Metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration: a phase IIb triple-blind placebo-controlled randomized clinical trial (MACSiMiSE-BRAIN)

2023-503190-38-00 Protocol MACSiMiSE-BRAIN_v1.0 Therapeutic exploratory (Phase II) Ongoing, recruitment ended

Start 23 Nov 2023 · Status Ongoing, recruitment ended · 1 EU/EEA countries · 5 sites · Protocol MACSiMiSE-BRAIN_v1.0

Overview

Sponsor-declared trial summary

Phase Therapeutic exploratory (Phase II)
Status Ongoing, recruitment ended
Participants planned 120
Countries 1
Sites 5

Progressive Multiple Sclerosis

The primary objective is to determine if treatment with metformin is able to delay disease progression in comparison to placebo in patients with non-active progressive multiple sclerosis. It is hypothesized that metformin, as add-on treatment, in patients with PMS is superior to placebo in slowing disease progression. …

Key facts

Sponsor
Antwerp University Hospital
Participant type
Patients
Age range
18-64 years, 65+ years
Gender
Male and Female
Therapeutic area
Diseases [C] - Nervous System Diseases [C10]
Trial duration
23 Nov 2023 → ongoing
Decision date (initial)
2023-04-24
Transition trial
No
Low-intervention
No
Rare-disease indication
No
Vulnerable population
No
Funding sources
FWO - Research Foundation Flanders · National MS Society USA · UZA Foundation · Belgian Charcot Foundation · Start2Cure Foundation

External identifiers

EU CT number
2023-503190-38-00
ClinicalTrials.gov
NCT05893225

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

The primary objective is to determine if treatment with metformin is able to delay disease progression in comparison to placebo in patients with non-active progressive multiple sclerosis. It is hypothesized that metformin, as add-on treatment, in patients with PMS is superior to placebo in slowing disease progression. This will be measured by the primary outcome that is change in walking speed as measured by the T25FW between baseline and 96 weeks of treatment, between the control (placebo) and intervention (metformin) group.

Secondary objectives 7

  1. To demonstrate that treatment with metformin, in comparison to placebo, will delay disease progression in several domains, including general disability, walking function, handfunction and cognitive function. This will be measured by the following clinically relevant outcome measures: (i) Expanded Disability Status Score (EDSS), (ii) 2-minute walking test, (iii) 9-Hole Peg Test (9HPT) and (iv) Symbol Digit Modalities Test (SDMT).
  2. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score, will be compared between metformine and placebo treated groups.
  3. To demonstrate slowing down of neurodegeneration, and/or improvement of remyelination by surrogate outcome measures. Brain MRI volumetrics (change in whole brain volume and gray matter volume, change in T2 lesion volume and change in T1 lesion volume) and brain MRI Diffusion Tensor Imaging analysis.
  4. To compare quality of life between groups.
  5. To compare paramagnetic (iron) rim lesions with SWI-MRI.
  6. To investigate caregiver strain.
  7. To perform a cost-effectiveness (health-economic) analysis.

Conditions and MedDRA coding

Progressive Multiple Sclerosis

VersionLevelCodeTermSystem organ class
21.1 PT 10053395 Progressive multiple sclerosis 100000004852
20.1 PT 10028245 Multiple sclerosis 100000004852
21.1 PT 10063400 Secondary progressive multiple sclerosis 100000004852
21.0 LLT 10013202 Disorder central nervous system 10029205
20.0 LLT 10007943 Central nervous system disorder 10029205
21.1 PT 10063401 Primary progressive multiple sclerosis 100000004852

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

  1. A diagnosis of non-active progressive multiple sclerosis (including PPMS and SPMS, in accordance with 2017 revisions of McDonald criteria and disease course definitions of Lublin 2013), as evidenced by: a. the absence of relapses and new T2 lesions and/or enhancing T1 lesions on brain MRI in the past 1-2 years or longer (NEDA-2) b. progression of disability independent of relapses in the past 1-2 years or longer If progression is defined as one of the following, over the past 1-2 years or less, the patient can be included without additional review: • minimum increase in the EDSS of 1.0, or 0.5 from a baseline level of 2.0–5.0, and 5.5-6.0, respectively • ≥20% in the T25W • ≥20% 9HPT (on average of both hands and/or the dominant hand and/or the non-dominant hand) • reduction of ≥4 points or a 10% worsening in the Symbol Digit Modality Test without concomitant depression or fatigue If the investigator is in the opinion that the patient is clearly progressing, but not enough data are available to demonstrate this, a narrative needs to be provided, which will be judged by at least 2 members of the TSC, from a center that is not submitting the case for review.
  2. Age 18-70 years inclusive
  3. EDSS 2.0-6.5 inclusive
  4. Able to give informed consent (signed, written) and to adhere to study procedures
  5. Dutch/Flemish and French speaking (patient reported outcomes and questionnaires available in Dutch/Flemish and French)
  6. Stable use of DMT or no treatment in the past year or longer
  7. Use of adequate contraceptive measures in females of reproductive age

Exclusion criteria 10

  1. A medical or neurological problem other than MS that is a cause of progressive or fluctuating gait dysfunction
  2. Diagnosis of diabetes mellitus or fasting glucose level of 126mg/dl or more; random glucose level of 200mg/dl or more; HbA1C of 6.5% or more at screening
  3. Unable to complete T25FW
  4. Unable to undergo MRI
  5. Current major disease or disorder other than MS (e.g., active malignancy, significant renal insufficiency eGFR <60 mL/min/1.73 m2, end-stage cardiopulmonary disease, alcoholism, liver insufficiency with AST >3 times ULN, chronic active infection etc.) that may interfere with study procedures and/or intake of study drug.
  6. Pregnant or breast-feeding or planning pregnancy
  7. Use of an experimental therapy in the past 6 months
  8. Ongoing immune reconstitution therapy schedule (cladribine second course ended at least 12 months before inclusion, alemtuzumab second/last course at least 12 months before inclusion, AHSCT at least 12 months before inclusion)
  9. Expected change in ongoing DMT or start of DMT if untreated
  10. Current use of metformin or known intolerance for metformin

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

  1. Change in walking speed, measured by T25FW, between baseline and 96 weeks of treatment.

Secondary endpoints 12

  1. Change in Expanded Disability Status Scale (EDSS) between baseline and after 96 weeks of treatment.
  2. Change in cognitive function as measured by Symbol Digit Modalities Test (SDMT) between baseline and 96 weeks of treatment.
  3. Change in hand function as measured by Nine-Hole Peg Test (9HPT) between baseline and 96 weeks of treatment.
  4. Change in the Compisite endpoint as measured by Overall Disability Response Score (ODRS) between baseline and 96 weeks of treatment.
  5. Change in 2 minute walk test between baseline and 96 weeks of treatment.
  6. Change in brain volume (whole brain volume and gray matter volume) as measured by MRI from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks.
  7. Change in brain MRI-DTI metrics (fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD)) from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks
  8. Change in quality of life as measured by EQ-5D-5L between baseline and 96 weeks of treatment.
  9. Change in quality of life as measured by Multiple Sclerosis Impact Scale-29 between baseline and 96 weeks of treatment.
  10. Change in number of SWI lesions from baseline to 48 weeks, from baseline to 96 weeks and from 48 to 96 weeks.
  11. Change in Modified Caregiver strain index (MCSI) from baseline to 96 weeks.
  12. Average total costs between baseline and 96 weeks of treatment and incremental cost-effectiveness ratio

Investigational products

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

Test 2

Metformin STADA® 850 mg Filmtabletten

PRD395262 · Product

Active substance
Metformin Hydrochloride
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL
Max daily dose
2550 mg milligram(s)
Max total dose
1713600 mg milligram(s)
Max treatment duration
96 Week(s)
Authorisation status
Authorised
ATC code
A10BA02 — METFORMIN
Marketing authorisation
36127.00.00
MA holder
STADAPHARM GMBH
MA country
Germany
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Metformin AL 850 mg Filmtabletten

PRD10974801 · Product

Active substance
Metformin Hydrochloride
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL
Max daily dose
2250 mg milligram(s)
Max total dose
1713600 mg milligram(s)
Max treatment duration
96 Week(s)
Authorisation status
Authorised
ATC code
A10BA02 — METFORMIN
Marketing authorisation
7005057.00.00
MA holder
ALIUD PHARMA GMBH
MA country
Germany
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Placebo 2

The placebo will be manufactured based on the Metformin Hydrochloride 850 mg (Metformin STADA® 850 mg) specifications to match the characteristics (appearance, size) of the IMP, without containing the active ingredient (see IMPD).

N/A · Product

Other product name
N/A
Pharmaceutical form
N/A
ATC code
N/A — N/A
Marketing authorisation
N/A
MA holder
N/A
MA country
Iceland
Paediatric formulation
No

The placebo will be manufactured based on the metformin hydrochloride 850 mg (metformin ALIUD® 850 mg) specifications to match the characteristics (appearance, size) of the imp, without containing the active ingredient (see impd).

N/A · Product

Other product name
N/A
Pharmaceutical form
N/A
ATC code
N/A — N/A
Marketing authorisation
N/A
MA holder
N/A
MA country
Iceland
Paediatric formulation
No

Auxiliary 18

AUBAGIO 14 mg film-coated tablets

PRD2675141 · Product

Active substance
Teriflunomide
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL
Max daily dose
14 mg milligram(s)
Max total dose
9800 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA31 — -
Marketing authorisation
EU/1/13/838/002
MA holder
SANOFI WINTHROP INDUSTRIE
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Gilenya 0.5 mg hard capsules

PRD4009317 · Product

Active substance
Fingolimod
Pharmaceutical form
CAPSULE, HARD
Route of administration
ORAL
Max daily dose
0.5 mg milligram(s)
Max total dose
350 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA27 — -
Marketing authorisation
EU/1/11/677/001
MA holder
NOVARTIS EUROPHARM LIMITED
MA country
Iceland
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

AVONEX 30 micrograms/0.5 ml solution for injection.

PRD335412 · Product

Active substance
Interferon BETA-1A
Substance synonyms
SNG001
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
INTRAMUSCULAR INJECTION
Max daily dose
30 Other
Max total dose
3 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AB07 — INTERFERON BETA-1A
Marketing authorisation
EU/1/97/033/004
MA holder
BIOGEN NETHERLANDS B.V.
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Glatiramyl 20 mg/ml oplossing voor injectie in een voorgevulde spuit

PRD4144118 · Product

Active substance
Glatiramer Acetate
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
20 mg milligram(s)
Max total dose
14000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AX13 — GLATIRAMER ACETATE
Marketing authorisation
BE497386
MA holder
MYLAN BV/SRL
MA country
Belgium
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Zeposia 0.92 mg hard capsules

PRD9257552 · Product

Active substance
Ozanimod
Pharmaceutical form
CAPSULE, HARD
Route of administration
ORAL
Max daily dose
0.92 mg milligram(s)
Max total dose
644 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA — SELECTIVE IMMUNOSUPPRESSIVE AGENTS
Marketing authorisation
EU/1/20/1442/002
MA holder
BRISTOL-MYERS SQUIBB PHARMA EEIG
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Mayzent 1 mg film-coated tablets

PRD9497446 · Product

Active substance
Siponimod
Substance synonyms
BAF312
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL
Max daily dose
1 mg milligram(s)
Max total dose
100 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA42 — -
Marketing authorisation
EU/1/19/1414/007
MA holder
NOVARTIS EUROPHARM LIMITED
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Plegridy 125 micrograms solution for injection in pre-filled syringe

PRD8643925 · Product

Active substance
Peginterferon BETA-1A
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
125 Other
Max total dose
6250 Other
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AB13 — -
Marketing authorisation
EU/1/14/934/008
MA holder
BIOGEN NETHERLANDS B.V.
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Kesimpta 20 mg solution for injection in pre-filled syringe

PRD8833233 · Product

Active substance
Ofatumumab
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
20 mg milligram(s)
Max total dose
500 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA52 — -
Marketing authorisation
EU/1/21/1532/001
MA holder
NOVARTIS IRELAND LIMITED
MA country
Norway
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Copaxone 40 mg/ml oplossing voor injectie in een voorgevulde spuit.

PRD4153212 · Product

Active substance
Glatiramer Acetate
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
40 mg milligram(s)
Max total dose
12000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AX13 — GLATIRAMER ACETATE
Marketing authorisation
BE467902
MA holder
TEVA GMBH
MA country
Belgium
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Ocrevus 300 mg concentrate for solution for infusion

PRD5771848 · Product

Active substance
Ocrelizumab
Pharmaceutical form
SOLUTION FOR INFUSION
Route of administration
INTRAVENOUS INFUSION
Max daily dose
600 mg milligram(s)
Max total dose
3000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA36 — -
Marketing authorisation
EU/1/17/1231/001
MA holder
ROCHE REGISTRATION GMBH
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

TYSABRI 300 mg concentrate for solution for infusion

PRD373745 · Product

Active substance
Natalizumab
Pharmaceutical form
SOLUTION FOR INFUSION
Route of administration
SUBCUTANEOUS AND INTRAVENOUS USE
Max daily dose
300 mg milligram(s)
Max total dose
7500 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA23 — -
Marketing authorisation
EU/1/06/346/001
MA holder
BIOGEN NETHERLANDS B.V.
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Rebif 22 micrograms solution for injection in pre-filled syringe

PRD5803680 · Product

Active substance
Interferon BETA-1A
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
44 Other
Max total dose
13.2 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AB07 — INTERFERON BETA-1A
Marketing authorisation
EU/1/98/063/020
MA holder
MERCK EUROPE B.V.
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Copaxone 20 mg/ml oplossing voor injectie in een voorgevulde spuit.

PRD4152084 · Product

Active substance
Glatiramer Acetate
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
20 mg milligram(s)
Max total dose
14000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AX13 — GLATIRAMER ACETATE
Marketing authorisation
BE260881
MA holder
TEVA GMBH
MA country
Belgium
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Betaferon 250 microgram/ml, powder and solvent for solution for injection

PRD3220039 · Product

Active substance
Recombinant Interferon BETA-1B
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
250 Other
Max total dose
87.5 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AB08 — INTERFERON BETA-1B
Marketing authorisation
EU/1/95/003/012
MA holder
BAYER AG
MA country
Norway
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Glatiramyl 40 mg/ml, oplossing voor injectie in een voorgevulde spuit

PRD5572345 · Product

Active substance
Glatiramer Acetate
Pharmaceutical form
SOLUTION FOR INJECTION
Route of administration
SUBCUTANEOUS INJECTION
Max daily dose
40 mg milligram(s)
Max total dose
12000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L03AX13 — GLATIRAMER ACETATE
Marketing authorisation
BE518524
MA holder
MYLAN BV/SRL
MA country
Belgium
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Ponvory 20 mg film-coated tablets

PRD9581686 · Product

Active substance
Ponesimod
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL
Max daily dose
20 mg milligram(s)
Max total dose
2000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA50 — -
Marketing authorisation
EU/1/21/1550/003
MA holder
JANSSEN-CILAG INTERNATIONAL NV
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Tecfidera 240 mg gastro-resistant hard capsules

PRD1168126 · Product

Active substance
Dimethyl Fumarate
Pharmaceutical form
GASTRO-RESISTANT CAPSULE, HARD
Route of administration
ORAL
Max daily dose
480 mg milligram(s)
Max total dose
336000 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AX07 — -
Marketing authorisation
EU/1/13/837/002
MA holder
BIOGEN NETHERLANDS B.V.
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Mayzent 2 mg film-coated tablets

PRD7835936 · Product

Active substance
Siponimod
Substance synonyms
BAF312
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL
Max daily dose
2 mg milligram(s)
Max total dose
1400 mg milligram(s)
Max treatment duration
100 Week(s)
Authorisation status
Authorised
ATC code
L04AA42 — -
Marketing authorisation
EU/1/19/1414/003
MA holder
NOVARTIS EUROPHARM LIMITED
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Antwerp University Hospital

16 Total trials 4 Recruiting 11 Ended
Academic / Non-commercial
Sponsor organisation
Antwerp University Hospital
Address
Drie Eikenstraat 655
City
Edegem
Postcode
2650
Country
Belgium

Scientific contact point

Organisation
Antwerp University Hospital
Contact name
Barbara Willekens

Public contact point

Organisation
Antwerp University Hospital
Contact name
Lauren Meers

Locations

1 EU/EEA country · 5 investigational sites

By country

CountryMS statusPlanned subjectsSites
Belgium Ongoing, recruitment ended 120 5
Rest of world — 0 —

Investigational sites

Belgium

5 sites · Ongoing, recruitment ended
Universitair Ziekenhuis Gent
Neurology, Corneel Heymanslaan 10, 9000, Gent
Antwerp University Hospital
Neurology, Drie Eikenstraat 655, 2650, Edegem
Nationaal Multiple Sclerose Centrum V.Z.W.
Neurology, Vanheylenstraat 16, 1820, Steenokkerzeel
Az St-Jan Brugge-Oostende A.V.
Neurology, Ruddershove 10, 8000, Brugge
Noorderhart
Neurology, Boemerangstraat 2, 3900, Pelt

Country notifications

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

Country Trial startTrial end Recruitment startRecruitment end Early termination
Belgium 2023-11-23 2023-11-23 2025-04-01

Results and documents

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

Documents 28 files

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

TypeTitleVersion
Protocol (for publication) D2_Protocol modification nr 2.0 EU CT number 2023-503190-38-00 2.0
Protocol (for publication) D2_Protocol modification nr 2.1 EU CT number 2023-503190-38-00 2.1
Protocol (for publication) D2_Protocol modification nr 2.2 EU CT number 2023-503190-38-00 2.2
Protocol (for publication) D2_Protocol modification nr 2.3 EU CT number 2023-503190-38-00 2.3
Recruitment arrangements (for publication) K1_Recruitment arrangements 2
Recruitment arrangements (for publication) K2_Recruitment material Dear doctor letter_FR_CLEAN 2.0
Recruitment arrangements (for publication) K2_Recruitment material Dear doctor letter_NL 2.0
Recruitment arrangements (for publication) K2_Recruitment material description_participant newsletter retention FR 2.0
Recruitment arrangements (for publication) K2_Recruitment material description_participant newsletter retention NL 2.0
Recruitment arrangements (for publication) K2_Recruitment material description_participant newsletter retention NL_clean 2.1
Recruitment arrangements (for publication) K2_Recruitment material Social media_NLenFR_CLEAN 2.0
Subject information and informed consent form (for publication) L1_SIS and ICF_App_FR 1.0
Subject information and informed consent form (for publication) L1_SIS and ICF_APP_NL 1.1
Subject information and informed consent form (for publication) L1_SIS and ICF_biobank_NL 1.1
Subject information and informed consent form (for publication) L1_SIS and ICF_biobanque_FR 1.0
Subject information and informed consent form (for publication) L1_SIS and ICF_EtudePrincipale_V1_FR 1.3
Subject information and informed consent form (for publication) L1_SIS and ICF_NL_hoofdstudie 1.3
Subject information and informed consent form (for publication) L1_SIS and ICF_NL_hoofdstudie_amendment_clean 1.5
Subject information and informed consent form (for publication) L1_SIS and ICF_partenaire_FR 1.0
Subject information and informed consent form (for publication) L1_SIS and ICF_zorgverlener_amendement_clean 1.2
Subject information and informed consent form (for publication) L1_SIS and ICF_zorgverlener_NL 1.1
Summary of Product Characteristics (SmPC) (for publication) E2 SMPC Metformin ALIUD 1
Summary of Product Characteristics (SmPC) (for publication) E2 SMPC Metformin ALIUD English translation 1
Summary of Product Characteristics (SmPC) (for publication) E2_SmPC Metformin STADA 1
Synopsis of the protocol (for publication) D1_Protocol synopsis BE EU CT number 2023-503190-38-00 1.0
Synopsis of the protocol (for publication) D1_Protocol synopsis EN EU CT number 2023-503190-38-00 DEU 1.0
Synopsis of the protocol (for publication) D1_Protocol synopsis EN EU CT number 2023-503190-38-00 FR 1
Synopsis of the protocol (for publication) D1_Protocol synopsis EN EU CT number 2023-503190-38-00 NL 1.0

Application history

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

#TypeCodeSubmittedReference MSConclusionDecision date
1 INITIAL IN 2023-01-14 Belgium Acceptable with conditions
2023-04-24
 2023-04-24
2 SUBSTANTIAL MODIFICATION SM-1 2023-06-02 Belgium Acceptable
2023-07-06
 2023-07-06
3 SUBSTANTIAL MODIFICATION SM-2 2024-06-05 Belgium Acceptable 2024-07-17
4 SUBSTANTIAL MODIFICATION SM-6 2024-06-06 Belgium Acceptable
2024-08-14
 2024-08-14
5 SUBSTANTIAL MODIFICATION SM-7 2024-08-23 Belgium Acceptable 2024-09-27
6 SUBSTANTIAL MODIFICATION SM-8 2024-11-15 Belgium Acceptable
2025-01-08
 2025-01-10
7 SUBSTANTIAL MODIFICATION SM-9 2025-06-13 Belgium Acceptable
2025-08-26
 2025-08-26
8 SUBSTANTIAL MODIFICATION SM-10 2025-10-15 Belgium Acceptable
2025-11-07
 2025-11-07
9 SUBSTANTIAL MODIFICATION SM-11 2025-12-14 Belgium Acceptable 2026-01-30
10 NON SUBSTANTIAL MODIFICATION NSM-2 2026-02-04 Belgium Acceptable 2026-02-04

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