Evidence Table 1Data Abstraction of Randomized Controlled Trials

Author
Year
Country
Trial name
(Quality rating)
PopulationInterventionsAllowed other medications/interventionsAge
Gender
Ethnicity
Other population characteristicsN (Number randomized)Number withdrawn/lost to fu/analyzedEfficacy/Effectiveness outcomesAdverse events reportedTotal withdrawals;
withdrawals due to adverse events
FundingComments
Altman 2009
U.S.
(Fair)
Men and women ≥40 years with diagnosis of primary OA in their dominant hand. Following ACR criteria, OA was defined as nodal enlargement in ≥2 of 10 joints.
  1. Diclofenac sodium gel 1% 2 g qd
  2. Placebo (Vehicle) For 8 weeks
Rescue medication (acetaminophen 500 mg tablets) at a maximum dose of 4 mg qd64 years
Male: 23%
White: 89%
Asian: 0.7%
Black: 3.9%
Other: 6.3%
Right handed: 91.2%
Painful CMC-1 joint: 71.4%
Painful DIP/PIP (Digits 2-3): 78.2%
Currently treated with NSAIDs before screening visit: 51.7%
Kellgren-Lawrence grade of 3: 52%
38551/3/385Diclofenac versus Placebo
Change from baseline at Week 6 mean, (SD), (%), p value vs placebo: OA pain intensity: -33.7 (27.8), (-45.8%) vs -26.7 (28.0), (-36.3), p=0.023
Total AUSCAN score mean: -25.9 (25.1), (-38.5%) vs -18.6 (26.2), (-27.9%), p=0.006
Pain index: -26.1 (25.6), (-39.4%) vs -20.1 (26.5), (-30.1%), p=0.021
Stiffness index: -25.2 (28.7), (-38.2%) vs - 17.2 (30.0), (-25.8%), p=0.005
Functional index: -25.8 (26.1), (-38.0%) vs -17.8 (26.9), (26.7%), p=0.005
Global rating of disease: -23.1 (27.0), (40.1%) vs 16.3 (28.0), (-28.8%), p=0.023

Change from baseline at Week 8 mean, (SD), (%), p value vs placebo: OA pain intensity: -35.5 (28.9), (-48.2%) vs -29.6 (29.5), (-40.2%), p=0.06
Total AUSCAN score: -26.7 (26.6), (-39.7%) vs -20.5 (27.3), (30.7%), p=0.028
Pain index: -27.2 (26.9), (-41.0%) vs -22.5 (27.8), (-33.7%), p=0.09
Stiffness index: -26.6 (30.0), (-40.3%) vs -21.1 (30.5), (-31.7%), p=0.048
Global rating of disease: -24.2 (28.1), (-42.0%) vs -18.8 (29.2), (-33.3%), p=0.11
Diclofenac vs placebo
At least one treatment-emergent AE: 52.0% vs 43.9%
GI AE: 7.6% vs 3.7%
Headache: 11.1% vs 10.2%
Back pain: 6.1% vs 7.5%
Arthralgia: 3.5% vs 7.0%
Pain in extremity: 3.5% vs 3.2%
Sinusitis: 3.0% vs 0.5%
Neck pain: 3.0% vs 0.5%
Application site paresthesia: 2.5% vs 1.1%
Pharyngolaryngeal pain: 2.5% vs 0%
Diarrhea: 2.0% vs 1.1%
Cough: 2.0% vs 1.1%
Upper respiratory tract infection: 2.0% vs 0.5%
Diclofenac vs Placebo
Total: 25 (12.6%)vs 26 (13.9%)
Due to AE: 10 (5%)vs 4 (2.1%)
Novartis Consumer Health Inc
Baer 2005
Canada
(Fair)
Men and women, age 40–85 years, with radiologically confirmed primary OA of at least one knee and a flare of pain at baseline following discontinuation of prior therapy (oral NSAID or acetaminophen used at least 3 days per week during the previous month). Excluded if they had secondary arthritis related to systemic inflammatory arthritis, recent corticosteroid use, ongoing use of prohibited medication (NSAID, other oral analgesic, muscle relaxant, or low-dose antidepressant for any chronic pain management, glucosamine or chondroitin)
  1. Topical diclofenac solution (Pennsaid)
  2. Vehicle control solution (carrier with no diclofenac) 40 drops 4 times daily directly to the painful knee(s), without massage, for 6 weeks
ASA (≤325 mg/day) was permitted for cardiovascular prophylaxis; acetaminophen (up to four 325-mg tablets per day) was permitted for residual knee or other body pain throughout the treatment period, but not during the washout period prior to baseline assessment or during the week prior to final assessment at week 6.64.8 years
Male: 43.5%
White: 82.9%
Black: 5.1%
Oriental: 2.3%
Weight: 86.7 kg
Height: 1.65 m
Heart rate: 74.2 bpm
BP: 135.6/80.5
Total x-ray score: 7.3
Baseline pain score: 12.9
Baseline physical function score: 40.5
Baseline stiffness score: 5.2
PGA score: 3.2
Patients treating two knees at baseline: 62%
Patients treating two knees at final: 80.1%
21660/0/212Topical diclofenac vs vehicle-control
Pain
Mean change in score: -5.2 vs -3.3 (p=0.003)
Mean difference in change: 1.9 (95% CI, 0.7 to 3.2)
Physical function
Mean change in score: -13.4 vs -6.9 (p=0.001)
Mean difference in change: 6.5 (95% CI, 2.5 to 10.5)
PGA
Mean change in score: -1.3 vs -0.7 (p=0.0001)
Mean difference in change: 0.6 (95% CI, 0.2 to 0.9)
Stiffness
Mean change in score: -1.8 vs -0.9 (p=0.002)
Mean difference in change: 0.9 (95% CI, 0.3 to 1.4)
Pain on walking
Mean change in score: -1.2 vs -0.8 (p=0.014)
Mean difference in change: 0.4 (95% CI, 0.1 to 0.7)
50% Reduction in pain: 43.8% vs 25.2% (p=0.004)
Good or very good PGA response: 43.8% vs 16.8% (p<0.0001)
Topical diclofenac vs vehicle-control

GI Reaction
Abdominal pain: 4 (3.7%) vs 1 (0.9%)
Constipation: 1 (0.9%) vs 1 (0.9%)
Diarrhea: 1 (0.9%) vs 0 (0%)
Dyspepsia: 4 (3.7%) vs 1 (0.9%)
Gastritis: 1 (0.9%) vs 0 (0%)
Melena: 0 (0%) vs 1 (0.9%)
Nausea: 1 (0.9%) vs 2 (1.8%)

Application-Site Skin Reaction
Dry skin/skin irritation: 42 (39%) vs 23 (21.1%); p=0.004
Rash: 2 (1.9%) vs 4 (3.7%)
Paresthesia: 2 (1.9%) vs 2 (1.8%)
Pruritus: 0 (0%) vs 2 (1.8%)

Other Reaction
Headache: 6 (5.6%) vs 10 (9.2%)
Halitosis: 2 (1.9%) vs 0 (0%)
Taste Perversion: 4 (3.7%) vs 2 (1.8%)
Topical diclofenac vs vehicle- control
Total: 21 (19.6%) vs 39 (35.8%); p=0.008
Due to AE: 9 (8.4%) vs 9 (8.3%)
Dimethaid Health Care Ltd.
Barkhuizen, 2006
USA
(Fair)
Male/Female 18-75 years old with AS with axial involvement and requiring NSAID during previous 30 days, with or without enthesopathy, large peripheral synovitis, psoriasis, pain intensity >50mm on a 100m VAS, no analgesic 8 hours or antiinflammatory 72 hours prior to study start, negative pregnancy test and continued use of effective contraception
  1. Celecoxib 200 mg po qd
  2. Celecoxib 400 mg po qd
Acetaminophen up to 2000mg/day40-45 years (mean 44.6 years)
Male: 73.8%
Caucasian: 76.6%
Asian: 4.1%
African American: 1.6%
Other: 17.7%
Height: 170.7 cm
Weight: 82.5 kg
Patient's: global assessment of pain intensity, mean: 71.9
Patient's: global assessment of disease activity, mean: 66.6
611NR/203/408Placebo vs Celecoxib 200mg vs Celecoxib 400 mg vs Naproxen
LS mean changes from baseline to Week 12 in Pain Intensity Score (VAS): -9.9 vs -29.5 vs -30.0 vs -36.3 (p<0.001 for all active treatments vs placebo)

LS mean changes from baseline to Week 12 in Disease Activity Score (VAS): -4.2 vs -21.1 vs -22.2 vs -27.6 (p<0.001 for all active treatments vs placebo; p<0.05 naproxen vs celecoxib 200 mg)

LS mean changes from baseline to Week 12 in Functional Impairment (BASFI) Score (VAS): 3.1 vs -8.5 vs -12.1 vs -15.8 (p<0.001 for all active treatments vs placebo; p<0.01 naproxen vs celecoxib 200 mg)

Physician's global assessment of disease activity, LS mean change from baseline to Week 12: -5.75 vs -18.7 (p<0.05 vs placebo) vs -23.4 (p<0.05 vs placebo) vs -26.7 (p≤0.05 vs placebo and celecoxib 200 mg)

Nocturnal Pain (VAS), LS mean change from baseline to Week 12: -3.05 vs -20.3 (p≤0.05 vs placebo) vs -22.3 (p≤0.05 vs placebo) vs -28.5 (p≤0.05)

BASDAI, LS mean change from baseline to Week 12: -1.74 vs -15.4 (p≤0.05 vs placebo) vs -19.5 (p≤0.05 vs placebo) vs -22.9 (p≤0.05 vs placebo)

Morning stiffness, min, median, change from baseline to Week 12: 0 vs -5 (p≤0.05 vs placebo) vs -20 (p≤0.05 vs placebo) vs -30 (p≤0.05 vs placebo and celecoxib 200 mg)

CRP, mg/l, LS mean, change from baseline to Week 12: 1.17 vs -2.46 (p≤0.05 vs placebo) vs -2.64 (p≤0.05 vs placebo) vs -3.60 (p≤0.05 vs placebo)
Placebo vs Celecoxib 200mg vs Celecoxib 400 vs Naproxen
Any event: 82 (52.6%) vs 73 (53.3%) vs 85 (52.8%) vs 78 (49.7%)
Headache: 11 (7.1%) vs 7 (5.1%) vs 13 (8.1%) vs 3 (1.9%)
Nausea: 3 (1.9%) vs 4 (2.9%) vs 9 (5.6%) vs 7 (4.5%)
Nasopharyngitis: 4 (2.6%) vs 10 (7.3%) vs 9 (5.6%) vs 5 (3.2%)
Dermatitis: 3 (1.9%) vs 3 (2.2%) vs 8 (5.0%) vs 0 (0.0%)
Arthralgia: 0 (0.0%) vs 5 (3.6%) vs 6 (3.7%) vs 1 (0.6%)
Dyspepsia: 5 (3.2%) vs 6 (4.4%) vs 6 (3.7%) vs 11 (7.0%)
Diarrhea: 3 (1.9%) vs 5 (3.6%) vs 5 (3.1%) vs 6 (3.8%)
Fatigue: 5 (3.2%) vs 3 (2.2%) vs 3 (1.9%) vs 5 (3.2%)
Upper respiratory tract infection: 7 (4.5%) vs 3 (2.2%) vs 3 (1.9%) vs 5 (3.2%)
Sinusitis: 4 (2.6%) vs 0 (0.0%) vs 2 (1.2%) vs 5 (3.2%)
Constipation: 2 (1.3%) vs 0 (0.0%) vs 1 (0.6%) vs 5 (3.2%)
Sore throat: 5 (3.2%) vs 1 (0.7%) vs 0 (0.0%) vs 1 (0.6%)
203; 32 (11 placebo, 3 celecoxib 200 mg, 9 celecoxib 400 mg, 9 Naproxen)Pfizer
Barthel 2009
U.S.
(Fair)
Ambulatory men and women ≥35 years with OA in one or both knees according to ACR criteria and with symptom onset ≥6 months before screening.
  1. Diclofenac sodium gel 1% 4 g qd
  2. Placebo For 12 weeks
Rescue medication (acetaminophen 500 mg tablets) at a maximum dose of 8 tablets (4 mg qd)59.5 years
Male: 22.3%
Ethnicity: NR
BMI: 31.3kg/m249245/5/491Diclofenac vs Placebo
Mean change in WOMAC pain from baseline at 12 weeks: -5.0 vs -4.0, p=0.01
Mean change in WOMAC function from baseline at 12 weeks: -15.0 vs - 10.9, p=0.001
Change in global rating of disease from baseline at 12 weeks: -27.0 vs - 18.2, p=0.001
Reduction in pain on movement from baseline at week 4: -27.7 vs -20.1 m.m; p<0.002 reflecting 44% reduction relative to baseline vs 32% reduction relative to placebo
% OARSI response based on WOMAC pain index at week 12: 64.0% vs 51.7%, p=0.006
% OARSI response based on pain on movement at week 12: 64.8% vs 49.2%, p=0.003
Global evaluation of treatment at 12 weeks, mean (SD): 2.23 (1.43) vs 1.86 (1.43), p=0.007
Rescue drug use over entire study: 91.3% vs 92.4%, p=Weeks 0.600 Weeks with no rescue drugs, mean (SD): 4.33 (4.45) vs 3.46 (4.21), p=0.04
Diclofenac vs Placebo
Any AE: 60.2% vs 53.8%
Severe AE: 5.1% vs 5.9%
GI AE: 5.9% vs 5.0%

AE occurring in ≥3% of randomized patients:
Headache 13.8% vs 14.3%
Arthralgia 13.4% vs 8.8%
Back pain: 9.1% vs 6.7%
Dermatitis: 4.3% vs 1.7%
Skin Dryness : 0.4% vs 0.8%
Eczema: 0.0% vs 0.4%
Erythema: 0.4% vs 0.4%
Papules: 0.4% vs 0.0%
Pruritus: 1.6% vs 0.4%
Unspecified reaction: 0.4% vs 0.0%
Pain: 4.3% vs 2.9%
Nasopharyngitis: 3.5% vs 5.9%
Upper RTI: 3.5% vs 5.5%
Sinusitis: 3.5% vs 2.5%
Cough 0.4% vs 3.4%
Diclofenac vs placebo
Total: 45 vs 60
Due to AE: 13 (5.1%)vs 9 (3.8%)
Novartis consumer health, Parsippany, NJ
Bookman 2007
Canada
(Fair)
Men and women 18-80 years with primary OA in at least 1 knee and at least moderate pain. Excluded patients with secondary arthritis related to syphilitic neuropathy, ochronosis, metabolic bone disease or acute trauma; for use of corticosteroids, oral analgesic or glucosamine, or another topical product at the application site.
  1. Topical diclofenac solution (1.5% wt/wt diclofenac sodium in a carrier containing dimethyl sulfoxide)
  2. Vehicle-control solution (the carrier containing dimethyl sulfoxide but no diclofenac)
  3. Placebo solution (a modified carrier with a token amount of dimethyl sulfoxide for blinding purposes but no diclofenac) For 4 weeks
ASA (≤ 325 mg/d) was permitted for cardiovascular prophylaxis; use of acetaminophen (up to two 325 mg tablets qd) was permitted for other body pain or residual knee pain throughout the washout and study periods, except during the 24 hours immediately before the baseline and final WOMAC assessments.61.8 years
Male: 36.4%
Ethnicity: NR
Weight: 83.3 kg
Height: 1.66 m

Topical diclofenac vs vehicle-control vs placebo
Patients treating 2 knees: 38% vs 49% vs 51% (p=0.09)

Radiographic analysis showed NSD between the treatment groups in the distribution of severity of joint-space narrowing and marginal osteophytes within each knee compartment
24839/0/247Topical diclofenac vs vehicle-control vs placebo
WOMAC LK3.0 OA Index
Pain
Change from baseline, mean (95% CI): -3.9 (-4.8 to-2.9; p<0.05) vs -2.5 (-3.3 to -1.7; p=0.023) vs -2.5 (-3.3 to -1.7; p=0.016)
Percent change from baseline: -42.9 vs -26.9 vs -26.6
Physical function
Change from baseline, mean (95% CI): -11.6 (-14.7 to-8.4; p=0.002 compared with vehicle and p=0.014 compared with placebo) vs -5.7 (-8.3 to -3.2) vs -7.1 (-9.3 to -4.4)
Percent change from baseline: -39.3 vs -18.7 vs -23.0
Stiffness
Change from baseline, mean (95% CI): -1.5 (-1.9 to -1.1; p=0.015 compared with vehicle and p=0.002 compared with placebo) vs -0.7 (-1.2 to -0.3) vs -0.6 (-1.0 to -0.2)
Percent change from baseline: -40.5 vs -20.0 vs -16.2
Pain on walking
Change from baseline, mean (95% CI): -0.8 (-1.1 to -0.6; p=0.003 compared with vehicle and p<0.015 compared with placebo) vs -0.4 (-0.6 to -0.2) vs -0.6 (-0.8 to -0.4)
Percent change from baseline: -44.4 vs -21.1 vs -30.0
PGA:
Sum, mean (95% CI): 6.7 (6.1 to 7.4; p<0.05) vs 7.8 (6.9 to 8.6) vs 7.8 (7.2 to 8.5)
Topical diclofenac vs vehicle-control vs placebo

At application site:
Dry skin: 36% (p=0.001 compared with vehicle-control group and p<0.0001 compared with placebo) vs 14% (p<0.01 compared with placebo) vs 1%
Paresthesia: 14% vs 22% (p<0.01 compared with placebo) vs 6%
Rash: 13% (p<0.05 compared with placebo) vs 8% vs 4%
Pruritus: 11% vs 8% vs 4%

GI and other:
Constipation: 1% vs 1% vs 1%
Diarrhea: 1% vs 2% vs 4%
Dyspepsia: 7% vs 5% vs 6%
Nausea: 0% vs 5% vs 1%
Vomiting: 0% vs 1% vs 1%
Halitosis: 5% vs 1% vs 0%
Body odor: 2% vs 0% vs 0%
Topical diclofenac vs vehicle-control vs placebo
Total: 10 (12%) vs 14 (17.5%) vs 15 (17.9%)
Due to AE: 5 (6%) vs 3 (3.8%) vs 0 (0%; p=0.06)
NR (though competing interests were disclosed)
Bruhlmann 2003
Switzerland
Men and women between 18-85 years affected by symptomatic OA of the knee.
  1. 1.3% DHEP Patch (corresponding to 1% of diclofenac sodium salt) bid
  2. Placebo For 14 days
Paracetamol 500 mg tablets allowed as rescue64.4 years
Male: 41.7%
Ethnicity: NR
Target knee (Left): 45.6%
Target knee (Right): 54.4%
Symptomatic involvement:
Bilateral: 43.7%
Unilateral left: 21.4%
Unilateral right: 35%
10310/2/103DHEP patch vs placebo
Lequesne index at baseline: 10.2 (3.3) vs 10.4 (3.5)
Lequesne index at day 14: 6.9 (3.2) vs 9.0 (3.9), p<0.01 (between group as well as compared to baseline)
Proportion of patients with reduction in Lequesne score at day 14: 32% vs 15%
Spontaneous pain as measured on a numeric rating scale at baseline: 5.7 (1.5) vs 5.6 (1.5)
Spontaneous pain as measured on a numeric rating scale at day 14: 2.1 (1.8) vs 3.9 (2.1), p<0.01 between group as well as compared to baseline
Walking time (sec) at baseline: 16.3 (6.7) vs 16.3 (4.2)
Walking time (Sec) at day 14: 13.3 (4.3) vs 14.5 (3.4), p<0.01 from baseline, NS between groups
Paracetamol consumption throughout the study: 22% vs 33%
Patient judqment (p<0.05)
Excellent: 24.5% vs 8.9%
No efficacy: 10.2% vs 17.8%
Physician Judgment (p<0.01)
Excellent: 10.2% vs 8.9%
No efficacy: 8.2% vs 20%
DHEP patch vs Placebo
Patient judgment of Good or Excellent: 91.8% vs 93.4%
Physician judgment of good or excellent: 95.9% vs 93.5%
% reporting AE: 4 (7.8%) vs 3 (5.8%)
DHEP patch vs Placebo
Total: 3 (5.9%) vs 7 (13.9%)
Due to AE: 1 (2%) vs 2 (3.8%)
Rush: 2 (3.9%) vs 1 (2%)
NR
Chan, 2007
China
Patients with upper gastro-intestinal bleeding and taking non-selective NSAIDs for arthritis200 mg bid celecoxib for all patients
Group A: 20 mg esomeprazole bid
Group B: Placebo
For 12 mos
Antacids, paracetamol, Non-NSAID analgesics, and disease-modifying anti-rheumatic drugs71 yrs
% Male: 48.4%
NR (could be 100% Asian)
Gastric ulcers: 57.5%
Duodenal ulcer: 35%
Gastric and duodenal More than 1 episode of ulcer bleeding: 18.7%

Types of arthritis:
OA: 86.4%
RA: 2.2%
Others: 11.4%
27345/1/237Combined treatment (celecoxib +esomeprazole) vs control group (celecoxib+placebo)
% of patients with decrease in hemoglobin of 20g/L: 0 vs 9 (6.6%)
Global assessment of disease activity at baseline mean, (SD): 3.2 (0.7) vs 3.1 (0.8)
Global assessment of disease activity at 12 mos: mean, (SD): 2.4 (0.8) vs 2.4 (0.7), change from baseline -0.8 vs -0.7, p<0.0001, p=0.85 between groups
Patient's assessment on a VAS at baseline mean (SD): 63.9 (18.9) vs 60.0(18.9)
Patient's assessment on a VAS at 12 mos: 46.6 (19.0) vs 43.3 (17.7), change from baseline -17.3 vs 17.0, p<0.0001, p=0.74 between groups
Combined treatment (celecoxib +esomeprazole) vs control group (celecoxib+placebo)
% patients with recurrent ulcer bleeding: 0 vs 12 (8.9%) [95% CI, 4.1 to 13.7], p=0.0004
Cumulative incidence of lower gastro-intestinal bleeding: 3.0% (95% CI 0.1 to 5.8) vs 1.6% (95% CI -0.6 to 3.7) (p=0.46)
Renal failure: 2.9% vs 2.9%, p=1.00
Unstable angina: 0.7% vs 0%, p=1.00
Stroke: 0% vs 1.5%, p=0.25
Heart failure: 0.7% vs 0.7%, p=1.00
Peripheral vascular disease: 0% vs 0.7%
Others (pneumonia, COAD, hypoglycemia, hypocalcemia, hyponatremia, vertigo, head injury, knee arthritis, carcinoma of the larynx): 5.1% vs 5.1%, p=0.72
Deaths: 0.7% (pneumonia) vs 1.5% (head injury, core pulmonale), p=0.62
Hypertension: 18.2% vs 20.6%, p=0.63
Dyspepsia: 5.1% vs 9.6%, p=0.16
Peripheral edema: 3.6% vs 7.4%, p=0.18
Skin allergy: 0.7% vs 0.7%, p=1.00
Combined treatment (celecoxib+esomeprazole) vs control group (celecoxib+placebo)
Total: 23 (17%) vs 22 (16%)
Due to AE: 8 (5.8%) vs 10 (7.4%)
Grant from Research Grant Hong-Kong (CUHK4455)
Chan, 2010
(CONDOR)
Multinational Good
Patients tested negative For helicobacter pylori, aged 60 years and older or 18 years or older with previous gastroduodenal ulceration
  1. Celecoxib 200mg BID
  2. Diclofenac slow release 75 mg BID +Omeprazole for 6 mo
Antacids and non-NSAID analgesic drugs, including paracetamol upto 4 gms/day and histamine 2 receptor antagonists≤ 3 days per week. Prednisolone ≤10 mg daily, disease-modifying antirheumatic drugs or biologic treatments were only allowed if patients had been taking a stable dose for 12 or more weeks at randomization.65yrs
Female: 82%
White: 54.6%
Black: 2.4%
Asian: 13.6%
Hispanic: 20.7%
Other: 8.7%
Region of origin
Western Europe: 20%
South America: 39%
Asia: 13%
Easter Europe: 28%
Haemoglobin (g/L): 140
Haematocrit: 41%
History of gastroduodenal ulcer or ulcer bleeding : 19%
Previous helicobacter pylori infection: 21.5%
Comorbidity (includes coronary hear disease or heart failure, diabetes mellitus, hypertension, chronic lung diseases, chronic liver diseases, deep vein thrombosis, kidney diseases and history of anaemia
44841133/NR/4484Celecoxib vs diclofenac plus omeprazole
% of patients reaching primary endpoint (composite of clinically significant events occuring throughout the GI tract
0.9% (95% CI, 0.5 to 1.3) vs 3.8 (95% CI 2.9 to 4.3), difference 2.9%, 2.0 to 3.8%, p<0.0001. Hazard ratio was 4.3 (2.6-7.0) in favor of celecoxib
Clinically significant events through GI tract, total: 0.9% vs 3.6%
Gastroduodenal haemorrhage: 0.1% vs 0.1%
Gastric outlet obstruction: 0% vs 0%
Gastroduodenal, small bowel or large bowel perforation: 0% vs 0%
Small bowel haemorrhage: 0% vs 0%
Large bowel haemorrhage: 0% vs 0%
Total clinically significant anaemia of defined GI origin: 0.2% vs 1.1%
-Gastroduodenal ulcer or erosions: 0.2% vs 0.9%
Clinically significant anaemia of presumed occult GI origin including possible small bowel blood loss: 0.4% vs 2.4%
Haemoglobin decrease of 20g/L, n (%): 15 (0.7%) vs 77 (3.4%). Among them, haemoglobin concentration lower than 115 g/L: 10% vs 90%
LSM change from baseline to visit 6 in patient's global assessmentof arthritis: improvement of 0.75 (0.02) vs 0.77 (0.02)
Clinically significant events throughout GI tract plus symptomatic ulcers: 1% vs 5%, p<0.0001
% of patients with moderate to severe abdominal symptoms at month 6: 16% vs 19%, p=0.03
Celecoxib vs diclofenac plus omeprazole
Death: 2 (due to pulmonary embolism and bronchopneumonia) vs 2 (cardiac arrest)
Patients with AE: 51% vs 58%
Patients with treatment related AE: 25% vs 33%
Patients with serious AE: 3% vs 3%
Patients with serious treatment related AE: 1% vs <1% types of secondary AE
Celecoxib group: 1stable angina, 2 transient ischaemic attacks, 1 peripheral arterial event, 4 venous thrombosis
Diclofenac plus omeprazole: 1 transient ischaemic attack
Celecoxib vs diclofenac plus omeprazole
Total withdrawals: 22.7% vs 27.8%
Withdrawals due to AE: 10.4% vs 13.6%
Withdrawals due to GI related AE: 6% vs 8%
Pfizer
Dahlberg 2009
Scandinavia
(Good)
Men and women ≥60 years with OA of the hip or knee with a functional capacity of I-III. Excluded patients with kidney/liver/heart disease or GI problems.
Paracetamol (Acetaminophen) 500 mg prn71 yrs
Male: 31%
Ethnicity: NR
OA of knee: 62%
OA of hip: 35%
OA of knee and hip: 2%
Functional Class:
I: 9%
II: 81%
III: 10%
925366/9/916Celecoxib vs Diclofenac
PGA of Arthritis (Good or Very Good):
Baseline: 11% vs 14%
End of Study: 36% vs 36%

Physician Global Assessment of Arthritis (Good or Very Good):
Baseline: 19% vs 19%
End of Study: 45% vs 42%
Patient Assessment of Arthritis Pain using VAS:
Baseline: 51% vs 49%
End of Study: 40% vs 42%
Patient Satisfaction Assessment (Pain Relief):
Baseline: 5.9 vs 5.8
End of Study: 6.2 vs 6.3
Patient Satisfaction Assessment (Walking/bending):
Baseline: 5.0 vs 5.0
End of Study: 6.1 vs 6.0
Physician Satisfaction assessment:
Baseline: 5.4 vs 5.2
End of Study: 6.0 vs 5.9
Celecoxib vs Diclofenac:
Total AEs: 19.7% vs 21.2%
Death: 1.3% vs 1.1%
MI: 0.9% vs 1.3% (although all judged by investigators as to not be related to study medication)
Angina: 0.4% vs 1.1% (all judged as not related to study drugs)
Heart failure: 0.9% vs 1.1% (1/4 vs 3/5 judged as related to study medication)
CVA: 0.2% vs 1.1%
GI hemorrhage: 0.2% vs 0% (hemorrhage judged to be related to study drug)
Ulcer: 0.2% vs 0.6% (1/1 vs 2/3 ulcers judged to be study drug related)
Total CV+Renal: 70 (15.3%) vs 95 (20.7%)
Total GI: 7 (1.5%) vs 10 (2.2%)
Total Hepatic: 10 (2.2%) vs 39 (8.5)
Celecoxib vs Diclofenac:
Total: 181 (39.5%) vs 185 (40.4%)
Due to AE: 117 (25.3%) vs 127 (27.5%)
Pfizer sponsored; Authors received a consulting fee from Pfizer; Pfizer provided expert review
Dentali 2006
Canada
Patients aged >18 yrs receiving long-term warfarin therapy (at least 3 months with a dose administered to achieve a target INR of 2.0–3.0 or 2.5–3.5), with stable anticoagulation, and a diagnosis of OA of the knee, hand, hip, or spine for ≥ 3 months, requiring an NSAID or a non-NSAID analgesic treatment for at least 10 weeks.
  1. Celecoxib 200 mg daily
  2. Codeine phosphate 7–15 mg tid or qd (titrated until pain was controlled) For 5 weeks per phase (crossover)
Warfarin therapy

No concomitant antiinflammatory or other analgesic treatment was allowed.
70 years
Male: 53%
Ethnicity: NR
Mean baseline INR: 2.43

Reason for anticoagulation:
Atrial fibrillation: 67%
Venous thromboembolic disease: 13%
Mechanical valves: 13%
Myocardial infarction: 7%

Concomitant disease:
Previous stroke: 20%
Hypertension: 47%
Coronary heart disease: 27%
155/0/15Mean INR values: NSD (mean difference [95% CI] 0.10 [–0.04 to 0.24]; p=0.16)

Insufficient evidence to reject the hypothesis that the two treatments had an equal effect on the INR (mean difference [95% CI] 0.10 [–0.04 to 0.24]; p=0.16) based on mean imputation.

Excessive anticoagulation: 1 patient during treatment with celecoxib (INR 4.9)
During treatment with Celecoxib vs Codeine
Cardiac arrest due to a myocardial infarction: 0 (0%) vs 1 (6.7%)
Dyspepsia: 1 (6.7%) vs (0%)
Constipation: 0 (0%) vs 1 (6.7%)
Excessive anticoagulation: 1 (6.7%) vs 0 (0%)
Celecoxib vs Codeine
Total: 5 (33%)
Due to AE: 2 (13.3%) vs 2 (13.3%)
NRCrossover trial
Dreiser 1993
France
Men and women 40-80 years treated with femorotibial and/or femoropatellar gonarthrosis diagnosed radiologically.
  1. DHEP containing 180 mg of active drug each
  2. Placebo for 15 days
Paracetamol 500 mg capsules65.8 years
Male: 22.6%
Ethnicity: NR
Mean weight male: 73.2 kg
Mean weight female: 66.9 kg
Mean height male: 170.5 cm
Mean height female: 159.8 cm
Gonarthrosis type
Femoropatellar: 19.4%
Femorotibial: 41.3%
Both: 38.1%
Unknown: 1.3%
15513/NR/unclearDHEP patch vs placebo, p-value between groups
Huskinsson's visual analogue scale values, evolution day 0-15, mean (S.E.): 33.7 (2.1) vs 22.4 (2.2), p<0.002
Change in Lequesne's index values at day 15: 5.0 (0.5) vs -2.8 (0.4), p<0.001
Change in patient's self evaluation at day 15: 1.16 (0.11) vs 0.59 (0.10), p<0.001
Mean nocturnal awakenings during 15 days of trial: 9.8 vs 23.3 (p<0.05)
Global judgment of efficacy
By the Investigator:
Good or Excellent: 64% vs 23% (p<0.001)
By the patient:
Good or Excellent: 71% vs 27% (p<0.0001)
DHEP vs Placebo
Total subjects with AE: 1 (1.3%) vs 4(5.2%)
Edema: 0 vs 1 (1.3%)
Nausea and vomiting: 0 vs 1 (1.3%)
Slight intermittent itching or burning sensation: 1 (1.3%) vs 2 (2.6%)

Global judgment of tolerability
By the investigator
Good or excellent (n): 67 vs 72
By the patient
Good or excellent (n): 77 vs 69
DHEP vs Placebo
Total: 1 vs 12, p<0.0001
Due to AE: 0 vs 1
NR
Emery 2008
UK
(Poor)
Men and women ≥45 years with OA of hip requiring joint replacement. Excluded patients with GI problems.
Acetaminophen at a max dose of 4 g as a rescue medication64 years
Male: 54%
White: 99%
Previous NSAID use: 65%24999/not clear, however, 29 (11.6%) "defaulted'/235Celecoxib vs Diclofenac:
Difference in change in Patients' assessment of arthritis pain by VAS from baseline to week 6 between Celecoxib vs Diclofenac: 12.1 mm favoring Diclofenac

Difference in change in Patients' assessment of arthritis pain by VAS from baseline to week 12 between Celecoxib vs Diclofenac: 10.0 mm favoring Diclofenac

Pain Satisfaction Scale ("relieve pain quickly enough"):
At week 6: 25.4% vs 36.8% (p≤0.041)
At week 12: 22.0% vs 41.0% (p=0.011)

Improved daily performance week 6: 27.1% vs 40.2% (p=0.021)
Better relationship with others week 6: 21.2% vs 30.8% (p=0.043)
Total subjects with adverse events: 133 (53%)
Celecoxib vs Diclofenac: 67 (53.6%) vs 66 (53.7%)

Serious AEs: 6/8 (4.8-6.4%) vs 1 (0.8%)
(Also: 1 MI before any study drug given, 1 Death occurred 1 day after conclusion of post treatment follow-up, 1-2 AEs reported 4 months after withdrawal from study)

Diarrhea: 10 (8%) vs 10 (8.1%)
Dyspepsia: 8 (6.4%) vs 2 (1.6%)
Nausea: 3 (2.4%) vs 4 (3.3%)
Upper Abdominal Pain: 2 (1.6%) vs 3 (2.4%)
Hypertension: 1 (0.8%) vs 6 (4.9%)
Headache: 6 (4.8%) vs 7 (5.7%)
Celecoxib vs Diclofenac:
Total: 54 (42.9%) vs 45 (36.6%)
Due to AE: 13 (10.3%) vs 18 (14.6%)
Sponsored by Pfizer; Primary author has undertaken clinical trials and provided expert advice for Pfizer and Novartisnoninferiority trial
Goldstein 2007
U.S.
(Good)
Men and women ≥18 years with OA and a clinical indication for low-dose ASA without GI disease, endoscopic ulcer, or a positive CLO-test for H. pylori.
  1. Celecoxib 200 mg po qd 81 mg or 325 mg ASA qd
  2. Naproxen 500 mg po bid Lansoprazole 30 mg po qd 81 mg or 325 mg ASA qd
Open-label antacids were self-administered not to exceed 12 tablets/24 hours56.7 years
Male: 34.6%
White: 72.2%
Black: 13.5%
Hispanic: 10.5%
Asian: 2.2%
Other: 1.5%
Low-dose ASA:
81 mg: 88.5%
325 mg: 11.5%

Neg H.pylori: 96.9%

No prior NSAID use for 90 days: 25.7%

Alcohol: 46.3%
Caffeine: 83.4%
Tobacco: 17.4%
1045354/12/1045Celecoxib vs Naproxen+ Lansoprazole:
GDU ulcer: 105 (20.3%) vs 95 (18.0%)

Week 12 change in pain scores: -18.2% vs -25%

Patients with GI complications by endoscopy: 0 vs 1
Celecoxib vs Naproxen+ Lansoprazole:
% of subjects reporting any AE: 53% vs 57%
% of subjects reporting serious AE: 1.2% vs 0.8%
URI: 9% vs 11%
Dyspeptic Sx: 10% vs 7%
Diarrhea: 4% vs 7%
Abdominal Pain: 6% vs 6%
Nausea/Vomiting: 6% vs 6%
Palpitations: 0% vs 0.2%
Celecoxib vs Naproxen+ Lansoprazole:
Total: 169 (32.8%) vs 185 (35.0%)
Due to AE: 33 (6.4%) vs 35 (6.6%)
NR
Herrera 2007
Venezuela
(Fair)
Men and women with OA of the knee (age variable). Major GI, liver, kidney, blood disease were excluded.
  1. Diclofenac 50mg IR po bid
Acetaminophen 500 mg rescue medication61.8 years
Male: 11.1%
Ethnicity: NR
Weight: 71.3 kg
Height: 1.57 m
BP systolic: 128.88 mmHg
BP diastolic: 80.42 mmHg
HTN: 46.8%
Diabetes: 5%
Hx of pain meds: 87.1%
62NR/NR/62Diclo CR vs DicIo IR:
Baseline VAS: 62.48 vs 61.39
After 24hr: 40.58 vs 38.28
After 72hr: 31.42 vs 29.72
Day 15: 33.24 vs 24.18
Day 30: 21.64 vs 17.29

WOMAC scores:
Baseline Function: 29.23 vs 27.55
Baseline Pain: 7.30 vs 6.74
Baseline Rigidity: 3.13 vs 2.42
Day 15 Function: 18.07 vs 15.55
Day 15 Pain: 4.00 vs 3.65
Day 15 Rigidity: 1.67 vs 1.17
Day 30 Function: 15.44 vs 11.75
Day 30 Pain: 3.44 vs 2.71
Day 30 Rigidity: 1.78 vs 1.07
Change in Total WOMAC score from baseline to day 30: -20.46 vs -22.21

Reported feeling better: 76% vs 94%
Clinically improved by physician assessment: 83% vs 97%
Needing rescue meds: 26% vs 36%
Diclo CR vs Diclo IR:
Total AEs: 7 (22.6%) vs 6 (19.4%)
NR;
Diclo CR vs Diclo IR: 0 (0%) vs 1 (3.2%)
NR
Niethard 2005
Germany
(Good)
Men and women ≥45 years with clinically diagnosed symptomatic unilateral OA of the knee for at least 6 mos.
  1. Diclofenac diethylamine gel 1.16%, 4 gqd
  2. Placebo for 3 weeks
Acetaminophen 500 mg rescue medication up to 4 tablets per day66 years
Male: 36.5%
Caucasian: 100%
Has periarticular pain: 29%

Has moderate or severe tenderness pressure
Joint space medially: 93%
Joint space laterally: 25.4%
Patella medially: 40.4%
Patella laterally: 14%

Has moderate or severe swelling of joint capsule: 27.5%
Joint effusion: 14.5%
Osteophytes: 99%
Sclerosis: 91%
Subchondral cysts: 14%
Joint space narrowing: 96.5%
23838/NR/327Diclofenac versus placebo
Decline from baseline in pain on movement as measured on VAS averaged over 8-21 days, mean (SD): 14 (16) vs 10 (13), p=0.005 (vs placebo)
Decline from baseline in spontaneous pain averaged over 8-21 days, mean, SD: 0.52 (0.55) vs 0.36 (0.54), p=0.02
Pain relief averaged over 8-21 days: 1.51 (0.93) vs 1.34 (0.79), p=0.10
Proportion of patients using any rescue medication overall: 39% vs 39%

Study center-based efficacy assessments:
Decline from baseline visit in pain intensity, mean (SD), p-value vs placebo
Week l: 18(20) vs 12 (18), p=0.03
Week 2: 27 (23) vs 17 (21), p=0.0002
Week 3: 34 (26) vs 25 (24), p=0.006
Decline from baseline visit in WOMAC pain score, mean (SD)
Week l: 11(14) vs 8 (14), p= 0.22
Week 2: 17 (18) vs 9 (18), p<0.0001
Week 3: 22 (21) vs 14 (23), p=0.0002
Physical function score, mean, (SD), p-value vs placebo
Week l: 11 (13)vs8(12), p=0.12
Week 2: 18 (17) vs 11(15), p=0.0002
Week 3: 23 (21) vs 16 (22), p=0.001
Stiffness Score, mean (SD), p value vs placebo
Week l: 11 (18)vs8(15), p=0.30
Week 2: 17 (21) vs 11 (20), p=0.002
Week 3: 22 (23) vs 14 (24), p=0.0004

End of study global treatment efficacy:
Good, very good or excellent: 69% vs 58%, p=0.03
OARSI/OMERACT response rate at final visit: 62% vs 46%, p=0.01
Diclofenac vs placebo
9% vs 9%
GI events (dry mouth and nausea): 0 vs 2
Edema: 1 vs 0
Allergic contact dermatitis: 1 vs 1
Application site reactions: 2 vs 2 (placebo patients had application site irritation and inflammation, application site burning)
SAE: 0 vs 1 (brain tumor)
Diclofenac versus placebo
Total: 15 (12.8%) vs 23 (19%)
Due to AE: 2(1.7) vs 0
Novartis consumer Health
Prabhu 2008
India
(Fair)
Males and females >18 years with confirmed diagnosis of OA.
  1. Paracetamol 500 mg
  2. Nimesulide 100 mg
  3. Nimesulide 100 mg/Racemethionine 50mg For 3 months
NRNR, except statement that age and weight factors were found to be comparable in all 5 groupsNR600/0/60Paracetamol vs Ibuprofen vs Nimesulide vs Diclofenac vs Nimesulide/Racemethionine

Pain intensity:
Change from baseline to final visit was significant at 5% level in all groups (p=0.02)
Reduction in pain intensity: 50% vs 49.35% vs 53.85% vs 50.63% vs 53.75%

Pain on movement:
Reduction was significant at 5% level for all groups over the course of the study (p=0.02)
Reduction in pain on movement: 58% vs 63.3% vs 66.6% vs 63.3% vs 66.6%

Tenderness:
Reduction was significant at 5% level for all groups over the course of the trial (p=0.02)
Reduction in tenderness: 95.8% vs 91.3% vs 95.4% vs 82.6% vs 100%
NRNoneNR
Roth 1995
U.S.
(Poor)
Included patients were those who provided evidence on
  1. pain aggravated by motion
  2. limitation of movement
  3. tenderness on pressure
  1. Placebo For 2 weeks
None67 years
Male: 27.7%
Caucasian: 96%
Duration of OA: 10.3 years
Percentage of patients by sentinel joint:
Hand: 24%
Foot: 7%
Cervical spine: 13%
Spine: 1%
Lower spine: 27%
Knee: 23%
Hip: 2%
Shoulder: 3%
1197/NR/NRDiclofenac vs placebo
Change from baseline in patient assessment of OA pain at week 2: -0.7 (1.0) vs -0.4 (0.9), p=0.0568
Diclofenac vs placebo
Pruritus: 7 vs 15
Rash: 5 vs 11
Diclofenac vs placebo
Total: 3 (5.08%) vs 4 (6.7%)
Due to AE: NR
NR
Roth 2004
U.S. and Canada
(Fair)
Men and non-pregnant women aged 40 to 85 years with primary OA of the knee.
  1. Topical diclofenac solution 1.5%
  2. Placebo For 12 weeks
Rescue analgesia with acetaminophen 325 mg X4 (max) tablets/day. Aspirin ≤325 mg/day permitted for cardiovascular prophylaxis.64.1 years
Male: 32.2%
White: 89%
Oriental: 0.3%
Black: 9.2%
Hispanic: 1.5%
Weight: 91 kg
Height: 166.8 cm
32698/3/320Diclofenac vs Placebo
Change from baseline in WOMAC pain, mean, (SD): -5.9 (4.7) vs -4.3 (4.4); p<0.005 vs diclofenac, % change -45.7% vs -33.3%
Change from baseline in WOMAC physical function, mean, (SD): -15.4(15.3) vs -10.1 (13.9), p<0.005 vs diclofenac, % change -36.7% vs -24.5%
Change from baseline in WOMAC stiffness, mean, (SD): -1.8 (2.1) vs -1.3 (2.0), p<0.005 vs diclofenac, % change -35.1% vs -24.1%
Change from baseline in PGA, mean, (SD): -1.3 (1.2) vs -0.9 (1.2), p<0.005 vs diclofenac, % change -42.2 vs -30.4%
Mean (SD) Pain on walking score change from baseline -1.18 (1.11) vs -0.87 (1.06), p<0.005 vs diclofenac, % change -45.0 % vs -32.7%
Diclofenac vs placebo Incidence of AE in GI tract: 12% vs 9% (p=0.49)
AE related to renal system: 0% vs 0%

GI tract infections
Abdominal pain: 3.0% vs 1.9%
Constipation: 1.2% vs 0.6%
Diarrhea: 0% vs 1.9%
Dyspepsia: 4.9% vs 3.7%
Flatulence: 2.4% vs 1.2%
Melena: 0% vs 1.2%
Nausea: 2.4% vs 0.6%
Vomiting: 0.6% vs 0%

Others
Asthma: 1.8% vs 0.6%
Dizziness: 1.2% vs 0%
Edema: 2.4% vs 1.2%
Headache: 5.5% vs 4.3%
Halitosis: 0% vs 1.2%
Taste perversion: 1.8% vs 3.1%
Diclofenac vs placebo
Total: 45 (27.4%) vs 53 (32.7%)
Due to AE: 8 (4.9%) vs (2.5%)
Dimethaid Healthcare Ltd.
Sieper, 2008
Germany
(Fair)
Male/Female 18-75 years AS, presence of axial involvement, no peripheral involvement and need of NSAID daily. Acute episode of moderate to severe pain at baseline or increase in pain from screening visit. Previous episodes of inflammatory bowel disease or GI ulcers within previous year and confirmed by endoscopy
  1. Celecoxib 200mg po qd
  2. Celecoxib 200mg po bid
Proton pump inhibitors; disease modifying antirheumatic drugs if stable dose for 3 months and no planned changes during study period; Prednisolone ≤10mg/day44.8 years

Male: 69%

NR
NR45877/8/373Celecoxib 200 mg qd vs Celecoxib 200 mg bid vs Diclofenac 75 mg bid VAS pain (0–100 mm)
Mean change from baseline (SD): -28.2 (27.2) vs -29.8 (25.1) vs -30.8 (25.6)
LS mean treatment contrast (SD): 2.9 (2.7) vs 2.1 (2.8) vs NA
95% CI for the treatment contrast: -2.4 to 8.2 vs -3.3 to 7.6 vs NA

BASDAI (0–10), mean (SD):
Mean change from baseline: -0.99 (2.11) vs -1.32 (1.72) vs -1.48 (1.76)
LS mean treatment contrast: 0.42 (0.20) vs 0.11 (0.20) vs NA
95% CI for the treatment contrast: 0.03 to 0.81 vs -0.29 to 0.51 vs NA

BASFI (0–10), mean (SD):
Mean change from baseline: -0.8 (2.0) vs -0.9 (1.5) vs -0.9 (1.8)
LS mean treatment contrast: 0.1 (0.2) vs -0.0 (0.2) vs NA
95% CI for the treatment contrast: -0.3 to 0.5 vs -0.4 to 0.3 vs NA

Global Assessment disease activity, subjects (0–10), mean (SD):
Mean change: -2.0 (2.7) vs -2.2 (2.5) vs -2.3 (2.6)
LS mean treatment contrast: 0.3 (0.3) vs 0.3 (0.3) vs NA
95% CI for the treatment contrast: -0.2 to 0.8 vs -0.2 to 0.8 vs NA

BASMI (0–10), mean(SD):
Mean change: -0.3 (1.4) vs -0.3 (1.4) vs -0.5 (1.3)
LS mean treatment contrast: 0.1 (0.1) vs 0.1 (0.1) vs NA
95% CI for the treatment contrast: -0.1 to 0.4 vs -0.1 to 0.4 vs NA
Celecoxib 200 mg qd vs Celecoxib 200 mg bid vs Diclofenac 75 mg bid
Any AEs: 92 (60.1%) vs 68 (45.3%) vs 91 (58.7%)
Drug-related AEs 29 (19.0%) vs 31 (20.7%) vs 41 (26.5%)
Subjects with drug-related serious AEs: 1 (0.7%) vs 0 vs 0

Gastrointestinal AEs: 23 (15.0%) vs 25 (16.7%) vs 44 (28.4%)
Upper GI AEs: 10 (6.5%) vs 11 (7.3%) vs 28 (18.1%)
Lower GI AEs: 9 (5.9%) vs 5 (3.3%) vs 20 (12.9%)
Abdominal distension: 3 (2.0%) vs 0 vs 1 (0.6%)
Abdominal pain (not otherwise specified): 1 (0.7%) vs 1 (0.7%) vs 4 (2.6%)
Abdominal pain upper: 5 (3.3%) vs 5 (3.3%) vs 14 (9.0%)
Diarrhea (not otherwise specified): 6 (3.9%) vs 4 (2.7%) vs 15 (9.7%)
Epigastric discomfort: 0 vs 1 (0.7%) vs 6 (3.9%)
Gastritis (not otherwise specified): 1 (0.7%) vs 4 (2.7%) vs 2 (1.3%)
Nausea: 0 vs 2 (1.3%) vs 5 (3.2%)
Stomach discomfort: 4 (2.6%) vs 1 (0.7%) vs 4 (2.6%)
Influenza-like illness: 8 (5.2%) vs 4 (2.7%) vs 2 (1.3%)
ALT increased: 0 vs 0 vs 6 (3.9%)
Arthralgia: 2 (1.3%) vs 3 (2.0%)vs 0
AS aggravated: 6 (3.9%) vs 5 (3.3%) vs 2 (1.3%)
Headache: 30 (19.6%) vs 22 (14.7%) vs 34 (21.9%)
Nasopharyngitis: 5 (3.3%) vs 5 (3.3%) vs 4 (2.6%)
Pharyngitis: 5 (3.3%) vs 1 (0.7%) vs 0
77; 35 (8 Celecoxib 200 mg qd, 12 Celecoxib 200 mg bid, 15 Diclofenac 75 mg bid)Pfizer
Simon, 2009
U.S.and Canada
(Fair)
Male/Female 40-85 years old with primary OA of knee based on: standard radiographic criteria for OA on xray within 3 months; pain with regular use of NSAID, flare of pain and minimum Likert pain score of 8 at baseline following washout
  1. Topical diclofenac solution 1.5% (Tdiclo)
  2. DMSO vehicle
  3. Oral doclofenac (Odiclo) 100 mg
  4. Topical diclofenac and oral diclofenac
Stable treatment with glucosamine, chondroitin, anti-depressants, proton pump inhibitors for previous 90 days or 325mg acetylsalicylic acid previous 30 days; acetaminophen up to 4 per day except for 3 days prior to assessment61.5 years
Male: 37.8%
Caucasian: 77.5%
Black: 5.3 %
Hispanic: 5.7 %
Asian: 9.1%
Other: 2.3%
Patients with bilateral disease: 95%
Hypertension: 3.2%
Normal BMI: 11.14%
Overweight: 29%
Obese: 58.7%
775248/13/772Topical diclofenac vs placebo vs DMSO vs Oral Diclofenac vs Topical diclofenac/oral diclofenac
WOMAC Pain, mean change in score: -6.0 (p=0.025 vs placebo, p=0.009 vs DMSO) vs -4.7 vs -4.7 vs -6.4 vs -7.0
WOMAC Physical Function, mean change in score: 15.8 (p=0.034 vs placebo, p=0.026 vs DMSO) vs 12.3 vs 12.1 vs 17.5 vs 18.7
Patient overall health assessment: mean change in score: 0.95 (p<0.0001 vs placebo, p=0.016 vs DMSO) vs 0.37 vs 0.65 vs 0.88 vs 0.95
PGA, mean change in score: 1.36 (p=0.016 vs placebo, p=0.018 vs DMSO) vs 1.01 vs 1.07 vs 1.42 vs 1.53
WOMAC Stiffness, mean change in score: 1.93 (p=0.035 vs DMSO) vs 1.52 vs 1.48 vs 2.07 vs 2.30
Topical diclofenac vs placebo vs DMSO vs Oral Diclofenac vs Topical diclofenac/oral diclofenac
Any AE: 96 (62.3%) vs 90 (57.3%) vs 97 (60.2%) vs 94 (62.3%) vs 98 (64.5%)
Any digestive system event: 10 (6.5%) vs 15 (9.6%) vs 18 (11.2%) vs 36 (23.8%) vs 39 (25.7%)
Abdominal pain: 5 (3.2%) vs 1 (0.6%) vs 5 (3.1%) vs 11 (7.3%) vs 3 (2.0%)
Dyspepsia: 4 (2.6%) vs 6 (3.8%) vs 6 (3.7%) vs 6 (4.0%) vs 5 (3.3%)
Diarrhea: 2 (1.3%) vs 3 (1.9%) vs 2 (1.2%) vs 7 (4.6%) vs 12 (7.9%)
Liver function tests abnormal: 3 (1.9%) vs 1 (0.6%) vs 6 (3.7%) vs 12 (7.9%) vs 11 (7.2%)
Rectal hemorrhage: 1 (0.6%) vs 0 vs 0 vs 0 vs 5 (3.3%)
Nausea: 0 vs 0 vs 1 (0.6%) vs 3 (2.0%) vs 5 (3.3%)

Any skin/appendages event: 41 (26.6%) vs 12 (7.6%) vs 27 (16.8%) vs 11 (7.3%) vs 47 (30.9%)
Headache: 27 (17.5%) vs 18 (11.5%) vs 21 (13.0%) vs 26 (17.2%) vs 21 (13.8%)
Back pain: 15 (9.7%) vs 10 (6.4%) vs 15 (9.3%) vs 11 (7.3%) vs 4 (2.6%)
Arthralgia: 14 (9.1%) vs 15 (9.6%) vs 25 (15.5%) vs 12 (7.9%) vs 7 (4.6%)
Pain: 7 (4.5%) vs 5 (3.2%) vs 11 (6.8%) vs 8 (5.3%) vs 1 (0.7%)
Respiratory disorder: 5 (3.2%) vs 6 (3.8%) vs 4 (2.5%) vs 8 (5.3%) vs 7 (4.6%)
Conjunctivitis: 4 (2.6%) vs 1 (0.6%) vs 0 vs 3 (2.0%) vs 0
Topical diclofenac vs placebo vs DMSO vs Oral Diclofenac vs Topical diclofenac/oral diclofenac
Total: 51 (33.1%) vs 54 (34.4%) vs 48 (29.8%) vs 44 (29.1%) vs 51 (33.6%)
Due to AE: 16 (10.4%) vs 18 (11.5%) vs 12 (7.5%) vs 19 (12.6%) vs 23 (15.1%)
Nuvo research
Tugwell 2004
Canada
(Fair)
Men and non pregnant women 40-85 years old, with symptomatic primary OA of the knee and a recent (within 3 mos) radiographic examination showing OA.
  1. Placebo topical solution+oral 50 mg tid diclofenac capsules For 12 weeks
NR64 years
Male: 43%
White: 94.1%
Oriental: 0.8%
Black: 1.1%
Hispanic: 0.2%
Other: 3.9%
Weight: 88 kg
Height: 166 cm
Heart rate: 74.5 bpm
622245/10/604Topical vs oral diclofenac
Mean (SD) Change in WOMAC pain score (mm): -118 (121) vs -134 (127), % improvement: 41% vs 46% , p=0.10 (between treatment groups)
Mean (SD) Change in WOMAC physical function (mm): -348 (400) vs -438 (426), % improvement: 36% vs 45%, p=0.008 (between treatment groups)
Mean (SD) Change in WOMAC stiffness score (mm): -45 (58) vs -52 (61), % improvement: 37% vs 42%, p=0.14 (between treatment groups)
Mean (SD) change in PGA score: -27 (31) vs -32 (32), % improvement: 39% vs 46%, p=0.08 (between treatment groups)
Pain on walking, difference in mean change score: 1.7 mm (95% CI, -2.9 to 6.4)
% of responders to treatment according to OMERACT-OARSI criteria: 66% vs 70%, p=0.37 (between treatment groups)
Topical diclofenac vs Placebo
All GI events: 35% vs 48%, p=0.0006
Abdominal pain: 12% vs 22%, p=0.0008
Constipation: 8% vs 10%, p=0.40
Diarrhea: 9% vs 7%, p=0.001
Dyspepsia: 15% vs 26%, p=0.001
Flatulence: 15% vs 26%, p=0.001
Melena: 1% vs 2%, p=0.36
Nausea: 8% vs 13%, p=0.04
Vomiting: 2% vs 2%, p=0.56

Other
Asthma: 0.6% vs 3%, p=0.02
Dizziness: 0.6% vs 4%, p=0.002
Dyspnea: 0% vs 2%, p=0.01
Edema: 7% vs 8%, p=0.65
Halitosis: 1% vs 0.3%, p=0.37
Headache: 5% vs 6%, p=0.29
Hypertension: 1% vs 2%, p=0.20
Pharyngitis: 4% vs 0.6%, p=0.004
Taste perversion: 2% vs 0.6%, p=0.29
Patients with clinically significant elevation of AST : 0.4% vs 1.4%
Patients with clinically significant elevation of ALT : 1.1% vs 4.7%
Mean (SD)Change from baseline in AST(U/I): 0.2 (8) vs 5.7 (23), p=0.0002
Mean (SD) Change from baseline in ALT(U/I): 1.2 (15) vs15 (60), p=0.0003
Patients changing from normal to abnormal AST: 2% vs 10%, p=0.0001
Patients changing from normal to abnormal ALT: 5% vs 17%, p<0.0001
Topical vs oral diclofenac
Total: 129 (41.5%) vs 116 (37.3%)
Due to AE: 64 (21%)vs 79 (25.4%)
Dimethaid Healthcare Ltd.equivalence study
Wagenitz 2007
Germany
(Good)
Men and women 18-75 years with OA of hip and/or knee with functional class I-III with no major GI, heart, kidney, or liver disease.
  1. Diclofenac 100 mg SR-CAP po
  2. Diclofenac 100 mg SR-TAB po
Low dose aspirin; Paracetamol rescue medication62.3 years
Male: 34%
Ethnicity: NR
Weight: 82.4 kg
Height: 166.9 cm
OA multiple joints: 88.5%
OA localized: 17.7%
20938/NR/209SR-CAP vs SR-TAB:
At rest:
Baseline: 64.8 vs 63.8; change from baseline:
Day 7: 37.4 vs 37.6
Change from baseline: 26.8 vs 26.1
Day 14: 21.2 vs 27.7
Change from baseline: 43.7 vs 36.6

With movement:
Baseline: 73.1 vs70.6
Day 7: 45.8 vs 43.5
Change from baseline: 27.3 vs 27.1
Day 14: 31.1 vs34.1
Change from baseline: 42.5 vs 36.4

Patient Global efficacy: 92.1% vs 86.6%
Investigator Global efficacy: 91.0% vs 89.0%

Patient Assessment of Tolerability good or very good: 85.4% vs 78.1%
Investigator Assessment of tolerability as poor: 1.1% vs 9.8%
SR-CAP vs SR-TAB:
Percent of subjects with ≥ 1 AE: 30.8% vs 39%
Percent with GI tract AE: 25.0% vs 32.4%
Percent with serious AE: 1% vs 1%
SR-CAP vs SR-TAB
Total withdrawals not reported by treatment group; 20 subjects withdrew due to AE: 8 (7.7%) vs 12(11.4%)
Funded by Maepha Ltd, Aesch, Switzerland who also provided the study medicationsNoninferiority study
Whelton, 2006
US and Canada companion to
CLASS
Outpatients ≥18 years of age diagnosed with RA or OA evident for ≥3 months that required continuous treatment with an NSAID for the duration of the trial. Excluded patients with significant renal disease or dysfunction.Group A: Celecoxib 400 mg bid
Group B: Ibuprofen 800 mg tid
Group C: Diclofenac 75 mg bid
For >180 days
Use of stable doses of aspirin up to 325 mg daily, antihypertensive and diuretic medications60.2 yrs
% Male: 68.8%
Ethnicity: NR
History of hypertension: 38.8%
History of diabetes: 8.3%
Mean blood pressure: 133/80 mmHg
Creatinine serum level (mg/dl): 0.79
Creatinine clearance (ml/min): 113.2
80594559/0/7968Celecoxib vs diclofenac vs ibuprofen
Blood pressure effects:
New-onset hypertension: 2% vs 2% vs 3.1% (P<0.05)
Aggravated hypertension: 0.8% vs 0.6% vs 1.2%
Mean change in blood pressure (systolic/diastolic): -0.6/-0.7 mmHg vs - 0.8/-1.1 mmHg vs 0.3/-0.6 mmHg
Percent of patients with increases in systolic blood pressure (>20 mmHg from baseline and absolute value >140 mmHg): 5.0% vs 6.6% (p<0.05) vs 7.0% (p<0.05)
Percent of patients with increases in diastolic blood pressure (>15 mmHg from baseline and absolute value >90 mmHg): 1.9 vs 1.2 vs 2.2

Renal Function:
Mean change in serum creatinine (mg/dl): 0.009 vs 0.027 (p<0.05) vs 0.017
Mean change in estimated creatinine clearance (ml/min): 0.08 vs -2.82 (p<0.05) vs -0.96
Incidence of ≥30% reductions in estimated creatinine clearance from baseline was significantly lower in patients treated with celecoxib as compared with diclofenac.
Clinically important reductions in renal function in patients with mild prerenal azotemia: 3.7% vs 7.3% (p<0.05) vs 7.3% (p<0.05)
Celecoxib vs diclofenac vs ibuprofen
Withdrawals for hypertension-related adverse events: 0.3% vs 0.2% vs 0.3%
Any edema-related adverse event: 4.1% vs 4.1% vs 6.2% (p<0.05)
Congestive heart failure: 0.3% vs 0.2% vs 0.5%
Increase in body weight of ≥3%: 20.7% vs 17.6% vs 21.1%
Uremia: 0 (0%) vs 0 (0%) vs 1 (0.05%)
Hyponatremia: 2 (0.05%) vs 0 (0%) vs 1 (0.05%)
Celecoxib vs diclofenac vs ibuprofen
Total: 2208 (55.4%) vs 1057 (53%) vs 1294 (65.2%)
Due to AE: 905 (22.7%) vs 540 (27.1%) vs 461 (23.2%)
NR

From: Evidence Tables

Cover of Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report [Internet].
Peterson K, McDonagh M, Thakurta S, et al.
Portland (OR): Oregon Health & Science University; 2010 Nov.
Copyright © 2010, Oregon Health & Science University.

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