1. PIASCLEDINE®300

2. Outline Osteoarthritis of the Hip and Knee
Definition, epidemiology, burden of disease, classification, risk factors, pathophysiology, diagnosis, and management by SYSADOAs
ASU Expanscience™ A Unique Product
PIASCLEDINE®300 Mechanism of Action
In vitro data
In vivo studies
PIASCLEDINE®300 Clinical Studies
PIASCLEDINE®300 Structural Data
PIASCLEDINE®300 In Practice
PIASCLEDINE®300 Conclusion

3. Osteoarthritis (OA)
Of the Hip and Knee

4. OA is characterized by joint pain & dysfunction
Degeneration of articular cartilage
Clinically characterized by
Usage-related pain
Functional limitation
At advanced stages of disease
Joint stiffness
Muscle atrophy
Limb deformity
Usually involves weight-bearing joints, especially
Hip
Lumbosacral and cervical spine
Knee
Hand

5. OA is the most common joint disease
All races and ethnic groups are affected throughout the world
Prevalence of OA varies according to:
Definition used
Specific joint under study
Characteristics of the study population
In 2010 the global age-standardized prevalence of knee OA was 3.8% and hip OA was 0.85%1
With a prevalence of 12.3%, OA is one of the most prevalent rheumatic and musculoskeletal diseases in France2
According to the WHO, 10% of the world’s population over 60 years of age has OA3
Between 1995 and 2005 in the US, the number of patients with symptomatic OA grew from 21 million to 27 million4
Increase likely due to aging population and the worsening obesity epidemic
Cross M, et al. Ann Rheum Dis 2014;73:
Palazzo C, et al. PLoS One 2014;9:e90633.
Symmons D, et al. Global burden of osteoarthritis in the year Geneva: WHO 2004.
Zhang Y, Jordan JM. Rheum Dis Clin N Am 2008;34:

6. Incidence of OA increases dramatically with age and is worse for women
After the age of 40, the incidence of OA increases rapidly with each passing decade in all joints1
Women experience higher rates of OA, especially after 502
Disease severity is often worse for women too
Men
Women
Joint group
Hand
Knee
Hip
Figure adapted from Arden et al
Buckwalter JA , Martin JA. Adv Drug Deliv Rev 2006;58:
Arden N, Nevitt MC. Best Pract Res Clin Rheumatol 2006;20:3-25.

7. Economic burden of OA is significant
Economic burden of OA accounts for a major share of the economic impact of arthritis, which is estimated at 1-2.5% of the annual gross national product of Western nations1
In 2004 WHO ranked OA as the 5th highest cause of years lost of disability in the whole population in high-income countries, and the 9th highest cause in low- and middle-income countries2
In the US, annual costs due to OA total >$60 billion3
The indirect cost of absenteeism was approximately $10.3 billion between 1996 and 20054
In France, estimated annual costs for hip and knee OA were €3.5 billion for 4.6 million patients in 20105
NSAIDs, nonsteroidal anti-infllammatory drugs
March LM, Bachmeier CHM. Baillieres Clin Rheumatol 1997;11:
The Global burden of disease: 2004 update, WHO 2008.
Buckwalter JA, Martin JA. Adv Drug Deliv Rev 2006;58:
Kotlarz H, et al. J Occup Environ Med 2010;52:263-8.
Bertin P, et al. J Musculoskelet Pain 2014;22:356-64

8. Economic burden of OA is significant
Cost of caring for OA includes:
Doctors’ visits
Prescription medications
Hospitalizations (mostly surgery-related)
Complications resulting from NSAID use
Conventional NSAIDs cause an increased risk of GI side effects (ulcers, perforations, bleeding)
COX-2 selective inhibitors are associated with cardio-renal toxicity, especially in elderly patients
NSAIDs, nonsteroidal anti-infllammatory drugs

9. OA impacts quality of life
OA affects physical functioning, patients' emotions and psychological well-being
The WHO estimates that among those with OA:1
80% are restricted in their movement
25% cannot perform major daily activities
Hip and knee arthroplasies are expected to increase:
Between 2005 and 2030, hip and knee arthroplasies are projected to grow by 174% and 673%, respectively, in the US2
Over the period , the number of hip and knee replacements have increased by one third and twofold in Europe, respectively3
OA is the most common cause of long-term disability in most populations of people over 65 years4
Symmons D, et al. Global burden of osteoarthritis in the year Geneva: WHO, 2004.
Kurtz S, et al. J Bone Joint Surg Am 2007;89:780-5.
Accessed on June 4, 2015: Health in Europe Report v5.pdf
Buckwalter JA, Martin JA. Adv Drug Deliv Rev 2006;58:

10. Primary OA is more common and is mostly a consequence of aging
Primary (idiopathic)
Secondary
Most cases of OA
Occurs less frequently
No identifiable cause
Joint degeneration results from a known cause, usually another disease or condition
(e.g. joint trauma, hereditary, inflammatory, developmental, metabolic, or neurological disorders)
Associated with older age, usually >40 years
May occur at any age

11. Susceptibility of joints to damage, repair failure and OA
OA results from the interplay between systemic and local mechanical factors
Systematic Factors
Age
Gender
Menopause
Genetics
Nutrition
Bone density
Mechanical Factors
Obesity (weight)
Injury, surgery
Muscle weakness
Joint deformity
Repetitive joint loading
Elite athletics
Susceptibility of joints to damage, repair failure and OA
These interactions determine:
Which joint(s) affected
Progression of disease
For all joints, age represents one of the strongest risk factors for OA
Site and Severity of OA
Figure adapted from: Arden N, Nevitt MC. Best Pract Res Clin Rheumatol 2006;20:3-25.

12. 3 main structures are involved in development and progression of OA
Articular cartilage
Joint trauma or ageing may stimulate chondrocytes within the cartilage
Activation of chondrocytes may upset the balance between cartilage synthesis and degradation, leading to OA
↑↑↑ production of inflammatory mediators and proteolytic enzymes
Mechanisms of cartilage destruction cartilage synthesis & repair
SYNTHESIS
TGF-β, IGF-1, Proteoglycans, Collagen II, Aggrecan, PAI-1, TIMPs
DEGRADATION
IL-1, TNF-α, MMPs (1,3,8,9,13) Aggrecanases NO, MIP-1β
Normal Cartilage
SYNTHESIS
TGF-β, IGF-1, Proteoglycans, Collagen II, Aggrecan, PAI-1, TIMPs
DEGRADATION
IL-1, TNF-α, MMPs (1,3,8,9,13) Aggrecanases NO, MIP-1β
Arthritic Cartilage

13. 3 main structures are involved in development and progression of OA (cont’d)
Synovial membrane (synovium)
Cartilage breakdown products are released into the synovial fluid, where they are phagocytosed by macrophages
Synovium responds with an inflammatory reaction, producing more factors that reinforce the destruction of cartilage (IL-1, IL-6, TNFα, MMPs, PGE2, free radicals)
Subchondral bone
As OA progresses, bone remodelling occurs and the subchondral bone hardens
IL, interleukin; TNF: tumour necrosis factor; MMP, matrix metalloprotease; PGE2, prostaglandin E2

14. 3 main structures are involved in development and progression of OA (cont’d)
IL-1: Interleukin 1, TNF: Tumour Necrosis Factor, PGE2: Prostaglandin E2,
MMPs: Matrix Metalloproteases, TGF-s: Transforming Growth Factor-ß,
IGF: Insulin-like Growth Factor, BMP: Bone Morphogenetic Protein,
FGF: Fibroblast Growth Factor.

15. ACR criteria: Diagnosis of hip OA
Clinical
Clinical & Radiographic
Hip pain for most days of the prior month
and
Hip internal rotation <15˚ and
ESR ≤45 mm/h (or hip flexion ≤115˚ if ESR not available) or
Hip internal rotation ≥15˚ and
Pain on internal rotation and
Morning stiffness ≤60 min and
Age >50 years
and ≥2 of 3 of the following features:
ESR ≤20 mm/h
Radiographic osteophytes (femoral or acetabular)
Radiographic joint space narrowing (superior, axial and/or medial)
ESR, erythrocyte sedimentation rate
Altman R, et al. Arthritis Rheum 1991;34:

16. ACR criteria: Diagnosis of knee OA
Clinical
Clinical & Radiographic
Knee pain for most days of prior month
and ≥3 to 6 of the following features:
Age >50 years
Morning stiffness <30 min
Crepitus on active joint motion
Bony tenderness
Bony enlargement of the knee on examination
No palpable warmth of synovium
and ≥1 to 3 of the following features:
and
Radiographic osteophytes
Altman R, et al. Arthritis Rheum 1986;29:

17. Diagnosis of knee OA New EULAR guidelines (1)
Knee OA is characterized clinically by usage-related pain and/or functional limitation
Risk factors which can help identify patients in whom knee OA is the most likely diagnosis include:
Age >50 years - Previous knee injury
Female gender - Occupational/recreational usage
Higher BMI - Family history
Subsets with different risk factors and outcomes can be defined according to:
Varying compartmental involvement (PF, medial or lateral TF)
Bone response (atrophic, hypertrophic) - Presence of crystals
Global pattern of OA (generalized/localized) - Degree of inflammation
Typical symptoms of knee OA include:
Usage-related pain, often worse towards the end of the day, relieved by rest
Joint instability
Mild morning or inactivity stiffness
Impaired function
More persistent rest and night pain may occur in advanced OA
Symptoms are often episodic or variable in severity and slow to change 1 2 3 4
PF, patellofemoral; TF, tibiofemoral
Zhang W, et al. Ann Rheum Dis 2010;69:483-9.

18. Diagnosis of knee OA New EULAR guidelines (2)
In adults >40 years, diagnosis can be made without radiographic examination if the following are present:
Usage-related knee pain
Short-lived morning stiffness
Functional limitation
≥1 typical examination finding (crepitus, restricted movement, bony enlargement)
Applies even if radiographs appear normal
Indicative physical findings include:
Crepitus - Painful and/or restricted movement
Bony enlargement - Absent or modest effusion
Additional features that may be present include:
Deformity (fixed flexion and/or varus - less commonly valgus)
Instability
Periarticular or joint-line tenderness
Pain on patellofemoral compression
Red flags that suggest sepsis, crystals or serious bone pathology include:
Severe local inflammation - Erythema
Progressive pain unrelated to usage
Other important considerations include:
Referred pain - Ligamentous and meniscal lesions
Localized bursitis - Involvement of other joints (suggest other diagnoses) 5 6 7
Zhang W, et al. Ann Rheum Dis 2010;69:483-9.

19. Diagnosis of knee OA New EULAR guidelines (3)
Plain radiography is the current "gold" standard for morphological assessment
Classical features are:
Focal joint space narrowing
Osteophyte
Subchondral bone sclerosis
Subchondral "cysts"
Other imaging modalities are seldom indicated for diagnosis of OA
Laboratory tests (blood, urine or synovial fluid) are not required for diagnosis
May confirm or exclude coexistent inflammatory disease, including:
Pyrophosphate crystal deposition
Gout
Rheumatoid arthritis
If a palpable effusion is present, synovial fluid should be aspirated and analyzed to exclude inflammatory disease and to identify urate and calcium pyrophosphate crystals
OA synovial fluid is typically non-inflammatory with <2000 leukocytes/mm3 8 9 10
Zhang W, et al. Ann Rheum Dis 2010;69:483-9.

20. EULAR recommendations have resulted in an algorithm, which makes diagnosing knee OA much simpler
Background risk
Risk Factors
Age
Gender
BMI
Occupation
Family history of OA
History of knee injury
Symptoms
Knee pain
Brief morning stiffness
Functional limitation
Radigraphic Changes
Osteophyte
Narrowing
Subchondral sclerosis
Subchondral cysts
Signs
Crepitus
Restricted movement
Bony enlargement OA
Mild
Moderate
Severe
Zhang W, et al. Ann Rheum Dis 2010;69:483-9.

21. OA management by SYSADOAs
From latest versions of treatment recommendations
Knee OA
Hip OA
EULAR 20031
SYSADOAs (glucosamine sulphate, chondroitin sulphate, diacerein, ASU and hyaluronic acid) have symptomatic effects and are likely to lead to structural changes NA
EULAR 20052
SYSADOAs have a symptomatic effect and low toxicity, but the effects are minimal, and patients likely to benefit most have not been identified. The structural changes and clinically significant pharmacoeconomic benefits have not been properly established
OARSI 20133
ASU, chondroitin, diacerein, glucosamine, intra-articular hyaluronic acid, are uncertain* treatments for specific clinical sub-phenotypes
ESCEO 20144
SYSADOAs are recommended as a first chronic therapy (background therapy), with as needed paracetamol for short- term, rescue analgesia
EULAR, European League Against Rheumatism; OARSI, Osteoarthritis Research Society International; ESCEO, European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; SYSDOAs, symptomatic slow-acting drugs for OA; ASU avocado soybean unsaponifiables; NA, not applicable
* An “Uncertain” recommendation may reflect ambiguous evidence or appropriateness due to a slightly unfavorable risk profile or to limited efficacy. However, the ‘uncertain’ classification is not expected to be a negative recommendation or prevent use of that therapy. An uncertain recommendation merely indicates that a patient and his/her physician should determine together whether the treatment is appropriate for his/her individual characteristics, co-morbidities and preferences.
Jordan KM, et al. Ann Rheum Dis 2003;62:
Zhang W, et al. Ann Rheum Dis 2005;64:
McAlindon TE, et al. Osteoarthritis Cartilage 2014; 22:
Bruyère O, et al. Semin Arthritis Rheum 2014;44:

22. ASU Expanscience™
A Unique Product

23. The Early Days of ASU Expanscience™
Research into the therapeutic benefits of avocado and soybean oil unsaponifiables (ASU) began by Professor Henri Thiers1
ASU combination is introduced as a successful treatment for epiphysitis and mild ichthyosis (diseases of the skin and cartilage)2
ASU are defined as being eutrophic (abundant in nutrients), acting primarily on the epidermis, mucosa and collagen of the skin and bone
The analgesic qualities of ASU in hip osteoarthritis are described with enthusiasm,
1971
"[ASU] are of great interest in vertebral and hip arthralgia, where they seem to slow progression."3
Thiers H, et al. Lyon Med 1955;87:
Thiers H, et al. Rhumatologie 1971;23:
Thiers H. Le Journal de Médecine de Lyon 1972; Feb 5.

24. ASU Expanscience™ A Unique Product
Unsaponifiables are derived from fatty substances
Key factors which determine the quality of an unsaponifiable:
Botanical origin
Harvest period
Extraction & refinement oil processes
Separation & purification unsaponifiable processes
Geographic origin
Pre-treatment of vegetal raw materials
Expanscience Laboratories™ is a global leader in the manufacture and evaluation of ASU
Pioneered and patented various processes for the extraction of unsaponifiables
Expert in the technical aspects of purifying unsaponifiables
ASU Expanscience™ is unique by its composition and scientific evidence

25. Mechanism of Action
In vitro data

26. ASU Expanscience™ reduces synthesis of inflammatory mediators & proteases involved in cartilage degradation
Objective
To investigate the in vitro effects of ASU on molecules involved in cartilage degradation in normal human articular chondrocytes
Methods
Isolated human chondrocytes were cultured ± IL-1β ± ASU for 72 hours
IL-1β: pro-inflammatory cytokine implicated in cartilage destruction
Results
Data showed that ASU are potent inhibitors of the production of:
Pro-inflammatory cytokines (IL-6, IL-8, PGE2)
ASU may have a protective role against cartilage degradation and that ASU may have a potential role in controlling inflammation in the osteoarthritic cartilage.
IL, interleukin; PGE2, prostaglandin E2; MMP, matrix metalloprotease
Henrotin YE, et al. Clin Rheumatol 1998;17:31-9.

27. ASU Expanscience™ enhances the production of growth factors involved in cartilage regeneration
Objective
To determine the effect of ASU on the production of growth factors that influence cartilage repair in articular chondrocytes
Methods
Cultured bovine articular chondrocytes were treated with ASU
Expression and production of growth factors was analyzed
Results
Chondrocytes treated with ASU had increased production of molecules involved in tissue regeneration (TGF-1, TGF-2, PAI-1)
Suggests that ASU may be involved in promoting cartilage homeostasis and repair.
TGF, transforming growth factor; PAI, plasminogen activator inhibitor
Boumediene K, et al. Arthritis Rheum 1999;42:

28. ASU Expanscience™ stimulates aggrecan production
Objective
To study the effects of ASU on the metabolism of human osteoarthritic (OA) chondrocytes
Methods
Human OA chondrocytes were cultured for 12 days ± IL-1β, with or without ASU
Production of catabolic and proinflammatory molecules was assayed
Results
ASU increased aggrecan production impaired by inflammation
ASU partially reversed the IL-1- induced inhibition of TIMP-1 synthesis (an inhibitor of MMP-3)
ASU inhibited the production of various inflammatory mediators
IL-6, IL-8, MIP-1β, and NO (see figure, next slide)
ASU may mitigate cartilage destruction and promote cartilage repair processes.
TIMP, tissue inhibitor of metalloproteases; MIP, macrophage inflammatory protein
Henrotin YE, et al. J Rheumatol 2003;30:

29. ASU Expanscience™ inhibits the production of pro-inflammatory mediators in vitro
Basal
ASU 10µg/ml
IL-6
MIP-1β
p<0.001
p<0.001
p<0.001
p<0.001
p<0.01
p<0.001
p<0.001
p<0.05
Basal
ASU
IL-8 NO
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.01
p<0.001
p<0.01
Henrotin YE, et al. J Rheumatol 2003;30:

30. ASU Expanscience™ modulates osteoblast phenotype
Objective
To determine the effects of ASU on osteoblast-induced dysregulation of chondrocyte metabolism
Methods
Osteoblasts isolated from nonsclerotic (NSC) or sclerotic (SC) zones of OA subchondral bone and were pretreated or not with ASU
OA human chondrocytes were cultured ± (osteoblasts ± ASU) for 4 or 10 days
Assayed expression of cartilage matrix or catabolic molecules
Results
Osteoblasts isolated from sclerotic zones on human OA chondrocytes showed inhibitory effects
ASU-incubated SC osteoblasts restored normal levels of cartilage matrix proteins (e.g. aggrecan and collagen II)
ASU may prevent cartilage degradation by acting directly on osteoblasts.
Henrotin YE, et al. J Rheumatol 2006;33:

31. Mechanism of Action
In vivo studies

32. ASU Expanscience™ increases levels of tissue-production stimulators (1)
Objective
To investigate the in vivo effect of ASU treatment on TGF-1 and TGF-2 levels in knee joint fluid
Methods
24 non-arthritic dogs were treated with either:
ASU 300 mg/day
ASU 300 mg every 3 days
Normal diet (control)
TGF-1 and TGF-2 levels from knee joint fluid were assayed at baseline and every month for 3 months
Altinel L, et al. Tohoku J Exp Med 2007;211:181-6.

33. ASU Expanscience™ increases levels of tissue-production stimulators (2)
Results
TGF-β1 level in joint fluid
TGF-β2 level in joint fluid
TGF-β1 and TGF-β2 levels in knee joint fluid significantly increased in both the low- and high- dose ASU groups.
Although levels of TGF-β1 declined somewhat at the end of month 3, they remained significantly better than control group levels.
Group 1: Control
Group 2: Low dose
Group 3: High dose
ASU cause an increase in TGF-β levels in knee joint fluid.
These findings support in vitro studies pointing to a
TGF-β–mediated increase of cartilage matrix production by ASU.
Altinel L, et al. Tohoku J Exp Med 2007;211:181-6.

34. ASU Expanscience™ may provide a chondroprotective benefit (1)
Objective
To determine if ASU show a chondroprotective effect in vivo
Methods
Articular cartilage from rats was wrapped in cotton and implanted beneath the skin of mice
The presence of cotton induces a granulomatous reaction which enhances the destruction of adjacent cartilage
The mice were treated with ASU or a control solution daily for 2 weeks
Implanted cartilage was removed and analyzed biochemically for parameters related to cartilage integrity:
Glycosaminoglycan and hydroxyproline content of the cartilage
Hydroxyproline content and β-D-glucosaminidase activity of the granulomatous tissue (a collection of immune cells, especially macrophages, that surround a foreign body)
Khayyal MT, el-Ghazaly MA. Drugs Exp Clin Res 1998;24:41-50.

35. ASU Expanscience™ may provide a chondroprotective benefit (2)
Administration of unsaponifiables [avocado (A), soybean (S), mixed A/S] reduced cartilage glycosaminoglycan and hydroxyproline content at 2 weeks post-implantation of cotton- wrapped cartilage.
FHC: femoral head cartilage
* Significant difference from control (p<0.05)
@ Significant difference from A and S (p<0.05)
Cartilage glycosaminoglycan content (µg) * * *
p<0.05
p<0.05 * * *
Cartilage hydroxyproline content (µg)
In addition, ASU significantly reduced the hydroxyproline content and β-D- glucosaminidase activity of the granulomatous tissue (induced by the cotton covering the cartilage).
Initial value (frozen FHC)
Control
(A)
(S)
(A/S)
These data suggest that ASU might exert a chondroprotective effect, possibly through an anti-inflammatory action.
Khayyal MT, el-Ghazaly MA. Drugs Exp Clin Res 1998;24:41-50.

36. ASU Expanscience™ protects against OA-induced structural changes (1)
Objective
To investigate the in vivo effects of ASU on the development of osteoarthritic structural changes and to explore their mode of action
Methods
OA was induced in the right knee of dogs by transecting the anterior cruciate ligament (ACL)
The dogs received daily ASU (10 mg/kg) or placebo for 8 weeks
Cartilage and subchondral bone structures were analyzed:
Tibial plateaus
Femoral condyles
Immunohistochemistry analysis of the cartilage was conducted to assess molecular changes associated with cartilage degradation
Boileau C, et al. Arthritis Res Ther 2009;11:R41.

37. ASU Expanscience™ protects against OA-induced structural changes (2)
ASU-treated dogs exhibited a significant decrease in indicators of cartilage matrix damage vs. dogs given placebo:
Significantly decreased severity of cartilage lesions (see figure)
Smaller macroscopic lesions on tibial plateau
Significantly reduced loss of subchondral bone volume and calcified cartilage thickness
Significantly reduced the levels of iNOS and MMP-13 in the cartilage
Femoral condyles
Tibial plateaus
Placebo
ASU (10 mg/kg)
Staining indicates aggrecan degradation.
The protective effect of ASU on osteoarthritic structural changes may be mediated by a reduction in cartilage catabolism and subchondral bone remodelling, which may be partly due to the inhibition of iNOS and MMP-13.
iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase
Boileau C, et al. Arthritis Res Ther 2009;11:R41.

38. Clinical studies

39. Symptomatic efficacy of PIASCLEDINE®300 in the treatment of hip and knee OA (Maheu et al. 1998)
Objective
To assess the efficacy and safety of PIASCLEDINE® 300 in the treatment of symptomatic OA of the knee or hip
Study design
Prospective, randomized, double-blind, placebo-controlled, multicentre trial conducted by 45 rheumatologists
6 month treatment period + 2 month post-treatment follow-up
164 patients (mean age 64 years) with regular, painful knee (n=114) or hip (n=50) OA
Patients were randomized to receive either PIASCLEDINE®300 mg (n=85) as one capsule per day or placebo (n=79) once daily for 6 months
Maheu E, et al. Arthritis Rheum 1998;41:81-91.

40. Symptomatic efficacy of PIASCLEDINE®300 in the treatment of hip and knee OA (Maheu et al. 1998)
Inclusion criteria
Outpatients who met ACR Criteria:
Active OA for ≥ 6 months, regular pain (≥ 30 mm on VAS) requiring NSAIDs ≥ 3 months, LFI between 4 and 14
No analgesics (except acetaminophen) or NSAIDs for 15 days
Clinical assessments
Primary endpoint: Change in the LFI score from baseline to month 6
Main secondary endpoints:
Success rate*
Overall spontaneous pain (VAS)
Overall functional disability (VAS)
Safety
*defined as ≥30% improvement on LFI and ≥ 50% improvement in pain vs baseline
NSAIDs, non-steroidal anti-inflammatory drugs; LFI, Lequesne’s functional impairment index;
VAS, visual analog scale
Maheu E, et al. Arthritis Rheum 1998;41:81-91.

41. Symptomatic efficacy of PIASCLEDINE®300 in the treatment of hip and knee OA (Maheu et al. 1998)
Results: Primary endpoint
Significant reduction in the mean LFI vs. placebo at 6 months: -2,1 + 0,5 (p<0,001)
Increased overtime (Baseline to month 6)
Persisted after treatment discontinuation (months 6-8)
Lequesne's Functional Index
Global Spontaneous Pain
Overall Functional Disability
VAS (mm)
VAS (mm)
p=0.04
p=0.02
p<0.001
p=0.002
p=0.22
p=0.39
p<0.001
p=0.04
p=0.14
p<0.001
p<0.001
p=0.001
p=0.006
p=0.003
p<0.001
2 months post-treatment period
2 months post-treatment period
2 months post-treatment period
Piascledine®300
Placebo
Maheu E, et al. Arthritis Rheum 1998;41:81-91.

42. 2 months post-treatment period
Symptomatic efficacy of PIASCLEDINE®300 in the treatment of hip and knee OA (Maheu et al. 1998)
Results
2 months post-treatment period
48%
39%
p=0.001
p<0.01
26%
18%
Results: Main secondary endpoints
Success rate was significantly higher among patients treated with PIASCLEDINE®300 vs. those who received placebo:
During treatment: 39% vs. 18% (p<0.01) at 6 months
After 2 months of treatment discontinuation: 48% vs. 26% (p=0.001) at 8 months
Maheu E, et al. Arthritis Rheum 1998;41:81-91.

43. Symptomatic efficacy of PIASCLEDINE®300 in the treatment of hip and knee OA (Maheu et al. 1998)
Results: Main secondary endpoints (cont’d)
Overall spontaneous pain was also significantly decreased after 6 months of PIASCLEDINE®300 (-10.4 ± 3.5 mm, p = 0.003)
Overall functional disability was significantly reduced with PIASCLEDINE®300 compared to placebo (-13.2 ± 3.5 mm, p < 0.001)
Safety and tolerability
No statistically significant differences of adverse events (AEs) between PIASCLEDINE®300 and placebo. AEs included gastrointestinal, neurologic, general and cutaneous symptoms
Maheu E, et al. Arthritis Rheum 1998;41:81-91.

44. PIASCLEDINE®300 reduces pain and improves function in knee and hip OA.
Symptomatic efficacy of PIASCLEDINE®300 in the treatment of hip and knee OA (Maheu et al. 1998)
Conclusion
Patients treated with PIASCLEDINE®300 for 6 months have significantly less pain and significantly less functional disability than those who receive placebo, highlighting a significant higher success rate with PIASCLEDINE®300
These benefits persist after treatment discontinuation
This demonstrates the symptomatic efficacy of PIASCLEDINE®300 in the treatment of knee and hip OA, along with a good tolerability profile
PIASCLEDINE®300 reduces pain and improves function in knee and hip OA.
Maheu E, et al. Arthritis Rheum 1998;41:81-91.

45. Efficacy & safety of PIASCLEDINE®300 for symptomatic OA of the hip and knee (Blotman et al. 1997)
Objective
To evaluate the NSAID-sparing effect of PIASCLEDINE®300 vs. placebo
Study design
Prospective, phase III, randomized, double-blind, placebo-controlled, parallel-group multicentre study
164 patients were randomized to receive either PIASCLEDINE®300 (n=81) or placebo (n=83) once daily for 3 months
All patients took 1 of 7 predefined oral NSAIDs during the first half of the study (D0 ̶ D45) and continued if needed during the second half (D45 ̶ D90)
NSAIDs, non-steroidal anti-inflammatory drugs
Blotman F, et al. Rev Rhum (Engl Ed) 1997;64:

46. Efficacy & safety of PIASCLEDINE®300 for symptomatic OA of the hip and knee (Blotman et al. 1997)
Inclusion criteria
Outpatients aged 45 to 80 years old, with primary OA of the hip or knee meeting ACR criteria
Disease duration ≥6 months
With pain, functional impairment requiring one of the 7 predefined oral NSAIDs daily for ≥ 3 months prior to inclusion and a LFI score ≥ 4
Clinical assessments
Primary endpoint: Proportion of patients resuming NSAID therapy after the first half of the study (D45)
Main secondary endpoints: Total dose of NSAIDs expressed in diclofenac equivalent, number of days on NSAID therapy, Lequesne functional index, overall ratings by the patient and physician and safety
NSAIDs, non-steroidal anti-inflammatory drugs
Blotman F, et al. Rev Rhum (Engl Ed) 1997;64:

47. Efficacy & safety of PIASCLEDINE®300 for symptomatic OA of the hip and knee (Blotman et al. 1997)
Results: Primary endpoint
Fewer patients resumed NSAIDs between D60 and D90 in the PIASCLEDINE®300 group than in the placebo group
At D75, only 35% of patients taking PIASCLEDINE®300 resumed NSAIDs vs 64.5% in the placebo group (p < 0.001)
At D90, only 43% of patients taking PIASCLEDINE®300 resumed NSAIDs vs 70% in the placebo group (p < 0.001)
NSAIDs, non-steroidal anti-inflammatory drugs
Blotman F, et al. Rev Rhum (Engl Ed) 1997;64:

48. Efficacy & safety of PIASCLEDINE®300 for symptomatic OA of the hip and knee (Blotman et al. 1997)
Results: Main secondary endpoints
Mean cumulative dose of NSAIDs between D45 and D90 was significantly lower in the PIASCLEDINE®300 group compared to the placebo group
Treatment
NSAIDs, non-steroidal anti-inflammatory drugs
Blotman F, et al. Rev Rhum (Engl Ed) 1997;64:

49. Efficacy & safety of PIASCLEDINE®300 for symptomatic OA of the hip and knee (Blotman et al. 1997)
Results: Main secondary endpoints (cont’d)
The number of days on NSAIDs was significantly smaller between D0 and D90 in the PIASCLEDINE®300 group than in the placebo group (6.3 days ± 10.7 vs days ± 10.2, p < 0.01)
Improvement in LFI: the decrease of the LFI was significantly larger with PIASCLEDINE®300 compared to placebo (-2.3 ± 2.6 vs -1.0 ± 2.6, p <0.01)
Compared to the placebo group, overall patient ratings were significantly better in the PIASCLEDINE®300 group
At D90, 60.5% of patients gave a ‘good’ or ‘very good’ rating vs 34% in the placebo group, p < 0.01
Overall physician ratings were also significantly better in the PIASCLEDINE®300 group
At D90, the proportions of ‘good’ and ‘very good’ ratings were 51% in the PIASCLEDINE®300 group vs 33% in the placebo group, p < 0.01
Treatment
NSAIDs, non-steroidal anti-inflammatory drugs
Blotman F, et al. Rev Rhum (Engl Ed) 1997;64:

50. PIASCLEDINE®300 has a valuable NSAID-sparing effect.
Efficacy & safety of PIASCLEDINE®300 for symptomatic OA of the hip and knee (Blotman et al. 1997)
Safety and tolerability
The numbers of patients with at least one AE were comparable between groups (11.3% in the PIASCLEDINE®300 group and 12% in the placebo group)
Most AEs were transient, gastrointestinal in nature and resolved spontaneously
Conclusion
Treatment with PIASCLEDINE®300 significantly reduces the need for NSAIDs in patients with OA after 3 months of treatment
Nearly 6 out of 10 patients on PIASCLEDINE®300 treatment remained off NSAID after 3 months of treatment
The NSAID- sparing effect is of value in OA patients, especially in patients with comorbidities and in older patients
The symptomatic efficacy of PIASCLEDINE®300 was associated with a well- tolerated safety profile
Treatment
PIASCLEDINE®300 has a valuable NSAID-sparing effect.
Blotman F, et al. Rev Rhum (Engl Ed) 1997;64:

51. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Objective
To compare the efficacy of two doses of PIASCLEDINE®300 in the symptomatic treatment of knee OA
Study design
Prospective, randomized, double-blind, and placebo-controlled multicentre study with 3 parallel groups
260 patients were randomized to receive once daily for 3 months:
PIASCLEDINE®300 (1 capsule/day) (n=86)
PIASCLEDINE®300 (2 capsules/day) (n=86)
Placebo (n=88)
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

52. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Inclusion criteria
Patients aged 45 to 80 years old, with primary OA of the knee according to ACR criteria
Active OA for ≥3 months, pain (≥30 mm on VAS) requiring NSAIDs and/or analgesics ≥3 months, LFI between 4 and 12
Daily intake of NSAIDs/analgesics between 90 and 110 mg equivalents of diclofenac, to remain unchanged from D0 to D30, and adapted to clinical needs from D30 to D90
NSAIDs, non-steroidal anti-inflammatory drugs; LFI, Lequesne’s functional impairment index;
VAS, visual analog scale
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

53. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Clinical assessments
Primary endpoint: NSAID/analgesic intake between days (expressed as mg equivalents of diclofenac)
Main secondary endpoints:
Number of days with NSAID/analgesic intake between D30 ̶ 90
Spontaneous pain (VAS)
Lequesne’s functional index
Overall assessment of efficacy by the patient and investigator
Safety
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

54. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Results: Primary endpoint
NSAID/analgesic intakes were significantly lower in the PIASCLEDINE® groups vs. the placebo group from D30 onwards (p<0.01)
In the PIASCLEDINE®300 (1 capsule/day) group, intakes decreased from 143 ± 48 mg diclofenac equivalent (mg dicl eq) at D0 to 45± 52 mg dicl eq at D90 vs 136 ± 55 mg dicl eq at D0 to 81±63 at D90 in the placebo group
In the PIASCLEDINE®300 (2 capsules/day) group, intakes decreased from 131± 51 mg dicl eq at D0 to 52±59 mg dicl eq at D90
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

55. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Results: Main secondary endpoint
By day 90, NSAID intake has dropped by at least 50% in 71% of patients taking PIASCLEDINE® 300 (1 capsule/day) and PIASCLEDINE® 300 (2 capsules/day) compared to 36% of patients in the placebo group (p<0.01)
% of patients with ≥ 50% reduction in NSAID/analgesic use
Day – 15 to D0/D30 to D60
Day – 15 to D0/D60 to D90
*p < 0.01 vs
PIASCLEDINE® 300
(1 cap/day)
and
(2 caps/day)
Piascledine®300 (1 cap/d) (n=83)
Piascledine®300 (2 caps/d) (n=87)
Placebo (n=42)
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

56. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Results: Main secondary endpoint (cont’d)
Patients in the two PIASCLEDINE®300 groups had significantly fewer days with NSAID intake than those in the placebo group during the D30 ̶ D60 and D60 ̶ D90 periods
During D30 ̶ D60: 17.8±11.2 days in the PIASCLEDINE®300 (1 capsule/day) group and 19.0±11.0 days in the PIASCLEDINE®300 (2 capsules/day) group vs 24.7±10.4 days in the placebo group (p < 0.01)
During D60 ̶ D90: 13.9±12.8 days in the PIASCLEDINE®300 (1 capsule/day) group and 13.1±12.1 days in the PIASCLEDINE®300 (2 capsules/day) group vs 21.2±12.4 days in the placebo group (p < 0.01)
Spontaneous pain significantly decreased in the PIASCLEDINE®300 groups (‘1 capsule/day’ and ‘2 capsules/day’) compared to the placebo group
D30: 41.9±18.6 mm, 39.4±19.7 mm vs 46.7±18.0, respectively (p = 0.004)*
D90: 24.2±21.2 mm, 28.3±20.8 mm vs 42.4±21.4, respectively (p < 0.01)
*placebo versus PIASCLEDINE®300 (2 capsules/day)
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

57. Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Results: Main secondary endpoint (cont’d)
Lequesne’s index was significantly improved at D90: 5.5±3.6 (1 capsule/day), 6.5±3.5 (2 capsules/day) vs 7.8±3.4 (p < 0.01)
Both patients and physicians assessed PIASCLEDINE®300 better than placebo
On the final visit, a rating ‘good’ was given in 68% of the PIASCLEDINE®300 (1 capsule/day) patients and 55% of the PIASCLEDINE®300 (2 capsules/day) patients vs 28% in the placebo group (p < 0.01)
Safety and tolerability
The incidence of side effects was low and comparable between groups
Most AEs were mild in severity and included gastrointestinal, neurologic, general and cutaneous symptoms
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

58. PIASCLEDINE®300 has a valuable NSAID-sparing effect.
Symptom modifying effect of PIASCLEDINE®300 in knee OA (Appelboom et al. 2001)
Conclusion
This study confirms that PIASCLEDINE®300 has an NSAID-sparing effect in patients with OA
The NSAID-sparing effect is of value in OA patients, especially in patients with comorbidities and in older patients
The symptomatic efficacy of PIASCLEDINE®300 was associated with a well- tolerated safety profile
PIASCLEDINE®300 has a valuable NSAID-sparing effect.
Appelboom T, et al. Scand J Rheumatol 2001;30:242-7.

59. PIASCLEDINE®300 Clinical Trials Key Points
Study
Key Points
Maheu et al. 1998
In patients with symptomatic OA of the knee or hip:
PIASCLEDINE®300 significantly reduced pain and functional disability
Symptomatic efficacy persisted after treatment discontinuation
Blotman et al
PIASCLEDINE®300 significantly reduced the need for NSAIDs (sparing effect)
Appelboom et al
In patients with symptomatic OA of the knee:
PIASCLEDINE® significantly reduced NSAID/analgesic intake (sparing effect)
In all of the above studies, PIASCLEDINE®300 was well-tolerated with a low incidence of adverse events

60. Symptomatic efficacy of PIASCLEDINE®300 in OA patients: a meta-analysis of randomized controlled trials (Christensen et al. 2008)
Objective
To evaluate the efficacy of PIASCLEDINE®300 in OA patients using meta- analysis on randomized controlled trials
Study design
Meta-analysis of 4 randomized, controlled clinical trials (Maheu, et al ; Blotman, et al. 2007; Appelboom, et al. 2001; Lequesne, et al ) in which patients were given either PIASCLEDINE® 300 or placebo to treat hip and/or knee OA
Christensen R, et al. Osteoarthritis Cartilage 2008;16:

61. Symptomatic efficacy of PIASCLEDINE®300 in OA patients: a meta-analysis of randomized controlled trials (Christensen et al. 2008)
Inclusion criteria
Clinical trials that included hip and/or knee OA patients who were randomized to either PIASCLEDINE® 300 or placebo
Clinical assessments
Primary endpoint: Pain reduction (effect size) with PIASCLEDINE® 300 compared to placebo
Secondary endpoints: Reduction in Lequesne’s functional index (effect size), number of responders to treatment
Christensen R, et al. Osteoarthritis Cartilage 2008;16:

62. Symptomatic efficacy of PIASCLEDINE®300 in OA patients: a meta-analysis of randomized controlled trials (Christensen et al. 2008)
Results
Four PIASCLEDINE® 300 clinical trials fulfilled the inclusion criteria, representing 664 patients with either hip (41.4%) or knee (58.6%) OA who were allocated to either PIASCLEDINE® 300 mg daily (n = 336) or placebo (n = 328)
Average trial length was 6 months
Primary endpoint:
Combined pain reduction significantly favoured PIASCLEDINE®300 with an Effect Size of 0.39 (95% CI: ) (p = 0.04). This ES corresponds to an improvement of pain scores by 10.7% and 11.3% in knee and hip OA, respectively
Christensen R, et al. Osteoarthritis Cartilage 2008;16:

63. Symptomatic efficacy of PIASCLEDINE®300 in OA patients: a meta-analysis of randomized controlled trials (Christensen et al. 2008)
Results
Christensen R, et al. Osteoarthritis Cartilage 2008;16:

64. Symptomatic efficacy of PIASCLEDINE®300 in OA patients: a meta-analysis of randomized controlled trials (Christensen et al. 2008)
Other endpoints:
Improvements in Lequesne’s function index also favoured PIASCLEDINE®300 over placebo with an Effect Size of 0.46 (95% CI: ) (p = )
One in 6 patient treated with PIASCLEDINE®300 would benefit from the treatment (NNT = 6)
Conclusion
This meta-analysis supports the use of PIASCLEDINE®300 in patients with hip and/or knee OA
Improvements in pain (Effect Size of 0.39) and function (Effect size of 0.46) were demonstrated with PIASCLEDINE®300, supporting its therapeutic efficacy
Christensen R, et al. Osteoarthritis Cartilage 2008;16:

65. Structural data

66. ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Objective
To evaluate the structural effect of PIASCLEDINE®300 in symptomatic hip OA by measuring its ability to slow radiographic progression over 3 years
Study design
Prospective, randomized, double-blinded, placebo-controlled multicentre study
399 patients were randomized to receive either PIASCLEDINE®300 mg (n=189) or placebo (n=210) once daily for 3 years
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

67. ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Inclusion criteria
Ambulatory patients, aged 45 to 75 years old, with primary hip OA according to ACR criteria and radiographic criteria
Symptomatic for ≥ 1 year, with pain present ≥ 50% of the time over the prior 3 months, with a Lequesne AlgoFunctional Index score (range 0‑24) for hip OA between 3 and 10, despite analgesics
Minimum JSW between 1-4 mm (radiograph)
Localised supero-lateral or supero-medial JSN with a minimal JSW between 1 to 4 mm at target hip
Clinical assessments
Primary endpoint: Change in hip JSW (target hip) between baseline and 3 years as measured on standing radiographs. The primary endpoint was subjected to 2 analyses:
Main analysis: Change in JSW at the narrowest point of the joint space (mm)
Secondary analysis: Percentage of progressors defined by a JSW loss of ≥ 0.5 mm after 3 years of treatment
JSW, joint space width; JSN, joint space narrowing
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

68. ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Clinical assessments (cont’d)
Main secondary endpoints:
Changes in Lequesne Index
WOMAC scores
Global hip pain (0-100mm VAS)
Global handicap (0-100mm VAS)
Patient’s global assessment (0-100mm VAS) between baseline and 3 years
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

69. ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Results: Main analysis of primary endpoint
Adjusted mean change in JSW at year 3 was not significantly different in the PIASCLEDINE®300 group (‑0.64 mm) vs the placebo group (‑0.67 mm) (95% CI ‑0.156 to 0.225; p=0.72)
50%
40%
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

70. ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Results: Secondary analysis of primary endpoint
At 3 years, significantly fewer patients progressed in the PIASCLEDINE®300 group (40.4%) than in the placebo group (50.3%; p=0.040)
50%
40%
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

71. ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Results: Secondary endpoints
No difference
Safety and tolerability
Musculoskeletal/connective tissue and infection/infestations were the most frequently reported AEs
Conclusion
ERADIAS is the first trial fulfilling the highest recommended methodological and statistical standards (based on the OARSI and OMERACT criteria) to examine the structural effect of a treatment for hip OA as a primary outcome measurement
This study shows that 3-year treatment with PIASCLEDINE®300 reduces the relative risk of JSW progression (loss of JSW ≥ 0.50mm) by 20% compared to placebo
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

72. PIASCLEDINE®300 slows the progression of OA.
ERADIAS: Structure-modifying effect of PIASCLEDINE®300 in hip OA (Maheu et al. 2014)
Conclusion (cont’d)
PIASCLEDINE®300 was shown to have a good tolerability profile over 3 years
This indicates a potential structure-modifying effect of PIASCLEDINE®300 in hip OA
PIASCLEDINE®300 slows the progression of OA.
Maheu E, et al. Ann Rheum Dis 2014;73:376‑84.

73. In Practice

74. PIASCLEDINE®300 In Practice
Easy to use
Favourable tolerability profile
One capsule, once daily*
To be taken during a meal
* Not recommended during pregnancy
Summary of Product Characteristics, PIASCLEDINE®300. Laboratoires Expanscience™.

75. Conclusion

76. PIASCLEDINE®300 Conclusion
In vitro studies suggest that PIASCLEDINE®300
Reduces the synthesis of molecules involved in cartilage degradation
Stimulates the production of growth factors and other molecules involved in cartilage repair and synthesis
In vivo research indicates that PIASCLEDINE®300
Provides a chondroprotective benefit
Protects against OA-induced structural changes
Controlled clinical trials demonstrate that, in patients with OA of the hip and/or knee, PIASCLEDINE®300
Reduces pain and improves disability
Reduces reliance on NSAIDs (NSAID-sparing effect) for pain relief
Reduces the progression of joint space narrowing in patients more severely affected by hip OA
Is safe and well-tolerated