Lymphedema
Conditions
Keywords
Lymphedema, edema, swelling
Brief summary
This study compares the effectiveness of a study drug versus placebo in the treatment of lymphedema.
Detailed description
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.
Interventions
DRUGKetoprofen
DRUGPlacebo
Placebo to match ketoprofen.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* a history of lymphedema of one or more limbs (unilateral or bilateral), with a duration of \> 6 months.
Exclusion criteria
* Patients with active cancer, infection or bleeding tendency will be excluded. * We will also exclude patients with medical contraindications to NSAIDs, including history of allergies, know gastrointestinal intolerance, or other serious systemic illness (e.g., renal failure, hepatic dysfunction, congestive heart failure, neurological or psychological impairment) that would impair the patients' ability to participate. * Minors (\<18 years of age) \*\>90 years of age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Count of Participants Able to Complete Ketoprofen Treatment | Baseline to month 6 | Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events. |
| Part 2: Change From Baseline in Cutaneous Histological Architecture | Baseline; Month 4 | 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. |
| Part 3: Measurement of Skin Thickness | Baseline and 4 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2/Part 3: Change in Limb Volume | Baseline; 4 months | Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values. |
| Part 2: Measurement of Skin Thickness | Baseline and 4 months | Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed. |
| Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | Baseline; 4 months | 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. |
| Part 3: Change From Baseline in Cutaneous Histological Architecture | Baseline; 4 months | 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. |
| Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Baseline; 4 months | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Exploratory Group Ketoprofen 225-300 mgs daily, taken orally
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months | 50 |
| Part 2: Open-label Group Ketoprofen 225 mg daily
Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months | 16 |
| Part 3: Placebo Group Participants randomized to receive placebo:
1 capsule, taken orally, three times daily, for four months | 16 |
| 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 | 14 |
| Total | 96 |
Baseline characteristics
| Characteristic | Part 1: Exploratory Group | Part 2: Open-label Group | Part 3: Placebo Group | Part 3: Ketoprofen Group | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 4 Participants | 2 Participants | 4 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 12 Participants | 14 Participants | 10 Participants | 75 Participants |
| Age, Continuous | 56.72 years STANDARD_DEVIATION 13.46 | 56.43 years STANDARD_DEVIATION 11.15 | 50.25 years STANDARD_DEVIATION 15.12 | 53.92 years STANDARD_DEVIATION 13.14 | 54.92 years STANDARD_DEVIATION 13.07 |
| Lymphedema classification Primary | 4 Participants | 5 Participants | 4 Participants | 2 Participants | 15 Participants |
| Lymphedema classification Secondary | 46 Participants | 11 Participants | 12 Participants | 12 Participants | 81 Participants |
| Lymphedema location Lower extremity | 32 Participants | 12 Participants | 11 Participants | 12 Participants | 67 Participants |
| Lymphedema location Upper extermity | 18 Participants | 4 Participants | 5 Participants | 2 Participants | 29 Participants |
| Sex: Female, Male Female | 41 Participants | 13 Participants | 14 Participants | 14 Participants | 82 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 2 Participants | 0 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 23 | 0 / 23 | 0 / 21 |
| other Total, other adverse events | 3 / 50 | 2 / 23 | 1 / 23 | 2 / 21 |
| serious Total, serious adverse events | 0 / 50 | 0 / 23 | 0 / 23 | 0 / 21 |
Outcome results
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.
Time frame: Baseline to month 6
Population: This outcome was assessed in Part 1 participants only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Exploratory Group | Part 1: Count of Participants Able to Complete Ketoprofen Treatment | 50 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.
Time frame: Baseline; Month 4
Population: This primary endpoint outcome was assessed in Part 2 participants only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 2: Change From Baseline in Cutaneous Histological Architecture | Baseline | 6.125 score on a scale | Standard Deviation 2.247 |
| Part 1: Exploratory Group | Part 2: Change From Baseline in Cutaneous Histological Architecture | Month 4 | 2.688 score on a scale | Standard Deviation 1.401 |
| Part 2: Unaffected Tissue Samples | Part 2: Change From Baseline in Cutaneous Histological Architecture | Baseline | 0.8 score on a scale | Standard Deviation 1.2 |
| Part 2: Unaffected Tissue Samples | Part 2: Change From Baseline in Cutaneous Histological Architecture | Month 4 | 0.6 score on a scale | Standard Deviation 1 |
Comparison: For the analysis, the 4-month post-minus-pre change in this score for ketoprofen was compared.p-value: <0.0001t-test, 2 sided
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.
Time frame: Baseline and 4 months
Population: Data for this outcome were collected in Part 3 participants only and for lymphedema-affected limbs only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 3: Measurement of Skin Thickness | Baseline | 47 mm | Standard Deviation 28 |
| Part 1: Exploratory Group | Part 3: Measurement of Skin Thickness | Month 4 | 45 mm | Standard Deviation 31 |
| Part 2: Unaffected Tissue Samples | Part 3: Measurement of Skin Thickness | Baseline | 49 mm | Standard Deviation 21 |
| Part 2: Unaffected Tissue Samples | Part 3: Measurement of Skin Thickness | Month 4 | 41 mm | Standard Deviation 21 |
p-value: =0.6t-test, 2 sided
p-value: =0.01t-test, 2 sided
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.
Time frame: Baseline and 4 months
Population: Data for this outcome were collected in Part 2 participants only and for lymphedema-affected limbs only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 2: Measurement of Skin Thickness | Baseline | 62 mm | Standard Deviation 34 |
| Part 1: Exploratory Group | Part 2: Measurement of Skin Thickness | Month 4 | 27 mm | Standard Deviation 22 |
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.
Time frame: Baseline; 4 months
Population: Data for this outcome were collected for Part 2 and Part 3 participants with unilateral lymphedema-affected limbs only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Baseline | 1.5 ratio of Ro values | Standard Deviation 0.5 |
| Part 1: Exploratory Group | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Month 4 | 1.6 ratio of Ro values | Standard Deviation 0.3 |
| Part 2: Unaffected Tissue Samples | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Baseline | 1.5 ratio of Ro values | Standard Deviation 0.4 |
| Part 2: Unaffected Tissue Samples | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Month 4 | 1.5 ratio of Ro values | Standard Deviation 0.3 |
| Part 3: Unaffected Tissue Samples | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Baseline | 1.4 ratio of Ro values | Standard Deviation 0.2 |
| Part 3: Unaffected Tissue Samples | Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | Month 4 | 1.4 ratio of Ro values | Standard Deviation 0.2 |
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.
Time frame: Baseline; 4 months
Population: Data for this outcome were collected only for lymphedema-affected limbs only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 2/Part 3: Change in Limb Volume | Baseline | 9866 ml | Standard Deviation 5821 |
| Part 1: Exploratory Group | Part 2/Part 3: Change in Limb Volume | Month 4 | 9465 ml | Standard Deviation 5115 |
| Part 2: Unaffected Tissue Samples | Part 2/Part 3: Change in Limb Volume | Baseline | 7196 ml | Standard Deviation 3519 |
| Part 2: Unaffected Tissue Samples | Part 2/Part 3: Change in Limb Volume | Month 4 | 7256 ml | Standard Deviation 3496 |
| Part 3: Unaffected Tissue Samples | Part 2/Part 3: Change in Limb Volume | Baseline | 8598 ml | Standard Deviation 3066 |
| Part 3: Unaffected Tissue Samples | Part 2/Part 3: Change in Limb Volume | Month 4 | 8675 ml | Standard Deviation 3103 |
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.
Time frame: Baseline; 4 months
Population: Data for this outcome were collected in Part 3 participants only and for lymphedema tissue samples only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 3: Change From Baseline in Cutaneous Histological Architecture | Baseline | 2.7 score on a scale | Standard Deviation 2.1 |
| Part 1: Exploratory Group | Part 3: Change From Baseline in Cutaneous Histological Architecture | Month 4 | 1.0 score on a scale | Standard Deviation 1.1 |
| Part 2: Unaffected Tissue Samples | Part 3: Change From Baseline in Cutaneous Histological Architecture | Baseline | 4.1 score on a scale | Standard Deviation 1.8 |
| Part 2: Unaffected Tissue Samples | Part 3: Change From Baseline in Cutaneous Histological Architecture | Month 4 | 1.18 score on a scale | Standard Deviation 1.08 |
| Part 3: Unaffected Tissue Samples | Part 3: Change From Baseline in Cutaneous Histological Architecture | Baseline | 0.8 score on a scale | Standard Deviation 1.2 |
| Part 3: Unaffected Tissue Samples | Part 3: Change From Baseline in Cutaneous Histological Architecture | Month 4 | 0.6 score on a scale | Standard Deviation 1 |
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.
Time frame: Baseline; 4 months
Population: Data for this outcome was collected for Part 3 participants only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Exploratory Group | Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | Baseline | 121 MFI (log10) | Standard Deviation 90 |
| Part 1: Exploratory Group | Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | Month 4 | 209 MFI (log10) | Standard Deviation 214 |
| Part 2: Unaffected Tissue Samples | Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | Baseline | 131 MFI (log10) | Standard Deviation 76 |
| Part 2: Unaffected Tissue Samples | Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | Month 4 | 126 MFI (log10) | Standard Deviation 107 |