2-[1-(3-{6-[(1E)-(HYDROXYIMINO)METHYL]-5-METHYL-4-OXO-7-PROPYL-3H,4H-PYRROLO[2,1-F][1,2,4]TRIAZIN-2-YL}-4-PROPOXYBENZENESULFONYL)PIPERIDIN-4-YL]ETHYL NITRATE for Scleroderma-associated digital ulcers

Inclusion criteria

• {"criterion_text":"- Participants who are able to understand and follow instructions during the clinical trial\n- Covered by health insurance system and/or in compliance with the recommendations of national law in force relating to biomedical research\n- Signed written informed consent in accordance with ICH-GCP and local legislation prior to admission to the clinical trial\n- Male or female participants aged ≥18 years at screening (V0) with SSc, limited or diffuse cutaneous, according to 2013 American College of Rheumatology (ACR)/EULAR criteria\n- 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 fingertip or ischemic DU distal to the metacarpophalangeal joint\n- Participants meeting one of the following 2 criteria: a. On stable PO sildenafil treatment at 20 mg TID [3 times per day] for at least 2 weeks prior screening (V0) or b.\tNot 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)\n- 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])\n- 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\n- Female volunteers of childbearing potential1 must either be permanently sterile1 or agree to use a highly effective birth control method (failure rate ˂1% per year when used consistently and correctly)2 throughout the clinical trial and for at least 7 weeks after last administration of IP\n- 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)"}

Exclusion criteria

• {"criterion_text":"- Any DU accompanied by one of the following complications: Clinical infection of active ulcer/peri-ulcer, osteitis, gangrene (screening [V0] and baseline [V1/V1b])\n- Major surgery within 8 weeks prior to the screening visit (V0)\n- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x upper limit of normal (ULN) and total Bilirubin >1.5 x ULN\n- 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\n- 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])\n- 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)\n- Positive test for human immunodeficiency virus (HIV) antibodies, unless known from medical history\n- Positive hepatitis B-virus surface antigen (HBsAg) test, unless known from medical history\n- Positive anti-hepatitis C-virus antibodies (anti-HCV) test, unless known from medical history\n- 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)\n- Pregnant women or breast-feeding women\n- Participants with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment)\n- In the opinion of the investigator the participant should not participate in the clinical trial if they are not expected to comply with the CTP requirements or not expected to complete the clinical trial as scheduled\n- 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\n- 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)\n- Participant is institutionalized because of legal or regulatory order\n- Participants with modified Rodnan Skin Score (mRSS) >35 (screening [V0])\n- 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\n- Intractable pain from DUs (NRS ≥6) (screening [V0] and baseline [V1/V1b])\n- Active or previous history of calcinosis at the site of the designated cardinal DU\n- 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\n- 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\n- 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\n- Participant is vulnerable (under legal protection)\n- 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\n- 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\n- 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])\n- Contraindications according to the IB of Sildenafil and SmPC of Sildenafil-Teva only applicable for those participants meeting inclusion criterion no 5a: a. Hypersensitivity to the active substance or to any of the excipients listed in Table 6 of the protocol. b. 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. c.\tThe co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension. d. Combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir). e. 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. f. Recent history of stroke or myocardial infarction\n- Known or suspected hypersensitivities or known allergic reactions to components of the IPs or other dressings required for SoC during the clinical trial treatment\n- Known allergy to local amide anesthetics"}

Primary endpoints

• {"endpoint_text":"- Local treatment emergent adverse events (TEAEs): Frequency of local TEAEs from treatment initiation until follow-up (FU) visit","definition_or_measurement_approach":"Frequency of local TEAEs will be recorded from treatment initiation until the FU visit; investigators will capture and classify local adverse events related to topical treatment during on-site assessments and safety follow-up."}
• {"endpoint_text":"- Investigator-solicited DU-related patient reported outcomes (DU-PROs)- Pain: Per dose/time escalation step at the respective assessment time points: - Frequency and mean score of pain (actual) at the cardinal DU as assessed by using a numeric rating scale (NRS, graduating intensity from 0 ['no pain'] to 10 ['worst imaginable pain'])","definition_or_measurement_approach":"Patient-reported pain at the cardinal DU measured using a numeric rating scale (NRS) 0–10; frequency and mean score per dose/time escalation step at specified assessment time points as solicited by investigators."}

Secondary endpoints

• {"endpoint_text":"- Daily diary DU-PROs: Per dose/time escalation step: - Frequency and mean score of pain (worst intensity during last 24 h) at the cardinal DU as assessed by using NRS (graduating intensity from 0 ['no pain'] to 10 ['worst imaginable pain'])","definition_or_measurement_approach":"Daily diary entries using NRS for worst 24 h pain intensity; frequency and mean scores calculated per dose/time step."}
• {"endpoint_text":"- Daily diary DU-PROs Per dose/time escalation step: - Frequency and mean score of itching (worst intensity during last 24 h) at the cardinal DU as assessed by using NRS (graduating intensity from 0 ['no pain'] to 10 ['worst imaginable pain'])","definition_or_measurement_approach":"Daily diary using NRS (0–10) for worst 24 h itch intensity; frequency and mean scores per escalation step."}
• {"endpoint_text":"- Daily diary DU-PROs: Per dose/time escalation step: - Frequency and mean score of RP by scoring using the RCS, an 0-10 ordinal scale from ‘no difficulty’ (0) to ‘extreme difficulty’, number of RP attacks and occurrence of tingling and numbness","definition_or_measurement_approach":"Daily diary using RCS 0–10 for Raynaud's Phenomenon (RP); number of RP attacks recorded and patient-reported tingling/numbness occurrences."}
• {"endpoint_text":"- Daily diary DU-PROs: Per dose/time escalation step: - Frequency of systemic TEAEs from treatment initiation until FU visit","definition_or_measurement_approach":"Recording of systemic treatment-emergent adverse events from initiation until follow-up using daily diary and investigator assessments; frequency tabulated per escalation step."}
• {"endpoint_text":"- Daily diary DU-PROs: Per dose/time escalation step at the respective assessment time points: - Vital signs: Mean systemic arterial BP and mean pulse rate, aural body temperature (only at screening, prior IP exposure when participant arrives, and at the FU visit), frequency of clinically significant abnormal values","definition_or_measurement_approach":"Vital signs measured at specified time points: mean BP and pulse rate, aural temperature at screening/prior exposure and FU; frequency of clinically significant abnormalities reported."}
• {"endpoint_text":"- Daily diary DU-PROs: Per cohort at screening (Days -10 to -3) and FU visit (7 + 2 days after last treatment): -\t12 lead electrocardiogram (ECG): mean and mean changes in ECG values, frequency of clinically significant abnormal values","definition_or_measurement_approach":"12-lead ECG at screening and FU; mean values and changes summarised, and frequency of clinically significant ECG abnormalities recorded."}
• {"endpoint_text":"- Daily diary DU-PROs: Per cohort at screening (Days -10 to -3) and FU visit (7 + 2 days after last treatment): -\tSafety laboratory (clinical chemistry, hematology, urinalysis, serology): mean and mean changes in laboratory values, frequency of clinically significant abnormal values","definition_or_measurement_approach":"Safety labs (chemistry, hematology, urinalysis, serology) at screening and FU; mean values and changes reported and clinically significant abnormalities counted."}
• {"endpoint_text":"- Clinical DU assessment (CDUA) endpoints: Per dose/time escalation step as assessed by the investigator live at the respective assessment time points: - Frequency and mean score of erythema at the peri ulcer area of the cardinal DU (by scoring using a 7-point Robinson scale)","definition_or_measurement_approach":"Investigator-assessed peri-ulcer erythema scored using the 7-point Robinson scale; frequency and mean scores per escalation step."}
• {"endpoint_text":"- Clinical DU assessment (CDUA) endpoints: Per dose/time escalation step as assessed by the investigator live at the respective assessment time points: - Frequency of bruising at the peri-ulcer area of the cardinal DU or beyond (as assessed by closed question: YES/NO)","definition_or_measurement_approach":"Investigator records presence/absence (YES/NO) of bruising at peri-ulcer area; frequency per escalation step."}
• {"endpoint_text":"- Clinical DU assessment (CDUA) endpoints Per dose/time escalation step as assessed by the investigator live at the respective assessment time points: - Frequency of hemorrhage in the cardinal DU (as assessed by closed question: YES/NO)","definition_or_measurement_approach":"Investigator records presence/absence (YES/NO) of hemorrhage at the cardinal DU; frequency per escalation step."}
• {"endpoint_text":"- Clinical DU assessment (CDUA) endpoints: Per dose/time escalation step as assessed by the investigator live at the respective assessment time points: - Frequency of perilesional newly emerging, wound related edema at the cardinal DU (as assessed by closed question: YES/NO)","definition_or_measurement_approach":"Investigator records new perilesional wound-related edema (YES/NO); frequency reported per escalation step."}
• {"endpoint_text":"- Clinical DU assessment (CDUA) endpoints: Per dose/time escalation step as assessed by the investigator live at the respective assessment time points: - Frequency of clinical infection at the cardinal DU (as assessed by closed question: YES/NO)","definition_or_measurement_approach":"Investigator-assessed clinical infection presence (YES/NO) at the cardinal DU; frequency per escalation step."}
• {"endpoint_text":"- Investigator-solicited DU-related patient reported outcomes (DU-PROs) - Itching: Per dose/time escalation step at the respective assessment time points: -\tFrequency and mean score of itching (actual) at the cardinal DU as assessed by using NRS (graduating intensity from 0 ['no itch'] to 10 ['worst imaginable itch'])","definition_or_measurement_approach":"Patient-reported itching at the cardinal DU using NRS 0–10; frequency and mean scores per escalation step."}
• {"endpoint_text":"- Further investigator-solicited DU-PRO: Per dose/time escalation step at the respective assessment time points: - Number of RP attacks since IP 1/2 initiation (0–5 min time point)","definition_or_measurement_approach":"Number of Raynaud's Phenomenon attacks recorded since IP initiation at the 0–5 min timepoint; counted per participant per escalation step."}
• {"endpoint_text":"- Further investigator-solicited DU-PRO: Per dose/time escalation step at the respective assessment time points: - Number of RP attacks since IP 1/2 removal (60 min time point)","definition_or_measurement_approach":"Number of RP attacks recorded since IP removal at 60 min timepoint; counted per escalation step."}
• {"endpoint_text":"- Further assessments: Per dose/time escalation step at the respective assessment time points: - Wound tissue type assessment (estimated percentage of granulating, epithelializing, necrotic, sloughy [fibrinous] tissue categorized in steps of 10% intervals) as assessed by clinical evaluation (investigator)","definition_or_measurement_approach":"Investigator estimates wound tissue composition (%) in 10% increments for granulating, epithelializing, necrotic, sloughy tissue; mean changes per escalation step reported."}
• {"endpoint_text":"- Further assessments: Per dose/time escalation step at the respective assessment time points: - Mean delta finger to palm (dFTP) [cm] reflecting hand function (finger motion) measured on the hand with the cardinal DU","definition_or_measurement_approach":"Mean change in distance finger-to-palm (dFTP in cm) measured to reflect hand function on the side with the cardinal DU; reported per escalation step."}

Methods

• Advertisement — powerMedia CRO Services GmbH (info@pmcro.com) listed with duty 'Advertisement' in sponsor third parties.
• Site-based recruitment at participating hospital sites in France (Centre Hospitalier Universitaire Grenoble Alpes; Centre Hospitalier Universitaire De Bordeaux; Centre Hospitalier Universitaire De Lille; Assistance Publique Hopitaux De Paris) — sites listed in Part II for France.
• Recruitment materials and procedures documented (documents: K2_Recruitment Material_Sites_2024-511861-12; K1_Recruitment procedure_FR_2024-511861-12; K2_Recruitment Material_doctor letter_2024-511861-12) — site and doctor-letter based channels indicated.

France

Earliest CTIS Part Ii Submission Date

11-11-2024

Latest Decision Or Authorization Date

20-01-2026

Processing Time Days

435

Number Of Sites

4

Number Of Participants

8

Primary sponsor

Full Name

Topadur Pharma Deutschland GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

powerMedia CRO Services GmbH

Responsibilities

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Third parties

• {"country":"Germany","full_name":"Eurofins bioskin GmbH","duties_or_roles":"Sponsor duties codes: 10,11,12,13,5,6 (as listed under sponsorDuties)","organisation_type":"Pharmaceutical company"}
• {"country":"Sweden","full_name":"Viedoc Technologies AB","duties_or_roles":"Sponsor duty code: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"France","full_name":"Centre Hospitalier Universitaire Grenoble Alpes","duties_or_roles":"Sponsor duties: 13; 15 (value: LSCI central reading)","organisation_type":"Health care"}
• {"country":"France","full_name":"Eurofins Optimed","duties_or_roles":"Sponsor duties: 1; 12","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"imito AG","duties_or_roles":"Sponsor duty: 15 (value: Imaging)","organisation_type":"Industry"}
• {"country":"Germany","full_name":"Pharmacelsus GmbH","duties_or_roles":"Sponsor duty: 15 (value: Pharmacokinetic analyses)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"powerMedia CRO Services GmbH","duties_or_roles":"Sponsor duty: 15 (value: Advertisement)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"spm²-safety projects & more GmbH","duties_or_roles":"Sponsor duty: 15 (value: Pharmacovigilance)","organisation_type":"Pharmaceutical company"}

Co-sponsors

• Topadur Pharma AG