Glucosamine Hydrochloride, capsule, 750 mg, Arthro-Aid®, July 2006
Page last updated: 10 November 2006
Public Summary Document
Product: Glucosamine Hydrochloride, capsule, 750 mg, Arthro-Aid®
Sponsor: Arkopharma Australia Pty Ltd
Date of PBAC Consideration: July 2006
1. Purpose of Application:
The submission sought a restricted benefit PBS listing for the symptomatic treatment
This drug had not previously been considered by the PBAC.
3. Registration Status:
Arthro-Aid was registered by the TGA on 15 February 2001 for the management of osteoarthritis
and the temporary relief of its associated pain.
4. Listing requested and PBAC’s View
The submission requested a restricted benefit listing for the symptomatic treatment
The PBAC noted that current guidelines and recommendations promote the use of non- pharmacological therapies and then the addition of oral analgesics (paracetamol) as first line treatment for symptomatic osteoarthritis.
5. Clinical place for the proposed therapy
The submission claimed glucosamine hydrochloride provides an alternative in osteoarthritis
management to NSAIDs or selective COX-2 inhibitors.
The submission nominated celecoxib as the most appropriate comparator.
The PBAC did not consider celecoxib to be the appropriate comparator. Celecoxib is specifically not subsidised for the treatment of arthrosis without an inflammatory component and the PBAC considered glucosamine is unlikely to replace celecoxib in clinical practice. The PBAC noted that current guidelines and recommendations promote the use of non- pharmacological therapies and then the addition of oral analgesics (paracetamol) as first line treatment for symptomatic osteoarthritis.
7. Clinical Trials
The submission provided both key and supportive evidence. Key evidence came from three
randomised trials. The first, by Clegg et al (2006), was a 24 week comparison of glucosamine
hydrochloride 1500 mg, chondroitin sulfate 1200 mg, glucosamine and chondroitin combination
(1500 mg and 1200 mg respectively) and celecoxib 200 mg with placebo on participants
with knee pain from osteoarthritis. This trial included a direct comparison of celecoxib
against glucosamine hydrochloride via the common reference of placebo. The second
trial, by Houpt et al (1999), compared glucosamine hydrochloride 1500 mg with placebo
on patients with knee osteoarthritis for an 8 week blinded and an 8 week open label
phase. This trial assessed the efficacy of glucosamine hydrochloride. The third trial,
by Qui et al (2005), compared glucosamine hydrochloride 1400 mg and glucosamine sulphate
1500 mg (two 750 mg capsules a day) on patients with knee osteoarthritis. This trial
was presented only as an English abstract.
|Trial/First author||Publication title||Publication citation|
|GAIT/Clegg D||Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.||New England Journal of Medicine, 2006; 354(8): 795-808|
|Houpt J||Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee.||Journal of Rheumatology, 1999; 26(11): 2423-2430|
|Qiu G-X||A multi-central randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis.||National Medical Journal of China, 2005; 85(43): 3067-3070|
Supportive evidence came from six randomised trials. Four trials compared glucosamine
sulfate with ibuprofen whilst two trials compared celecoxib with ibuprofen.
8. Results of Trials
Both Clegg et al (2006) and Houpt et al (1999) measured pain change using the same validated WOMAC index 1. Clegg et al (2006) measured the responder rate, defined as a 20% decrease in knee pain from baseline to week 24, whilst Houpt et al (1999) measured the continuous variable of the difference in change in pain score between Week 0 and Week 8.
1 Western Ontario and McMaster Universities Osteoarthritis knee and hip osteoarthritis Index.
The preliminary economic evaluation was based on the trial by Clegg et al (2006). Clegg et al. (2006) demonstrated that for all randomised patients, the rate of response (a 20% decrease in WOMAC pain score) to glucosamine hydrochloride was 3.9% higher than placebo (p=0.30), to glucosamine hydrochloride in combination with chondroitin sulfate was 6.5% higher than placebo (p=0.09), and to chondroitin sulfate alone was 5.3% higher than placebo (p=0.17). These rates were not statistically significantly different when compared to placebo. However, the rate of response to celecoxib was 10% higher than placebo and this response was statistically significant (p=0.008). The trend was the same for the secondary outcome OMERACT-OARSI 2. Similarly, in Houpt et al (1999), glucosamine hydrochloride performed no better than placebo at reducing pain after 8 weeks of treatment.
2Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International.
In the key trial by Clegg et al (2006), 77 serious adverse events were reported in
61 patients. Three serious adverse events were judged by the investigators to be related
to study treatment: 1 congestive heart failure (combination therapy), 1 stroke (celecoxib)
and 1 chest pain (glucosamine hydrochloride). The number of patients who withdrew
because of adverse events was similar among treatment and control groups in the second
key trial by Houpt et al (1999).
9. Clinical Claim
The clinical claim that glucosamine hydrochloride is no worse than celecoxib in terms
of effectiveness and toxicity was not considered by the PBAC to be supported by the
evidence presented. The PBAC considered that the claim for non-inferiority between
glucosamine hydrochloride and celecoxib was poorly supported by the key trials.
For further information see Recommendation and Reasons
10. Economic Analysis
A preliminary economic evaluation was presented. However, the PBAC agreed that the
choice of the cost-minimisation approach was only valid if non-inferiority was accepted.
A modelled economic evaluation was presented and provided a cost comparison that took account of downstream health costs associated with adverse events. The base case modelled incremental savings per year were $265 per person.
11. Estimated PBS Usage and Financial Implications
The likely number of packs dispensed per year was > 200,000 in Year 2010. The direct
financial implication of listing glucosamine hydrochloride on the PBS (considering
only financial implications with glucosamine hydrochloride and celecoxib 100 mg) was
cost saving to the PBS, as was the overall impact on the PBS when including savings
on PPI scripts.
The DUSC advised it considered there is a likely underestimate of the number of eligible patients. The DUSC noted that in the submission the number of patients with osetoarthritis is at least 700,000 (over 65 years of age). Other information has shown that 1.8 million Australians described themselves as having ‘arthritis’ in the ABS 2003 Survey of Disability, Ageing and Carers (2). This same report noted that the 2003 survey was designed to collect information about chronic disease associated with disability and includes persons in long term residential care. DUSC considered that if 1.8 million were the eligible population, 5% penetration of this potential market would result in that range of 10 - 30 million dollars expenditure by the Government.
12. Recommendation and Reasons
The PBAC did not consider celecoxib to be the appropriate comparator. Celecoxib is
specifically not subsidised for the treatment of arthrosis without an inflammatory
component and the PBAC considered glucosamine is unlikely to replace celecoxib in
clinical practice. The PBAC noted that current guidelines and recommendations promote
the use of non- pharmacological therapies and then the addition of oral analgesics
(paracetamol) as first line treatment for symptomatic osteoarthritis.
The PBAC considered that the claim for non-inferiority between glucosamine hydrochloride and celecoxib was poorly supported by the key trials. In both trials (Clegg et al 2006, Houpt et al 1999), glucosamine hydrochloride performed no better than placebo (no statistically significant difference), whereas in Clegg et al (2006), celecoxib was found to perform better than placebo at reducing pain. More importantly, the key clinical trial suggested that there is no difference between glucosamine and placebo as no statistically significant reduction in WOMAC pain scores was found in either study for glucosamine compared to placebo.
The PBAC noted no clear evidence of excess toxicity over placebo had been demonstrated in short and long term studies with glucosamine, but that cross reactivity of shell fish allergy to glucosamine had not been well evaluated.
Therefore, the clinical claim that glucosamine hydrochloride is no worse than celecoxib in terms of effectiveness and toxicity was not considered by the PBAC to be supported by the evidence presented.
The PBAC agreed that given this finding, the economic evaluation seeking listing on a cost-minimisation basis against celecoxib had no foundation, although the Committee considered that the modelled cost comparison approach adopted was reasonable.
The PBAC also considered that multiple and appropriate issues raised by DUSC regarding the usage estimates were valid.
The PBAC rejected the submission on the basis of a lack of evidence demonstrating relevant clinical efficacy with an appropriate comparator.
13 Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia.
It considers submissions in this context. A PBAC decision not to recommend listing
or not to recommend changing a listing does not represent a final PBAC view about
the merits of the medicine. A company can resubmit to the PBAC or seek independent
review of the PBAC decision.
14. Sponsor’s Comment
The sponsor is considering its position.