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

Inclusion criteria

• Participants who are able to understand and follow instructions during the clinical trial.
• Signed written informed consent in accordance with ICH-GCP and local legislation prior to admission to the clinical trial.
• Male or female participants aged ≥18 years of age at screening (V0) with SSc, limited or diffuse cutaneous, according to 2013 American College of Rheumatology (ACR)/EULAR criteria (*sex refers to biological characteristics).
• At least one active DU, considered as the cardinal DU, due to SSc, ≥2 mm in diameter at screening (V0) and baseline (V1/V1b) with at least an involvement of the dermis, located at the interphalangeal fingertip or on the volar surface distal to the proximal joint.
• Participants meeting one of the following 2 criteria:

• On stable PO sildenafil treatment at 20 mg TID [3 times per day] for at least 2 weeks prior screening (V0).
• 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).
• The physical examination must be without disease findings except SSc unless the investigator considers an abnormality to be irrelevant to the outcome of the clinical trial (screening [V0] and baseline [V1/V1b]).
• Concomitant medication as endothelin receptor antagonists, calcium channel blockers, and antiplatelets must have been used at stable doses at least 2 weeks prior to screening (V0), if applicable.
• Female volunteers of childbearing potential1 must either be permanently sterile or agree to use a highly effective birth control method (failure rate ˂1% per year when used consistently and correctly) throughout the clinical trial and for at least 7 weeks after last administration of IP.
• A male participant with a female partner of childbearing potential1 must agree to use adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice).
• Covered by health insurance system and/or in compliance with the recommendations of national law in force relating to biomedical research.

Exclusion criteria

• Any DU accompanied by one of the following complications: Clinical infection of active ulcer/peri-ulcer, osteitis, gangrene (screening [V0] and baseline [V1/V1b]).
• Participants with modified Rodnan Skin Score (mRSS) >35 (screening [V0]).
• Intractable pain from DUs (NRS ≥6) (screening [V0] and baseline [V1/V1b]).
• Active or previous history of calcinosis at the site of the designated cardinal DU.
• Unstable organ manifestations of SSc that require immediate medical attention and treatment e.g., scleroderma renal crisis, or where other organ manifestations of SSc (interstitial lung disease [ILD], pulmonary hypertension, gastrointestinal with malabsorption syndrome or bleeding, symptomatic primary myocardial involvement) are poorly controlled and/or are determinants of clinical symptomatology.
• Any documented active or suspected malignancy or history of malignancy within 5 years prior to the screening visit (V0), except appropriately treated basal cell carcinoma of the skin, actinic keratoses, "under surveillance" prostate cancer or in situ carcinoma of uterine cervix.
• Participants with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
• Participants with a significant disease or condition other than SSc which in the opinion of the investigator, may put the participant at risk because of participation, interfere with clinical trial procedures, or cause concern regarding the participant's ability to participate in the clinical trial or any medical condition which is expected to lead to a life expectancy <12 months.
• Systolic BP (SBP) <95 mmHg or diastolic BP (DBP) <50 mmHg , pulse rate <50 beats per minute at sitting position (if participant is very athletic as assessed by the investigator, exception to a pulse <50 bpm is permissible) at the screening visit (V0) or baseline visit (V1/V1b); one repeat measurement will be permitted.
• Clinically significant findings in the ECG at the screening visit (V0) or in historic ECG including 24 h Holter recordings, in particular prolongation of the QT interval corrected for HR (QTcB) ≥450 msec for men and ≥460 msec for women, ventricular arrhythmias or ectopic ventricular beats.
• Major surgery within 8 weeks prior to the screening visit (V0).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x upper limit of normal (ULN) and total Bilirubin >1.5 x ULN.
• Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) formula ≤60 ml/min/1.73 m2 (corresponds to ≥ mildly to moderately reduced glomerular filtration rate [GFR]).
• Clinical laboratory values outside the reference range that in the investigator's opinion require further investigation and preclude enrollment into the clinical trial (clinically significant).
• Positive test for human immunodeficiency virus (HIV) antibodies, unless known from medical history.
• Positive hepatitis B-virus surface antigen (HBsAg) test, unless known from medical history.
• Positive anti-hepatitis C-virus antibodies (anti-HCV) test, unless known from medical history.
• Treatment with IV prostanoids: Either ongoing, or taken in the 4 weeks before enrollment or intended for the 4 weeks after last treatment with IP during the clinical trial.
• Treatments with PO prostanoids (selexipag), nitrovasodilators (e.g., glycerol trinitrate, isosorbide dinitrate, isosorbide mononitrate, molsidomine), soluble guanylate cyclase stimulators (riociguat) for 1 week prior screening (V0).
• Treatment with any other PDE5 inhibitor (tadalafil, vardenafil) except sildenafil if meeting inclusion criterion no. 5a or unselective PDE inhibitor (theophylline, dipyridamole) at any posology for the 4 weeks prior screening (V0) and during the clinical trial.
• Treatment with systemic glucocorticoids and immunosuppressants (unless used as stable background treatments for SSc at unchanged doses [as prescribed by participant's treating physicians] for at least 4 weeks prior to screening [V0]).
• Contraindications according to the IB of sildenafil and SmPC of Sildenafil-Teva only applicable for those participants meeting inclusion criterion no 5a:

• Hypersensitivity to the active substance or to any of the excipients of sildenafil.
• Co-administration with NO donors (such as amyl nitrite) or nitrates in any form due to the hypotensive effects of nitrates.

However, in the current clinical trial with the topical, on wound administration of the NO donor and PDE5 inhibitor TOP-N53 as IP 2 in patients on sildenafil any risk of hypotensive effects are minimal because the plasma exposure of TOP-N53 is expected as < MABEL.

• The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension.
• Combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).
• Participants who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.
• Recent history of stroke or myocardial infarction.
• Known or suspected hypersensitivities or known allergic reactions to components of the IPs or other dressings required for SoC during the clinical trial treatment.
• Known allergy to local amide anesthetics.
• 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 investigative clinical trials with PDE5 inhibitors, guanylate cyclase activators or stimulators, or any other intervention interfering with the broader cGMP pathway) since ending another clinical investigation or clinical trial(s), or receiving other investigational treatment(s).
• Pregnant women or breast-feeding women.
• In the opinion of the investigator the participant should not participate in the clinical trial if they are not expected to comply with the clinical trial protocol requirements or not expected to complete the clinical trial as scheduled.
• Close affiliation with the investigator (e.g., a close relative) or persons working at the clinical trial center(s) or participant is an employee of sponsor(s).
• Participant is institutionalized because of legal or regulatory order.
• Participant is vulnerable (under legal protection).