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ORIGINAL ARTICLE
Clinical impac o i amin D ea men in cys ic fib osis: a pilo
andomized, con olled ial
T Pinciko a
1,2,3,4
, D Paquin-P oulx
3
, JK Sandbe g
3
, M Flods öm-Tullbe g
3
and L Hjel e
1,2
BACKGROUND/OBJECTIVES: Vi amin D insu ficiency in cys ic fib osis is common. Vi amin D3 is cu en ly p e e ed o e D2. We
aimed o s udy he e ficacy o i amin D2 and D3 a inc easing se um 25-hyd oxy i amin D (s25OHD) concen a ions and hei
e ec on espi a o y heal h in cys ic fib osis.
SUBJECTS/METHODS: Six een CF pa ien s we e andomized o ecei e i amin D2 o D3 o o se e as con ols. The s a ing dose
o 5000 IU (o16 yea s old) o 7143 IU/day (⩾16 yea s old) was u he indi idually adjus ed. Th ee mon hs o in e en ion we e
ollowed by wo o washou (ClinicalT ials.go NCT01321905).
RESULTS: To inc ease s25OHD, he mean daily dose o i amin D2 and D3 had o be inc eased up o 15650 and 8184 IU,
espec i ely. The combined g oup o i amin D2 and D3 ea ed pa ien s dec eased plasma IL-8 (Po0.05). Pa ien s p o ided
i amin D3 imp o ed FVC a he end o he ial (Po0.05). Change in s25OHD was posi i ely co ela ed wi h changes in he adul
Quali y-o -Li e espi a o y sco e a he end o supplemen a ion (P= 0.006, = 0.90), and wi h changes in FEV1 (P= 0.042, = 0.62) and
FVC (P= 0.036, = 0.63) a one mon h o washou .
CONCLUSIONS: Vi amin D supplemen a ion may con ibu e o educed inflamma ion and imp o ed lung unc ion in CF.
Eu opean Jou nal o Clinical Nu i ion (2017) 71, 203–205; doi:10.1038/ejcn.2016.259; published online 14 Decembe 2016
INTRODUCTION
In cys ic fib osis (CF), he majo cause o mo bidi y and mo ali y is
p og essi e lung disease d i en by ecu ing acu e ai way in ec ions
and ch onic bac e ial lung coloniza ion.
1
Vi amin D insu ficiency is
common in CF despi e i amin D supplemen a ion.
2,3
In addi ion o i s
impo ance o bone heal h, i amin D ac s as a po en immune
modula o y agen wi h complex e ec s.
4,5
In CF, i amin D
concen a ions ha e been associa ed wi h lung unc ion,
2,6
annual numbe o pulmona y exace ba ions
7
and wi h o al se um
IgG le els.
2
The cu en ecommenda ions o i amin D supplemen a ion in
CF we e designed wi h ocus on bone heal h. Because o i s highe
e ficiency a inc easing se um 25-hyd oxy i amin D (s25OHD),
i amin D3 (D3) is cu en ly p e e ed o e i amin D2 (D2). Mos
Table 1. To -s25OHD concen a ion, FVC and FEF25% in pa ien s comple ing he s udy
Pa ien s comple ing he s udy All pa ien s (n= 13) Con ol g oup (n= 4) D2 g oup (n= 4) D3 g oup (n=5)
To -s25OHD a baseline (nmol/l; mean ±s.d.) 58.1 ±21.9 49.0 ±38.7 55.7 ±16.0 65.0 ±13.9
To -s25OHD a 1 week (nmol/l; mean ±s.d.) 61.3 ±23.8 57.3 ±40.9 53.0 ±15.8 70.4 ±18.7
To -s25OHD a 1 mon h (nmol/l; mean ±s.d.) 82.9 ±15.8 74.3 ±19.2 79.0 ±6.9 92.8 ±14.9
To -s25OHD a 2 mon hs (nmol/l; mean ±s.d.) 88.4 ±21.2 78.0 ±23.2 79.3 ±13.4 104.0 ±17.6*
To -s25OHD a 3 mon hs (nmol/l; mean ±s.d.) 78.9 ±15.3 62.5 ±14.9 81.5 ±10.7 90.0 ±4.2*
FVC a baseline (% p edic ed; mean ±s.d.) 86.3 ±20.6 89.3 ±15.0 87.8 ±24.9 83.2 ±23.8
FVC a 3 mon hs (% p edic ed; mean ±s.d.) 92.4 ±13.3 89.7 ±6.1 87.3 ±16.4 99.5 ±13.5
FVC a 5 mon hs (% p edic ed; mean ±s.d.) 87.9 ±20.8 92.8 ±7.3 84.0 ±27.9 87.0 ±25.1*
FEF25% a baseline (% p edic ed; mean ±s.d.) 92.2 ±45.3 107.0 ±23.5 85.8 ±58.9 87.5 ±51.9
FEF25% a 1 mon h (% p edic ed; mean ±s.d.) 86.8 ±43.0 102.3 ±25.6 78.8 ±53.4 83.3 ±50.2
FEF25% a 2 mon hs (% p edic ed; mean ±s.d.) 86.3 ±40.0 89.3 ±14.2 (P=0.086) 80.0 ±55.7 89.4 ±43.8
FEF25% a 3 mon hs (% p edic ed; mean ±s.d.) 95.1 ±39.2 91.7 ±43.2 82.5 ±54.9 110.3 ±18.4
FEF25% a 5 mon hs (% p edic ed; mean ±s.d.) 84.7 ±42.7 76.7 ±20.0 (P=0.073) 90.5 ±61.9 84.8 ±43.0
Abb e ia ions: s.d., s anda d de ia ion; FVC, o ced i al capaci y; FEF25%, o ced expi a o y flow a e. Pai ed - es was used o compa ison wi h baseline
alues wi hin he g oups; *Po0.05.
1
S ockholm CF Cen e , Ka olinska Uni e si y Hospi al Huddinge, S ockholm, Sweden;
2
Di ision o Pedia ics, Depa men o Clinical Science, In e en ion and Technology,
Ka olinska Ins i u e , S ockholm, Sweden and
3
Cen e o In ec ious Medicine, Depa men o Medicine, Ka olinska Ins i u e , Ka olinska Uni e si y Hospi al, S ockholm, Sweden.
Co espondence: D T Pinciko a, S ockholm CF Cen e , K56, Ka olinska Uni e si y Hospi al Huddinge, 141 86 S ockholm, Sweden.
E-mail: [email p o ec ed]
Da a om he manusc ip ha e been p esen ed a a mee ing: 36 h Eu opean Cys ic Fib osis Con e ence, Lisbon, Po ugal, 14 June 2013, Abs ac WS16.3.
4
Cu en add ess: Respi a o y, Alle gy and Sleep Resea ch, Uppsala Uni e si y, Uppsala, Sweden.
Recei ed 7 Ap il 2016; e ised 24 Oc obe 2016; accep ed 26 Oc obe 2016; published online 14 Decembe 2016
Eu opean Jou nal o Clinical Nu i ion (2017) 71, 203–205
www.na u e.com/ejcn
o he ecommenda ions a e consensus-based due o lack o
knowledge on benefi –sa e y a io.
8,9
In he p esen pilo s udy, he p ima y goal was o es ablish an
e ficien once-daily dosing s a egy and o in es iga e he e ficacy
o D2 and D3 a inc easing s25OHD concen a ions. The seconda y
goal was o explo e he e ec o he in e en ions on cy okine
concen a ions and espi a o y heal h.
SUBJECTS AND METHODS
T ial design
The s udy was app o ed by he Regional E hical Re iew Boa d in S ockholm,
Sweden (2009/1723-31/1). Pa ien s we e en olled be ween 9 Ap il 9 2010 and
16 May 2011. The ial was conduc ed in acco dance wi h he Helsinki
Decla a ion o 1975 as e ised in 1983. Six een CF pa ien s we e andomized o
ecei e ei he D2 o D3 o o become a con ol (Supplemen a y Figu e E1).
Pa ien s andomized o he in e en ion a ms ecei ed a s a ing dose o 35 000
Figu e 1. Immunological and clinical impac o i amin D supplemen a ion. (a) To -s25OHD le els in con ol g oup, D2 g oup and D3 g oup.
The e was no change in o -s25OHD le els in con ol pa ien s h oughou he s udy, whe eas he e was a endency o inc ease in o -s25OHD
in D2 g oup a he end o supplemen a ion (P=0.106). D3 g oup had inc eased o -s25OHD le els a 8 weeks o supplemen a ion and a he
end o supplemen a ion (Po0.05). (b) F ee-s25OHD le els in con ol g oup, D2 g oup and D3 g oup. The e was no change in ee-s25OHD
le els in con ol and D2 pa ien s h oughou he s udy, whe eas D3 g oup had inc eased ee-s25OHD le els a 8 weeks o supplemen a ion
and a he end o supplemen a ion (Po0.05). (c) To al i amin D dose inges ed a he end o supplemen a ion e sus o -s25OHD in all
pa ien s (P=0.03; =0.76). (d) The combined g oup o pa ien s ecei ing D2 and D3 had dec eased IL-8 concen a ion in ci cula ion a he end
o supplemen a ion and a 1 mon h and 2 mon hs o washou (Po0.05). (e) Change om baseline in ee-s25OHD e sus change om
baseline in IL-1βa he end o he s udy in all pa ien s (P=0.004; =−0.95). ( ) Change om baseline in ee-s25OHD e sus change om
baseline in ci cula ing neu ophil coun a he end o supplemen a ion in all pa ien s (P=0.017; =−0.80). (g) Change om baseline in ee-
s25OHD e sus change om baseline in QoL- espi a o y sco e a he end o supplemen a ion (P=0.006, =0.90). (h) Change om baseline in
o -s25OHD e sus change om baseline in FEV1 a 1 mon h o washou (P=0.042, =0.62). (i) Change om baseline in o -s25OHD e sus
change om baseline in FVC a 1 mon h o washou (P=0.036, =0.63).
Vi amin D in cys ic fib osis: a pilo ial
T Pinciko a e al
204
Eu opean Jou nal o Clinical Nu i ion (2017) 203 –205
IU (i o16 yea s old) o 50 000 IU (i ⩾16 yea s old) D2 o D3 pe week. The
weekly dose was gi en as se en once-daily doses. The con ol g oup did no
ecei e any ex a i amin D. All s udy pa ien s con inued hei o dina y i amin
supplemen a ion unchanged. The s udy was open-label and consis ed o
3 mon hs o supplemen a ion ollowed by 2 mon hs o washou . Thi een
pa ien s comple ed he ial and we e analyzed. The p ima y ou come o he
ial was o al s25OHD ( o -s25OHD) a 3 mon hs isi . The goal o he
supplemen a ion was o each o -s25OHD4100 nmol/l (ClinicalT ials.go
Iden ifie : NCT01321905). Mo e in o ma ion is a ailable in he online
Supplemen a y In o ma ion.
RESULTS
The e we e no significan di e ences in he baseline cha ac e is ics
be ween he s udy a ms (Supplemen a y Table E1). One pa ien in
each s udy a m le he ial sho ly a e comple ing he baseline
isi . The 13 pa ien s comple ing he s udy we e included in he
analyses (Supplemen a y Table E2). Fo some analyses, pa ien s
andomized o ecei e D2 o D3 we e pooled in o one g oup
(Supplemen a y Table E3). The adhe ence wi h i amin D ea men
was o e all e y good (median sco e 7/7; lowes sco e 5/7).
The e we e no di e ences in o -s25OHD o ee s25OHD ( ee-
s25OHD) le els be ween he g oups a baseline. The con ol g oup
did nei he change hei o -s25OHD no ee-s25OHD h oughou
he s udy. A he end o supplemen a ion, he mean (s.d.) inges ed
o al D2 and D3 dose was 771.173 (296.870) and 598.066 (132.126)
IU, espec i ely. A his ime poin , he D3 g oup had highe o -
s25OHD han he con ols had (P= 0.019), which was no he case o
he D2 g oup (Table 1, Figu e 1a). In line wi h his, all pa ien s in bo h
in e en ion a ms had o -s25OHD475 nmol/l a he end o
supplemen a ion. None o he pa ien s alloca ed o he D2 g oup
eached he goal o 100 nmol/l, whe eas wo ou o fi e D3 g oup
pa ien s eached his goal. Pos hoc powe calcula ion showed ha
fi e pa ien s a e needed o find a di e ence o 25 uni s in o -
s25OHD (end o in e en ion compa ed wi h baseline) in 70% o
cases. In he combined g oup o all pa ien s ecei ing i amin D, ee-
s25OHD d opped du ing washou , and was significan ly lowe han
ha a baseline (Figu e 1b). To -s25OHD a he end o supplemen a-
ion co ela ed closely wi h o al i amin D dose (Figu e 1c).
Pa ien s andomized o ecei e D2 o D3 showed dec eased le els
o IL-8 in plasma a he end o supplemen a ion. Mo eo e , IL-8
emained dec eased a bo h 1 mon h and 2 mon hs o washou , as
compa ed wi h baseline (Figu e 1d). A he end o he s udy, he
change in IL-1β om baseline was nega i ely co ela ed wi h he
change in ee-s25OHD (Figu e 1e). A he end o supplemen a ion,
he change om baseline in ee-s25OHD was in e sely co ela ed
wi h changes in neu ophil coun (Figu e 1 ). A 1 mon h o washou ,
he change in neu ophil coun s con inued o be in e sely co ela ed
wi h he change in o - and ee-s25OHD. No ably, he changes in
neu ophil coun s ollowed he changes in ee-s25OHD mo e closely
han changes in o -s25OHD (Supplemen a y Figu es E2–E3).
A baseline, o -s25OHD co ela ed posi i ely wi h he adul
quali y-o -li e (QoL)- espi a o y sco e (Supplemen a y Figu e E4).
Mo eo e , he change om baseline in ee-s25OHD a he end o
supplemen a ion co ela ed posi i ely wi h change in he adul QoL-
espi a o y sco e (Figu e 1g). A baseline, o -s25OHD co ela ed
posi i ely wi h o ced expi a o y olume in 1 s (FEV1), FEV1 exp essed
as pe cen age FVC (FEV%) and o ced expi a o y flow a 75% o FVC
(FEF75%) (Supplemen a y Figu es E5–E7). Pa ien s alloca ed o se e
as con ols had a endency o dec ease hei o ced expi a o y flow a
25% o FVC (FEF25%) a he 2- and 5-mon h isi s, compa ed wi h
baseline (Table 1). Pa ien s alloca ed o he D3 a m imp o ed hei
o ced i al capaci y (FVC) a he las s udy isi compa ed wi h
baseline, whe eas hose ecei ing D2 did no change hei lung
unc ion h oughou he s udy (Table 1). A 1 mon h o washou , he
change in o -s25OHD om baseline was posi i ely co ela ed wi h
changes in FEV1 and FVC (Figu es 1h–i).
SUMMARY
This pilo ial sugges s ha high doses a e needed o imp o e
i amin D s a us in CF pa ien s. Vi amin D supplemen a ion may
posi i ely a ec he immune sys em in pa ien s wi h CF, which
migh e en ually lead o be e espi a o y unc ion. The esul s
also sugges he possibili y ha ee-s25OHD may be a be e
co ela e o he clinical impac o i amin D ea men , as
compa ed wi h he cu en ly used o -s25OHD. La ge long- e m
placebo-con olled s udies a e needed o es he new hypo heses
gene a ed by his pilo ial.
CONFLICT OF INTEREST
The au ho s decla e no conflic o in e es .
ACKNOWLEDGEMENTS
This s udy was suppo ed by he Ka olinska Ins i u e , he S ockholm Coun y Council,
S i elsen Sama i en, E ica Lede hausens Minness i else, he Swedish Cys ic Fib osis
Associa ion, S i elsen F imu a e Ba nhuse i S ockholm, he Swedish Resea ch Council,
he Hea and Lung Founda ion and he Swedish Cance Socie y. DPP is he ecipien o
a pos doc o al ellowship om he Canadian Ins i u es o Heal h Resea ch. The s udy
was egis e ed a ClinicalT ials.go as NCT01321905.
AUTHOR CONTRIBUTIONS
TP and LH designed he s udy and delinea ed hypo heses. TP collec ed he
da a, analyzed and in e p e ed hem, wi h con ibu ion o LH, DPP, MFT and JS.
TP w o e he a icle, wi h con ibu ions om he LH, JS, DPP and MFT; TP and
LH had p ima y esponsibili y o final con en . All au ho s ead and app o ed
he final manusc ip .
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Supplemen a y In o ma ion accompanies his pape on Eu opean Jou nal o Clinical Nu i ion websi e (h p://www.na u e.com/ejcn)
Vi amin D in cys ic fib osis: a pilo ial
T Pinciko a e al
205
Eu opean Jou nal o Clinical Nu i ion (2017) 203 –205