Randomized controlled trial to assess the effect of vitamin K supplementation on the rate of elastin degradation in COPD

Rationale: Elastin is a unique protein providing elasticity and resilience to dynamic organs, such as lungs. Elastin is a basic requirement for both respiration and circulation. The rate of elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD). Desmosine (DES) is an amino acid that is only found in elastin fibers, and consequently, plasma (p)DES levels reflect the rate of elastin degradation. pDES is a strong predictor of mortality in COPD. We regard decelerating elastin degradation as an attractive novel therapeutic target in COPD. Elastin calcification stimulates elastin degradation and vice versa. Elastin calcification is inhibited by Matrix Gla Protein (MGP), a protein which needs vitamin K to become activated. Serum inactive levels of MGP, dephospho-uncarboxylated (dp-uc) MGP, are inversely associated with vitamin K status. Recently, we found significantly lower vitamin K status in COPD patients compared to controls. Furthermore, we found an inverse association between vitamin K-status and the rate of elastin degradation in both subjects with COPD and controls with no lung disease. Vitamin K epoxide reductase (VKOR) is an enzyme that plays a role in vitamin K recycling. Certain polymorphisms in the gene coding for VKOR, the VKOR complex 1 (VKORC1) gene, are associated with reduced vitamin K recycling. Possibly, these polymorphisms are, in part, responsible for inter-individual differences in vitamin K-status. We hypothesize that improving vitamin K-status by vitamin K supplementation could have a favorable decelerating effect on elastin degradation.

Objective: To evaluate whether supplementation of vitamin K2 decelerates the rate of elastin degradation in patients with COPD.

Study design: Double-blind randomized placebo-controlled intervention trial.

Study population: A total of 40 COPD patients who participate in the inpatient rehabilitation program of CIRO.

Intervention: Supplementation of 360 mcg vitamin K2 once daily for eight weeks.

Main study parameters/endpoints: The primary endpoint is the difference in the rate of elastin degradation (quantified by the plasma desmosine assay) after 8 weeks of vitamin K versus placebo supplementation. Secondary endpoints (after 8 weeks of treatment) are: vitamin K-status (quantified by dp-ucMGP), proteins induced by vitamin K abcense (PIVKA)-II levels (inversely associated with vitamin K status), vitamin D levels, lung function parameters, questionnaires concerning psychosocial functioning/functional effects/health status, physical functioning, body composition, arterial stiffness and exacerbations during the study period. In addition, we want to evaluate if different polymorphisms of the VKORC1 gene are associated with desmosine and dp-ucMGP levels at baseline and after vitamin K2 supplementation.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This study has two evaluation moments which coincide with the start of rehabilitation and the evaluation assessment of the inpatient rehabilitation program, which implies that there is no additional visit for study participants. The evaluation moments will be scheduled at baseline (t=0, start of rehabilitation) and at the end of the study (t=8, after 8 weeks of rehabilitation). Time between the intake assessment and start of the rehabilitation is 1 to 6 weeks. One tube of blood is drawn at the start of rehabilitation, which implies an additional needle stick for study purposes. After 8 weeks, blood is drawn as part of the standard rehabilitation program and one extra tube of blood will be drawn for this study. The other additional tests for the study (not part of the regular assessments) are arterial stiffness measurements (pulse wave velocity) (at t=0 and t=8). Participating in the study has negligible risks as adverse side-effects from vitamin K2 supplementation have never been described in persons who do not use vitamin K antagonists (VKAs).

Vitamin K supplementation will lead to a deceleration of elastin degradation in COPD patients.

Baseline and 8 weeks (i.e. after pulmonary rehabilitation)

Patients participating in a 8-week inpatient rehabilitation program at CIRO+ will be randomized to receive either 360 mcg vitamin K2 or placebo orally once a day during 8 weeks.