EP4 receptor antagonism and PGE2 in a human headache model

INTERVENTION: Trade Name: BGC20‐1531 Product Name: BGC20‐1531 Pharmaceutical Form: Capsule* Pharmaceutical form of the placebo: Capsule* Route of administration of the placebo: Oral use CONDITION: PGE2 will induce headache in healthy subjects and BGC20‐1531 or placebo will be used to block the developement of headache. In the future BGC20‐1531 might be a possible anti‐migraine drug. PRIMARY OUTCOME: Main Objective: The primary objective is:; • to investigate the blocking effects of two different single doses of the EP4 receptor antagonist, BGC20‐1531, on PGE2‐induced headache in healthy male and female subjects; Primary end point(s): Phase 1 ; Calculation of the number of trial subjects is based on the measurement of differences in pain intensity between treatments with reduction of pain in VRS at 5% significance limit with 90% power. It is assumed that each trial subject will show 20% variation in VRS. A 70% pain reduction will be considered to be of clinical significance. ; ; Phase 2; Calculation of the sample size is based on detection of a difference between treatments in VMCA reduction at 5% significance (two‐sided) with 80% power. It is assumed that each patient would show a 10% standard variation in VMCA. A true change in the dependent variables is considered 20%. Secondary Objective: The secondary objectives are:; • to investigate the blocking effects of two different single doses of BGC20‐1531 on PGE2‐induced drop in mean flow velocity in the middle cerebral artery (Vmean MCA), dilatation of superficial temporal artery (STA) and the radial artery (RA) in healthy subjects,; • to investigate the effects of a single dose of BGC20‐1531 on Vmean MCA and diameter of the STA and RA in healthy subjects.; • to assess the pharmacokinetic/pharmacodynamic interactions of two different single doses of BGC20‐1531.; • to confirm the safety of single doses of BGC20‐1531 in healthy subjects.; INCLUSION CRITERIA: • Healthy trial subjects of either gender, 18–55 years of age. • Body Mass Index 21–29 kg/m2 [body mass index = body weight (kg) ÷ height (m)]2. • Fertile women must use reliable contraception; this does not apply to women who have had hysterectomies or to women 2 years post‐menopause or longer. Reliable contraception is either an IUD + condom, birth control pills + condom, surgical sterilisation of the woman, or a depot gestagen. • Non‐smokers or ex‐smokers who have not smoked in the last 6 months (determined by urine cotinine < 500 ng/ml at screening). • No clinically significant out of range values in tests of serum biochemistry, hæmatology or urinalysis at screening (see Appendix 1). Negative urinary drugs of abuse screen at screening (see Appendix 1). • Negative HIV and hepatitis B and C results • Trial subjects must fulfil the inclusion criteria entirely, be willing and able to comply fully with the requirements of the study and be a