Randomized placebo-controlled trial to investigate clinical efficacy, anti-inflammatory properties and
safety of prednisolone in hand osteoarthritis: a proof-of-concept study

Hand osteoarthritis is a prevalent joint disorder affecting finger and thumb
base joints. Hand osteoarthritis leads to pain, which is especially experienced
during flares, periods of pain often accompanied by redness and soft tissue
swelling. It also results in restriction in daily activity and decreased
quality of life. Despite this, hand osteoarthritis has been a *forgotten
disease* for many years. No treatments are available to modify the disease
course; the usual aim is to alleviate symptoms. However there is limited
efficacy, which may be due to a lack of understanding of pathogenetic
mechanisms, a limited number of high quality studies and low effect sizes of
existing treatments. Therefore there is a great unmet need for effective
treatment in patients with hand osteoarthritis.

Osteoarthritis results from an imbalance between degradation and repair
processes, in which all compartments of the joint are involved. Insights have
emerged that synovial inflammation negatively affects the balance between
degradation and repair and plays a crucial role in the osteoarthritic process.
Inflammation is prevalent in osteoarthritic joints. We and others have shown in
ultrasonography (US) and MRI studies that synovitis and effusion are frequently
seen. The presence of inflammation seems to be dependent on disease stage and
is especially prevalent during severe stages. Inflammation is associated with
pain. We and others have shown that pain in an osteoarthritic joint -in hand,
but also in knee and hip osteoarthritis- is associated with synovitis. The
causality of this association is supported by clinical trials in knee or hip
osteoarthritis, showing that strong anti-inflammatory medication, such as
intra-articular corticosteroids, alleviate pain. Furthermore, inflammation
leads to structural damage and impairment at the long term, since synovitis and
effusion are associated with cartilage damage.

The efficacy of anti-inflammatory medication in hand osteoarthritis is scarcely
investigated and has led to equivocal results. Two randomized controlled trials
investigating intra-articular corticosteroids for thumb base osteoarthritis did
not show efficacy over placebo. Of two randomized controlled trials with
systemic corticosteroids in hand osteoarthritis one did and the other did not
show efficacy of prednisolone over placebo. In a randomized controlled trial
comparing two adalimumab injections with placebo no effect on pain after 6
weeks was seen. The controversial results from these trials could be due to the
differences in hand osteoarthritis phenotypes and disease stages studied,
outcome measures used to evaluate efficacy, use of concomitant medication, and
whether inflammation, such as synovitis or effusion, was present.

Therefore, a study with a strong anti-inflammatory drug in a homogeneous
patient population, during a flare of the disease with evidence of synovitis,
and evaluated by outcome measurements sensitive to change is warranted, not
only to find new treatment modalities for hand osteoarthritis, but also to
better understand the underlying pathogenetic mechanisms.

Primary Objective: The main objective of this study is to identify a new
treatment to alleviate pain and diminish inflammation in patients with hand
osteoarthritis with symptoms and signs of inflammation.

Secondary Objectives: The secondary objectives of this study are to increase
our knowledge on synovial inflammation in hand osteoarthritis, e.g. it*s role
in pain experience, it*s course over three months and it*s responsiveness to
prednisolone. Moreover, we want to gain insight in the differences in
sensitivity-to-change of several instruments to assess pain, physical function,
and synovitis in patients with hand osteoarthritis.

Our research proposal comprises a randomized double-blind placebo-controlled
trial of 14 weeks duration to investigate oral prednisolone in hand
osteoarthritis. This clinical trial is set up as proof-of-concept study aiming
not only to investigate the clinical efficacy and safety of prednisolone in
hand osteoarthritis, but also its anti-inflammatory effects as mechanism of
action. Patients will be randomly assigned to either of 2 treatment groups of
45 patients each: receiving treatment with prednisolone 10 mg daily or placebo
during 6 weeks. After 6 weeks the medication will be tapered (one week of 5 mg
prednisolone daily or placebo and thereafter one week 2.5 mg prednisolone daily
or placebo). Between week 8 and the end of the study, patients will be followed
to assess lasting efficacy, safety and anti-inflammatory effects.
A flare study design will be employed. After entering the study patients will
discontinue their NSAIDs. After a washout period of at least 48 hours, those
with a flare (defined as worsening by > 20mm on a 100 mm visual analogue scale
(VAS) pain scale) will be randomized. Study visits will be performed at
baseline, 2, 4, 6, 8 and 14 weeks.

Patients in the intervention group will receive 2 ml prednisolone oral solution
once daily (10 mg) during 6 weeks. The control group will receive 2 ml placebo
oral solution once daily during 6 weeks. After 6 weeks the medication will be
tapered (one week of 1 ml prednisolone oral solution once daily (5 mg) or 1 ml
placebo oral solution once daily and thereafter one week 0.5 ml prednisolone
oral solution once daily (2.5 mg) or 0.5 ml placebo oral solution once daily).

The outcome of this study could be a new evidence based treatment option to
alleviate pain and inflammation for patients with osteoarthritis of the hand.
Even if this study will be negative, patients will benefit, since nowadays in
clinical practice patients are regularly treated with prednisolone. However,
prednisolone is not without adverse effects and should not be administered when
no effect can be expected. Also society will benefit, since osteoarthritis is a
frequent health problem which occurs, contrary to general beliefs, already in
relatively early years of life. In the Netherlands it was estimated that 1.5
million people suffer from osteoarthritis; 348.000 persons suffer from hand
osteoarthritis. The direct health costs are estimated at minimal 1% of the
gross national product. In addition extra indirect costs for society are
expected since the working capacity of osteoarthritis patients is diminished.

At the screening visit patient characteristics will be assessed using
standardized questionnaires. The following questionnaires will be collected at
each study visit (baseline, 2, 4, 6, 8 and 14 weeks): digital pain and thumb
base pain on 100 mm VAS scales, the Australian/Canadian Osteoarthritis Hand
Index (AUSCAN) pain, disability, and stiffness subscales, the functional index
for hand osteoarthritis (FIHOA) and health assessment questionnaire (HAQ),
patient and physician global assessment on a 100 mm VAS scale, Short Form-36,
and consumption of rescue paracetamol. The Michigan Hand Outcomes Questionnaire
(MHOQ) and fatigue on a 100 mm VAS scale will be collected at baseline, 6 and
14 weeks. The Illness Perception Questionnaire (IPQ) and the Coping with
Rheumatic Stressors questionnaire (CORS) will both be collected at baseline and
14 weeks. The Hospital Anxiety Depression Scale (HADS) will only be collected
at baseline. Anchor questions regarding pain, physical function, fatigue and
quality of life will be collected once after 6 weeks. At each study visit a
physical examination will be performed and grip strength will be assessed by a
hydraulic hand dynamometer. Hand radiographs will be made at screening (or
existing hand radiographs will be used in case these are not longer than 6
months old). At baseline and after 6 and 14 weeks ultrasonography will be
obtained of the hand joints. At baseline and after 6 weeks MR images of both
hands will be obtained. All patients will be monitored for clinical and
laboratory evidence of adverse events on a routine basis throughout the study.

Prednisolone is a drug that is used very frequently in general clinical
practice for many indications. The mechanisms of action as well as the
potential adverse events are very well-known. A side effect of prednisolone is
that it can increase blood glucose levels, especially in patients diagnosed
with diabetes mellitus. Therefore, patients* blood glucose levels will be
monitored during the six week treatment course. Patients will also be informed
that if they are known to have diabetes mellitus, they should be aware that
their blood glucose levels may be altered during the course of the treatment.
The effect of prednisolone on blood glucose will go away a day or two after the
patient has stopped taking it. A potential issue of concern when prescribing
prednisolone for longer periods of time could be the development of adrenal
insufficiency. Although it seems unlikely that adrenal insufficiency will
develop after 6 weeks of 10 mg prednisolone daily, we changed the protocol
following the advice of the endocrinologists from the LUMC, adding a tapering
scheme of prednisolone after 6 weeks of treatment to avoid any risk (after 6
weeks of 10 mg prednisolone or placebo treatment 1 week of 5 mg prednisolone
daily or placebo and 1 week of 2.5 mg prednisolone or placebo). Another risk of
chronic prednisolone use could be the development of osteoporosis. The risk of
developing osteoporosis after 6 weeks of 10 mg prednisolone use is also very
low. However, to minimize the risks, calcium and vitamin D status will be
accessed before start of the study and in case of insufficiency these will be
supplied before start of the trial. Since prednisolone 10 mg daily is only
supplied for 6 weeks, no bisphosphonate prescription is needed. Patients who
have one or more of the following risk factors for developing gastric or
duodenal ulcers will be prescribed a proton pump inhibitor at the start of the
study: age >=60 years, previous gastric or duodenal ulcer, concomitant use of
anticoagulants or salicylates or selective serotonin reuptake inhibitors, heart
failure or diabetes mellitus.