The OK Daily Study

Official title

Oral Vitamin K2 (Menaquinone-7; MK-7) Supplementation and Effect on Vitamin K Status of Breastfed Term Infants in Early Infancy; a Four-cohort Prospective, Part-randomised, Part-blinded Study.

Overview

The OK Daily Study is a multi-centred, part-randomised, part blinded, four cohort study. We are exploring daily dietary supplementation with vitamin K2, specifically menaquinone-7 (MK-7), given to breastfed infants or breastfeeding mothers to see whether this improves the incidence of biochemical vitamin K deficiency in the infants at 2 months postnatal age. The overall aims are: * To compare infant MK-7 supplementation with placebo * To compare maternal MK-7 supplementation with placebo * To compare infant MK-7 supplementation and maternal MK-7 supplementation * To compare infant MK-7 supplementation with vitamin K1 supplementation via infant formula milk. Once recruited, mother and infant pairs will be grouped initially based on the families' feeding choice. Breastfed infants will then be randomised 2:1 to the infant supplementation or maternal supplementation group. Within the infant supplementation group, infants will either receive MK-7 with vitamin D or a placebo containing vitamin D. Follow up will occur at 2 months postnatal age (range 2-3 months postnatal age), where bloods and breastmilk samples will be collected to assess the infant and maternal vitamin K status.

Detailed description

The OK Daily Study is a multi-centre study taking place in the Norfolk and Norwich University Hospital, Norwich, UK, and Ashford and St Peters' Hospital, Chertsey, UK.

Infants born at ≥37 weeks' gestation will be recruited in the participating site if they meet eligibility criteria and are born within the recruitment window. Recruitment will take place before the mother and infant are discharged from the hospital following birth.

The two main arms of this study are breastfeeding and formula feeding. Mother and infant pairs will initially be allocated based on the family's feeding preferences.

Infants in the breastfeeding arm will be randomised into group 1 or group 2 in a 2:1 ratio. Group 1 allocation will be blinded; group 2 allocation will be open label.

* Group 1 - infant supplementation group. Infants will receive either 45 micrograms/day of MK-7 with 10 micrograms/day vitamin D3 or a placebo consisting of 10 micrograms/day vitamin D3 * Group 2 - maternal supplementation group. Mothers in this group will receive 2 mg/day MK-7. All breastfeeding infants in this group will receive 10 micrograms/day of vitamin D3.

Formula fed infants will be in group 3 and will not require any additional supplementation as part of this study. This is because infant formula is already supplemented with adequate amounts of vitamin K1 and vitamin D.

All supplements will be started within 7 days of birth. Vitamin D drops are included for breastfed infants as per national UK guidelines.

Follow up will be as follows:

* 1 month postnatal visit (range 1-1.5 months) - phone call.

o Confirmation of eligibility to continue, assessment of compliance with the intervention, and to schedule the in person follow up visit * 2 months postnatal (range 2-3 months) - in person visit.

* All babies will have a single blood sample taken. * Mothers who are in group 2 (mothers who have had MK-7 supplementation) and a selection of mothers from group 1 (breastfeeding mothers who are not supplemented with MK-7) will have a single blood sample taken and will be asked to provide a single breastmilk sample * Mothers will be asked about their opinions on practising the supplementation.

Blood samples will be analysed for vitamin K status, including Proteins Induced by Vitamin K Absence/antagonism of prothrombin (PIVKA-II) and of osteocalcin (undercarboxylated osteocalcin), dephosphorylated-undercarboxylated matrix gla-protein (dp-ucMGP) and serum vitamin K concentrations (including of vitamin K1 and MK-7). Breastmilk samples will be analysed for vitamin K concentrations (including vitamin K1 and MK-7)

Once this in person follow up visit has been completed, the mother and baby pair will have completed the study.

Interventions

• Other Combined MK-7 + vitamin D3 drops
  6 drops/day providing 45 micrograms/day MK-7 plus 10 micrograms/day of vitamin D3
• Other Vitamin D3 Drops
  6 drops/day providing 10 micrograms/day vitamin D3 and no supplementary MK-7.
• Other MK-7 capsules
  1 mg capsules of menaquinone-7, with a daily dose of 2 mg (i.e. 2 capsules per day)

Primary outcome measures

• Comparison of the proportion of participants who have a PIVKA-II >0.05 AU/mL in the unsupplemented and supplemented infants. [Time frame: 2 months postnatal age (range 2-3 months).]

Secondary outcome measures (8)

• Comparison of the proportion of participants who have a PIVKA-II >0.05 AU/mL in the various study groups. [Time frame: 2 months postnatal age (range 2-3 months).]
• Comparison of serum levels of osteocalcin (undercarboxylated and carboxylated) between the study groups. [Time frame: 2 months postnatal age (range 2-3 months).]
• Comparison of the percentage of undercarboxylated osteocalcin as a proportion of total osteocalcin (%GluOC) between the study groups. [Time frame: 2 months postnatal age (range 2-3 months).]
• Comparison of serum levels of dephosphorylated undercarboxylated matrix Gla Protein in included participants between the study groups. [Time frame: 2 months postnatal age (range 2-3 months).]
• Comparison of levels of serum K vitamers (including, but no limited to, vitamin K1 and menaquinone-7) between the study groups. [Time frame: 2 months postnatal age (range 2-3 months).]
• Comparison of the levels of breastmilk K vitamers (including, but not limited to, vitamin K1 and menaquinone-7) between unsupplemented and supplemented mothers. [Time frame: 2 months postnatal age (range 2-3 months).]
• Investigation of percentage compliance to study supplementation. [Time frame: 2 months postnatal age (range 2-3 months).]
• Investigation regarding families' opinions about infant and maternal vitamin supplementation. [Time frame: 2 months postnatal age (range 2-3 months).]

Eligibility criteria

Inclusion criteria

• Infants, and mothers of infants, born ≥37 weeks gestational age
• Standard dose of intramuscular (IM) vitamin K prophylaxis given to the neonate following birth
• For breastfeeding mothers: the mother intends to exclusively/predominantly breastfeed their baby for at least 2 months

Exclusion criteria

• Inability or refusal to provide informed consent
• Inability to adhere to or comply with study procedures
• Babies who meet the inclusion gestation but would otherwise, as part of routine neonatal care, be provided with daily vitamin K drops (i.e. NeoKay drops) at discharge
• IM vitamin K prophylaxis not received at birth (parents declined vitamin K prophylaxis or parents chose for neonate to receive an oral course of vitamin K prophylaxis instead)
• Evidence of conjugated hyperbilirubinaemia (these babies are at higher risk of VKDB)
• Mothers, and babies born to mothers, who are taking any medication that could affect or antagonise vitamin K metabolism (i.e. warfarin, the anti-epileptic drugs phenytoin or carbamazepine, and cephalosporin, rifampicin and isoniazid antimicrobials)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007 Apr 15;109(8):3279-83. doi: 10.1182/blood-2006-08-040709. Epub 2006 Dec 7. PMID 17158229
• Perrone S, De Bernardo G, Lembo C, Dell'Orto V, Giordano M, Beretta V, Petrolini C, Gambini L, Toni AL, Parigi G, Fontanarosa I, Natale MP, D'Amato G, Sordino D, Buonocore G. Vitamin K insufficiency and the prophylaxis strategy in term healthy infants: A multicentre study. Eur J Clin Invest. 2024 Apr;54(4):e14141. doi: 10.1111/eci.14141. Epub 2023 Dec 9. PMID 38071415
• Clarke P, Shearer MJ, Card DJ, Nichols A, Ponnusamy V, Mahaveer A, Voong K, Dockery K, Holland N, Mulla S, Hall LJ, Maassen C, Lux P, Schurgers LJ, Harrington DJ. Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth. J Thromb Haemost. 2022 Dec;20(12):2773-2785. doi: 10.1111/jth.15874. Epub 2022 Oct 3. PMID 36087073
• Clarke P, Mitchell SJ, Shearer MJ. Total and Differential Phylloquinone (Vitamin K1) Intakes of Preterm Infants from All Sources during the Neonatal Period. Nutrients. 2015 Sep 25;7(10):8308-20. doi: 10.3390/nu7105393. PMID 26426042
• Clarke P, Embleton ND, Fewtrell M, Harrington DJ, Kelly AM, Moris N, Patto A, Ponnusamy V, Vasu V, Shearer MJ. Vitamin K: missed at peril-the case for extra supplementation to prevent deficiency in breastfed preterm infants. Arch Dis Child Fetal Neonatal Ed. 2024 Oct 18;109(6):679-680. doi: 10.1136/archdischild-2023-326737. No abstract available. PMID 38429074

Identifiers

NCT: NCT07620236 · 150-12-25

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗