Randomized response surface pathway design with skewed starting point and stochastic dose window

Holand, Trond; Evensen, Øystein; Dewi, Sagita; Larsen, Stig

doi:10.18203/2349-3259.ijct20200202

Cited by 2 publications

(2 citation statements)

References 22 publications

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“…The RSP-design has been developed for such situation in which all the results at one design level recommended the same dose. 24 In clinical trials this is not always the case.…”

Section: Discussionmentioning

confidence: 99%

Increased serum osteocalcin levels and vitamin K status by daily cheese intake

Lundberg¹,

Holand

Holo

et al. 2020

Int J Clin Trials

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Background: Cheese is a major source of long-chained vitamin K2 variants. How intake of vitamin K2 rich cheese affects vitamin K and osteocalcin has not been studied. The aim was to establish a maximum efficacy dose (MED) after daily intake of vitamin K2-rich cheese (Jarlsberg®) based on increase in ratio between carboxylated and undercarboxylated osteocalcin during a five-week diet.Methods: 20 healthy healthy volunteers (HV) were recruited. The daily intake of Jarlsberg® cheese in the study varied from 20 to 152 g. Clinical investigation was performed initially and after three, four and five weeks with measurement of vital signs, hematological and biochemical variables, carboxylated and undercarboxylated osteocalcin and vitamin K. The ratio OR= carboxylated/undercarboxylated osteocalcin was the main variable.Results: The MED decreased with treatment duration and was estimated to 57 g/day (95% CI: 47-67) after five weeks diet, resulting in a mean OR increase of 30% (95% CI: 23.8-36.8). Both OR and serum osteocalcin followed a quadratic dose response curve. For osteocalcin, a maximal increase of 46% was estimated at 59 g/day for five weeks. The serum content of long-chained vitamin K2 increased significantly with increasing cheese dose. The increase were mainly obtained the first three weeks and kept unchanged the following two weeks. The cheese doses close to the MED caused nearly significant reductions in total cholesterol, LDL-cholesterol, the LDL/HDL ratio and significant reduction in the blood pressures after five weeks diet (p≤0.05).Conclusions: MED of Jarlsberg® cheese was estimated to 57 g/day. Daily intake of Jarlsberg® cheese increased the osteocalcin level, vitamin K2 and positively affected the lipid patterns and blood pressure.

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“…The RSP-design has been developed for such situation in which all the results at one design level recommended the same dose. 24 In clinical trials this is not always the case.…”

Section: Discussionmentioning

confidence: 99%

Increased serum osteocalcin levels and vitamin K status by daily cheese intake

Lundberg¹,

Holand

Holo

et al. 2020

Int J Clin Trials

Self Cite

View full text Add to dashboard Cite

show abstract

“…10,11 RSP design with skewed starting point is previously introduced, but will not be able to correct for the expected individual deviations in osteocalcin increase. 12,13 In order to optimize the study, it is necessary to develop a within-patient RSP design with an individual starting dose, which will depend on the individual tOC increase after 6 weeks on MED.…”

Section: Introductionmentioning

confidence: 99%

Determination of maintenance Jarlsberg® cheese dose to keep the obtained serum osteocalcin level; a response surface pathway designed de-escalation dose study with individual starting values

Lundberg¹,

Holo

Holand

et al. 2021

Int J Clin Trials

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Background: Daily maximum effective dose (MED) of Jarlsberg® increased the serum osteocalcin (tOC) level, vitamin K2 and affected the lipid pattern positively. The aim of the study was to estimate and verify a daily maintenance dose.Methods: 12 healthy female volunteers (HV) were included in a de-escalation study after a six week run-in period on the daily MED of 57 g Jarlsberg® cheese. A 3-level within-patient response surface pathway (RSP) design with individual starting values was developed. Another 12 HVs were included in a new study with a six week run-in period on MED followed with six weeks on the estimated maintenance dose. All HVs were premenopausal female between 20 and 52 years of age. The main variable in the studies was the tOC level.Results: tOC, cOC and the vitamin K2 variants increases significantly (p<0.01) during the run-in period on daily MED of Jarlsberg® in both studies. The maintenance daily dose was estimated to 45 g (95% CI: 38-52 g/day) and used in the new study. The tOC level was reduced from 19.8 ng/ml (95% CI: 12.0-27.6) obtained in the run-in period to 18.5 ng/ml (95% CI: 11.7-25.3) during the maintenance part. This represents a reduction of 6.6%. The sum of vitamin K2 variants changed from 0.58 ng/ml on MED of Jarlsberg® to 0.59 ng/ml (95% CI: 0.37-0.82) during the maintenance period.Conclusions: Daily MED of Jarlsberg® cheese increases tOC, cOC and the vitamin K2 level. The maintenance Jarlsberg® dose was estimated to 45 g/day and verified as sufficient.

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Randomized response surface pathway design with skewed starting point and stochastic dose window

Cited by 2 publications

References 22 publications

Increased serum osteocalcin levels and vitamin K status by daily cheese intake

Increased serum osteocalcin levels and vitamin K status by daily cheese intake

Determination of maintenance Jarlsberg® cheese dose to keep the obtained serum osteocalcin level; a response surface pathway designed de-escalation dose study with individual starting values

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