Clinical Trials Register

Summary
EudraCT Number:	2015-001006-34
Sponsor's Protocol Code Number:	2015C104
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-07-26
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2015-001006-34

A.3

Full title of the trial

Groningen Intervention study for the Preservation of cardiac function with sodium thiosulfate after ST-segment elevation myocardial infarction

Groningen Interventiestudie voor de preservatie van de hartfunctie met natriumthiosulfate na ST-segmentelevatie myocardinfarct

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Groningen intervention study for the protection of heart function after a heart attack

Groningen Interventiestudie voor de bescherming van de hartfunctie na een hartaanval

A.3.2

Name or abbreviated title of the trial where available

GIPS-IV

A.4.1

Sponsor's protocol code number

2015C104

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Medical Centre Groningen (UMCG)
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	UMCG
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UMCG
B.5.2	Functional name of contact point	CardioResearch
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9700RB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310503616161

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sodium thiosulfate pentahydrate
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sodium thiosulfate pentahydrate
D.3.9.1	CAS number	10102-17-7
D.3.9.3	Other descriptive name	SODIUM THIOSULFATE PENTAHYDRATE
D.3.9.4	EV Substance Code	SUB22204
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

ST-segment elevated myocardial infarction, decompensatio cordis

ST-segmentelevatie myocardinfarct, decompensatio cordis

E.1.1.1

Medical condition in easily understood language

heart attack, heart failure

hartaanval, hartfalen

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the GIPS-IV is to evaluate the efficacy of sodium thiosulfate treatment compared to placebo on top of optimal reperfusion therapy for STEMI on myocardial infarct size 4 months after randomization as measured with late gadolinium enhancement cardiac magnetic resonance imaging (CMR-imaging).

Het evalueren van de effectiviteit van natriumthiosulfaat in vergelijking met placebobehandeling, als aanvulling op optimale reperfusie therapie,
bij patienten met een acuut myocardinfarct op infarctgrootte gemeten met MRI-onderzoek 4 maanden na randomisatie.

E.2.2

Secondary objectives of the trial

Secondary CMR-imaging efficacy measures include left ventricular ejection fraction (LVEF) and myocardial perfusion reserve (MPR) at 4 month follow up. Furthermore, N-terminal fragment brain natriuretic peptide (NT-proBNP) will be assessed 4 months after randomisation. Other secondary efficacy endpoint measures will be obtained from non-mandatory CMR-imaging during hospitalization to study myocardial haemorrhage, microvascular obstruction (MVO) and myocardial salvage index (MSI). Clinical safety endpoints include all-cause mortality and combined incidence of cardiovascular events: cardiovascular death, re-infarction, re-intervention and stroke. As additional safety endpoints we will evaluate the incidence of internal cardiac defibrillator (ICD) implantation and hospitalization for heart failure or chest pain. Finally, enzymatic infarct size as assessed by peak creatine kinase, muscle-brain isoenzymes (CK)-MB) during hospitalization will be used as very early safety parameter.

Secundaire CMR-beeldvorming effectiviteit-uitkomstmaten zijn linkerventrikel ejectiefractie (LVEF) en myocardiaal perfusie reserve (MPR), beide na 4 maanden. Op 4 maanden wordt tevens N-terminal fragment brein natriurisch peptide (NT-proBNP) gemeten. Andere secundaire effectiviteit-uitkomstmaten worden verkregen uit niet-verplichte CMR-beeldvorming tijdens hospitalisatie om myocardiale bloeding, microvasculaire obstructie en de myocardiale reddingsindex te beoordelen. Klinische veiligheidseindpunten omvatten mortaliteit van elke oorzaak en de gecombineerde incidentie van cardiovasculaire events: cardiovasculaire dood, re-infarct, re-interventie en beroerte. Als additionele veligheidsuitkomstmaten evalueren we de incidentie van interne cardiale defibrillator-implantatie en hospitalisatie voor hartfalen of pijn op de borst. Tot slot wordt het CK-MB tijdens hospitalisatie gebruikt als zeer vroege veiligheidsparameter.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years;
2. The diagnosis STEMI defined by (1) chest pain suggestive for myocardial ischemia for at least 30 minutes, the time from onset of the symptoms less than 12 hours before hospital admission, and (2) an electrocardiogram recording with ST- segment elevation of more than 0.1 mV in 2 or more contiguous leads or new left bundle branch block;
3. Symptoms and/or ST-segment deviation should be present (persisting) at time of arrival in the catheterization laboratory;
4. Primary percutaneous intervention is being considered as treatment;
5. Patient is willing to cooperate with follow-up during 2 years.

1. Leeftijd ≥ 18 jaar;
2. De diagnose STEMI gedefinieerd als (1) pijn op de borst typisch voor myocardischemie voor ten minste 30 minuten, aanvang van klachten is minder dan 12 uur voor ziekenhuisopname, en (2) een elektrocardiogram met ST-segmentelevatie van meer dan 0.1mV in 2 of meer aanliggende afleidingen of nieuw linker bundeltakblok;
3. Symptomen en/of ST-segmentafwijkingen zijn (nog steeds) aanwezig bij aanvang op de hartkatheterisatie;
4. Primaire percutane coronaire interventie wordt overwogen als behandelmethode;
5. Patient is bereid om mee te doen aan de follow-up gedurende twee jaar.

E.4

Principal exclusion criteria

1. Prior myocardial infarction, unless maximum troponin T< 50 ng/L (STEMI/non-STEMI/acute coronary syndrome);
2. Known permanent atrial fibrillation;
3. Prior CABG;
4. Prior PCI, complicated by periprocedural infarction, unless maximum troponin T < 50ng/L;
5. Known cardiomyopathy;
6. Previous hospitalization for heart failure
7. Active malignancy (requiring chemotherapy, radiation or surgery at the time of randomization), except for adequately treated non-melanoma skin cancer or other noninvasive or in situ neoplasm (e.g., cervical cancer in situ);
8. History of chemotherapy;
9. History of radiotherapy in chest region;
10. Relieve of symptoms and complete ST-segment resolution prior to arrival at the catheterization laboratory;
11. Presentation with cardiogenic shock (systolic blood pressure < 90 mmHg);
12. Severe hypertension (systolic blood pressure > 220 mmHg);
13. Sedated and/or intubated patients;
14. The existence of a condition with a life expectancy of less than 1 year;
15. Contraindication for 3 Tesla (T) CMR-imaging (e.g. body weight >;150kg; known claustrophobia; 3T MRI incompatible ferromagnetic objects in the body, end-stage renal disease);
16. Pregnancy or breastfeeding women; women of childbearing potential with clinical suspicion of possible pregnancy;
17. A condition which, according to the clinical judgment of the investigator and/or treating physician, does not allow the patient to successfully participate in the study.

1. Eerder myocardinfarct, tenzij maximaal troponine T< 50ng/L (STEMI/non-STEMI/acuut coronair syndroom);
2. Bekend permanent boezemfibrilleren;
3. CABG in de voorgeschiedenis;
4. Eerdere PCI, gecompliceerd door periprocedureel infarct, tenzij maximaal troponine T < 50ng/L;
5. Bekende cardiomyopathie;
6. Opname vanwege hartfalen in de voorgeschiedenis;
7. Actieve maligniteit (die chemotherapie, radiotherapie of operatie behoeft ten tijde van randomisatie), met uitzondering van adequaat behandelde non-melanoma huidkanker of adequaat behandeld carcinoom in situ;
8. Behandeling met chemotherapie in de voorgeschiedenis;
9. Voorgeschiedenis van bestraling in de thorax regio;
10. Verdwijnen van symptomen en compleet herstel van ST-segmentafwijkingen voor aankomst op de hartkatheterisatiekamer;
11. Presentatie met cardiogene shock (systolische bloeddruk < 90mmHg);
12. Ernstige hypertensie (systolische bloeddruk > 220mmHg);
13. Gesedeerde en/of geintubeerde patienten;
14. Het bestaan van een aandoening met een levensverwachting van minder dan 1 jaar;
15. Contra-indicaties voor 3 Tesla CMR-beeldvorming (o.a. lichaamsgewicht>150kg, claustrofobie; 3T MRI incompatibele ferromagnetische objecten in het lichaam, eindstadium nierfalen);
16. Zwangere of borstvoeding gevende vrouwen; vrouwen in de vruchtbare levensfase met een klinische verdenking op een mogelijke zwangerschap;
17. Een aandoening die, volgens de klinische blik van de onderzoeker en/of behandelend arts, er voor zorgt dat patient niet succesvol mee kan werken aan de studie.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy parameter is myocardial infarct size as measured with LGE CMR-imaging at 4 months after randomization.

Het primaire eindpunt is infarctgrootte gemeten met cardiale magnetische resonantie beeldvorming (CMR-beeldvorming) 4 maanden na randomisatie.

E.5.1.1

Timepoint(s) of evaluation of this end point

4 months after randomization

4 maanden na randomizatie

E.5.2

Secondary end point(s)

Efficacy:
- LVEF as assessed by CMR-imaging at 4 months follow-up;
- Myocardial perfusion reserve, assessed with rest and stress CMR imaging at 4 months follow-up;
- NT pro-BNP at 4 months follow-up;
- Other CMR-imaging parameters obtained from non-mandatory CMR-imaging during hospitalization and CMR-imaging at 4 months, including myocardial haemorrhage, MVO, MSI, LVEF, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV mass;

Safety:
- Incidence of cardiovascular events within 4 months and after 2-year follow-up (all cause mortality, cardiovascular death, re-infarction, re-intervention both re-PCI and CABG [except for scheduled revascularization based on the index CAG to diagnose and treat coronary artery lesions identified during the procedures and heart team discussion, including concomitant treatment of valvular conditions, see 9.2.2 disease related adverse events], stroke, ICD implantation, hospitalization for heart failure or chest pain (defined as an overnight stay, with different dates for admission and discharge) and combined endpoints MACE defined as death, re-infarction, any revascularization not planned on index CAG) (see Table 1);
- A division between cardiac and non-cardiac death is made, with a subdivision in cardiac death, namely heart failure, sudden cardiac death and other. Cardiovascular death will be confirmed by a cardiologist by examining medical records obtained from attending physicians and hospitals or general practitioners if patient died at home. Sudden cardiac death is either defined as witnessed, un-witnessed, cardiac arrest without evidence of circulatory collapse, such as hypotension, exacerbation of congestive heart failure, or altered mental status, before the disappearance of the pulse or abrupt collapse occurring within one hour of the onset of the symptoms that resulted in death. Death due to heart failure will be defined as death due to clinically end-stage heart failure during hospital admission or by exacerbation of congestive heart failure reported by an attending general practitioner. For all these deaths, no probable non-cardiac cause should be suggested by the history or autopsy;
- Enzymatic infarct size as assessed by peak CK-MB during hospitalization.

Secundaire CMR-beeldvorming effectiviteit-uitkomstmaten zijn linkerventrikel ejectiefractie (LVEF) en myocardiaal perfusie reserve (MPR), beide na 4 maanden. Op 4 maanden wordt tevens N-terminal fragment brein natriurisch peptide (NT-proBNP) gemeten. Andere secundaire effectiviteit-uitkomstmaten worden verkregen uit niet-verplichte CMR-beeldvorming tijdens hospitalisatie om myocardiale bloeding, microvasculaire obstructie en de myocardiale reddingsindex te beoordelen.

Klinische veiligheidseindpunten omvatten mortaliteit van elke oorzaak en de gecombineerde incidentie van cardiovasculaire events: cardiovasculaire dood, re-infarct, re-interventie en beroerte. Als additionele veligheidsuitkomstmaten evalueren we de incidentie van interne cardiale defibrillator-implantatie en hospitalisatie voor hartfalen of pijn op de borst. Tot slot wordt het CK-MB tijdens hospitalisatie gebruikt als zeer vroege veiligheidsparameter.

E.5.2.1

Timepoint(s) of evaluation of this end point

4 months after randomization and after 2 years follow-up

4 maanden na randomizatie en na 2 jaar follow-up

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

the last visit of the last subject undergoing the trial

laatste studievisite van de laatste proefpersoon die deelneemt aan de trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

380

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

380

F.4.2

For a multinational trial

F.4.2.1

In the EEA

380

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

none

geen

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-25

P. End of Trial
P.	End of Trial Status	Ongoing

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