Overview
Sponsor-declared trial summary
Phase
Therapeutic use (Phase IV)
Status
Authorised, recruiting
Participants planned
88
Countries
3
Sites
8
Diffuse cutaneous systemic sclerosis according to the ACR/EULAR criteria
To determine the optimal treatment strategy in early dcSSc: the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc, with respect to survival and prevention of major organ failure (reflected in the Global Rank Composite Score, the primary endpoint).
Key facts
- Sponsor
- University Medical Center Utrecht, University Medical Center Utrecht
- Participant type
- Patients
- Age range
- 18-64 years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Immune System Diseases [C20]
- Trial duration
- 18 Aug 2020 → ongoing
- Decision date (initial)
- 2023-09-01
- Transition trial
- Yes
- Low-intervention
- Yes
- Rare-disease indication
- Yes
- Vulnerable population
- Yes
- Funding sources
- Boehringer Ingelheim, the Netherlands · ZonMW, the Netherlands · Van Leerzemfonds, the Netherlands
External identifiers
- EU CT number
- 2023-505877-34-00
- EudraCT number
- 2019-004718-32
- ClinicalTrials.gov
- NCT04464434
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy
To determine the optimal treatment strategy in early dcSSc: the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc, with respect to survival and prevention of major organ failure (reflected in the Global Rank Composite Score, the primary endpoint).
Secondary objectives 4
- To evaluate (in both treatment arms) whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies. We will also determine the cost-effectiveness of HSCT as first line treatment versus usual care and try to identify factors associated with response to treatment.
- Safety
- Impact on skin thickening, visceral involvement, functional status, sexual functioning and quality of life
- cost-effectiveness
Conditions and MedDRA coding
Diffuse cutaneous systemic sclerosis according to the ACR/EULAR criteria
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | SOC | 10021428 | Immune system disorders | 4 |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 3
- Age between 18 and 65 years.
- Fulfilling the 2013 ACR-EULAR classification criteria
- Disease duration ≤ 3 years (from onset of first non-Raynaud's symptoms) and -mRSS ≥ 15 (diffuse skin pattern) and/ or - clinically significant organ involvement as defined by either: a) respiratory involvement b) renal involvement c) cardiac involvement, OR Disease duration ≤ 1 year and diffuse cutaneous disease with mRSS>10 and high risk ANA for organ based disease and/or acute phase response
Exclusion criteria 7
- Pregnancy or unwillingness to use adequate contraception during study
- concomitant severe disease (respiratory, renal, cardiac, liver failure, psychiatric disorders, concurrent neoplasms or myelodysplasia, bone marrow insufficiency, uncontrolled hypertension, uncontrolled acute or chronic infection, ZUBROD-ECOG-WHO PSS > 2, known hypersensitivity to any of the study drug constituents)
- Previous treatments with immunosuppressants > 12 months including MMF, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
- Previous treatments with TLI, TBI or alkylating agents including CYC.
- Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica
- eosinophilic myalgia syndrome; eosinophilic fasciitis
- Poor compliance of the patient as assessed by the referring physicians
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Global Rank Composite Score (GRCS); an analytic tool that accounts for multiple disease manifestations simultaneously
Secondary endpoints 6
- Progression-free survival, defined as the time in days since the day of randomisation until any of the relative changes from baseline as defined in the protocol has been documented.
- Treatment related mortality is defined as any death during the study period following randomisation that cannot be attributed to progression of the disease according to the consensus opinion of the DSMB
- Treatment toxicity will be assessed using WHO CTCAE v5.0 toxicity parameters (adverse events =/> grade 3) and infections according to the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) grading (Appendix A), in consecutive 3-month periods following randomisation until five years follow-up.
- The area under the curve (AUC) of the CRISS over time, measuring the ‘predicted probability of being improved’ over 2 and 5 years. This AUC is calculated based on 4 repeated measures (6, 12, 18 and 24 months) with back translation to the original scale between 0 and 1.
- Change over years follow-up of the clinical parameters as defined in the protocol
- Event-free survival at two years follow-up. Event-free survival is defined as the time in days from the day of randomisation until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney).
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 2
SCP771503 · ATC
- Active substance
- Mycophenolate Mofetil
- Route of administration
- ORAL
- Max daily dose
- 3 g gram(s)
- Max total dose
- 2190 g gram(s)
- Max treatment duration
- 24 Month(s)
- Authorisation status
- Authorised
- ATC code
- L04AA06 — MYCOPHENOLIC ACID
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP1728208 · ATC
- Active substance
- Anhydrous Cyclophosphamide
- Route of administration
- INJECTION
- Max daily dose
- 750 mg/m2 milligram(s)/sq. meter
- Max total dose
- 9000 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 12 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01AA01 — CYCLOPHOSPHAMIDE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Auxiliary 2
SCP813954 · ATC
- Active substance
- Filgrastim
- Substance synonyms
- NT100H, FILGRASTIM (GENETICAL RECOMBINATION)
- Route of administration
- SUBCUTANEOUS USE
- Max daily dose
- 0.02 mg/kg milligram(s)/kilogram
- Max total dose
- 0.07 mg/kg milligram(s)/kilogram
- Max treatment duration
- 5 Day(s)
- Authorisation status
- Authorised
- ATC code
- L03AA02 — FILGRASTIM
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Anti-T Lymphocyte Immunoglobulin for Human Use, Rabbit
SCP5487322 · ATC
- Active substance
- Anti-T Lymphocyte Immunoglobulin for Human Use, Rabbit
- Substance synonyms
- RABBIT HUMAN T LYMPHOCYTE IMMUNOGLOBULIN, ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
- Route of administration
- INTRAVENIOUS INFUSION
- Max daily dose
- 2.5 mg/kg milligram(s)/kilogram
- Max total dose
- 7.5 mg/kg milligram(s)/kilogram
- Max treatment duration
- 3 Day(s)
- Authorisation status
- Authorised
- ATC code
- L04AA04 — ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT)
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
University Medical Center Utrecht
- Sponsor organisation
- University Medical Center Utrecht
- Address
- Heidelberglaan 100
- City
- Utrecht
- Postcode
- 3584 CX
- Country
- Netherlands
Scientific contact point
- Organisation
- University Medical Center Utrecht
- Contact name
- dr. J. Spierings
Public contact point
- Organisation
- University Medical Center Utrecht
- Contact name
- dr. J. Spierings
University Medical Center Utrecht
- Sponsor organisation
- University Medical Center Utrecht
- Address
- Heidelberglaan 100
- City
- Utrecht
- Postcode
- 3584 CX
- Country
- Netherlands
Locations
3 EU/EEA countries · 8 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Italy | Ongoing, recruiting | 8 | 2 |
| Netherlands | Ongoing, recruiting | 60 | 4 |
| Sweden | Authorised, recruiting | 10 | 2 |
| Rest of world
United Kingdom
|
— | 10 | — |
Investigational sites
Ospedale San Raffaele S.r.l.
Hematology, Via Olgettina 60, 20132, Milan
Fondazione Policlinico Universitario Campus Bio-medico In Forma A Bbreviata Fon
Immunoreumatologia, Via Alvaro Del Portillo N 200, 00128, Rome
University Medical Center Utrecht
Rheumatology& Clinical Immunology, Heidelberglaan 100, 3584 CX, Utrecht
Stichting Radboud University Medical Center
Rheumatology, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen
Amsterdam UMC
Rheumatology, De Boelelaan 1117, 1081 HV, Amsterdam
Academisch Ziekenhuis Leiden
Rheumatology, Albinusdreef 2, 2333 ZA, Leiden
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Italy | 2022-07-18 | 2024-07-16 | |||
| Netherlands | 2020-08-18 | 2020-10-30 | |||
| Sweden | 2022-09-30 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 1 · Art. 52 CTR
Serious breach SB-70597
- Sponsor became aware
- 2025-02-06
- Date of breach
- 2024-12-26
- Submission date
- 2025-02-14
- Member states concerned
- Italy, Sweden, Netherlands
- Categories
- Protocol
- Areas impacted
- Data reliability or robustness
- Benefit-risk balance changed
- No
- Description
- Use of 2x2g/m2 mobilisation dose of Cyclophosphamide in 5 patients, according to their local regular practice.
The study protocol prescribes 1x2g/m2 CYC. - Sponsor actions
- The study protocol was checked and the SIV presentation/slides were checked on correctness of the dose of cyclophosphamide during the protocol training, this was correct. The other 5 study sites were informed and asked what dose they have been using in the trial patients. All other study sites confirmed to have followed the study protocol and administered the correct dose according to the study protocol. The breach has been discussed within the study team at the Radboudumc and the involved hematologist and will be discussed by the sponsor with the team to determine what is needed to prevent reoccurrence. Suggestions will be a new training of the protocol with all members of the hematology team from Radboudumc and adjustment of the standard operation procedures used for the stem cell transplantation procedure.
| Organisation | City | Country | Type |
|---|---|---|---|
| Stichting Radboud University Medical Center | Nijmegen | Netherlands | Clinical investigator |
Application history
3 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2023-06-23 | Netherlands | Acceptable 2023-07-26
|
2023-07-26 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2023-10-02 | Netherlands | Acceptable 2024-01-22
|
2024-01-23 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2024-04-18 | Acceptable | 2024-07-23 |