An open-label extension multi-centre trial in adult subjects diagnosed with Type 1 diabetes mellitus exploring the effect of long-term Verapamil SR therapy on the preservation of beta-cell function.

Start 21 Nov 2024 · Status Ongoing, recruitment ended · 5 EU/EEA countries · 6 sites · Protocol Ver-A-Long

Overview

Sponsor-declared trial summary

Phase Therapeutic exploratory (Phase II)

Status Ongoing, recruitment ended

Participants planned 40

Countries 5

Sites 6

Type 1 diabetes mellitus (T1D)

To determine the change in Beta-cell function in type 1 diabetes patients measured by C-peptide response to a mixed-meal tolerance test (MMTT) at baseline and after 24 months for 360 mg Verapamil SR administered orally once daily. This will be assessed separately in those with a fasting C-peptide ≥ 50 pmol/L previo…

Key facts

Sponsor: Medical University Of Graz
Participant type: Patients
Age range: 18-64 years
Gender: Male and Female
Therapeutic area: Phenomena and Processes [G] - Metabolism [G03]
Trial duration: 21 Nov 2024 → ongoing
Decision date (initial): 2024-11-18
Transition trial: No
Low-intervention: No
Rare-disease indication: No
Vulnerable population: No
Funding sources: Breakthrough T1D (former Juvenile Diabetes Research Foundation) · Medical University of Graz

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To determine the change in Beta-cell function in type 1 diabetes patients
measured by C-peptide response to a mixed-meal tolerance test (MMTT) at
baseline and after 24 months for 360 mg Verapamil SR administered orally
once daily.
This will be assessed separately in those with a fasting C-peptide ≥ 50 pmol/L
previously treated with a) placebo or b) Verapamil SR for 12 months in the
Ver-A-T1D trial.

Secondary objectives 6

To determine the changes in Beta-cell function in type 1 diabetes patients measured by C-peptide response to a mixed-meal tolerance test (MMTT) at baseline and after 6-, 12 and 18 months for 360 mg Verapamil SR administered orally once daily.
To determine the changes in HbA1c in type 1 diabetes patients measured at baseline and after 6-, 12-, 18- and 24 months for 360 mg Verapamil SR administered orally once daily.
To determine the changes in insulin requirements as the total daily insulin dose (seven days average) in units per kg body weight (BW) in type 1 diabetes patients measured at baseline and after 6-, 12-, 18- months and 24 months for 360 mg Verapamil SR administered orally once daily.
To determine the number of severe hypoglycaemic and ketoacidosis episodes in adults diagnosed with T1D given 360 mg oral Verapamil SR once daily.
To determine safety of short-term (weekly) titration of Verapamil SR (titrated over the first 3 weeks from 120 mg to 360 mg).
To determine safety (vital signs, ECG) over 24 months in adults diagnosed with T1D given 360 mg oral Verapamil SR once daily.

Conditions and MedDRA coding

Type 1 diabetes mellitus (T1D)

Version	Level	Code	Term	System organ class
21.1	PT	10067584	Type 1 diabetes mellitus	100000004861

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

Be either eligible for Visit 6 of Ver-A-T1D trial on active treatment defined as Placebo or Verapamil SR (240 mg or 360 mg) (option 1) OR have completed V5 of the Ver-A-T1D study and plan to continue with Ver-AT1D Visit 6 on active treatment defined as Placebo or Verapamil SR (240mg or 360mg) up to 28 days prior to Ver-A-T1D Visit 6 (option 2)
Have given written informed consent (Ver-A-Long).
Age ≥18 years at consent.
Must have fasting C-peptide levels ≥ 50 pmol/L measured at V-1 (according to option 1) or measured at V-2 (according to option 2).

Exclusion criteria 14

Be currently pregnant, lactating or anticipate getting pregnant during the 24 months study period.
Have any complicating medical issues or history that may interfere with the study conduct, as judged by the investigator.
Have persistent history of malignancies other than skin.
History of liver insufficiency or laboratory evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limits of normal.
History of renal insufficiency or evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal.
Current use of calcium channel blockers (except IMP administrated in the Ver-A-T1D trial).
Known hypersensitivity to Verapamil SR or to any of its excipients.
Concomitant medication known for inducing or inhibiting CYP3A4 and/or glycoprotein-P metabolism.
Intake of grapefruit juice, licorice, St. John’s Wort, cannabidiol, ginkgo biloba.
Substrate intake of CYP3A4 and/or glycoprotein-P metolism, as judged by the investigator
Hypotension (of less than 90 mmHg systolic), sick sinus syndrome (except patients with a functioning artificial pacemaker), uncompensated heart failure or severe left ventricular dysfunction, marked bradycardia (less than 45 beats/minute), atrioventricular block second or third degree, atrial flutter or atrial fibrillation in the presence of an accessory bypass tract (e.g. Wolff-Parkinson-White syndrome), hypertrophic cardiomyopathy, acute myocardial infarction, attenuated neuromuscular transmission (e.g. by myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).
Atrioventricular block first degree (>320ms).
Current use of ß-blockers.
Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

Change over time in C-peptide Area under the curve (C-pep AUC % change) in adults diagnosed with T1D receiving 360 mg oral Verapamil daily undergoing MMTT, measured at baseline (V-1) and 24 months of therapy (V8)

Secondary endpoints 6

Changes over time in C-peptide Area under the curve (C-pep AUC % change) in adults diagnosed with T1D receiving 360 mg oral Verapamil Option 2 Fig. 2a Option 2 Fig. 2b EU CT Number:2024-515234-33-00 Page 15 of 59 Protocol Short Title Ver-A-Long Version Number: 2.0 Version Date: 12.06.2024 daily undergoing MMTT, measured at 6-, 12-, and 18 months of therapy (V5 to V7)
Changes over time in blood glucose control as assessed by HbA1C in adults diagnosed with T1D receiving 360 mg oral Verapamil daily, measured at baseline (V-1) and 6-, 12-, 18- and 24 months of therapy (V5 to V8)
Changes over time in insulin requirements as the total daily insulin dose (seven days average) in units per kg body weight (BW) in adults diagnosed with T1D receiving 360 mg oral Verapamil SR once daily, assessed at baseline (V-1) and 6-, 12- 18- and 24 months of therapy (V5 to V8)
The number of treatment emergent severe hypoglycaemic episodes. Severe hypoglycaemia denotes severe cognitive impairment requiring external assistance for recovery according to the American Diabetes Association (ADA)
The number of treatment emergent episodes of diabetic ketoacidosis (DKA).
Adverse events, vital signs variation, ECG, laboratory safety parameters, measured at baseline (V-1) and 6-, 12- 18- and 24 of therapy (V5 to V8)

Investigational products

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

Test 11

Verapamil 120 ret - 1A-Pharma 120 mg Retardtabletten

PRD811365 · Product

Active substance: Verapamil Hydrochloride
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 33984.01.00
MA holder: 1 A PHARMA GMBH
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Isoptin® retard 120 mg - Filmtabletten

PRD11396684 · Product

Active substance: Verapamil Hydrochloride
Substance synonyms: VERAPAMIL (CHLORHYDRATE DE)
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 1-16150
MA holder: VIATRIS AUSTRIA GMBH
MA country: Austria
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

VERAPAMIL HEXAL 120 mg compresse a rilascio prolungato

PRD755226 · Product

Active substance: Verapamil Hydrochloride
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 031228 024
MA holder: SANDOZ S.P.A.
MA country: Italy
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

VERAPAMIL DOC Generici 120 mg capsule rigide a rilascio prolungato

PRD361124 · Product

Active substance: Verapamil Hydrochloride
Pharmaceutical form: PROLONGED-RELEASE CAPSULE, HARD
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 034255036
MA holder: DOC GENERICI S.R.L.
MA country: Italy
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

VeraHEXAL® KHK 120 mg retard, Retardtabletten

PRD828130 · Product

Active substance: Verapamil Hydrochloride
Substance synonyms: VERAPAMIL (CHLORHYDRATE DE)
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 33952.01.00
MA holder: HEXAL AG
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Half Securon SR

PRD4614361 · Product

Active substance: Verapamil Hydrochloride Ph. Eur.
Pharmaceutical form: MODIFIED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: PL 46302/0025
MA holder: MYLAN PRODUCTS LIMITED
MA country: XI
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Verapamil Hennig 120 mg retard Retardtabletten

PRD847611 · Product

Active substance: Verapamil Hydrochloride
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 33941.00.00
MA holder: HENNIG ARZNEIMITTEL GMBH & CO. KG
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

ISOPTINE L.P. 240 mg, comprimé pelliculé sécable à libération prolongée

PRD4591633 · Product

Active substance: Verapamil Hydrochloride
Substance synonyms: VERAPAMIL (CHLORHYDRATE DE)
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 34009 328 674 1 7
MA holder: VIATRIS MEDICAL
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

LODIXAL 240 mg, Tabletten met verlengde afgifte

PRD4567989 · Product

Active substance: Verapamil Hydrochloride
Substance synonyms: VERAPAMIL (CHLORHYDRATE DE)
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: BE 139736
MA holder: VIATRIS HEALTHCARE
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Vera-Til SR 120mg Tablets

PRD10753891 · Product

Active substance: Verapamil Hydrochloride
Pharmaceutical form: MODIFIED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: PL 11311/0077
MA holder: TILLOMED LABORATORIES LTD
MA country: XI
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Isoptin® KHK retard 120 mg, Retardtabletten

PRD11439541 · Product

Active substance: Verapamil Hydrochloride
Substance synonyms: VERAPAMIL (CHLORHYDRATE DE)
Pharmaceutical form: PROLONGED-RELEASE TABLET
Route of administration: ORAL USE
Max daily dose: 360 mg milligram(s)
Max total dose: 360 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: C08DA01 — VERAPAMIL
Marketing authorisation: 6899934.00.00
MA holder: VIATRIS HEALTHCARE GMBH
MA country: Germany
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Graz

Sponsor organisation: Medical University Of Graz
Address: Neue Stiftingtalstrasse 6
City: Graz
Postcode: 8010
Country: Austria

Scientific contact point

Organisation: Medical University Of Graz
Contact name: Chief Investigator

Public contact point

Organisation: Medical University Of Graz
Contact name: Trial management

Locations

5 EU/EEA countries · 6 investigational sites

By country

Country	MS status	Planned subjects	Sites
Austria	Ongoing, recruitment ended	2	1
Belgium	Ongoing, recruitment ended	2	1
France	Ongoing, recruitment ended	7	1
Germany	Ongoing, recruitment ended	1	1
Italy	Ongoing, recruitment ended	7	2
Rest of world United Kingdom	—	21	—

Investigational sites

Austria

1 site · Ongoing, recruitment ended

Medical University Of Graz

Division of Endocrinology and Metabolism, Department of Internal Medicine, Neue Stiftingtalstrasse 6, 8010, Graz

Belgium

1 site · Ongoing, recruitment ended

UZ Leuven

Department of Endocrinology, Herestraat 49, 3000, Leuven

France

1 site · Ongoing, recruitment ended

Institut National De La Sante Et De La Recherche Medicale

Service de Diabétologie, Hôpital Cochin, 101 Rue De Tolbiac, 75654, Paris Cedex 13

Germany

1 site · Ongoing, recruitment ended

Hannoversche Kinderheilanstalt

Division of Pediatric Diabetology/Endocrinology/Gastroenterology and Clinical Research, Janusz Korczak Avenue 12, Bult, Hanover

Italy

2 sites · Ongoing, recruitment ended

Ospedale San Raffaele S.r.l.

Internal Medicine, Via Olgettina 60, 20132, Milan

Azienda Ospedaliera Universitaria Senese

Departmet of Medicine, Surgery and Neuroscience, Strada Delle Scotte 14, 53100, Siena

Country notifications

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

Country	Trial start	Recruitment start	Recruitment end
Austria	2024-11-21	2024-11-22	2024-11-22
Belgium	2025-01-17	2025-01-22	2025-01-22
France	2024-12-19	2024-12-20	2025-04-11
Germany	2025-02-25	2025-03-18	2025-03-18
Italy	2024-12-20	2024-12-23	2025-04-23

Results and documents

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

Documents 43 files

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

Type	Title	Version
Protocol (for publication)	D1_Protocol 2024-515234-33-00_redacted	3.0
Protocol (for publication)	D4_ Patient facing documents_patient diary_DE	1.0
Protocol (for publication)	D4_ Patient facing documents_patient diary_FR	1.0
Protocol (for publication)	D4_ Patient facing documents_patient diary_IT	1
Protocol (for publication)	D4_ Patient facing documents_patient diary_NL	1.0
Recruitment arrangements (for publication)	K1_recruitment arrangements_informedconsent_patientrecruitmentprocedure _BE	1
Recruitment arrangements (for publication)	K1_recruitment arrangements_informedconsent_patientrecruitmentprocedure _IT UNISI	1
Recruitment arrangements (for publication)	K1_recruitment arrangements_informedconsent_patientrecruitmentprocedure_AT	1
Recruitment arrangements (for publication)	K1_recruitment arrangements_informedconsent_patientrecruitmentprocedure_DE	1
Recruitment arrangements (for publication)	K1_recruitment arrangements_informedconsent_patientrecruitmentprocedure_FR FR	3
Recruitment arrangements (for publication)	K1_recruitment arrangements_informedconsent_patientrecruitmentprocedure_IT UniSR	1
Subject information and informed consent form (for publication)	L1_ SIS and ICF_AT_redacted	3
Subject information and informed consent form (for publication)	L1_ SIS and ICF_BE_EN_redacted	3
Subject information and informed consent form (for publication)	L1_ SIS and ICF_BE_NL_redacted	3
Subject information and informed consent form (for publication)	L1_ SIS and ICF_DE_redacted	3
Subject information and informed consent form (for publication)	L1_ SIS and ICF_FR_redacted	5
Subject information and informed consent form (for publication)	L1_ SIS and ICF_IT UNISI_redacted	3
Subject information and informed consent form (for publication)	L1_ SIS and ICF_IT UniSR_redacted	3
Subject information and informed consent form (for publication)	L1_ SIS and ICF_Pregnant Partner_BE_EN	2
Subject information and informed consent form (for publication)	L1_ SIS and ICF_Pregnant Partner_BE_NL	2
Subject information and informed consent form (for publication)	L1_SIS and ICF_Pregnant Participant_BE_EN	2
Subject information and informed consent form (for publication)	L1_SIS and ICF_Pregnant Participant_BE_NL	2
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Half Securon SR	1
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Isoptin KHK retard 120 mg	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Isoptin LP 240 mg	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Isoptin retard 120 mg - Filmtabletten	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_LODIXAL 240 mg Tabletten met verlengde afgifte	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Vera-Til SR 120mg Tablets	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Verahexal KHK 120 mg retard	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Verapamil 120 ret 1APharma	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_VERAPAMIL DOC Generici 120 mg capsule rigide a rilascio prolungato	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Verapamil Hennig 120mg retard Retardtabletten	0
Summary of Product Characteristics (SmPC) (for publication)	G2_SmpC_Verapamil Hexal 120 mg compresse a rilascio prolungato	0
Synopsis of the protocol (for publication)	D1_ Protocol synopsis_DE 2024-515234-33-00	3.0
Synopsis of the protocol (for publication)	D1_ Protocol synopsis_ENG 2024-515234-33-00	3.0
Synopsis of the protocol (for publication)	D1_ Protocol synopsis_FR 2024-515234-33-00	3.0
Synopsis of the protocol (for publication)	D1_ Protocol synopsis_IT 2024-515234-33-00	3.0
Synopsis of the protocol (for publication)	D1_Protocol synopsis Layman Language_DE	2.0
Synopsis of the protocol (for publication)	D1_Protocol synopsis Layman Language_ENG	2.0
Synopsis of the protocol (for publication)	D1_Protocol synopsis Layman Language_FR	3.0
Synopsis of the protocol (for publication)	D1_Protocol synopsis Layman Language_IT	2.0
Synopsis of the protocol (for publication)	D1_Protocol synopsis Layman Language_NL	2.0
Synopsis of the protocol (for publication)	D1_Protocol synopsis NL 2024-515234-33-00	3.0

Application history

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

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2024-07-24	Austria	Acceptable 2024-11-11	2024-11-11

An open-label extension multi-centre trial in adult subjects diagnosed with Type 1 diabetes mellitus exploring the effect of long-term Verapamil SR therapy on the preservation of beta-cell function.

Overview

Key facts

Trial design

Main objective

Secondary objectives 6

Conditions and MedDRA coding

Eligibility criteria

Inclusion criteria 4

Exclusion criteria 14

Endpoints

Primary endpoints 1

Secondary endpoints 6

Investigational products

Test 11

Sponsors and contacts

Medical University Of Graz

Scientific contact point

Public contact point

Locations

By country

Investigational sites

Country notifications

Results and documents

Documents 43 files

Application history

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