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Lymphedema Study for Arm or Leg Lymphedema

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ClinicalTrials.gov Identifier: NCT02257970
Recruitment Status : Completed
First Posted : October 7, 2014
Results First Posted : September 14, 2018
Last Update Posted : September 14, 2018
Sponsor:
Information provided by (Responsible Party):
Stanley Rockson, Stanford University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Sequential Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Lymphedema
Interventions Drug: Ketoprofen
Drug: Placebo
Enrollment 117
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.
Pre-assignment Details  
Arm/Group Title Part 1: Exploratory Group Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Hide Arm/Group Description

Ketoprofen 225-300 mgs daily, taken orally

Ketoprofen-exploratory group: 225-300 mgs daily for four to six months

Ketoprofen 225 mg daily, taken orally

Open-label group: 75 mgs, three times daily, for four months

Participants randomized to receive placebo: placebo, three times daily, taken orally

Placebo: 1 capsule, three times daily, for four months

Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally

Ketoprofen: 1 capsule, three times daily, for four months

Period Title: Part 1
Started 50 0 0 0
Completed 50 0 0 0
Not Completed 0 0 0 0
Period Title: Part 2
Started 0 23 0 0
Completed 0 16 0 0
Not Completed 0 7 0 0
Period Title: Part 3
Started 0 0 23 21
Completed 0 0 16 14
Not Completed 0 0 7 7
Arm/Group Title Part 1: Exploratory Group Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group Total
Hide Arm/Group Description

Ketoprofen 225-300 mgs daily, taken orally

Ketoprofen-exploratory group: 225-300 mgs daily for four to six months

Ketoprofen 225 mg daily

Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months

Participants randomized to receive placebo:

1 capsule, taken orally, three times daily, for four months

Participants randomized to receive active medication, Ketoprofen 225 mg daily:

Ketoprofen: 75 mgs, 1 capsule, three times daily, for four months

Total of all reporting groups
Overall Number of Baseline Participants 50 16 16 14 96
Hide Baseline Analysis Population Description
Participants that completed the protocol were included in Baseline Characteristics.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 16 participants 16 participants 14 participants 96 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
39
  78.0%
12
  75.0%
14
  87.5%
10
  71.4%
75
  78.1%
>=65 years
11
  22.0%
4
  25.0%
2
  12.5%
4
  28.6%
21
  21.9%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 50 participants 16 participants 16 participants 14 participants 96 participants
56.72  (13.46) 56.43  (11.15) 50.25  (15.12) 53.92  (13.14) 54.92  (13.07)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 16 participants 16 participants 14 participants 96 participants
Female
41
  82.0%
13
  81.3%
14
  87.5%
14
 100.0%
82
  85.4%
Male
9
  18.0%
3
  18.8%
2
  12.5%
0
   0.0%
14
  14.6%
Lymphedema classification   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 16 participants 16 participants 14 participants 96 participants
Primary
4
   8.0%
5
  31.3%
4
  25.0%
2
  14.3%
15
  15.6%
Secondary
46
  92.0%
11
  68.8%
12
  75.0%
12
  85.7%
81
  84.4%
[1]
Measure Description:

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)).

Lymphedema location  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 16 participants 16 participants 14 participants 96 participants
Upper extermity
18
  36.0%
4
  25.0%
5
  31.3%
2
  14.3%
29
  30.2%
Lower extremity
32
  64.0%
12
  75.0%
11
  68.8%
12
  85.7%
67
  69.8%
1.Primary Outcome
Title Part 1: Count of Participants Able to Complete Ketoprofen Treatment
Hide Description Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.
Time Frame Baseline to month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This outcome was assessed in Part 1 participants only.
Arm/Group Title Part 1: Exploratory Group
Hide Arm/Group Description:

Ketoprofen 225-300 mgs daily, taken orally

Ketoprofen-exploratory group: 225-300 mgs daily for four to six months

Overall Number of Participants Analyzed 50
Measure Type: Count of Participants
Unit of Measure: Participants
50
 100.0%
2.Primary Outcome
Title Part 2: Change From Baseline in Cutaneous Histological Architecture
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This primary endpoint outcome was assessed in Part 2 participants only.
Arm/Group Title Part 2: Open-label Group Part 2: Unaffected Tissue Samples
Hide Arm/Group Description:

Ketoprofen 225 mg daily, taken orally

Open-label group: 75 mgs, three times daily, for four months

Results from normal samples from Part 2 participants are presented in this reporting group.
Overall Number of Participants Analyzed 16 16
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline 6.125  (2.247) 0.8  (1.2)
Month 4 2.688  (1.401) 0.6  (1.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Open-label Group
Comments For the analysis, the 4-month post-minus-pre change in this score for ketoprofen was compared.
Type of Statistical Test Equivalence
Comments The likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P<0.05
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method t-test, 2 sided
Comments paired t-test
3.Primary Outcome
Title Part 3: Measurement of Skin Thickness
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data for this outcome were collected in Part 3 participants only and for lymphedema-affected limbs only.
Arm/Group Title Part 3: Placebo Group Part 3: Ketoprofen Group
Hide Arm/Group Description:
Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months
Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months
Overall Number of Participants Analyzed 16 14
Mean (Standard Deviation)
Unit of Measure: mm
Baseline 47  (28) 49  (21)
Month 4 45  (31) 41  (21)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 3: Placebo Group
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments Pre-to-post comparison: the likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P<0.05
Statistical Test of Hypothesis P-Value =0.6
Comments [Not Specified]
Method t-test, 2 sided
Comments Paired t-test
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part 3: Ketoprofen Group
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments Pre-to-Post comparison: The likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P<0.05
Statistical Test of Hypothesis P-Value =0.01
Comments [Not Specified]
Method t-test, 2 sided
Comments paired t-test
4.Secondary Outcome
Title Part 2: Measurement of Skin Thickness
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data for this outcome were collected in Part 2 participants only and for lymphedema-affected limbs only.
Arm/Group Title Part 2: Open-label Group
Hide Arm/Group Description:

Ketoprofen 225 mg daily, taken orally

Open-label group: 75 mgs, three times daily, for four months

Overall Number of Participants Analyzed 16
Mean (Standard Deviation)
Unit of Measure: mm
Baseline 62  (34)
Month 4 27  (22)
5.Secondary Outcome
Title Part 3: Change From Baseline in Cutaneous Histological Architecture
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data for this outcome were collected in Part 3 participants only and for lymphedema tissue samples only.
Arm/Group Title Part 3 Placebo Part 3: Ketoprofen Group Part 3: Unaffected Tissue Samples
Hide Arm/Group Description:
Placebo, 1 capsule taken orally, three times daily, for four months
Ketoprofen, 75 mgs, 1 capsule taken orally, three times daily, for four months
Results from normal samples from Part 3 participants are presented in this reporting group.
Overall Number of Participants Analyzed 16 14 30
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline 2.7  (2.1) 4.1  (1.8) 0.8  (1.2)
Month 4 1.0  (1.1) 1.18  (1.08) 0.6  (1.0)
6.Secondary Outcome
Title Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data for this outcome were collected for Part 2 and Part 3 participants with unilateral lymphedema-affected limbs only.
Arm/Group Title Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Hide Arm/Group Description:

Ketoprofen 225 mg daily, taken orally

Open-label group: 75 mgs, three times daily, for four months

Participants randomized to receive placebo:

1 capsule, three times daily, for four months

Participants randomized to receive active medication:

Ketoprofen 75 mgs., 1 capsule, taken orally, three times daily, for four months

Overall Number of Participants Analyzed 10 12 13
Overall Number of Units Analyzed
Type of Units Analyzed: Limbs
20 24 26
Mean (Standard Deviation)
Unit of Measure: ratio of Ro values
Baseline 1.5  (0.5) 1.5  (0.4) 1.4  (0.2)
Month 4 1.6  (0.3) 1.5  (0.3) 1.4  (0.2)
7.Secondary Outcome
Title Part 2/Part 3: Change in Limb Volume
Hide Description Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.
Time Frame Baseline; 4 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data for this outcome were collected only for lymphedema-affected limbs only.
Arm/Group Title Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Hide Arm/Group Description:

Ketoprofen 225 mg daily

Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months

Participants randomized to receive placebo:

1 capsule, taken orally, three times daily, for four months

Participants randomized to receive active medication:

Ketoprofen 75 mgs., 1 capsule, taken orally, three times daily, for four months

Overall Number of Participants Analyzed 16 16 14
Mean (Standard Deviation)
Unit of Measure: ml
Baseline 9866  (5821) 7196  (3519) 8598  (3066)
Month 4 9465  (5115) 7256  (3496) 8675  (3103)
8.Secondary Outcome
Title Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data for this outcome was collected for Part 3 participants only.
Arm/Group Title Part 3: Placebo Part 3: Ketoprofen Group
Hide Arm/Group Description:
Placebo, 1 capsule taken orally, three times daily, for four months
Ketoprofen, 75 mgs, 1 capsule taken orally, three times daily, for four months
Overall Number of Participants Analyzed 16 14
Mean (Standard Deviation)
Unit of Measure: MFI (log10)
Baseline 121  (90) 131  (76)
Month 4 209  (214) 126  (107)
Time Frame Four months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Part 1: Exploratory Group Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Hide Arm/Group Description

Ketoprofen 225-300 mgs daily, taken orally

Ketoprofen-exploratory group: 225-300 mgs daily for four to six months

Ketoprofen 225 mg daily, taken orally

Open-label group: 75 mgs, three times daily, for four months

Participants randomized to receive placebo: placebo, three times daily, taken orally

Placebo: 1 capsule, three times daily, for four months

Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally

Ketoprofen: 1 capsule, three times daily, for four months

All-Cause Mortality
Part 1: Exploratory Group Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/50 (0.00%)      0/23 (0.00%)      0/23 (0.00%)      0/21 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Part 1: Exploratory Group Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/50 (0.00%)      0/23 (0.00%)      0/23 (0.00%)      0/21 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Part 1: Exploratory Group Part 2: Open-label Group Part 3: Placebo Group Part 3: Ketoprofen Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/50 (6.00%)      2/23 (8.70%)      1/23 (4.35%)      2/21 (9.52%)    
Gastrointestinal disorders         
Hemorrhoidal hemorrhag  1  0/50 (0.00%)  0 0/23 (0.00%)  0 0/23 (0.00%)  0 1/21 (4.76%)  1
Skin and subcutaneous tissue disorders         
Cellulitis  1  3/50 (6.00%)  3 1/23 (4.35%)  1 0/23 (0.00%)  0 0/21 (0.00%)  0
Rash  1  0/50 (0.00%)  0 1/23 (4.35%)  1 1/23 (4.35%)  1 1/19 (5.26%)  1
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Stanley Rockson
Organization: Stanford University, School of Medicine
Phone: 650-725-7571
Responsible Party: Stanley Rockson, Stanford University
ClinicalTrials.gov Identifier: NCT02257970     History of Changes
Other Study ID Numbers: 7781
First Submitted: August 25, 2014
First Posted: October 7, 2014
Results First Submitted: July 19, 2018
Results First Posted: September 14, 2018
Last Update Posted: September 14, 2018