An open-label, crossover study to assess the pharmacokinetics, safety and tolerability of pulsatile intra-vaginal delivery of insulin aspart in females with diabetes mellitus type 1

Eligible subjects must meet all the following inclusion criteria at screening:
1. Willing to give written informed consent and willing and able to comply with
the study protocol.
2. Female subjects with diabetes mellitus type 1 of childbearing potential
(women of childbearing potential, WOCBP) aged between 18 and 45 years
(inclusive).
3. Subject is on insulin therapy under multiple daily injection (MDI) or
continuous subcutaneous insulin infusion (CSII).
4. Subject is on continuous glucose monitoring (CGM) with a CGM device or a
flash monitoring device (e.g. Abbott Freestyle Libre) more than 24 hours in
situ.
5. Subject is in good general health (apart from T1DM), according to the
investigator*s judgement based on vital signs, medical history, physical
examination, and laboratory tests performed.
6. Body mass index between 18-32 kg*m2 (inclusive) and with a minimum body
weight of 50 kg at screening.
7. Ability to communicate well with the investigator in the Dutch language and
willing to comply with the study restrictions.
8. Using contraceptives of second generation containing ethinylestradiol and
progesterone derivate. This includes a hormone-containing IUD (e.g. Mirena),
second generation oral contraceptive pill, hormonal contraception using
parenteral medroxyprogesteron or subcutaneous etonogestrel.

Eligible subjects must meet none of the following exclusion criteria at
screening:
1. (A history of) any clinically significant medical condition or abnormality,
as judged by the investigator, in physical examination, laboratory test results
(including chemistry panel with hepatic and renal panels, complete blood count,
and urine dipstick) or electrocardiography (ECG) at screening. In the case of
uncertain or questionable results, tests performed during screening may be
repeated to confirm eligibility or judged by the investigator to be clinically
irrelevant for healthy subjects.
2. Patients on (hybrid) closed loop systems, i.e. Medtronic 670G/780 pump.
3. Patients with unstable glucose regulation in opinion of the investigators,
for example frequent hypo- or hyperglycemia or with hypoglycemia unawareness.
4. Being a virgin.
5. History of sexual abuse/violence.
6. First day of last withdrawal bleeding <10 days before both study days.
7. Plan to discontinue oral contraceptive during study period.
8. Positive pregnancy test at screening or at baseline prior to IMP
administration and/or lactating.
9. Having given birth vaginally or by caesarean section 6 months prior to
screening.
10. Having had sexual intercourse or objects inserted vaginally that could
potentially lacerate or damage the vaginal wall 24 hours prior to dosing.
11. Positive screening test for Hepatitis B/C and/or Human Immunodeficiency
Virus (HIV) test at screening.
12. Positive screening PCR test for Chlamydia trachomatis or gonorrhoea at
screening.
13. Medical history of intra- and/or transvaginal operations that in the
opinion of the investigator may interfere with placement or stability of the
MedRing or absorption of the IMP. Exceptions may include endometrial curettage
for e.g. miscarriage or abortion or LIS-excision of the cervix for CIN if
performed > 3 months prior to screening.
14. High risk for sexual transmitted diseases (STD):
a. 3 or more different sexual contacts in last 6 months, and/or
b. is a sex worker or visits them and/or
c. has a partner with an STD risk as described (a. and/or b.), and/or
d. partner is a male who has sex with male.
15. Any confirmed significant allergic reactions (urticaria or anaphylaxis)
against insulin aspart (Fiasp), or multiple drug allergies (non-active hay
fever is acceptable).
16. Participation in any marketed or investigational drug or device study
within 3 months or 5 half-lives (whichever is longer) prior to first dosing.
17. Use of prescription medication or any other substance that in the opinion
of the investigators may influence the outcome of the study (e.g. systemic
steroids) within 21 days prior to study drug administrations, or less than five
half-lives (whichever is longer, and during the course of the study).
Exceptions are the incidental use of OTC medications paracetamol (up to 4
g/day) and ibuprofen (up to 1 g/day) which are allowed within two days of
clinical assessments.
18. Use of alcohol during the 24 hours prior to screening and/or an
unwillingness to abstain from alcohol consumption during the stay at the
clinical unit, and for at least 24 hours prior to each study visit.
19. Positive urine drug screen or alcohol test at screening and/or at study
days.
20. Loss or donation of blood over 500 mL within four months prior to screening.
21. Any other condition that in the opinion of the investigator would
complicate or compromise the study or the well-being of the subject.