Does Nifedipine 60 mg per day per os 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 nifedipine are described in only
one publication with a randomized clinical trial of 10 participants and a open
trial of 34 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 investigate the possible effectiveness of nifedipine in more detail.

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: ongepubliceerde 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. Rustin MHA, Newton JA, Smith NP, Dowd PM. Tjhe treatment of chillblains with
nifedipine: the results of a pilotstudy, a double-blind pracebo-controlled
randomized trial and al long term open trial. B J Derm 1989;120:167-275.

Research question: Does oral administration with regulated release of 60 mg
nifedipine a day reduce the symptoms of patients as determined in 1st. line
health care, provided there is a good tolerancy of the medication.

Study design
This research has been set up as an 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 nifedipine
or a placebo for 6 weeks in turns, blindfold to the 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 Royal Duch Meteorological Institute 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; 2
weeks placebo once a day and 4 weeks placebo twice a day followed by 2 weeks
nifedipine 30 mg regulated release once a day and 4 weeks nifedipine 30 mg
regulated release twice a day . Regime 2: 1 week no medication; 2 weeks
nifedipine 30 mg regulated release once a day and 4 weeks nifedipine 30 mg
regulated release twice a day followed by 2 weeks placebo once a day and 4
weeks placebo twice a day.

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 3 (t3), end of week 7 (t4), end of
week 9 (t5) and end of week 13 (t6). Control and correction on completeness of
the diary and consistency of the therapy used is performed by counting
forgotten tablets. During contols at t2-t6 bloodpresure and pulsrate are
monitored. At t6 we will (after concent only) take a bloodsample for nifedipine
level assesment.



Primary endpoint
We consider the intervention effective if a reduction of the experienced
complaints 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 itch or pain, depending on the highest
score. Secondary we register scores for impairment 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 counting forgotten tablets.

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 38 patients are
required to show a significant difference between the treatment with nifedipine
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 oral
administration 30mg nifedipine with regulated release once a day for two weeks
and twice a day for four weeks.

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; 2
weeks placebo once a day and 4 weeks placebo twice a day followed by 2 weeks
nifedipine 30 mg regulated release once a day and 4 weeks nifedipine 30 mg
regulated release twice a day . Regime 2: 1 week - no medication; 2 weeks
nifedipine 30 mg regulated release once a day and 4 weeks nifedipine 30 mg
regulated release twice a day followed by 2 weeks placebo once a day and 4
weeks placebo twice a day. 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 3 (t3), end of week 7 (t4), end of week 9 (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 counting the tablets that are
left.
During controls at t2-t6 Blod pressure and pulsrate are monitored.

At t6 we will (after concent only) take a bloodsample for nifedipine level
assesment.

We do not expect major side effects.