Overview
Sponsor-declared trial summary
Phase
Therapeutic use (Phase IV)
Status
Ongoing, recruitment ended
Participants planned
126
Countries
1
Sites
9
EGFRmutated/T790M Mutation negative non-squamous NSCLC
The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.
Key facts
- Sponsor
- Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Respiratory Tract Diseases [C08]
- Trial duration
- 30 Nov 2022 → ongoing
- Decision date (initial)
- 2024-06-21
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- Boehringer Ingelheim Pharmacy GmbH & Co KG
External identifiers
- EU CT number
- 2024-511625-55-00
- EudraCT number
- 2019-002197-31
- ClinicalTrials.gov
- NCT04413201
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Efficacy, Safety
The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive
group compared to osimertinib.
Secondary objectives 7
- Time to EGFR-TKI failure (afatinib versus osimertinib)
- Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT)
- Overall Survival (OS)
- Response Rate (RR)
- Disease Control Rate (DCR)
- Safety and Tolerability
- Symptom control assessed by patient-reported quality of life (QoL)
Conditions and MedDRA coding
EGFRmutated/T790M Mutation negative non-squamous NSCLC
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10079440 | Non-squamous non-small cell lung cancer | 10029104 |
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Period 1 Eligible patients will be randomized to afatinib or osimertinib ratio 2:1 as first treatment.
Treatment will be continued until disease progression so far as there is no clinical benefit
to treatment as judged by the investigator.
After first line afatinib treatment, patients will be stratified according to T790M status at
this time point. T790M mutation positive patients will receive osimertinib as second
therapy; T790M-negative patients will receive ICT.
Patients receiving osimertinib as first line treatment will receive ICT as second therapy.
Second therapies will be continued until disease progression so far as there is no clinical
benefit to treatment as judged by the investigator.
|
Randomised Controlled | None | Afatinib: After first line afatinib treatment, patients will be stratified according to T790M status at this time point. T790M mutation positive patients will receive osimertinib as second therapy; T790M-negative patients will receive ICT. Osimertinib: Patients receiving osimertinib as first line treatment will receive ICT as second therapy. Second therapies will be continued until disease progression so far as there is no clinical benefit to treatment as judged by the investigator. |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 9
- Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative by local testing
- Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease
- TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed
- At least one evaluable lesion according to RECIST v1.1
- Age ≥ 18 years
- ECOG performance status 0 - 2
- Adequate organ function, defined as all of the following: a. Absolute neutrophil count (ANC) ≥ 1500/mm3. (ANC > 1000/mm3 may be considered in special circumstances such as benign cyclical neutropenia as judged by the investigator and in discussion with the coordinating investigator) b. Platelet count ≥ 75,000/mm3 c. Estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73 m2 according to the Cockcroft-Gault formula (Refer to Appendix 1) d. If history of cardiac comorbidity: Left ventricular function with resting ejection fraction ≥ 50% or above the institutional lower limit of normal (LLN) e. Total Bilirubin ≤ 1.5 times upper limit of normal (ULN), (if related to liver metastases ≤ 3 times ULN). (Patients with Gilbert’s syndrome total bilirubin must be ≤ 4 times institutional upper limit of normal) f. Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ 3 times the upper limit of normal (ULN) (if related to liver metastases ≤ 5 times ULN)
- Recovered from any previous therapy related toxicity to ≤ Grade 1 at before randomization (except for stable sensory neuropathy ≤ Grade 2 and alopecia)
- Written informed consent
Exclusion criteria 11
- Any investigational drug within 30 days or hormonal anticancer treatment within 2 weeks prior to randomization (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted)
- T790M mutation positive tumors (by local testing)
- Radiotherapy within 2 weeks prior to randomization, except as follows: a. Palliative radiation to target organs other than chest may be allowed up to 1 week prior to randomization b. Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with coordinating investigator prior to enrolling
- Major surgery within 2 weeks before starting study treatment or scheduled for surgery during the projected course of the study
- Known hypersensitivity to afatinib or osimertinib or the excipients of any of the trial drugs
- History or presence of clinically relevant cardiovascular abnormalities such as a. uncontrolled hypertension b. congestive heart failure NYHA classification of ≥ 3 c. unstable angina or poorly controlled arrhythmia as determined by the investigator d. Myocardial infarction within 6 months prior to randomization e. Clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 ms) or QTc interval prolongation with signs/symptoms of serious arrhythmia f. Congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or intake of medicinal products that are known to prolong the QTc interval
- Patients with a past or present medical history of a. Interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD b. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug c. Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) d. Known active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier e. Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured
- Pregnancy and contraception: a. Women who are pregnant, nursing, or who plan to become pregnant while in the trial b. Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at informed consent, for the duration of study participation and for at least 2 months for females and 4 months for males after last dose
- Requiring treatment with any of the prohibited concomitant medications (P-Glycoprotein Inhibitors/Inductors CYP3A4/5 Inhibitors/Inductors as listed in Section 4.1.9.2 and Appendix 3) that cannot be stopped for the duration of trial participation or concomitant St. John’s Wort
- Uncontrolled brain metastases (Patients with brain or subdural metastases are not eligible, unless they have completed local therapy (≤ 2 weeks apart from last radiotherapy or radiosurgery) and have discontinued the use of corticosteroids, anticonvulsants or have been on stable dose of corticosteroids (i.e. Dexamethasone ≤ 8 mg) for at least 4 weeks before starting study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment) or Leptomeningeal carcinomatosis
- Other contraindications to study treatment (Investigators opinion) or legal incapacity or limited legal capacity
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Time to EGFR-TKI failure within 24 months for afatinib followed by osimertinib in T790Mpositive group vs osimertinib
Secondary endpoints 7
- Time to EGFR-TKI failure (afatinib versus osimertinib)
- Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT)
- Overall Survival (OS)
- Response Rate (RR) at 12 months and 24 months
- Disease Control Rate (DCR) at 12 months and 24 months
- Safety and Tolerability
- Symptom control assessed by patient-reported quality of life (QoL) with EQ-5D, EORTC QLQ-C30, EORTC QLQ-LC29
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 13
GIOTRIF 40 mg film-coated tablets
PRD1777305 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 40 mg milligram(s)
- Max total dose
- 58400 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/008
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 30 mg film-coated tablets
PRD1776818 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 30 mg milligram(s)
- Max total dose
- 43800 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/005
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 30 mg film-coated tablets
PRD1776825 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 30 mg milligram(s)
- Max total dose
- 43800 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/004
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Liechtenstein
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 20 mg film-coated tablets
PRD1776954 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 20 mg milligram(s)
- Max total dose
- 29200 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/002
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 20 mg film-coated tablets
PRD1776955 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 20 mg milligram(s)
- Max total dose
- 29200 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/001
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 40 mg film-coated tablets
PRD1777306 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 40 mg milligram(s)
- Max total dose
- 58400 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/009
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 30 mg film-coated tablets
PRD1776819 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 30 mg milligram(s)
- Max total dose
- 43800 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/006
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 40 mg film-coated tablets
PRD1777304 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 40 mg milligram(s)
- Max total dose
- 58400 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/007
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GIOTRIF 20 mg film-coated tablets
PRD1776953 · Product
- Active substance
- Afatinib
- Substance synonyms
- BIBW-2992, BIBW 2992
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 20 mg milligram(s)
- Max total dose
- 29200 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB03 — -
- Marketing authorisation
- EU/1/13/879/003
- MA holder
- BOEHRINGER INGELHEIM INTERNATIONAL GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
TAGRISSO 80 mg film-coated tablets
PRD4954972 · Product
- Active substance
- Osimertinib
- Substance synonyms
- AZD9291
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 80 mg milligram(s)
- Max total dose
- 116800 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01XE35 — -
- Marketing authorisation
- EU/1/16/1086/004
- MA holder
- ASTRAZENECA AB
- MA country
- Liechtenstein
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
TAGRISSO 40 mg film-coated tablets
PRD3702399 · Product
- Active substance
- Osimertinib
- Substance synonyms
- AZD9291
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 40 mg milligram(s)
- Max total dose
- 58400 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB04 — -
- Marketing authorisation
- EU/1/16/1086/001
- MA holder
- ASTRAZENECA AB
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
TAGRISSO 40 mg film-coated tablets
PRD4954971 · Product
- Active substance
- Osimertinib
- Substance synonyms
- AZD9291
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 40 mg milligram(s)
- Max total dose
- 58400 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01EB04 — -
- Marketing authorisation
- EU/1/16/1086/003
- MA holder
- ASTRAZENECA AB
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
TAGRISSO 80 mg film-coated tablets
PRD3702398 · Product
- Active substance
- Osimertinib
- Substance synonyms
- AZD9291
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 80 mg milligram(s)
- Max total dose
- 118800 mg milligram(s)
- Max treatment duration
- 48 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01XE35 — -
- Marketing authorisation
- EU/1/16/1086/002
- MA holder
- ASTRAZENECA AB
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
- Sponsor organisation
- Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
- Address
- Langenbeckstrasse 1, Oberstadt Oberstadt
- City
- Mainz
- Postcode
- 55131
- Country
- Germany
Scientific contact point
- Organisation
- Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
- Contact name
- Sponsor contact point clinical trials
Public contact point
- Organisation
- Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
- Contact name
- Sponsor contact point clinical trials
Third parties 1
| Organisation | City, country | Duties |
|---|---|---|
| Institut für Immunologie und Genetik ORL-000007001
|
Germany | Laboratory analysis |
Locations
1 EU/EEA country · 9 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Germany | Ongoing, recruitment ended | 126 | 9 |
| Rest of world | — | 0 | — |
Investigational sites
Universitaetsklinikum Regensburg AöR
Pneumologie, Klinik und Poliklinik für Innere Medizin II, Franz-Josef-Strauss-Allee 11, Grass-Oberisling, Regensburg
Universitaetsklinikum Giessen und Marburg GmbH
Organonkologie, Rudolf-Buchheim-Strasse 8, 35392, Giessen
Evangelische Lungenklinik Berlin Krankenhausbetriebs gGmbH
Pneumologie, Lindenberger Weg 27, Buch, Berlin
Evangelisches Krankenhaus Hamm gGmbH
Innere Medizin II, Werler Strasse 110, Mitte, Hamm
Sana Klinikum Offenbach GmbH
KLINIK FÜR HÄMATOLOGIE UND INTERNISTISCHE ONKOLOGIE, Starkenburgring 66, 63069, Offenbach Am Main
Klinikum der Universitaet Muenchen AöR
Medizinische Klinik V, Ziemssenstrasse 1, Ludwigsvorstadt-Isarvorstadt, Munich
Klinikverbund Allgaeu gGmbH
Klinik für Pneumologie, Im Stillen 2, 87509, Immenstadt I. Allgäu
Klinikum Bremen-Ost
KlinikumKlinik für Pneumologie und Beatmungsmedizin, Züricher Str. 40, 28325, Bremen
Klinikum Konstanz GmbH
Innere Medizin, Hämatologie und Onkologie, Mainaustrasse 35, Petershausen, Konstanz
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 |
|---|---|---|---|---|---|
| Germany | 2020-06-10 | 2020-09-08 | 2022-11-30 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Temporary halts 1 · Art. 38 CTR
Temporary halt TH-34510
- Halt date
- 2022-11-30
- Member states concerned
- Germany
- Publication date
- 2024-07-11
- Reason
- Feasibility (recruitment issues etc.)
- Benefit-risk balance changed
- No
- Treatment stopped
- No
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 17 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol_2024-511625-55-00_redacted | 1.5 |
| Recruitment arrangements (for publication) | K1_Recruitment Arrangements | 1 |
| Recruitment arrangements (for publication) | K2_Recruitment Arrangements_text | 1.1 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adult_DE | 3.2 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adult_DE_Datenschutzhinweise | 1.1 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adult_DE_kurz | 3.3 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adult_DE_kurz_2025 | 4.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adult_DE_kurz_2026 | 4.1 |
| Subject information and informed consent form (for publication) | L2_Patient facing documents_Patient Diary | 1 |
| Subject information and informed consent form (for publication) | L2_Patient facing documents_Patient ID card | 1.1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC Tagrisso_80mg_40mg | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC_GIOTRIF_20mg_30mg_4mg | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | FI Tagrisso 2023-07 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | FI Tagrisso 2023-09 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | FI Tagrisso 2024-02 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | FI Tagrisso 2024-06 | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis DE_2024-511625-55-00 | 1.3 |
Application history
5 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-05-31 | Germany | Acceptable 2024-06-12
|
2024-06-21 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2024-11-20 | Germany | Acceptable 2024-12-11
|
2024-12-12 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2025-03-28 | Germany | Acceptable 2025-04-30
|
2025-05-08 |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2025-12-10 | Germany | Acceptable | 2025-12-12 |
| 5 | SUBSTANTIAL MODIFICATION | SM-4 | 2026-02-24 | Germany | Acceptable 2026-03-16
|
2026-04-02 |