Trial Outcomes & Findings for Lymphedema Study for Arm or Leg Lymphedema (NCT NCT02257970)

NCT ID: NCT02257970

Last Updated: 2022-10-27

Results Overview

Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 117 participants
• Primary outcome timeframe: Baseline to month 6
• Results posted on: 2022-10-27

Participant Flow

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.

Participant milestones

Measure	Part 1: Exploratory Group Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Open-label Group Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months	Part 3: Placebo Group Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months	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
Part 1 STARTED	50	0	0	0
Part 1 COMPLETED	50	0	0	0
Part 1 NOT COMPLETED	0	0	0	0
Part 2 STARTED	0	23	0	0
Part 2 COMPLETED	0	16	0	0
Part 2 NOT COMPLETED	0	7	0	0
Part 3 STARTED	0	0	23	21
Part 3 COMPLETED	0	0	16	14
Part 3 NOT COMPLETED	0	0	7	7

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Lymphedema Study for Arm or Leg Lymphedema

Baseline characteristics by cohort

Measure	Part 1: Exploratory Group n=50 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Open-label Group n=16 Participants Ketoprofen 225 mg daily Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months	Part 3: Placebo Group n=16 Participants Participants randomized to receive placebo: 1 capsule, taken orally, three times daily, for four months	Part 3: Ketoprofen Group n=14 Participants Participants randomized to receive active medication, Ketoprofen 225 mg daily: Ketoprofen: 75 mgs, 1 capsule, three times daily, for four months	Total n=96 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	39 Participants n=5 Participants	12 Participants n=7 Participants	14 Participants n=5 Participants	10 Participants n=4 Participants	75 Participants n=21 Participants
Age, Categorical >=65 years	11 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	21 Participants n=21 Participants
Age, Continuous	56.72 years STANDARD_DEVIATION 13.46 • n=5 Participants	56.43 years STANDARD_DEVIATION 11.15 • n=7 Participants	50.25 years STANDARD_DEVIATION 15.12 • n=5 Participants	53.92 years STANDARD_DEVIATION 13.14 • n=4 Participants	54.92 years STANDARD_DEVIATION 13.07 • n=21 Participants
Sex: Female, Male Female	41 Participants n=5 Participants	13 Participants n=7 Participants	14 Participants n=5 Participants	14 Participants n=4 Participants	82 Participants n=21 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	14 Participants n=21 Participants
Lymphedema classification Primary	4 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	15 Participants n=21 Participants
Lymphedema classification Secondary	46 Participants n=5 Participants	11 Participants n=7 Participants	12 Participants n=5 Participants	12 Participants n=4 Participants	81 Participants n=21 Participants
Lymphedema location Upper extermity	18 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	2 Participants n=4 Participants	29 Participants n=21 Participants
Lymphedema location Lower extremity	32 Participants n=5 Participants	12 Participants n=7 Participants	11 Participants n=5 Participants	12 Participants n=4 Participants	67 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline to month 6

Population: This outcome was assessed in Part 1 participants only.

Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.

Outcome measures

Measure	Part 1: Exploratory Group n=50 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples Results from normal samples from Part 3 participants are presented in this reporting group.
Part 1: Count of Participants Able to Complete Ketoprofen Treatment	50 Participants	—	—

PRIMARY outcome

Timeframe: Baseline; Month 4

Population: This primary endpoint outcome was assessed in Part 2 participants only.

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.

Outcome measures

Measure	Part 1: Exploratory Group n=16 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples n=16 Participants Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples Results from normal samples from Part 3 participants are presented in this reporting group.
Part 2: Change From Baseline in Cutaneous Histological Architecture Baseline	6.125 score on a scale Standard Deviation 2.247	0.8 score on a scale Standard Deviation 1.2	—
Part 2: Change From Baseline in Cutaneous Histological Architecture Month 4	2.688 score on a scale Standard Deviation 1.401	0.6 score on a scale Standard Deviation 1.0	—

PRIMARY outcome

Timeframe: Baseline and 4 months

Population: Data for this outcome were collected in Part 3 participants only and for lymphedema-affected limbs only.

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.

Outcome measures

Measure	Part 1: Exploratory Group n=16 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples n=14 Participants Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples Results from normal samples from Part 3 participants are presented in this reporting group.
Part 3: Measurement of Skin Thickness Baseline	47 mm Standard Deviation 28	49 mm Standard Deviation 21	—
Part 3: Measurement of Skin Thickness Month 4	45 mm Standard Deviation 31	41 mm Standard Deviation 21	—

SECONDARY outcome

Timeframe: Baseline and 4 months

Population: Data for this outcome were collected in Part 2 participants only and for lymphedema-affected limbs only.

Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed.

Outcome measures

Measure	Part 1: Exploratory Group n=16 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples Results from normal samples from Part 3 participants are presented in this reporting group.
Part 2: Measurement of Skin Thickness Baseline	62 mm Standard Deviation 34	—	—
Part 2: Measurement of Skin Thickness Month 4	27 mm Standard Deviation 22	—	—

SECONDARY outcome

Timeframe: Baseline; 4 months

Population: Data for this outcome were collected in Part 3 participants only and for lymphedema tissue samples only.

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.

Outcome measures

Measure	Part 1: Exploratory Group n=16 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples n=14 Participants Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples n=30 Participants Results from normal samples from Part 3 participants are presented in this reporting group.
Part 3: Change From Baseline in Cutaneous Histological Architecture Baseline	2.7 score on a scale Standard Deviation 2.1	4.1 score on a scale Standard Deviation 1.8	0.8 score on a scale Standard Deviation 1.2
Part 3: Change From Baseline in Cutaneous Histological Architecture Month 4	1.0 score on a scale Standard Deviation 1.1	1.18 score on a scale Standard Deviation 1.08	0.6 score on a scale Standard Deviation 1.0

SECONDARY outcome

Timeframe: Baseline; 4 months

Population: Data for this outcome were collected for Part 2 and Part 3 participants with unilateral lymphedema-affected limbs only.

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.

Outcome measures

Measure	Part 1: Exploratory Group n=10 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples n=24 limbs Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples n=26 limbs Results from normal samples from Part 3 participants are presented in this reporting group.
Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy Baseline	1.5 ratio of Ro values Standard Deviation 0.5	1.5 ratio of Ro values Standard Deviation 0.4	1.4 ratio of Ro values Standard Deviation 0.2
Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy Month 4	1.6 ratio of Ro values Standard Deviation 0.3	1.5 ratio of Ro values Standard Deviation 0.3	1.4 ratio of Ro values Standard Deviation 0.2

SECONDARY outcome

Timeframe: Baseline; 4 months

Population: Data for this outcome were collected only for lymphedema-affected limbs only.

Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.

Outcome measures

Measure	Part 1: Exploratory Group n=16 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples n=16 Participants Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples n=14 Participants Results from normal samples from Part 3 participants are presented in this reporting group.
Part 2/Part 3: Change in Limb Volume Baseline	9866 ml Standard Deviation 5821	7196 ml Standard Deviation 3519	8598 ml Standard Deviation 3066
Part 2/Part 3: Change in Limb Volume Month 4	9465 ml Standard Deviation 5115	7256 ml Standard Deviation 3496	8675 ml Standard Deviation 3103

SECONDARY outcome

Timeframe: Baseline; 4 months

Population: Data for this outcome was collected for Part 3 participants only.

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.

Outcome measures

Measure	Part 1: Exploratory Group n=16 Participants Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Unaffected Tissue Samples n=14 Participants Results from normal samples from Part 2 participants are presented in this reporting group.	Part 3: Unaffected Tissue Samples Results from normal samples from Part 3 participants are presented in this reporting group.
Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) Baseline	121 MFI (log10) Standard Deviation 90	131 MFI (log10) Standard Deviation 76	—
Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) Month 4	209 MFI (log10) Standard Deviation 214	126 MFI (log10) Standard Deviation 107	—

Adverse Events

Part 1: Exploratory Group

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 2: Open-label Group

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Part 3: Placebo Group

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Part 3: Ketoprofen Group

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Part 1: Exploratory Group n=50 participants at risk Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months	Part 2: Open-label Group n=23 participants at risk Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months	Part 3: Placebo Group n=23 participants at risk Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months	Part 3: Ketoprofen Group n=21 participants at risk Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months
Skin and subcutaneous tissue disorders Cellulitis	6.0% 3/50 • Number of events 3 • Four months	4.3% 1/23 • Number of events 1 • Four months	0.00% 0/23 • Four months	0.00% 0/21 • Four months
Skin and subcutaneous tissue disorders Rash	0.00% 0/50 • Four months	4.3% 1/23 • Number of events 1 • Four months	4.3% 1/23 • Number of events 1 • Four months	5.3% 1/19 • Number of events 1 • Four months
Gastrointestinal disorders Hemorrhoidal hemorrhag	0.00% 0/50 • Four months	0.00% 0/23 • Four months	0.00% 0/23 • Four months	4.8% 1/21 • Number of events 1 • Four months

Additional Information

Dr. Stanley Rockson

Stanford University, School of Medicine

Phone: 650-725-7571

Email: rockson@stanford.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place