Does local application of betamethasonvalerate 0.1% cream twice a day reduce the complaints of chronic chilblains?

Chilblained hands, toes and thighs form an acute and clinical picture labelled
as perniones. Chronic perniones is a nasty and painful disorder often returning
every winter and can cause considerable limitations in every day life (1,2).
Little is known about nature and treatment. There is uncertainty about
incidence and prevalence. Data of the Continual Morbidity Registration point to
four new cases per GP per year, mostly women (3). Prevalence is probably
significantly higher, also in our experience sofar.
There is limited evidence for three interventions: Vitamin D3, nifedipine and
corticosteroïd cream (4).
We have already proven the unlikeliness of a positive effect of Vitamin D3 (5).
Indications for possible positve effects of a corticosteroïd creme are
described in only one publication with a case series of 20 participants and
therefore aren't very strong (6).
As patients with perniones do have a need for effective treatment to relieve
them from their complaints and limitations (2), we are of the opinion that it
is useful to further investigate the possible effectiveness of corticosteroïd
cream.

References:
1. Souwer IH, Lagro-Janssen ALM. Perniones. Winterhanden, Wintertenen en
*Winterdijen*. HuisartsWet
2004;47:594-6.
2. Souwer IH, Robins LJH, Lagro-Janssen ALM. Chilblains from the patient*s
perspective. Eur J Gen
Pract. 2007;13:159-60.
3. Continue Morbiditeit Registratie Nijmegen: unpublished data.
4. Souwer IH, Lagro-Janssen ALM. De behandeling van perniones. Een
literatuuronderzoek. Huisarts
Wet 2004;47:561-2.
5. Souwer IH, Lagro-Janssen ALM. Vitamin D3 is not effective in the treatment
of chronic chilblains. Int
J Clin Pract 2009;63:282-6.
6. Ganor S. The treatment of chilblains with fluocinolone cream under occlusive
dressing. Harefuah
1973;84:163.

Research question:

Does thin application of betamethasonvaleraat cream 0,1% on perniones lesions
twice a day reduce the symptoms of patients as determined in 1st. line health
care, with at least 10 mm expressed on a visual analogue scale, together with a
good tolerancy of the medication.

This research has been set up as RCT of the cross over type. A group of 50
perniones patients is randomised over two sub groups. After one week of
baseline measurements withhout intervention, they are treated with betamethason
cream or a placebo cream for 6 weeks in turns, blindfold to patient and
researcher.

The duration of the research is 13 weeks for each patient. The most important
confounder, exposure to cold, is monitored by asking for the twenty-four hours
data of "de Bilt" at the KNMI and specific questions at intake.

Informed consent.
Participants are included in the study after informed consent only. All
required information, written and oral, will be provided to the potential
participant in the initial interview and is also incorporated in the diary that
is kept up to date by the participant during the research .

Procedure and randomisation.
After application an intake interview takes place. The diagnosis is then
confirmed by the researcher. It is checked whether the participant satisfies
the inclusion criteria and should not be rejected on basis of the exclusion
criteria.
After informed consent the lesions are documented by means of description and
fotos. Additional information is gathered about the way of dressing, exposure
to cold, housing conditions and working environment.
Randomisation takes place over two regimes by means of *permuted block
randomisation* with a block size of 10.
Regime 1: 1 week - no medication; 6 weeks - placebo cream locally twice a day
and 6 weeks - betamethasonvaleraat cream 0,1% locally twice a day.
Regime 2: 1 week - no medication; 6 weeks - betamethasonvaleraat cream 0,1%
locally twice a day and 6 weeks - placebo cream locally twice a day. The
research medication is provided in tubes of 15 grammes, one for each week of
research.


Measuring instrument.
The measuring instrument is a diary kept up to date daily by the participant
for the complete research period.
Per day, experienced complaints of perniones (itch or pain), experienced
limitations in daily life, experienced headache, experienced dizziness and
experienced general indisposition are scored on a 100 mm visual analogue scale.
For the complete research period of each individual patient the exposure to
cold is registered by asking for the average day temperature as measured in "de
Bilt" at the KNMI.
There are 6 contact moments: intake (t1), end of week 1 (t2), end of week 4
(t3), end of week 7 (t4), end of week 10 (t5) and end of week 13 (t6). Control
and correction on completeness of the diary and consistency of the therapy used
is performed by weighing the used tubes.

Primary result measurement.
We consider the intervention effective if a reduction of the experienced
complaints or is discovered, displayed in a decline of the score "complaint"
with at least 10 mm on the visual analogue scale concerned. "Complaint" is
defind as Max (itch,pain): the Vas score for or itch or pain, depending on the
highest score.

Secondary we register scores for impairement and the experienced side effects,
skin irritation, and symptoms of skin atrophy: purpurae, inclination to bleed
and depigmentation.

Analysis.
A statistical analysis will be performed with a repeated measures mixed effects
model. The effect of a possible change in temperature will be taken into
account. An intention to treat analysis will take place. A check on the
consistent use of the therapy will be done by weighing the used tubes.

Power measurement.
In previous research we found baseline VAS scores for complaint of 27.97
millimeter (SD 18.82mm) on average We regard the intervention effective when
the VAS score has dropped by 10 millimeter or more. For the power measurement
we took a paired T-test as a baseline. With one measurement per person for
medication and placebo this is a considerable simplification of the real test.
Repeated measurements allow less participants, which is more favourable.
At alpha =0.05, beta=0.10 (power 90%) and an effect of 10mm VAS 38patients are
required to show a significant difference between the treatment with
betamethason cream and the placebo.

Numeric Results for One-Sample T-Test
Null Hypothesis: Mean0=Mean1 Alternative Hypothesis: Mean0<>Mean1
The standard deviation was assumed to be known.
Power N Alpha
Beta Mean0 Mean1 Sigma
0.90583 38 0.05000 0.09417
27.97 17.97 18.82

The intervention which is compared to the placebo consists of the thin
application of betamethasonvaleraat cream 0,1 % twice a day for 6 weeks where
the perniones laesions are located .

After application an intake interview takes place. The diagnosis is then
confirmed by the researcher. It is checked whether the participant answers to
the inclusion criteria and should not be rejected on basis of the exclusion
criteria.
After informed consent the lesions are documented by means of description and
fotos. Additional information is gathered about the way of dressing, exposure
to cold, housing conditions and working environment.

Randomisation takes place over two regimes by means of *permuted block
randomisation* with a block size of 10.
Regime 1: 1 week - no medication; 6 weeks - placebo cream locally twice a day
and 6 weeks - betamethasonvaleraat cream 0,1% locally twice a day.
Regime 2: 1 week - no medication; 6 weeks - betamethasonvaleraat cream 0,1%
locally twice a day and 6 weeks - placebo cream locally twice a day. The
research medication is provided in tubes of 15 grammes, one for each week of
research.
The measuring instrument is a diary kept up to date daily by the participant
for the complete research period. Experienced perniones complaints (itch or
pain) and limitations in daily life are scored daily.

For the complete research period of each individual patient the exposure to
cold is registered by asking for the average day temperature as measured in "de
Bilt" at the KNMI.
There are 6 contact moments: intake (t1), end of week 1 (t2), end of week 4
(t3), end of week 7 (t4), end of week 10 (t5) and end of week 13 (t6). Control
and correction on the completeness of the diary and the consistency of the
therapy used is performed by weighing the used tubes.

We do not expect any side effects of the creams used.