BASICS Trial Protocol Amendment#3

30 Pages·2015·0.41 MB·English

BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015

BASICS Trial

Basilar Artery International Cooperation Study

Research Protocol
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
BASICS Trial protocol

Protocol ID NL33550.100.10 / 2010B151 NHS
Short title BASICS Trial
Version 3.0
Date 02-02-2015
Coordinating investigator/project E.J.R.J. der Hoeven, MD
leader
St. Antonius Hospital, Nieuwegein

Koekoekslaan 1
3435 CM Nieuwegein
The Netherlands
+31 (0) 88 - 320 30 00
[email protected]
Principal investigator(s) (in W.J. Schonewille, MD, Neurology PI
Dutch:
St. Antonius Hospital, Nieuwegein
hoofdonderzoeker/uitvoerder)
Koekoekslaan 1

3435CM Nieuwegein

The Netherlands

+31 (0) 88 - 320 30 00

[email protected]

J.A. Vos, MD, PhD, Radiology PI

St. Antonius Hospital, Nieuwegein

Koekoekslaan 1

3435CM Nieuwegein

The Netherlands

+31 (0) 88 - 320 30 00

[email protected]
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
Multicenter research: per site
The Netherlands:
St. Antonius Hospital W.J. Schonewille
University Medical Centre Utrecht L.J. Kappelle
MC Haaglanden J. Boiten
St. Elisabeth Hospital Tilburg P. de Kort
Rijnstate Hospital Arnhem J. Hofmeijer
Maastricht University Medical Center J. Staals
Academic Medical Center Amsterdam P. Nederkoorn
Leiden University Medical Center M. Wermer
University Medical Center Groningen M. Uyttenboogaart
Haga Hospital The Hague K. de Laat
Switzerland:
CHUV Lausanne P. Michel
Italy :
University of Modena and Reggio Emilia A. Zini
Roma Umberto I Hospital M. De Michele
Varese Hospital M.L. Delodovici
Genua Hospital L. Malfatto
Bergamo Hospital B.Censori
Czech republic:
Olomouc Hospital R. Herzig
Norway:
University Hospital North Norway Malmø S.H. Johnsen
St Olavs Hospital Trondheim G. Rohweder
Germany:
Dresden University Medical Center
  V. Puetz
Berlin Charité H. Audebert
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
Mannheim University Medical Center K. Szabo
Ravensburg C. Rueckert
Sponsor (in Dutch: BASICS Study Group
verrichter/opdrachtgever)
Independent physician(s) P.J.A.M. Brouwers, MD, PhD
Medisch Spectrum Twente
Department of Neurology
Postbus 50.000
7500KA Enschede
The Netherlands
+31 (0) 53 - 487 28 50
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
PROTOCOL SIGNATURE SHEET

Name Signature Date
For non-commercial research,
Head of Department:
H. Koers

Coordinating Investigator:
E.J.R.J. van der Hoeven, MD
St. Antonius Hospital, Nieuwegein
University Medical Centre Utrecht

Principal Investigator:
W. J. Schonewille, MD
St. Antonius Hospital, Nieuwegein
University Medical Centre Utrecht
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
TABLE OF CONTENTS
1
  INTRODUCTION AND RATIONALE................................................................................10

1.1
  Introduction.................................................................................................................10

1.2
  Rationale....................................................................................................................11

2.
  OBJECTIVES ..................................................................................................................13

3.
  STUDY DESIGN..............................................................................................................13

4.
  STUDY POPULATION ....................................................................................................14

4.1
  Population (base).......................................................................................................14

4.2
  Inclusion criteria.........................................................................................................15

4.3
  Exclusion criteria........................................................................................................15

4.4
  Sample size calculation..............................................................................................15

5.
  TREATMENT OF SUBJECTS.........................................................................................16

5.1
  Investigational product/treatment...............................................................................16

6.
  INVESTIGATIONAL MEDICINAL PRODUCT.................................................................16

6.1
  Name and description of investigational medicinal product(s)...................................16

6.2
  Summary of findings from non-clinical studies...........................................................17

6.3
  Summary of findings from clinical studies..................................................................17

6.4
  Summary of known and potential risks and benefits..................................................17

6.5
  Description and justification of route of administration and dosage...........................17

6.6
  Dosages, dosage modifications and method of administration..................................17

6.7
  Preparation and labelling of Investigational Medicinal Product..................................17

6.8
  Drug accountability.....................................................................................................17

7.
  METHODS.......................................................................................................................17

7.1
  Study parameters/endpoints......................................................................................17

7.1.1
  Main study parameter/endpoint............................................................................17

7.1.2
  Secondary study parameters/endpoints...............................................................18

7.1.3
  Other study parameters.......................................................................................18

7.2
  Randomisation, blinding and treatment allocation......................................................18

7.3
  Study procedures.......................................................................................................19

7.4
  Withdrawal of individual subjects...............................................................................21

7.5
  Replacement of individual subjects after withdrawal..................................................21

7.6
  Follow-up of subjects withdrawn from treatment........................................................21

7.7
  Premature termination of the study............................................................................21

8.
  SAFETY REPORTING ....................................................................................................21

8.1
  Section 10 WMO event..............................................................................................21

8.2
  Adverse and serious adverse events.........................................................................21

8.2.1
  Suspected unexpected serious adverse reactions (SUSAR)...............................22

8.2.2
  Annual safety report.............................................................................................23

8.3
  Follow-up of adverse events......................................................................................23

8.4
  Data Safety Monitoring Board (DSMB)......................................................................23

9.
  STATISTICAL ANALYSIS ...............................................................................................24

9.1
  Descriptive statistics...................................................................................................24

9.2
  Univariate analysis.....................................................................................................24
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
9.3
  Multivariate analysis...................................................................................................24

9.4
  Interim analysis..........................................................................................................24

10.
  ETHICAL CONSIDERATIONS ......................................................................................25

10.1
  Regulation statement................................................................................................25

10.2
  Recruitment and consent..........................................................................................25

10.3
  Benefits and risks assessment.................................................................................26

10.4
  Compensation for injury............................................................................................26

11.
  ADMINISTRATIVE ASPECTS AND PUBLICATION .....................................................27

11.1
  Handling and storage of data and documents..........................................................27

11.2
  Amendments............................................................................................................27

11.3
  Annual progress report.............................................................................................27

11.4
  End of study report...................................................................................................28

11.5
  Public disclosure and publication policy...................................................................28

12.
  REFERENCES ..............................................................................................................29

13.
  APPENDIX 1. Allowed IA strategies..............................................................................30
BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS

ABR ABR form, General Assessment and Registration form, is the application
form that is required for submission to the accredited Ethics Committee (In
Dutch, ABR = Algemene Beoordeling en Registratie)
AE Adverse Event
AR Adverse Reaction
CA Competent Authority
CCMO Central Committee on Research Involving Human Subjects; in Dutch:
Centrale Commissie Mensgebonden Onderzoek
CV Curriculum Vitae
DSMB Data Safety Monitoring Board
EU European Union
EudraCT European drug regulatory affairs Clinical Trials
GCP Good Clinical Practice
IB Investigator’s Brochure
IC Informed Consent
IMP Investigational Medicinal Product
IMPD Investigational Medicinal Product Dossier
METC Medical research ethics committee (MREC); in Dutch: medisch ethische
toetsing commissie (METC)
(S)AE (Serious) Adverse Event
SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie
IB1-tekst)
Sponsor The sponsor is the party that commissions the organisation or performance
of the research, for example a pharmaceutical company, academic hospital,
scientific organisation or investigator. A party that provides funding for a
study but does not commission it is not regarded as the sponsor, but
referred to as a subsidising party.
SUSAR Suspected Unexpected Serious Adverse Reaction
Wbp Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)
WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen

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BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015
SUMMARY

Rationale: Recently our study group reported the results of the Basilar Artery International
Cooperation Study (BASICS), a prospective registry of patients with an acute symptomatic
basilar artery occlusion. Our observations in the BASICS registry underscore that we
continue to lack a proven treatment modality for patients with an acute BAO and that current
clinical practice varies widely. Furthermore, the often-held assumption that intra-arterial
therapy (IAT) is superior to intravenous thrombolysis (IVT) in patients with an acute
symptomatic BAO is challenged by our data.
The BASICS registry was observational and has all the limitations of a non-randomised
study. Interpretation of results is hampered by the lack of a standard treatment protocol for all
patients who entered the study.
Objective: Evaluate the efficacy and safety of IAT in addition to best medical management
(BMM) in patients with basilar artery occlusion.
Study design: Randomised, multi-centre, open label, controlled phase III, treatment trial.
Study population: Patients, aged 18 or older, with CTA or MRA confirmed basilar occlusion.
Intervention: Patients will be randomised between BMM with additional IAT versus BMM
alone. IAT has to be initiated within 6 hours from estimated time of BAO. If treated with IVT
as part of BMM, IVT should be started within 4.5 hours of estimated time of BAO.
Main study parameters/endpoints: Favourable outcome at day 90 defined as a modified
Rankin Score (mRS – functional scale) of 0-3.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness: Although, to date, no data from a randomised controlled trial support the
use of IAT for BAO, IAT was by far the most commonly used treatment type in the BASICS
registry. The use of IAT is supported by the results of trials performed with patients with
occlusions in other vascular territories. Patients randomised into the additional IAT group will
undergo intra-arterial catheterization and IAT will be initiated if indicated. Effective amount of
radiation during this 1-2 hour procedure will be about 20 mSv. Main risks for catheterization
and IAT comprise local and intracranial haemorrhage. In the BASICS registry we reported a
risk for symptomatic intracranial haemorrhage of 14% in patients treated with IAT versus 6%
in patients treated with IVT. Follow-up telephone surveys at 1 and 12 months and blinded
exam at 3 months will take up to 50 minutes in total.
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BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015

1 INTRODUCTION AND RATIONALE
1.1 Introduction
Recently our study group reported the results of the Basilar Artery International
Cooperation Study (BASICS), a prospective registry of patients with an acute
symptomatic basilar artery occlusion (BAO). The purpose of the registry was to obtain a
better understanding of outcomes following acute BAO and to study potential differences
in treatment response in anticipation of a definitive randomised controlled acute treatment
trial in these patients. We were not able to identify a statistically significant superior
treatment strategy. However, by including more than 600 patients in the registry over a 5
years period, we did show that the performance of a randomised trial in patients with
basilar artery occlusion is feasible.
Our observations in the BASICS registry underscore that we continue to lack a proven
treatment modality for patients with an acute BAO and that current clinical practice varies
widely. Furthermore, the often-held assumption that IAT is superior to IVT in patients with
an acute symptomatic BAO is challenged by our data. Although recanalization rates after
IAT are consistently higher after IAT as compared to IVT in observational studies, this
was not accompanied by improved outcome.
The BASICS registry was observational and has all the limitations of a non-randomised
study. Reasons for clinicians to select a specific treatment option are more complex than
can be captured in the scope of a prospective registry. Multivariable analyses can never
adjust completely for systematic differences between treatment groups – the aim of
randomisation in clinical trials. A bias towards a more aggressive treatment approach in
patients who were thought to have a worse prognosis may have influenced the outcome
in the IAT group and relinquishing both IVT and IAT in patients with a severe deficit may
have been an expression of a more palliative approach. Crossover to another treatment
group because of clinical worsening or lack of treatment response was not taken into
account. There may be variables relevant to outcome that are imbalanced between
groups, but that we did not measure. However, the registry collected standard
neurological and functional scores and risk factor data across all sites. In the analyses we
have adjusted for baseline imbalances between the treatment groups as much as
possible.

As the IA treatment approach becomes increasingly available and utilized throughout the
world, we believe that a large randomised controlled phase III trial investigating the added
value of this therapy in patients with an acute symptomatic BAO is a high priority.
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