Safety and Tolerability of TOP-N53 Applied on Digital Ulcers in Patients With Systemic Sclerosis

Inclusion Criteria:

1. Participants who are able to understand and follow instructions during the clinicaltrial.

2. Signed written informed consent in accordance with ICH-GCP and local legislationprior to admission to the clinical trial.

3. Male or female participants aged 18 to 69 years* at screening (V0) with SSc, limitedor diffuse cutaneous, according to 2013 American College of Rheumatology (ACR)/EULARcriteria (*sex refers to biological characteristics).

4. At least one active DU, considered as the cardinal DU, due to SSc, ≥3 mm in diameterat screening (V0) and baseline (V1/V1b) with at least an involvement of the dermis,located at the fingertip.

5. Participants meeting one of the following 2 criteria:

6. On stable PO sildenafil treatment at 20 mg TID [3 times per day] for at least 2weeks prior screening (V0).

7. Not on any PO PDE5 inhibitor (sildenafil, tadalafil, vardenafil, mirodenafil)or unselective PDE inhibitors (theophylline, dipyridamole) at any dose (including for recreational purposes) for at least 4 weeks prior screening (V0).

8. The physical examination must be without disease findings except SSc unless theinvestigator considers an abnormality to be irrelevant to the outcome of theclinical trial (screening [V0] and baseline [V1/V1b]).

9. Concomitant medication as endothelin receptor antagonists, calcium channel blockers,and antiplatelets must have been used at stable doses at least 2 weeks prior toscreening (V0), if applicable.

10. Female volunteers of childbearing potential1 must either be permanently sterile oragree to use a highly effective birth control method (failure rate ˂1% per year whenused consistently and correctly) throughout the clinical trial and for at least 7weeks after last administration of IP.

11. A male participant with a female partner of childbearing potential1 must agree touse adequate contraceptive methods (adequate contraceptive measures as required bylocal regulation or practice).

12. Covered by health insurance system and/or in compliance with the recommendations ofnational law in force relating to biomedical research.

Exclusion Criteria:

1. Any DU accompanied by one of the following complications: Clinical infection ofactive ulcer/peri-ulcer, osteitis, gangrene (screening [V0] and baseline [V1/V1b]).

2. Participants with modified Rodnan Skin Score (mRSS) >35 (screening [V0]).

3. Intractable pain from DUs (NRS ≥6) (screening [V0] and baseline [V1/V1b]).

4. Active or previous history of calcinosis at the site of the designated cardinal DU.

5. Unstable organ manifestations of SSc that require immediate medical attention andtreatment e.g., scleroderma renal crisis, or where other organ manifestations of SSc (interstitial lung disease [ILD], pulmonary hypertension, gastrointestinal withmalabsorption syndrome or bleeding, symptomatic primary myocardial involvement) arepoorly controlled and/or are determinants of clinical symptomatology.

6. Any documented active or suspected malignancy or history of malignancy within 5years prior to the screening visit (V0), except appropriately treated basal cellcarcinoma of the skin, actinic keratoses, "under surveillance" prostate cancer or insitu carcinoma of uterine cervix.

7. Participants with underlying chronic liver disease (Child Pugh A, B or C hepaticimpairment).

8. Participants with a significant disease or condition other than SSc which in theopinion of the investigator, may put the participant at risk because ofparticipation, interfere with clinical trial procedures, or cause concern regardingthe participant's ability to participate in the clinical trial or any medicalcondition which is expected to lead to a life expectancy <12 months.

9. Systolic BP (SBP) <95 mmHg or diastolic BP (DBP) <50 mmHg , pulse rate <50 beats perminute at sitting position (if participant is very athletic as assessed by theinvestigator, exception to a pulse <50 bpm is permissible) at the screening visit (V0) or baseline visit (V1/V1b); one repeat measurement will be permitted.

10. Clinically significant findings in the ECG at the screening visit (V0) or inhistoric ECG including 24 h Holter recordings, in particular prolongation of the QTinterval corrected for HR (QTcB) ≥450 msec for men and ≥460 msec for women,ventricular arrhythmias or ectopic ventricular beats.

11. Major surgery within 8 weeks prior to the screening visit (V0).

12. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x upperlimit of normal (ULN) and total Bilirubin >1.5 x ULN.

13. Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease EpidemiologyCollaboration [CKD-EPI] formula) formula ≤60 ml/min/1.73 m2 (corresponds to ≥ mildlyto moderately reduced glomerular filtration rate [GFR]).

14. Clinical laboratory values outside the reference range that in the investigator'sopinion require further investigation and preclude enrollment into the clinicaltrial (clinically significant).

15. Positive test for human immunodeficiency virus (HIV) antibodies, unless known frommedical history.

16. Positive hepatitis B-virus surface antigen (HBsAg) test, unless known from medicalhistory.

17. Positive anti-hepatitis C-virus antibodies (anti-HCV) test, unless known frommedical history.

18. Treatment with IV prostanoids: Either ongoing, or taken in the 4 weeks beforeenrollment or intended for the 4 weeks after last treatment with IP during theclinical trial.

19. Treatments with PO prostanoids (selexipag), nitrovasodilators (e.g., glyceroltrinitrate, isosorbide dinitrate, isosorbide mononitrate, molsidomine), solubleguanylate cyclase stimulators (riociguat) for 1 week prior screening (V0).

20. Treatment with any other PDE5 inhibitor (tadalafil, vardenafil) except sildenafil ifmeeting inclusion criterion no. 5a or unselective PDE inhibitor (theophylline,dipyridamole) at any posology for the 4 weeks prior screening (V0) and during theclinical trial.

21. Treatment with systemic glucocorticoids and immunosuppressants (unless used asstable background treatments for SSc at unchanged doses [as prescribed byparticipant's treating physicians] for at least 4 weeks prior to screening [V0]).

22. Contraindications according to the IB of sildenafil and SmPC of Sildenafil-Teva onlyapplicable for those participants meeting inclusion criterion no 5a:

23. Hypersensitivity to the active substance or to any of the excipients ofsildenafil.

24. Co-administration with NO donors (such as amyl nitrite) or nitrates in any formdue to the hypotensive effects of nitrates.However, in the current clinical trial with the topical, on woundadministration of the NO donor and PDE5 inhibitor TOP-N53 as IP 2 in patientson sildenafil any risk of hypotensive effects are minimal because the plasmaexposure of TOP-N53 is expected as < MABEL.

25. The co-administration of PDE5 inhibitors, including sildenafil, with guanylatecyclase stimulators, such as riociguat, is contraindicated as it maypotentially lead to symptomatic hypotension.

26. Combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole,itraconazole, ritonavir).

27. Participants who have loss of vision in one eye because of non-arteriticanterior ischaemic optic neuropathy (NAION), regardless of whether this episodewas in connection or not with previous PDE5 inhibitor exposure.

28. Recent history of stroke or myocardial infarction.

29. Known or suspected hypersensitivities or known allergic reactions to components ofthe IPs or other dressings required for SoC during the clinical trial treatment.

30. Known allergy to local amide anesthetics.

31. Currently enrolled in another clinical investigation or clinical trial, or less than 30 days prior to screening visit (V0) (less than 2 months for any investigativeclinical trials with PDE5 inhibitors, guanylate cyclase activators or stimulators,or any other intervention interfering with the broader cGMP pathway) since endinganother clinical investigation or clinical trial(s), or receiving otherinvestigational treatment(s).

32. Pregnant women or breast-feeding women.

33. In the opinion of the investigator the participant should not participate in theclinical trial if they are not expected to comply with the clinical trial protocolrequirements or not expected to complete the clinical trial as scheduled.

34. Close affiliation with the investigator (e.g., a close relative) or persons workingat the clinical trial center(s) or participant is an employee of sponsor(s).

35. Participant is institutionalized because of legal or regulatory order.

36. Participant is vulnerable (under legal protection).