Trials

Author YearEligibility CriteriaDemographics (Age, Gender, Race)Study Design/TypeInterventions (Drug, Dose, Duration)Run-in/Washout PeriodAllowed Other Medications/InterventionsOther Population Characteristics (Diagnosis, etc)Number Screened/Eligible/EnrolledNumber Withdrawn/Lost to fu/AnalyzedResultsAdverse Effects Assessment: Pre-Specified, Active or Passive Ascertainment, Measured the Severity of Adverse Effect?Adverse Effects ReportedTotal Withdrawals; Withdrawals due to Adverse EventsNotes
Herrero-Beaumont, 2007206
(GUIDE)		Male and female outpatients, diagnosed with primary symptomatic knee OA in 1 or both knees according to the American College of Rheumatology criteria. Grade II or III on the Kellgren/Lawrence radiographic system. Discouraged enrollment of obese patients. Excluded patients with inflammatory joint disease.Age: Mean age NR overall
Placebo: 64.5 +/− 7.2
Acetaminophen: 63.8 +/− 6.9
Glucosamine sulfate: 63.4 +/− 6.9
Female: 278/318 (87.4%)
Placebo: 89/104 (86%)
Acetaminophen: 93/108 (86%)
Glucosamine: 96/106 (91%)
Race/Ethnicity NR		RCT
  1. Glucosamine: 1500 mg glucosamine sulfate, oral solution, once daily. Rottapharm.
  2. Acetaminophen side comparator: 1 gram tablets 3 times per day
  3. Placebo
6 month treatment duration		Narcotic, non-narcotic analgesics or anti-inflammatory symptomatic medications including topical agents were discontinued for the duration of at least 5 half-lives or 72 hours, whichever was longer.

Recommended washout for corticosteroids was 3 months and was 6 months for glucosamine or other drugs considered specific for OA.		Ibuprofen 400mg tablets as rescue medication. Physical and/or occupational therapy were allowed if the regimen had been stable for at least 3 months prior to randomization.Duration of knee OA:
7.4+/−6.0 vs. 6.5 +/−5.3 vs. 7.2+/−5.8

Baseline Lequesne index:
11.0+/−3.1 vs. 11.1+/−2.7 vs. 10.8+/−2.6

Baseline Kellgren/Lawrence grade:
Grade 2:
50% vs. 56% vs. 52%
Grade 3:
41% vs. 31% vs. 36%
Grade 2/3 unspecified:
9% vs. 12% vs. 11%

Baseline WOMAC:
Total: 38.3+/−15.2 vs. 40.4+/−14.8 vs. 37.9+/−14.3
Pain: 7.8+/−3.0 vs. 8.0+/−2.9 vs. 7.9+/−3.0
Function: 27.8+/−11.4 vs. 29.4+/−11.0 vs. 27.2+/−10.9		334 screened
325 randomized
7 excluded with no efficacy data
318 ITT population
  1. 4 adverse events; 7 Lack of efficacy; 5 loss to followup;12 Protocol violations
    Analyzed 78 protocol completers.
    106 ITT population.
  2. 12 adverse events; 5 Lack of efficacy; 3 loss to fu; 8 protocol violations
    Analyzed 80 protocol completers. 108 ITT population
  3. 9 adverse events; 8 Lack of efficacy; 5 Loss to fu; 12 Protocol violations
    Analyzed 70 protocol completers
    104 ITT population
Comparisons to Placebo. No head-to-head.
6 month change in Lequesne Index from baseline
  1. −3.1 (−3.8, −2.3); p=0.032
  2. NS: −2.7 (−3.3,−2.1); p=0.18
  3. −1.9 (−2.6, −1.2)
6 month change in WOMAC from baseline
Total:
  1. −12.9 (−15.6, −10.1); p=0.039
  2. NS: −12.3 (−14.9, −9.7); p=0.08
  3. −8.2 (−11.3,−5.1)
Pain:
  1. NS: −2.7 (−3.3, −2.1); p=0.12
  2. NS: −2.4 (−3.0, −1.8); p=0.41
  3. −1.8 (−2.6, −1.1)
Function:
  1. −9.2 (−11.2, −7.2); p=0.022
  2. −8.7 (−10.6, −6.8); p=0.049
  3. −5.5 (−7.7, −3.3)
OARSI-A responders:
  1. 39.6 (p=0.004)
  2. 33.3 (p=0.047)
  3. 21.2
OARSI-B, Pain MCII, Function MCII, Pain PASS, Function PASS also reported as secondary outcomes
Per-protocol Completers- For all 3 treatments, the degree of improvement in per-protocol completers was higher than that in the ITT population.		Pre-specified: For non- lab AEs: No (general question): For lab AEs: Yes, laboratory tests including measurement of serum glucose and liver function tests were preformed at enrollment, 3 months and 6 months of treatment.

Active or passive ascertainment: Active- asked a non leading question during clinic visits and drew labs

Assessment of severity: Yes, MedDRA		A vs. B vs. C
Total AEs: 95 vs. 96 vs. 89

Symptoms occurring in at least 3 patients during treatment:
Dyspepsia: 5 vs. 2 vs. 4
Abdominal pain: 3 vs. 4 vs. 4
Diarrhea: 3 vs. 4 vs. 4
Respiratory tract infections: 8 vs. 4 vs. 9
Gastroenteritis: 4 vs. 0 vs. 2
Coughing and associated symptoms: 1 vs. 4 vs. 0
Headache: 2 vs. 6 vs. 4
Dizziness: 1 vs. 4 vs. 1
Back pain: 7 vs. 4 vs. 5
Neck pain: 3 vs. 2 vs. 0
Fall: 5 vs. 3 vs. 2
Injury: 2 vs. 4 vs. 0

Laboratory:
Liver function (transaminases and/or GGT) : 2 vs. 21 vs. 6
Glucose: no change		Withdrawal due to AEs:

4 vs. 12 vs. 9
Kahan, 2009209Male and female outpatients 45–80 years, primary knee OA of the medial tibiofemoral compartment diagnosed according to ACR.Chondroitin Sulfate:
Age: 62.9 ± 0.5; Female: 70%; Race: NR
Placebo: Age: 61.8 ± 0.5; Female: 67%; Race: NR		RCT
  1. Chondroitin Sulfates 4&6 800 mg sachet daily, every evening with glass of water
  2. Placebo sachet daily, every evening with glass of water
2 years		24 hours for acetaminophen, 5 days for NSAIDs prior to symptom assessmentsAcetaminophen in 500 mg tablets (max dosage 4 gm/day)
NSAIDs in cases of acute pain		Duration of knee OA:
Left knee: 6.1 ± 0.3 vs. 6.5 ± 0.4; Right knee: 6.6 ± 0.4 vs. 6.3 ± 0.4
KL grade 1: 17.4% vs. 19.7%; KL grade 2: 26.2% vs. 21.6%; KL grade 3: 56.4 vs. 58.7%
Minimum JSW, mm:
3.73 ± 0.08 vs. 3.81 ± 0.07
Pain score, 100 mm VAS:
57.2 ± 0.9 vs. 57.3 ± 1.0
WOMAC score, normalized 100mm scales: Total: 40.5 ±1.2 vs. 41.6 ± 1.2; Pain: 40.0±1.2 vs. 40.5±1.2; Function: 39.2±1.3 vs. 39.0±1.2; Stiffness: 42.3±1.5 vs. 43.5±1.5		1052/NR/622103 vs. 96 withdrawals/18 vs. 18 lost to followup/ITT analysis 622Interaction between time and treatment effect, indicating that the effect of treatment significantly increased over time (p<0.01)
Decrease in minimum JSW loss: −0.07 ± 0.03 vs. −0.31 ±0.04, median effect of treatment 0.14mm (0.06–0.21mm), p<0.0001
Percentage of patient with radiographic progression: 28% vs. 41%, p<0.0005.
Relative risk reduction: 33% (16%, 46%)
Reduction in minimum JSW loss at 2 years: −0.11 ± 0.04mm vs. −0.39±0.04 mm. treatment effect= 0.20mm (0.11,0.30 mm), p<0.0001
Percentage of responder patients at 6 months:
reduction in VAS pain score of at least 40%: 53% vs. 45%, p=0.04
reduction in VAS pain score of at least 60%: 41% vs. 32%, p=0.03
reduction in VAS pain score of at least 40mm: 28% vs. 19%, p=0.01
reduction in VAS pain score of at least 60mm: 9% vs. 4%, p<0.01
decreased WOMAC of at least 40%: 41% vs. 34%, p=0.05
patient assessed VAS at 6 months: 42.2 ± 1.8mm vs. 36.6 ± 1.7mm, p<0.02
doctor assessed VAS at 6 months: 39.6 ± 1.6mm vs. 34.8±1.7mm, p<0.04		Pre-specified: NR
Active or passive ascertainment: NR
Severity: NR		Gastrointestinal side effects were the most frequently reported, 6% vs. 5.9%
No significant laboratory abnormalities		103 vs. 96 withdrawals.

16 vs. 17 withdrawals due to AE
Mazieres, 2007210Male and female outpatients 50–80 years with medial OA, defined according to ACR criteria. Patients with symptomatic knee OA that had lasted for >6 months, with pain during daily activity ≥ 40 mm on a 0–100 mm visual analogue scale, a Lequesne’s Index Score of between 6 and 12, and Kellgren/Lawrence grade 2 or 3 on an anterior-posterior view in an extended standing position taken within the previous 6 months. Exclusions: secondary knee OA, isolated patella-femoral OA and those requiring knee surgery in the coming year, know hypersensitivities to CS or paracetamol, NSAID use for >50% of the time during the previous 2 months, NSAID use within 48 hours before inclusion or SYSADOA, steroid by any route, intra-articular hyaluronic acid or arthroscopic debridement within 6 months before inclusionCS:
Age: 66 (8.8)
Female 71%
Race: NR

Placebo:
Age: 66 (7.7)
Female: 69%
Race: NR		RCT
  1. Chondroitin Sulfate 500mg, twice daily by oral route
  2. Placebo, twice daily by oral route
    24 weeks
NRStart with paracetamol (up to 4 gm/day). NSAIDS allowed if paracetamol was not effective. NSAIDs not allowed 2 days and paracetamol not allowed 12 hours prior to evaluation visits.Duration of disease: 6.2 (6.8) vs. 6.6 (7.6)
VAS pain during activity: 62 (13) vs. 61 (12)
VAS pain at rest: 40 (20) vs. 40 (22)
Lequesne’s Index: 9.5 (2) vs. 9.4 (2)
KL stages 2–3: 69% vs. 59%		322/NR/307 (153 CS, 154 Placebo)14 vs. 14 withdrawals during treatment period, 12 vs. 11 withdrawals during washout period. 307 ITT populationPain During Activity: VAS, mm; Mean (SD) Week 0: 61 (13) vs. 61 (13) Week 4: 48 (21) vs. 51 (20) Week 12: 40 (23) vs. 42 (21) Week 24: 36 (24) vs. 41 (23) Week 32: 33 (23) vs. 40 (24) Change from baseline to week 24: –26.2 (24.9) mm vs. −19.9 (23.5) mm, p= 0.029 Lequesne’s Index: Mean (SD): Week 0: 9.5 (2.1) vs. 9.4 (1.8) Week 4: 8.3 (2.8) vs. 8.4 (2.4) Week 12: 7.8 (3.6) vs. 7.9 (3.1) Week 24: 7.2 (3.7) vs. 7.7 (3.3) Week 32: 6.8 (3.9) vs. 7.5 (3.6) Change from baseline to week 24: −2.4 (3.4) vs. −1.7 (3.3), p=0.109. OMERACT-OARSI responders: 68% vs. 56% (p=0.03) Change in pain at rest (VAS; mm): −18.8 (23.8) vs. −16.6 (24.2), NS Patient’s global assessment: 3.1 (3.0) vs. 2.5 (3.1), NS Investigator’s global assessment: 3.1 (2.7) vs. 2.5 (3.0), p=0.044 Consumption of analgesics (days): 28 (29) vs. 28 (32), NS Consumption of NSAIDs (days): 6.9 (20.2) vs. 9.2 (24.6), NS QOL, mental: 1.2 (10.4) vs. 0.3 (11.3), NS QOL, physical: 5.8 (9.0) vs. 3.8 (10.2), p=0.021 Carry over effect: changes at the end of the follow-up (week 32) compared to the end of the treatment period (week 24): Change in pain on activity −1.9 (20.9) vs. −0.4 (18.7), NS Change in Lequesne’s index: −0.4 (2.3) vs. −0.2(2.6), NSPre-specified: No
Active ascertainment: requested at visits
Severity: NR		Total Number of AEs: 141 vs. 155, majority were gastro-intestinal troubles including dyspepsia, nausea, vomiting, abdominal pain and diarrhea.
Patients with at least one AE: 49% vs. 49%
Patients with at least on SAE: 6.5% vs. 5.2%, one in each group was considered related to treatment, eczema and urticaria		Total withdrawals: 26 vs. 25 due to AE: 13 vs. 8
Michel, 2005211Male and female patients 40–85 years with clinically symptomatic knee OA (knee pain while standing, walking, and/or on motion for at least 25 of the 30 days prior to study entry) diagnosed according to the ACR clinical and radiographic criteria for OA of the knee. Exclusion criteria: Kellgren/Lawrence grade 4, any causes of secondary OA, traumatic knee lesions, severe comorbidity (severe renal, heart, lung, or neurologic disease), previous joint surgery, intraarticular medications, including corticosteroids into he last month, and the foreseeable prospect of major surgery during the 2- year study period.Chondroitin Group:
Mean age: 62.5 ± 9.1
Female: 51%
Race: NR

Placebo Group:
Mean age: 63.1 ± 10.7
Female: 52%
Race: NR		RCT
  1. Chondroitin Sulfates 4 & 6, 800mg tablet daily
  2. Placebo
2 years		3 month washout required for potentially longer acting substances such as Chondroitin Sulfate and GlucosamineAcetaminophen in 500-mg tablets at a maximum dose of 3 gm/day.
Secondary rescue with NSAIDs were allowed up to a maximum 5 consecutive days if the primary rescue analgesia with acetaminophen was insufficient.
Physical therapy was limited to application of warmth and strengthening exercises
No other interventions allowed		ITT Group:
Minimum JSW, mm:
2.41 ± 0.14 vs. 2.35 ± 0.14
Mean JSW, mm:
3.04 ± 0.14 vs. 3.00 ± 0.15
WOMAC score, range 0–10:
Total: 2.3 ± 1.6 vs. 2.6 ± 1.7
Pain: 2.5 ± 1.6 vs. 2.7 ± 1.8
Function: 2.1 ± 1.6 vs. 2.5 ±1.8
Stiffness: 3.0 ± 2.3 vs. 3.5 ± 2.5		341/300/30040 vs. 41 withdrawals during treatment

300 ITT analysis		A vs. B, at 2 years
JSN Minimum: 0.045 ± 0.48 vs. −0.07 ± 0.56, difference: 0.12 (95% CI 0.00 to 0.24), p=0.05
JSN Mean: 0.00 ± 0.53 vs. −0.14 ± 0.61, difference 0.14 (95% CI 0.01 to 0.27), p =0.04

NS changes in WOMAC:
Total: −3.9% vs. 2.1%
Pain: −11.0% vs. −6.2%
Stiffness: −7.8% vs. −4.6%
Function: −0.8% vs. 5.9%		Pre-specified: No
Active ascertainment
Assessment of severity: No		AEs with frequencies of at least 5% in one of the two study groups:
Upper respiratory tract infection: 29% vs. 31%
Headache: 7% vs. 9%
Abdominal pain: 4% vs. 11%
Allergic episode: 6% vs. 6%
Cardiac problem: 6% vs. 5%
Urinary tract infection: 5% vs. 5%		9 vs. 9 withdrawals due to AE
2 events judged to be related to Chondroitin: abdominal pain and nausea in 1 patient each.
Messier, 2007213Males and females ≥ 50 years with radiographic evidence of mild to moderate knee OA, Kellgren-Lawrence grade II–III; radiographic classification criteria or confirmation of mild to moderate radiographic evidence of knee OA from a personal physician; not participating in any other intervention study.Mean Age Overall NR
GH/CS: 70.0 ± 1.28
Placebo: 74.1 ± 1.32, p0.03

Female: GH/CS: 75.6%
Placebo: 65.9%

Race, GH/CS vs. Placebo:
Caucasian: 68.9% vs. 77.3%
African American: 20% vs. 11.4%
Asian/Pacific Islander: 6.7% vs. 2.3%
Native American: 4.4% vs. 6.8%		RCT with run-in/washout period, Phase 1 treatment. Phase 2 treatment plus exercise.
  1. Glucosamine hydrochloride 1500mg/day and Chondroitin sulfate 1200mg/day taken either once or three times per day
  2. Placebo taken either once or three times per day
1 year treatment period		2-week discontinuation of all over-the-counter or prescription medications.
Rescue medication with acetaminophen up to 4g per day and any other necessary medications unrelated to OA were permitted.		Rescue medication of acetaminophen up to 4g/day--865 screened/435 not interested/341 ineligible

89 randomized		17 withdrawn/89 analyzed using ITT last observation carried forwardFunction (WOMAC physical function 0–68) Mean(SE):
Baseline: 25.9 (1.7) vs. 21.1 (1.5), p=0.04
6 months: 21.9 (1.1) vs. 22.9 (1.1), NS
12 months: 19.4 (1.2) vs. 20.6 (1.2), NS
Pain (WOMAC pain 0–20):
Baseline: 7.1 (0.5) vs. 5.9 (0.5), NS
6 months: 6.2 (0.4) vs. 6.2 (0.4), NS
12 months: 6.0 (0.5) vs. 5.18 (0.5), NS
6 minute walk (meters):
Baseline: 384.7 (17.6) vs. 398.7 (17.3), NS
6 months: 393.6 (8.0) vs. 396.5 (7.9), NS
12 months: 409.2 (8.7) vs. 410.5(8.6), NS
Knee concentric extension strength (N):
Baseline: 209.4 (31.2) vs. 163.9 (20.6), NS
6 months: 176.9 (16.3) vs. 202.7 (17.5), NS
12 months: 207.6 (14.1) vs. 209.7 (15.0), NS
Knee concentric flexion strength (N):
Baseline: 106.0 (16.1) vs. 83.0 (10.9), NS
6 months: 106.1 (7.3) vs. 106.7 (7.8), NS
12 months: 102.9 (7.7) vs. 124.8 (8.3), p=0.05
Balance (foot length):
Baseline: 0.52 (0.04) vs. 0.53 (0.03)
6 months: 0.523 (0.014) vs. 0.583 (0.017), p=0.01
12 months: 0.538 (0.017) vs. 0.591 (0.020), p=0.05

During Phase II:
Pill compliant GH/CS group had less pain than the non-compliant group (p=0.02) and a nonsignificant trend in function (p=0.06)		Pre-specified: NR
Active or passive: NR
Severity: NR		17 withdrawals, 0 due to adverse events

1 AE reported: Hair loss		Groups differ at baseline on age, BMI, gender, annual household income and WOMAC function
Moller, 2010212Males and females ≥ 40 years of age, with OA of the knee as defined by criteria of the American College of Rheumatology, with pain in the affected knee scoring ≥ 30 on Huskisson’s VAS, and a confirmatory knee X-ray diagnosis, Kellgren-Lawrence grades I–III, associated to cutaneous plaque-type psoriasis with a Psoriasis Area and Severity Index score of >5. Exclusion criteria were Kellgren-Lawrence grade IV, VAS ≥ 30 due to pain of any cause in other sites, non- plaque type psoriasis forms, concurrent arthritic conditions that could confound evaluation of the index joint, presence of any clinically significant cutaneous disease that may interfere with the assessment of lesions during the study and presence of any medical condition judged by the investigator to preclude the patient’s inclusion in the study.Age (mean ± SD):
Overall: 59.8±10.8
CS: 58.6±11.4
Placebo: 61.0±10.4

Gender (% female):
Overall: 52.6%
CS: 48.3%
Placebo: 57.1%

Race: NR		Randomized controlled trial
  1. Chondroitin Sulfate 800mg daily
  2. Placebo
3 months duration		Washout periods: 6 months for intra-articular hyaluronic acid; 3 months for intra-articular corticosteroids and SYSADOAs; 1 month for oral corticosteroids, 1 week for oral NSAIDs; 1 month for high-potency topical corticosteroids, psoralen photochemotherapy and systemic treatment for psoriasis; 2 weeks for ultraviolet and topical treatment for psoriasis.Acetaminophen allowed for osteoarthritic symptoms. Syndet soap and moisturizing body milk for daily skin care were provided by the study.Kellgren-Lawrence grade I:
A: 6.7%, B: 7.1%
Kellgren-Lawrence grade II:
A: 78.3%, B: 75.0%
Kellgren-Lawrence grade III:
A: 15.0%, B: 21.4%

Pain intensity, VAS score, mm, mean ± SD:
A: 58.1 ± 16.7, B: 56.8 ± 16.0		181 screened, 129 randomized
  1. 4- No data for at least one follow-up
    2- Non compliance
    60- ITT population analyzed
    58- Per protocol population analyzed
  2. 5- No data for at least one follow-up
    3- No fulfillment of inclusion criteria
    3- Non-compliance
    2- Use of medication other than study drug or paracetamol
    56- ITT population analyzed
    51- Per protocol population analyzed
Pain intensity, VAS, mm, mean ± SD:
Baseline: A: 58.8 ± 1.7, B: 56.8 ± 15.3
1 month: A: 43.5 ± 2.8, B: 50.3 ± 2.4; Mean difference: −6.8; 95% CI −13.3 to −0.3; p = 0.041
2 months: A: 36.5 ± 2.7, B: 42.0 ± 2.8; Mean difference: −5.5; 95% CI −13.3 to 2.3; p = 0.165
3 months: A: 31.3 ± 2.8, B: 43.2 ± 2.9; Mean difference: −11.8; 95% CI −19.9 to −3.7; p = 0.0004

Lequesne index, mean ± SD:
Baseline: A: 9.0 ± 3.5, B: 9.9 ± 3.5
1 month: A: 7.5 ± 0.3, B: 7.3 ± 0.3; Mean difference: 0.19, 95% CI −0.8 to 1.1, p = 0.700
2 months: A: 5.4 ± 0.4, B: 6.3 ± 0.4; Mean difference: −0.93, 95% CI −2.1 to 0.2, p = 0.109
3 months: A: 4.5 ± 0.5, B: 6.1 ± 0.5; Mean difference: −1.7, 95% CI −3.0 to −0.4, p = 0.013

Acetaminophen, number pills/month, mean ± SD:
1 months: A: 29.5 ± 31.4, B: 29.5 ± 29.6; Mean difference: 3.4, 95% CI 22.7 to 36.3, p = 0.991
2 months: A: 32.3 ± 33.9, B: 28.8 ± 28.2; Mean difference: 3.9, 95% CI 22.6 to 38.7, p = 0.668
3 months: A: 38.2 ± 42.6, B: 30.2 ± 33.8; Mean difference: 5.1, 95% CI 23.1 to 43.7, p = 0.453		Prespecified: Yes for laboratory blood tests, NR for others

Active ascertainment for blood tests, NR for other

Severity NR
  1. 2 withdrawals, 0 for adverse events
  2. 13 withdrawals, 0 for adverse events
Rozendaal, 2008207Patients met the American College of Rheumatology clinical criteria for hip osteoarthritis and were able to complete questionnaires in Dutch. Excluded patients who had undergone or were awaiting hip replacement surgery, Kellgren and Lawrence score of 4, renal disease, liver disease, diabetes mellitus, or a disabling comorbid condition that would make visits to the research center impossible, patients receiving glucosamine.Age: Mean age NR overall
Placebo: 63.7 (8.5)
Glucosamine sulfate: 63.1 (9.5)

Female: Placebo: 70.3%
Glucosamine: 68.5%

Race/Ethnicity NR		RCT1500mg oral glucosamine sulfate, administered once daily or as two 750 mg tablets

Placebo

24 months treatment duration		NRBaseline Pain Med use: Placebo overall: Daily 18.9%
Sometimes: 27.9%
None: 53.2%

Glucosamine overall: Daily: 28.8%
Sometimes: 25.2%
None: 46.0%

Interventions NR, except Total Hip Arthroplasty was collected and used in analyses.		Kellgren and Lawrence Score (%):
1: 49.5 vs. 53.2
≥2: 50.5 vs. 46.8

Mean minimum JSW (SD), mm:
2.13 (1.00) vs. 2.33 (0.90)

Mean WOMAC score (SD):
Pain: 35.9 (23.0) vs. 32.4 (23.2)
Function: 36.0 (24.1) vs. 34.1 (21.7)
Stiffness: 44.2 (27.2)

Mean pain in past week (SD), mm:
34.3 (26.5) vs. 30.5 (25.2)		Screened: 387
Eligible & Randomized: 222		Withdrawals during treatment period: NR

Lost to follow-up: 7 vs. 8

ITT analysis: 111 vs. 111		Primary Outcomes:
WOMAC (negative difference favors glucosamine):
Pain overall (SE): −1.90 ± 1.6 vs. −0.30 ± 1.6; Unadjusted difference: −1.60 (−5.60, 2.40); Adjusted difference: −1.54 (−5.43, 2.36)
Function overall (SE): −1.69 ± 1.3 vs. 0.38 ± 1.3; Unadjusted difference: −2.07 (−5.53, 1.39); Adjusted difference: −2.01 (−5.38, 1.36)

JSN, mm (positive difference favors glucosamine sulfate):
Minimal: −0.094 (0.32) vs. −0.057 (0.32); Unadjusted difference: −0.038 (−0.130, 0.055); Adjusted difference: −0.029 (−0.122, 0.064)
Lateral: −0.180 (0.34) vs. −0.159 (0.36); Unadjusted difference: −0.020 (−0.124, 0.083); Adjusted difference: −0.017 (−0.121, 0.088)
Superior: −0.123 (0.36) vs. −0.129 (0.30); Unadjusted difference: 0.006 (−0.090, 0.101); Adjusted difference: 0.016 (−0.079, 0.111)
Axial: −0.070 (0.48) vs. −0.079 (0.30); Unadjusted difference: 0.009 (−0.108, 0.124); Adjusted difference: −0.005 (−0.118, 0.108)

Secondary Outcomes:
WOMAC (Negative difference favors glucosamine):
Pain, 3mos. −2.50 (19.2) vs. −1.79 (16.2); Unadjusted difference: −0.71 (−5.47, 4.05); Adjusted difference: 0.06 (−4.11, 4.22). 12 mos. −0.54 (19.9) vs. −0.89 (23.3); Unadjusted difference: 0.35 (−5.66, 6.36); Adjusted difference: 1.42 (−3.82, 6.67). 24 mos. −1.47 (20.7) vs.0.88 (26.4); Unadjusted difference: −2.34 (−9.16, 4.48); Adjusted difference: −0.77 (−6.53, 4.98)
Function, 3 mos. −3.29 (14.9) vs. −1.08 (12.7); Unadjusted difference: −2.22 (−5.97, 4.05); Adjusted difference: −2.04 (−5.48, 1.40). 12 mos. −0.98 (14.9) vs. −0.88 (17.6); Unadjusted difference: −0.11 (−4.63, 4.42); Adjusted difference: 0.11 (−4.14, 4.35). 24 mos. −0.84 (19.1) vs. 1.92 (19.7); Unadjusted difference: −2.76 (−8.35, 2.84); Adjusted difference: −1.63 (−6.73, 3.47).
Stiffness, 3 mos. −4.59 (22.6) vs. −3.39 (17.7). Unadjusted difference: −1.20 (−6.66, 4.26); Adjusted difference: −0.12 (−4.94, 4.71). 12 mos. −1.38 (22.1) vs. −3.43 (21.6); Unadjusted difference: 2.06 (−4.00, 8.12); Adjusted difference: 3.11 (−2.07, 8.28). 24 mos. −3.43 (26.2) vs. −2.19 (24.1); Adjusted difference: −1.24 (−8.47, 5.98); Unadjusted difference: 0.66 (−5.27, 6.59).

VAS pain also reported.		Prespecified: yes, used a checklist

Active ascertainment; used a checklist at baseline and every 3 months

Severity measured: NR		Serious Adverse Events: 4 vs. 2
AE resulting in treatment termination: 4 vs. 6

Abdominal pain: 14 vs. 10
Stomach symptoms: 25 vs. 19
Intestinal symptoms: 19 vs. 17
Increased blood pressure: 11 vs. 19
Decreased blood pressure: 4 vs. 3
Fatigue: 24 vs. 18
Headache: 16 vs. 26
Vertigo: 16 vs. 18
Cardiac problems: 6 vs. 9
Depressive mood: 10 vs. 6
Allergic episode: 7 vs. 5		Lost to follow up: 7 vs. 8, withdrawal during treatment NR.

Withdrawal of treatment due to AE: 4 vs. 6
Rozendaal, 2009207See Rozendall, 2008See Rozendall, 2008RCT, subgroup analysis of Rozendall, 2008 data
Predefined subgroups: KL=1, KL ≥ 2, localized OA, generalized OA

Exploratory subgroups: VAS ≤ 30, VAS > 30, No pain medication, pain medication, no knee OA, knee OA, JSN ≥ 2.5mm, <2.5 mm		See Rozendall, 2008See Rozendall, 2008See Rozendall, 2008See Rozendall, 2008See Rozendall, 2008See Rozendall, 2008The predefined subgroup analyses based on radiographic severity of OA and type of OA did not yield differences between GS and placebo in WOMAC pain, function and JSN.

The exploratory analyses showed no difference in WOMAC pain, function and JSN.

WOMAC Pain ( Negative value favors glucosamine): No Knee OA: 0.3 (21.5) vs. 0.1 (26.2); Unadjusted difference: 0.3 (−7.9, 8.5); Adjusted difference: −0.1 (−4.9, 4.7).
WOMAC pain: Concomitant Knee OA: −5.8 (18.1) vs. 2.9 (27.1); Unadjusted difference: −8.7 (−21.2, 3.8); Adjusted difference: −5.68 (−12.62, 1.26).		See Rozendall, 2008See Rozendall, 2008See Rozendall, 2008
Sawitzke, 2008214 (GAIT)Males and females ≥ 40 years of age, had knee pain for at least 6 months occurring on the majority of days in the month preceding their enrollment in GAIT, and had Kellgren/Lawrence gade 2 or 3 knee OA determined on a screening AP radiograph of the knee in a weight bearing position. Exclusion: Minimum baseline medial tibiofemoral JSW of <2mm, predominant lateral compartment OA on any film of the MTP joints, history of significant trauma or surgery to the kneeAge (mean ± SD years):
Glucosamine: 56.7± 10.4
CS: 56.4± 9.2
Glucosamine + CS: 56.5± 9.9
Celecoxib: 58.3± 10.7
Placebo: 56.6± 8.4
Female (%):
Glucosamine: 61.0
CS: 71.8
Glucosamine + CS: 55.9
Celecoxib: 63.8
Placebo: 64.3
Race: NR		Prospective observational study of GAIT enrollees; ancillary study to assess structural changes in knee OA
  1. Glucosamine 500 mg 3 times daily
  2. Chondroitin sulfate (400mg 3 times daily)
  3. Combination of Glucosamine and Chondroitin
  4. Celecoxib 200mg daily
  5. Placebo 24 months
NR-check other GAIT pubsNR- check other GAIT pubsKellgren/Lawrence Grade 2, %: 80.5 vs. 81.0 vs. 69.2 vs. 72.6 vs. 80.5

Kellgren/Lawrence Grade 3, %: 19.5 vs. 19.0 vs. 30.9 vs. 27.4 vs. 19.5		662 GAIT participants consented to this study
  1. (177 initial): 33/NR/77
  2. (123 initial): 30/NR/71
  3. (128 initial): 40/NR/59
  4. (143 initial): 32/NR/80
  5. (134 initial): 36/NR/70
Mean loss in JSW over 2 years: All NS
0.013 vs. 0.107 vs. 0.194 vs. 0.111 vs. 1.166
Difference from placebo (negative value = less JSW loss):
−0.153 (−0.379, 0.074) vs. −0.059 (−0.287, 0.169) vs. 0.028 (−0.214,0.271) vs. −0.055 (−0.279, 0.170)
Disease progression over 2 years, % of patients: All NS
18.6 vs. 21.4 vs. 24.4 vs. 20.2 vs. 22.4
OR vs. placebo for disease progression:
0.79 (0.48,1.3) vs. 0.94 (0.57,1.55) vs. 1.12 (0.67,1.88) vs. 0.87 (0.53,1.43)		NR- check earlier GAIT pubWithdrawals: 33 vs. 30 vs. 40 vs. 32 vs. 36
Technical Loss: 9 vs. 6 vs. 11 vs. 10 vs. 8
Withdrawals due to AE: see earlier GAIT report
Sawitzke, 2010215Males and females ≥ 40 years of age, had knee pain for at least 6 months occuring on the majority of days in the month preceding their enrollment in GAIT, and had Kellgren/Lawrence gade 2 or 3 knee OA determined on a screening AP radiograph of the knee in a weight bearing position. Exclusion: Minimum baseline medial tibifemoral JSW of <2mm, predominant lateral compartment OA on any film of the MTP joints, history of signicant trauma or surgery to the kneeAge (mean ± SD years):
Glucosamine: 56.7± 10.5
CS: 56.3± 8.8
Glucosamine + CS: 56.7± 10.7
Celecoxib: 57.6± 10.6
Placebo:56.9± 9.8

Female (%):
Glucosamine: 68.7
CS: 73.0
Glucosamine + CS: 65.1
Celecoxib: 65.5
Placebo: 65.7

Race: NR		Prospective observational study of GAIT enrollees; ancillary study to assess structural changes in knee OA
  1. Glucosamine 500mg 3 times daily
  2. Chondroitin sulfate (400mg 3 times daily)
  3. Combination of Glucosamine and Chondroitin
  4. Celecoxib 200mg daily
  5. Placebo
24 months		NRNRKellgren/Lawrence Grade 2, %:
59.7 vs. 66.7 vs. 51.9 vs. 62.0 vs. 61.1, p=0.19

Duration of OA symptoms, mean years (SD):
9.7 (10.3) vs. 9.0 (9.0) vs. 10.0 (9.4) vs. 10.2 (9.2) vs. 10.1 (9.4)		662 GAIT participants consented to this studySee Sawitzke, 2008Odds of pain response over 24 months versus placebo by WOMAC, OR (95% CI):
  1. 1.16 (0.65 to 2.04)
  2. 0.69 (0.40 to 1.21)
  3. 0.83 (0.51 to 1.34)
  4. 1.21 (0.71 to 2.07)
  5. reference
Odds of a pain response over 24 months versus placebo by OMERACT/OARSI, OR (95% CI):
  1. 1.16 (0.74 to 1.83)
  2. 0.89 (0.53 to 1.50)
  3. 0.85 (0.55 to 1.31)
  4. 1.45 (0.86 to 2.42)
  5. reference
Change in WOMAC pain and function score over 24 months		NR in ancillary studyNR in ancillary study
Wilkens, 2010208INCLUSION: Nonspecific chronic LBP (defined as the area below the 12th rib and above the gluteal folds); LBP for at least 6 months with summed score of at least 3 out of 24 points on the Roland Morris Disability Questionnaire, older than 25 years of age. Patients with concomitant leg pain were included as long as the LBP pain rating was higher than the leg pain rating. MRI scans no older than 1 year prior to inclusion consisting of at least 1 axial view and 2 sagittal views were required. MRI confirmed degenerative process. At least one of the following MRI criteria: disk signal intensity changes, reduced disk height compared with adjacent superior disk, facet joint changes, modic changes, or high-intensity zone.
EXCLUSION: symptomatic intervertebral disk herniation or spinal stenosis, previous lumbar fracture or surgery, pregnancy or breastfeeding, seafood allergy, ongoing psychiatric or somatic disease potentially influencing a patient’s pain and use of any type of glucosamine 1 year prior to enrollment.		Age; mean (SD):
Total: 48.5 (11.24)
Glucosamine: 47.5 (11.5)
Placebo: 49.4 (11.0)

Female:
Total: 121/250 (48.4%)
Glucosamine: 54/125 (43.2%)
Placebo: 67/125 (53.6%)
Race: NR		RCT
  1. Glucosamine sulfate 1500mg or placebo administered as three 500-mg capsules per day. Could be taken as one pill 3 times per day or all at once.
  2. Placebo
    6 month treatment period
NRRescue medication: Pain killers or NSAIDs, existing analgesics, or usual LBP therapy (e.g., manipulation, physiotherapy, massage)Mean (SD) Roland Morris Disability Questionnaire (RMDQ) (0–24): 9.2 (3.9) vs. 9.7 (4.5)
Numeric Rating Scale (NRS) (0–10): LBP at rest: 3.7 (2.6) vs. 3.9 (2.4) Leg pain at rest: 1.8 (2.2) vs. 2.0 (2.3) LBP when active: 4.9 (2.5) vs. 5.1 (2.3) Leg pain when active: 2.4 (2.6) vs. 2.7 (2.6)
EuroQol-5 Dimensions (EQ-5D) (−0.59 to 1.0): 0.57 (0.3) vs. 0.63 (0.2) EuroQol-Visual analog scale (EQ-VAS) (0–100): 5.8 (2.2) vs. 6.4 (2.0)		473 screened/250 randomized and enrolledWithdrawals during treatment period: 7 vs. 10
Loss to followup: 4 vs. 4
Primary analysis is ITT and includes all 250 randomized patients		Mean SD (95% CI); All results NS:
RMDQ (0–24): 6 weeks: 7.0 (6.1, 7.8) vs. 7.1 (6.3, 7.9); 3 months: 5.8 (5.0, 6.6) vs. 6.5 (5.7, 7.3); 6 months: 5.0 (4.2, 5.8) vs. 5.0 (4.2,5.8); 1 year: 4.8 (3.9, 5.6) vs. 5.5 (4.7, 6.4)
NRS LBP at rest (0–10): 6 weeks: 2.9 (2.5, 3.3) vs. 2.9 (2.5, 3.3); 3 months: 2.7 (2.4, 3.1) vs. 2.9 (2.5, 3.3); 6 months: 2.5 (2.1, 2.9) vs. 2.4 (2.0, 2.8); 1 year: 2.5 (2.1, 2.9) vs. 2.8 (2.4, 3.1)
NRS Leg pain at rest (0–10): 6 weeks: 1.3 (1.0, 1.7) vs. 1.5 (1.2, 1.9); 3 months: 1.4 (1.0, 1.8) vs. 1.7 (1.4, 2.1); 6 months: 1.4 (1.0, 1.7) vs. 1.5 (1.1, 1.8); 1 year: 1.5 (1.1, 1.8) vs. 1.6 (1.3, 2.0)
NRS LBP when active (0–10): 6 weeks: 3.7 (3.2, 4.1) vs. 3.6 (3.2, 4.0); 3 months: 3.3 (2.9, 3.7) vs. 3.2 (2.8, 3.6); 6 months: 3.1 (2.7, 3.5) vs. 2.9 (2.5, 3.3); 1 year: 3.0 (2.5, 3.4) vs. 2.9 (2.5, 3.3)
NRS Leg pain when active (0–10): 6 weeks: 1.8 (1.4, 2.2) vs. 1.9 (1.5, 2.3); 3 months: 1.7 (1.2, 2.1) vs. 1.9 (1.5, 2.3); 6 months: 1.6 (1.2, 2.0) vs. 1.9 (1.5, 2.3); 1 year: 1.7 (1.3, 2.1) vs. 2.0 (1.5, 2.4)
EQ-5D (−0.59 to 1.0): 6 weeks: 0.68 (0.64, 0.72) vs. 0.69 (0.65, 0.72); 3 months: 0.73 (0.70, 0.78) vs. 0.69 (0.65, 0.73); 6 months: 0.74 (0.70, 0.78) vs. 0.76 (0.65, 0.74); 1 year: 0.74 (0.70, 0.78) vs. 0.70 (0.65, 0.74)
EQ-VAS (0–100): 6 weeks: 6.8 (6.2, 7.3) vs. 6.7 (6.1, 7.2); 3 months: 7.2 (6.7, 7.8) vs. 6.8 (6.2, 7.3); 6 months: 7.2 (6.6, 7.8) vs. 7.1 (6.7, 7.4); 1 year: 7.4 (7.0, 7.7) vs. 6.6 (6.3, 7.0)
Global perceived effect: No. (%): 6 weeks: 22 (18.6) vs. 27 (22.0); 3 months: 26 (21.5) vs. 26 (22.2); 6 months: 39 (33.1) vs. 42 (36.2); 1 year: 14 (30.9) vs. 32 (29.4)		Pre-specified: NR
Ascertainment: NR
Severity: NR		OR (95% CI) All NS differences
AEs resulting in treatment discontinuation: 0.66 (0.48–1.36)
All AEs: 0.83 (0.49–1.40)
Skin problems: 0.79 (0.35–1.76)
Neurological: 0.65 (0.31–1.38)
Heartburn: 0.99 (0.06–15.9)
Flatulence: 0.55 (0.21–1.44)
Abdominal pain: 1.32 (0.29–6.04)
Nausea/vomiting: 1.77 (0.50–6.21)
Constipation: 4.03 (0.44–36.69)
Diarrhea: 0.55 (0.16–1.92)
Headache/vertigo: 0.98 (0.28–3.49)
Musculoskeletal concerns: 0.42 (0.14–1.25)
10 AEs resolved with treatment discontinuation; 7 resolved with continuation of study drug; 2 Serious AEs (death and surgery) were considered unrelated to study drug. Fasting blood glucose, cholesterol, and blood pressure levels did not deviate from normal fluctuations during the trial		Total during treatment period: 7 vs. 10
Withdrawals due to AE:
Glucosamine: 6 vs. 6

ACR = American College of Rheumatology; AE = adverse event; BMI = body mass index ; CI = confidence interval; CS = chondroitin sulfate; EQ-VAS = EuroQol visual analogue scale; GAIT = Glucosamine/chondroitin Arthritis Intervention Trial; GH = glucosamine hydrochloride; GS = glucosamine sulfate; GUIDE = Glucosamine Unum-in-Die (Once a Day) Efficacy trial; ITT = intention to treat; JSN = joint space narrowing; JSW = joint space width; KL = Kellgren-Lawrence scale; LBP = low back pain; MCII = minimal clinically important improvement; MRI = magnetic resonance imaging; MTP = metatarsophalangeal; NR = not reported; NRS = nonrandomized study; NS = not significant; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; OARSI = Osteoarthritis Research Society International; OMERACT-OARSI = Outcomes Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International; PASS = Patient Acceptable Symptom Scale; QOL = quality of life; RCT = randomized controlled trial; RMDQ = Roland Morris Disability Questionnaire; SD = standard deviation; SE = standard error; SYSADOA = Symptomatic Slow Acting Drugs in Osteoarthritis; UTI = urinary tract infection; VAS = visual analogue scale; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index

From: Appendix I, Evidence Tables: Glucosamine and Chondroitin Studies

Cover of Analgesics for Osteoarthritis
Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review [Internet].
Comparative Effectiveness Reviews, No. 38.
Chou R, McDonagh MS, Nakamoto E, et al.
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