participants that completed the protocol were included in Baseline Characteristics.
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| ID | Title | Description |
|---|---|---|
| BG000 | Part 1: Exploratory Group | Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months |
| BG001 | Part 2: Open-label Group |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Part 1: Count of Participants Able to Complete Ketoprofen Treatment | Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events. | This outcome was assessed in Part 1 participants only. | Posted | Count of Participants | Participants | Baseline to month 6 |
|
|
Four months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part 1: Exploratory Group | Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cellulitis | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Stanley Rockson | Stanford University, School of Medicine | 650-725-7571 | rockson@stanford.edu |
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| ID | Term |
|---|---|
| D008209 | Lymphedema |
| D004487 | Edema |
| ID | Term |
|---|---|
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D007660 | Ketoprofen |
| ID | Term |
|---|---|
| D010666 | Phenylpropionates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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| Drug |
Placebo to match ketoprofen. |
|
Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology. |
| Baseline; 4 months |
| Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal. | Baseline; 4 months |
| Part 2/Part 3: Change in Limb Volume | Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values. | Baseline; 4 months |
| Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed. | Baseline; 4 months |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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Ketoprofen 225 mg daily
Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months
| BG002 | Part 3: Placebo Group | Participants randomized to receive placebo: 1 capsule, taken orally, three times daily, for four months |
| BG003 | Part 3: Ketoprofen Group | Participants randomized to receive active medication, Ketoprofen 225 mg daily: Ketoprofen: 75 mgs, 1 capsule, three times daily, for four months |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Lymphedema classification | Primary lymphedema is defined as having been born with the condition, or developed the condition in the first year of life. Secondary lymphedema is defined as a condition that results due to some other event (e.g., trauma, cancer treatment, May-Turner Syndrome (MTS)). | Count of Participants | Participants |
|
| Lymphedema location | Count of Participants | Participants |
|
|
|
| Primary | Part 2: Change From Baseline in Cutaneous Histological Architecture | Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology. | This primary endpoint outcome was assessed in Part 2 participants only. | Posted | Mean | Standard Deviation | score on a scale | Baseline; Month 4 |
|
|
|
|
| Primary | Part 3: Measurement of Skin Thickness | Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study. | Data for this outcome were collected in Part 3 participants only and for lymphedema-affected limbs only. | Posted | Mean | Standard Deviation | mm | Baseline and 4 months |
|
|
|
|
| Secondary | Part 2: Measurement of Skin Thickness | Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed. | Data for this outcome were collected in Part 2 participants only and for lymphedema-affected limbs only. | Posted | Mean | Standard Deviation | mm | Baseline and 4 months |
|
|
|
| Secondary | Part 3: Change From Baseline in Cutaneous Histological Architecture | Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology. | Data for this outcome were collected in Part 3 participants only and for lymphedema tissue samples only. | Posted | Mean | Standard Deviation | score on a scale | Baseline; 4 months |
|
|
|
| Secondary | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal. | Data for this outcome were collected for Part 2 and Part 3 participants with unilateral lymphedema-affected limbs only. | Posted | Mean | Standard Deviation | ratio of Ro values | Baseline; 4 months | limbs | limbs |
|
|
|
| Secondary | Part 2/Part 3: Change in Limb Volume | Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values. | Data for this outcome were collected only for lymphedema-affected limbs only. | Posted | Mean | Standard Deviation | ml | Baseline; 4 months |
|
|
|
| Secondary | Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed. | Data for this outcome was collected for Part 3 participants only. | Posted | Mean | Standard Deviation | MFI (log10) | Baseline; 4 months |
|
|
|
| 0 |
| 50 |
| 0 |
| 50 |
| 3 |
| 50 |
| EG001 | Part 2: Open-label Group | Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months | 0 | 23 | 0 | 23 | 2 | 23 |
| EG002 | Part 3: Placebo Group | Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months | 0 | 23 | 0 | 23 | 1 | 23 |
| EG003 | Part 3: Ketoprofen Group | Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months | 0 | 21 | 0 | 21 | 2 | 21 |
| Rash | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Hemorrhoidal hemorrhag | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
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paired t-test |
| =0.01 |
| Equivalence |
Pre-to-Post comparison: The likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P<0.05 |
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