Safety and tolerability of TOP-N53 applied on digital ulcers in patients with systemic sclerosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Topadur Pharma Deutschland GmbH, Topadur Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

4 Feb 2025 → ongoing

Decision date (initial)

2024-12-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511861-12-00

ClinicalTrials.gov

NCT06954597

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

Clinical assessment of local safety and tolerability of the investigational product (IP) TOP N53/Vehicle, administered on wound by the topical route of administration on (active, ischemic) DUs located at fingertips, in SSc, at escalating dose levels (0 µg [Vehicle], 2 µg, 4 µg, 8 µg TOP-N53 in a hydrogel formulation, per wound) over 3 h exposure time (any dose) and 24 h exposure time (8 µg TOP-N53)

Secondary objectives 1

1. Clinical assessment of systemic safety and tolerability (particular attention shall be given to any loss in blood pressure (BP) and increase in pulse rate) following ascending dose, on wound administered TOP-N53 (0 µg [Vehicle], 2 µg, 4 µg, 8 µg)

Conditions and MedDRA coding

Digital ulcers in systemic sclerosis

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Participants who are able to understand and follow instructions during the clinical trial
2. Signed written informed consent in accordance with ICH-GCP and local legislation prior to admission to the clinical trial
3. 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
4. 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
5. 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. 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)
6. 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])
7. 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
8. 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
9. 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)
10. Covered by health insurance system and/or in compliance with the recommendations of national law in force relating to biomedical research

Exclusion criteria 30

1. Any DU accompanied by one of the following complications: Clinical infection of active ulcer/peri-ulcer, osteitis, gangrene (screening [V0] and baseline [V1/V1b])
2. Participants with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment)
3. 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
4. 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
5. 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
6. 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])
7. 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. 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. 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
8. Known or suspected hypersensitivities or known allergic reactions to components of the IPs or other dressings required for SoC during the clinical trial treatment
9. Known allergy to local amide anesthetics
10. Major surgery within 8 weeks prior to the screening visit (V0)
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 x upper limit of normal (ULN) and total Bilirubin >1.5 x ULN
12. 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
13. 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])
14. 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)
15. Positive test for human immunodeficiency virus (HIV) antibodies, unless known from medical history
16. Positive hepatitis B-virus surface antigen (HBsAg) test, unless known from medical history
17. Positive anti-hepatitis C-virus antibodies (anti-HCV) test, unless known from medical history
18. 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)
19. Pregnant women or breast-feeding women
20. 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
21. 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
22. 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)
23. Participant is institutionalized because of legal or regulatory order
24. Participants with modified Rodnan Skin Score (mRSS) >35 (screening [V0])
25. 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
26. Intractable pain from DUs (NRS ≥6) (screening [V0] and baseline [V1/V1b])
27. Active or previous history of calcinosis at the site of the designated cardinal DU
28. 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
29. 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
30. Participant is vulnerable (under legal protection)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Local treatment emergent adverse events (TEAEs): Frequency of local TEAEs from treatment initiation until follow-up (FU) visit
2. 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’])

Secondary endpoints 17

1. 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’])
2. 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’])
3. 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
4. Daily diary DU-PROs: Per dose/time escalation step: - Frequency of systemic TEAEs from treatment initiation until FU visit
5. 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
6. Daily diary DU-PROs: Per cohort at screening (Days -10 to -3) and FU visit (7 + 2 days after last treatment): - 12 lead electrocardiogram (ECG): mean and mean changes in ECG values, frequency of clinically significant abnormal values
7. Daily diary DU-PROs: Per cohort at screening (Days -10 to -3) and FU visit (7 + 2 days after last treatment): - Safety laboratory (clinical chemistry, hematology, urinalysis, serology): mean and mean changes in laboratory values, frequency of clinically significant abnormal values
8. 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)
9. 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)
10. 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)
11. 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)
12. 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)
13. Investigator-solicited DU-related patient reported outcomes (DU-PROs) - Itching: Per dose/time escalation step at the respective assessment time points: - Frequency 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’])
14. 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)
15. 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)
16. 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)
17. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Topadur Pharma Deutschland GmbH

Sponsor organisation

Topadur Pharma Deutschland GmbH

Address

Georges-Koehler-Strasse 2

City

Loerrach

Postcode

79539

Country

Germany

Scientific contact point

Organisation

Topadur Pharma Deutschland GmbH

Contact name

Chief Scientific Officer

Public contact point

Organisation

Topadur Pharma Deutschland GmbH

Contact name

Managing Director

Third parties 8

Topadur Pharma AG

Sponsor organisation

Topadur Pharma AG

Address

Grabenstrasse 11a

City

Schlieren

Postcode

8952

Country

Switzerland

Sponsor responsibilities

Contact point sponsor

Topadur Pharma Deutschland GmbH

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications