Characterisation of ovulation inhibition and effects on metabolic parameters and haemostatic system of multiple administrations of a fixed-dose combination product containing 0.02 mg ethinylestradiol and 2 mg dienogest (24+4) in a multiple administration, comparative parallel-group trial vs. a marketed product containing 0.02 mg ethinylestradiol and 0.10 mg levonorgestrel with healthy females of childbearing potential

The present trend in development of oral contraceptives is to reduce hormonal
content especially with regard to the oestrogen component to maintain efficacy
and to minimise oestrogen-related side effects. Historically, oral
contraceptives with lower doses of ethinylestradiol were sought after because
of the cardiovascular risks associated with the use of higher doses of EE [6].

Such an approach has successfully been applied for a combination of 0.02 mg EE
with LNG (Microgynon® 20, Miranova®). However, reduction in daily EE dose comes
along with a reduced inhibition of ovulation so that an increase in the risk of
follicular rupture and ovulation is expected.

As a consequence of these mechanistic and pharmacological considerations, it is
the intention to develop a combination product with 0.02 mg EE and 2.0 mg DNG
specified for 24 active treatment days and 4 days of treatment-free interval.

descriptive characterisation of the influence of Test or Reference on ovarian
activity determined by means of maximum follicular diameter and Hoogland score

descriptive characterisation of the effect of Test or Reference on endometrial
thickness, cervical mucus as well as on the pituitary and ovarian hormones the
latter determined via follicle stimulating hormone (FSH), luteinising hormone
(LH), estradiol (E2) and progesterone (P)

descriptive characterisation of effect of Test or Reference on sex hormone
binding globulin (SHBG) and corticosteroid binding globulin (CBG) levels,
C-reactive protein, lipid profile as well as haemostatic and carbohydrate
parameters

descriptive characterisation of bleeding pattern

descriptive characterisation of return of ovulation

descriptive characterisation of overall safety and tolerability in the study
population

This clinical trial will be performed in a single centre, open-label,
randomised (assignment to treatment group), parallel-group, two-arm
multiple-dose design.

60 healthy pre-menopausal women aged between 18 and 35 years with proven
potential for ovulation are intended to be randomised.
The clinical trial comprises three phases, i.e. pre-treatment phase, treatment
phase and follow-up phase.
The pre-treatment phase includes a pre-treatment menstrual cycle for check of
subjects* potential for ovulation as well as baseline assessment of SHBG and
CBG levels, C-reactive protein, lipid profile, haemostatic and carbohydrate
parameters. After subjects have been found eligible for the clinical trial they
will be randomised.

Afterwards, subjects will enter the treatment phase and will receive either
Test or Reference treatment stratified by time point of ovulation in the
pre-treatment cycle. IMPs will be administered as multiple oral doses over
three treatment cycles (T1, T2 and T3) of 28 days each. Per treatment cycle, in
case of Test 24 tablets containing each 0.02 mg EE and 2 mg DNG will be
administered over 24 days followed by a treatment-free interval of 4 days. In
case of Reference 21 tablets containing each 0.02 mg EE and 0.1 mg LNG will be
administered over 21 days followed by a treatment-free interval of 7 days.
Overall, 72 tablets of Test or 63 tablets of Reference will be administered.
Ovarian activity will be monitored under treatment. During the treatment cycle
3 changes from baseline of the above mentioned clinical laboratory parameters
will be assessed.

Subsequently, subjects will enter the follow-up phase, for monitoring of return
of ovulation over one menstrual cycle.

n.a.

The following side effects have been described for the investigational products.

Common side effects (>= 1/100 and < 1/10) are: headache, abdominal pain, and
breast pain.
Uncommon side effects (>= 1/1000 and < 1/100) are: fungal infection of the
vagina, increased appetite, depressed mood, migraine, dizziness, nervousness,
eye complaints, vein complaints, hypertension, gastrointestinal disturbances,
nausea, vomiting, acne, exanthema, eczema, alterations of the skin, chloasma
(increased pigmentation), alopecia (loss of hair), cramps in the legs, urinary
tract infection, bleeding disturbances, dysmenorrhoea (menstrual pain), breast
enlargement, ovarian cyst (benign swelling of ovaries), dyspareunia (disorder
of sexual function), vaginitis (inflammation of the vagina), vulvo-vaginitis
(inflammation of the outer sexual organs), changes in vaginal secretion, hot
flushes, fatigue/weakness, back pain, oedema (swelling).

Rare side effects (>= 1/10.000 and < 1/1000) are: allergic reactions, anorexia
(diminished appetite), decreased libido (sexual desire), aggressive reactions,
indifference, abnormal vision, conjunctivitis (inflammation of the
conjunctiva), deafness, thrombophlebitis (inflammation of veins with blood
clot), thrombosis (vascular disease with formation of blood clot)/pulmonary
embolism (obstruction of lung artery), tachycardia (increased heart rate),
cardiac complaints, haematoma, cerebrovascular (related to blood vessels of
brain) disturbances, sinusitis (inflammation of paranasal sinus), asthma, upper
respiratory tract infection, diarrhoea (loose bowels), erythema multiforme
(inflammatory disease of skin or mucosa), pruritus (itchiness), hypertrichosis
(excessive hairiness), virilism (masculinisation), hypomenorrhoea (weak
menstruation), mastitis (inflammation of mammary gland), fibrocystic disorders
of the breast (changes in breast tissue), breast secretion, leiomyoma (benign
tumour of smooth muscle layer), endometritis, (inflammation of uterine lining),
salpingitis (inflammation of oviduct), influenza-like symptoms, anaemia (lack
of blood).

The following Serious Adverse Reactions have been reported upon use of combined
oral contraceptives:
• venous thromboembolic disorders (blood clots in the veins)
• arterial thromboembolic disorders (blood clots in the arteries)
• hypertension
• irregular bleeding
• chloasma (increased pigmentation of skin)
• in women with hereditary angioedema (genetic disease with swelling of
skin and various organs) exogenous (applied from the outside) oestrogens may
induce or exacerbate symptoms of angioedema
• liver tumours
• cervical carcinoma (tumours of neck of uterus)
The frequency of diagnosis of breast cancer is slightly increased among users
of oral contraceptives. As breast cancer is rare in women under 40 years of
age, the risk to develop cancer is small in relation to the overall risk.

Furthermore, the following Adverse Events have been reported upon use of
combined oral contraceptives; frequency is not calculable based on available
reports:
• neuritis nervi optici (partial or total loss of vision possible)
• deterioration of varicose veins (enlarged and tortuous veins)
• pancreatitis (inflammation of pancreas) in case of concurrent
hypertriglyceridemia (increase in blood fat values)
• cholecystic diseases including cholelithiasis (crystalline concretion
formed within the gallbladder)
• haemolytic-uremic syndrome (disease of small blood vessels)
• herpes gestationis (immune mediated disease during pregnancy)
• otosclerosis (disease of bones of inner ear )
• deterioration of systemic lupus erythematosus (immune mediated
disease)
• deterioration of porphyria (metabolic disease)
• deterioration of Sydenham's chorea (neurologic immune mediated
disease)
• deterioration of depression
• deterioration of chronic inflammatory bowel diseases (Crohn's
disease, ulcerative colitis)