DELTA Trial: Does Embolization With Larger Coils Lead to Better Treatment of Aneurysms Trial
Phase: NA
Conditions: Cerebral Aneurysm
Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

 
 
Principal Investigators 
Jean Raymond, MD 
 
Sponsor: 
Centre hospitalier de l’Université de Montréal 
Hôpital Notre-Dame 
 
Financial support: 
DePuy Synthes – Codman Neuro and Johnson & Johnson Medical Companies 
An Investigator-initiated Randomized Trial Comparing Treatment with 
15-caliber Platinum Coils to Standard 10-caliber Platinum Coils 
Version 1.8 | June 23, 2015 
ClinicalTrials.gov Identifier: 
NCT01943591 
Does Embolization with Larger coils lead to 
better Treatment of Aneurysms trial 
 
 
Page 1 of 31 
 

EXECUTIVE SUMMARY 
 
Endovascular treatment with platinum coils is safe and effective in preventing rebleeding of intracranial 
aneurysms.  Unfortunately, endovascular treatment has been associated with incomplete occlusion at 
initial treatment (remnant) or at follow-up (recurrence).  This in some studies has been as high as 33%.   
While many such aneurysm remnants or recurrences exhibit benign behavior, many require retreatment 
to prevent future hemorrhage.   
 
A recent randomized controlled trial of aneurysm coiling revealed that aneurysms between 2 and 9.9 
mm diameter were more likely to have an improved angiographic and composite clinical outcome when 
treated with hydrogel-coated coils, an improvement inferred to result from higher packing density 
afforded by hydrogel expansion.1 The use of hydrogel coils is associated with technical difficulties 
related to expansion and limited time for deployment. We theorize that similar results could be 
achieved by using more voluminous bare platinum coils, leading to improved packing density compared 
to smaller caliber coils, and thus result in lower incidence of remnants or residuals. Aneurysms varying in 
size from 4 to 12 mm are most prevalent, and it is in these smaller aneurysms that both smaller caliber 
or larger caliber coils can be used. The relationship between packing densities and clinical endpoints 
having never been shown in a robust fashion in these small aneurysms, we therefore propose a 
randomized clinical trial opposing coiling with soft 15-caliber coils to 10-caliber bare platinum coils in 
aneurysms varying in size from 4 to 12 mm. 
 
To test the hypothesis that 15-caliber coiling systems are superior to standard 10-caliber coils in 
achieving better composite outcomes, we propose the DELTA trial: Does Embolization with Larger coils 
lead to better Treatment of Aneurysms trial, a randomized controlled blinded trial with 2 subgroups of 
282 patients each, 564 total: 
 
 
Subgroup 1: Coiled with a maximum proportion of 15-caliber platinum coils  
                      (including  Deltamaxx) as conditions allow 
 
Subgroup 2: Coiled with 10-caliber platinum coils. 
 
The pivotal trial will be preceded by a pilot phase of approximately 165 patients designed to verify the 
feasibility of the coiling strategy, compliance to treatment group allocation, the safety of an 15-caliber 
platinum coil embolization strategy, recruitment rates, and the capacity to improve packing density (to 
28%) with a standardized effect size (E/S) of 0.6, with a power of 95% and a two-sided alpha error of 
0.05 (assuming the packing density of the control group will be approximately 25%). 
 
Page 2 of 31 
 

PROTOCOL SUMMARY 
 
Title: 
DELTA: Does Embolization with Larger coils lead to better Treatment of 
Aneurysms trial 
 
Patients: 
Inclusion Criteria: 
 
At least one ruptured or unruptured aneurysms with a dimension 
≥4mm (longest axis) and ≤12 mm 
 
For ruptured lesions, patients should be in WFNS grade ≤ III. 
 
The anatomy of the lesion is such that endovascular treatment is 
possible with caliber 0.015 (including Deltamaxx) or caliber 0.010 
platinum types of coils (not necessarily certain or probable) 
 
Patient is 18 or older 
 
Life expectancy is more than 2 years  
Exclusion Criteria: 
 
Patients with planned treatment of an associated cerebral 
arteriovenous malformations 
 
When parent vessel occlusion, without simultaneous endosaccular 
coiling of the aneurysm, is the primary intent of the procedure 
 
Any 
absolute 
contraindication 
to 
endovascular 
treatment, 
angiography, or anaesthesia such as severe allergies to contrast or 
medications 
 
Number of Sites (Pilot phase): 
12-14 centres  
 
Study Duration (Pilot Phase): 
24 months accrual + 12 months follow-up 
 
Subject Participation Duration: 
12 months 
 
Description of  Intervention: 
Comparison of endovascular aneurysm coiling with 15-caliber coils 
(including Deltamaxx coils) vs. coiling with other commercially available 
10-caliber platinum coils. 
Page 3 of 31 
 

Hypotheses: 
 
 
Primary Hypothesis of the pivotal phase: 
The use of Deltamaxx, within a strategy of using larger caliber coils for 
small aneurysms (4-12mm) will lead to a lesser number of incomplete 
occlusions at 12 months, as compared with smaller caliber 0.010 coils. 
The primary endpoint will be mainly composed of major angiographic 
recurrences or the presence of a ‘residual aneurysm’ as judged by the 
core lab at 12 month. 
 
Secondary Endpoints: 
Secondary endpoints will include:  
 
Major recurrence on 12-month follow-up angiography 
 
Morbidity and mortality that precludes angiographic follow-up 
 
Initial technical success of the coiling strategy 
 
Packing density  
 
Number of coils implanted. 
 
Time of fluoroscopic exposure 
 
Immediate angiographic results 
 
Peri-procedural serious adverse events 
 
mRS at 1 year follow-up 
 
Description of Study Design: 
Allocation:  
 
 
Randomized 
Endpoint Classification:  
Safety/Efficacy Study 
Intervention Model:  
 
Parallel Assignment 
Masking:  
 
 
Single-blind 
Primary Purpose:  
 
Treatment 
 
Estimated Time to Complete 
(Pilot phase) 
36 months 
 
 
 
Page 4 of 31 
 

Key Roles 
Individuals: 
 
 
Principal Investigators:   
Jean Raymond, MD 
 
 
 
 
 
 
Core Lab:  
 
 
TBD 
Sponsor: 
 
CHUM (Centre Hospitalier de l’Université de Montréal) 
 
Financial support: 
DELTA is an investigator-initiated study that is 
supported through research funding from DePuy Synthes – Codman 
Neuro and Johnson & Johnson Medical Companies 
SCHEMATIC OF STUDY DESIGN:  
 
 
 
Page 5 of 31 
 

TABLE OF CONTENTS 
EXECUTIVE SUMMARY ................................................................................................... II 
PROTOCOL SUMMARY .................................................................................................. III 
OBJECTIVES: ................................................................................................................................................... IV 
KEY ROLES ...................................................................................................................................................... V 
SCHEMATIC OF STUDY DESIGN: ........................................................................................ VI 
SECTION 1:   BACKGROUND ............................................................................................. 9 
ENDOVASCULAR TREATMENT ............................................................................................................................. 9 
PACKING DENSITY ............................................................................................................................................ 9 
MISSION STATEMENT ..................................................................................................................................... 10 
SECTION 2:   THE PROPOSED TRIAL ................................................................................... 11 
DESIGN ........................................................................................................................................................ 11 
HYPOTHESES ................................................................................................................................................. 11 
INTERVENTIONS ............................................................................................................................................. 11 
SELECTION CRITERIA: INCLUSION AND EXCLUSION CRITERIA ................................................................................... 12 
INCLUSION CRITERIA: ...................................................................................................................................... 12 
EXCLUSION CRITERIA: ..................................................................................................................................... 12 
TECHNICAL FREEDOM ..................................................................................................................................... 12 
RANDOMIZATION ........................................................................................................................................... 13 
TYPE, FREQUENCY AND DURATION OF FOLLOW-UP ............................................................................................... 13 
TABLE 1: SCHEDULE OF EVALUATION................................................................................................................. 14 
OUTCOMES ................................................................................................................................................... 14 
PRIMARY OUTCOME ....................................................................................................................................... 14 
PRIMARY ENDPOINT: ...................................................................................................................................... 14 
SECONDARY OUTCOME: .................................................................................................................................. 15 
INITIAL TECHNICAL SUCCESS ............................................................................................................................. 15 
MORTALITY ................................................................................................................................................... 16 
ADVERSE EVENTS ........................................................................................................................................... 16 
MORBIDITY ................................................................................................................................................... 16 
SAMPLE SIZE ................................................................................................................................................. 16 
RECRUITMENT RATE AND CENTRES .................................................................................................................... 17 
DURATION OF THE TRIAL ................................................................................................................................. 17 
PLANNED ANALYSES ....................................................................................................................................... 17 
PILOT PHASE ................................................................................................................................................. 18 
PROTECTION AGAINST BIAS .............................................................................................................................. 18 
PUBLICATION OF RESEARCH FINDINGS ................................................................................................................ 18 
REGULATORY CONSIDERATIONS ........................................................................................................................ 18 
TRIAL MANAGEMENT AND COORDINATION ......................................................................................................... 19 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 6 of 31 
 

SECTION 3:   TRIAL MANAGEMENT ................................................................................... 20 
INVESTIGATORS ............................................................................................................................................. 20 
STEERING COMMITTEE (SC)............................................................................................................................. 20 
DELTA STEERING COMMITTEE TERMS OF REFERENCE .......................................................................................... 20 
DATA SAFETY AND MONITORING COMMITTEE (DSMC) ....................................................................................... 20 
DATA SAFETY AND MONITORING COMMITTEE TERMS OF REFERENCE ...................................................................... 21 
IMAGING CENTER (CORE LAB) .......................................................................................................................... 21 
OTHER COMMITTEES TO BE DETERMINED BY DECISION OF STEERING COMMITTEE ..................................................... 21 
DAY TO DAY MANAGEMENT ............................................................................................................................. 21 
SECTION 4:   GUIDELINES .............................................................................................. 22 
DELTA TREATMENT PLAN ............................................................................................................................... 22 
CENTRE REQUIREMENTS .................................................................................................................................. 23 
APPENDIX 1: REFERRAL CENTER DETAILS ........................................................................................................... 24 
APPENDIX 2:   INVESTIGATOR DECLARATION AND AGREEMENT .............................................................................. 25 
APPENDIX 3: ADJUDICATION OF OUTCOMES ....................................................................................................... 27 
 
 
REFERENCES ........................................................................................................... 30 
 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 7 of 31 
 

SECTION 1:   BACKGROUND 
Endovascular treatment 
Endovascular treatment with platinum coils is safe and effective in preventing rebleeding of intracranial 
aneurysms in the acute phase after subarachnoid haemorrhage; it is now the preferred method of 
treatment in many centers, because it can improve the outcome of patients as compared to surgical 
clipping.2-6 While treatment of ruptured aneurysms is imperative to prevent rebleeding, the management 
of unruptured aneurysms remains controversial, because of a low annual risk of haemorrhage and a high 
surgical risk.7-8 An effective endovascular treatment could offer a less morbid alternative to surgical 
treatment of unruptured aneurysms and thus prevent the morbidity associated with SAH.7, 9-11 
Unfortunately, endovascular treatment of aneurysms with coils has been associated with incomplete 
occlusion at initial treatment (remnant) or at follow-up (recurrence).  This in some studies has been as 
high as 20%-33%.   While many such aneurysm remnants or recurrences exhibit benign behavior, many 
require retreatment to prevent future hemorrhage.  This has been rare so far (in less than 1% of 
patients).12-19 A multicenter registry has reported up to 15% retreatment rates 2 years after coiling of 
ruptured aneurysms, but a yearly re-rupture rate of only 0.20% after the first year. 2, 20 
Packing Density 
Previous attempts at decreasing recurrences include second-generation coils with surface modification or 
bioactive moiety.21-24  The HELPS trial revealed that aneurysms between 2 and 9.9 mm diameter were 
more likely to have an improved angiographic and composite clinical outcome when treated with 
hydrogel-coated coils, an improvement inferred to result from the higher packing density afforded by 
hydrogel expansion.1  New, bare platinum 15-caliber coil systems25 are now available which may achieve 
consistent high packing density compared to previously available coils. Aneurysm packing density26, an oft 
argued surrogate marker for coiling efficacy26-32, has not been proven however to equate to angiographic 
or clinical long-term efficacy, although the data, at least for small aneurysms with satisfactory packing 
densities, is compelling.33-37 Given the lack of scientific evidence that these new voluminous coils improve 
the clinical outcome of patients with small aneurysms (≤12mm) treated endovascularly, we propose a 
randomized trial to address this question.  
DELTA Protocol Version 1.8  |  June 23, 2015   
    Page 8 of 31 

Mission Statement 
DELTA Protocol Version 1.8  |  June 23, 2015   
    Page 9 of 31 
Mission Statement
The DELTA trial is a large multicentre prospective randomized trial of endovascular management of 
aneurysms comparing voluminous coils to standard, commercially available platinum coils. It aims to 
recruit 564 patients with ruptured or unruptured small and medium sized aneurysms (≥4 and ≤12 mm). 
The clinical impact will be of major significance if substantial differences are found in the outcome 
according to a randomized procedure. 

SECTION 2:   THE PROPOSED TRIAL 
Design 
Delta is an investigator-initiated multicenter randomized, single-blind controlled trial comparing 15-
caliber coils to standard 10-caliber coils in patients harboring small to medium size aneurysms. All 
patients with aneurysm ≥ 4 and ≤ 12 mm or with a recurrence will be eligible. Adjudication of 
angiographic results will be done by a committee blinded to treatment allocation in an independent core 
laboratory. The study will be conducted in 10-25 centers. The study aims to enroll 564 patients equally 
divided between the two groups (15-caliber platinum coils vs. standard 10-caliber platinum coils), to 
obtain statistical significance in the primary endpoint, the occurrence of a recurrence at follow-up. The 
forecast duration of the study will be 6 years, the first 4 years for patient recruitment and accrual plus 12 
months of follow-up. 
The pivotal trial will be preceded by a pilot phase of approximately 165 patients, over approximately 3 
years, designed to confirm the feasibility of the coiling strategy, its safety, the enrolment rates, as well as 
to compare packing densities between the 2 groups. 
Hypotheses 
The use of 15-caliber platinum coils will lead to a decrease in the number of patients that reach the 
primary endpoint from 33 to 20% at 12 ± 2 months. 
 
The pilot phase has been powered to test the hypothesis that  the use of 15-caliber platinum coils will 
lead to an increased packing density as compared to caliber 10 coils from an expected mean of 25% to 
28% (95% power; alpha 0.05). 
 
Interventions 
The goal of the study is to assess if the use of voluminous 15-caliber coils could reduce the number of 
patients reaching the primary endpoint with little if any additional risk compared to standard caliber 10 
commercially available platinum coils. Thus the interventions will consist of either:  
A/ Standard, commercially available 10-caliber coil embolization of aneurysms, using standard or 
adjunct techniques. 
Or  
B/ The use of the highest safely achievable proportion of 15-caliber coils, including Deltamaxx, the 
operator being unrestricted in the use of the coil he/she believes is appropriate at any time during 
the procedure using standard or adjunct techniques. 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 10 of 31 
 

 
The aim of treatment is the complete angiographic exclusion of the aneurysm, or, as complete an 
exclusion from circulation as is feasible while minimizing risks of the procedure as per practice standards. 
 
The interventionist and therefore the clinical and interventional research team cannot be blinded to the 
nature of the coils used. However, the imaging center (core lab) that will determine the success of the 
procedure will be blinded during its evaluation.  
Although the mechanism evoked to support the potential benefit of 15-caliber coils is an increase in 
‘packing density’, the trial does not require the use of a minimal number or length of coils of either 
nature, nor to reach a certain packing density. To attempt to introduce more coils, even after 
angiographic exclusion of the lesion, to increase packing density, could be seen as taking unjustified 
additional risks. The use of balloon assistance for coil deployment or stents deployed after coiling is 
authorized but will be recorded. Parent vessel occlusion concomitant to endosaccular coiling can be 
performed as long as it was not the procedure’s primary intent.  
Selection criteria  
Inclusion criteria 
 
At least one ruptured or unruptured aneurysms with a dimension ≥4 mm and ≤12 mm (longest 
axis) 
 
For ruptured lesions, patients should be in WFNS grade < IV. 
 
The anatomy of the lesion is such that endovascular treatment is possible with both types of coils 
(not necessarily certain or probable) 
 
Patient is 18 or older 
 
Life expectancy is more than 2 years  
Exclusion criteria 
 
Patients with planned treatment of an associated cerebral arteriovenous malformations 
 
When parent vessel occlusion, without simultaneous endosaccular coiling of the aneurysm, is the 
primary intent of the procedure 
 
Any absolute contraindication to endovascular treatment, angiography, or anaesthesia such as 
severe allergies to contrast or medications 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 11 of 31 
 

Treatments 
Patients allocated to caliber-15 coiling will preferably receive caliber-15 coils (perhaps including a caliber-
15 framing coil (or not), as many Deltamaxx filling coils as safely achievable, but the procedure can be 
completed with caliber-10 or smaller finishing coils, in order to achieve as complete an occlusion as 
possible, keeping the procedure as safe as possible. 
Patients allocated to caliber-10 coiling will preferably receive caliber-10 coils (perhaps including a caliber-
10 framing coil, caliber-10 filling and finishing coils), once more to achieve as complete an occlusion as 
possible, keeping the procedure as safe as possible. 
Both groups will receive platinum coils only.  Balloon-assisted or stent-assisted coil embolization is 
permitted, but should be noted in the procedure CRF.   
Technical freedom  
The goal of the endovascular procedure is (as usual) to realize the most complete exclusion of the lesion 
that is judged to be possible, while keeping risks as small as possible, using the randomization algorithm’s 
assigned embolization material. At any time during the procedure the interventionist is unrestricted in the 
use any device, technique or drug judged important to the safety and success of the endovascular 
procedure.  
If a patient is randomized to 15-caliber coils but the operator prefers, for strong clinical reasons not 
initially thought of at the time of recruitment, not to deploy predominantly voluminous coils in this 
particular case, he should proceed using appropriate coils in the best interests of the patient. The 
converse is also true.  In any such case, the operator details reasons on the endovascular treatment case 
report form. Analysis will be on an intention to treat and per-protocol basis.  
Randomization 
DELTA is designed with 1:1 randomization. 
  
A minimization algorithm will be used whether the aneurysm is ruptured or unruptured and previously 
treated or not (major recurrence). 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 12 of 31 
 

Type, frequency and duration of follow-up 
For the analysis of the safety data, clinical examinations will be recorded at end of procedure, at 
discharge, and at the time of follow-up imaging (to 12 ± 2months). Follow-up CT-scan or MRI will be 
performed at 24 hrs or before discharge to detect silent periprocedural events, as standardly performed 
in each institution. In certain cases, when patients are unable or unwilling to come to the hospital for 
follow-up visits information may be collected via telephone.  Also, Rankin scores may be obtained through 
phone interviews (using a standardized questionnaire) by the study coordinator or the Principal 
Investigator.  
 
Adverse events will be recorded immediately after the procedure and during the 12-month follow-up 
period.  First, the number and nature of adverse events for each patient is recorded.  Then the relation to 
the aneurysm itself, to the endovascular coil embolization (not possibly or probably related) will be 
recorded. Clinical assessments will include the modified Rankin scale (mRS) at 6-12 months. Follow-up 
imaging studies will be performed at 12 (±2) months by either catheter angiography or non-invasive 
vascular imaging according to the preference of the participating center.  The commonly recommended 6 
month follow-up angiogram may not be sufficient to detect most recurrences.38      
 
Table 1: Schedule of Evaluation  
* According to standard of care of participating centre 
 
Evaluation 
Pre-entry 
Entry 
Treatment 
Discharge 
6 months 
12 ± 2 
months 
Informed consent 
 
x 
 
 
 
 
Documentation of 
Disease/disorder 
x 
 
 
 
 
 
Medical/treatment 
history 
x 
 
 
 
 
 
Clinical assessment 
x 
 
x 
x 
x 
x 
Neurological exam 
x 
 
 
x 
 
x 
Vascular imaging 
x 
 
x 
 
 
x 
Brain imaging 
x 
 
 
x* 
 
 
WFNS (for HSA patient) 
 
x 
 
 
 
 
mRS 
 
x 
 
x 
x 
x 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 13 of 31 
 

Outcomes 
Primary outcome 
The primary outcome determines the size of the population to be studied to reach statistical significance. 
Although the clinical significance of angiographic recurrences remains to be determined, the primary 
outcome cannot be limited to hemorrhagic events, estimated to be quite rare, in the range of 0.1-1% per 
year. New coils or embolic agents are meant to improve long-term results, including a reduction in the 
recurrence rate.   
Primary endpoint: 
The primary efficacy endpoint will mainly consist in the occurrence of a major recurrence or a residual 
aneurysm at the time of follow-up angiography at 12 (±2) months.  
An independent committee will adjudicate, for each patient, whether he or she has reached the endpoint.  
In the absence of follow-up imaging, the committee will adjudicate other potential cases of treatment 
failures (expected to be rare) such as: 
 
Hemorrhage during the follow-up period  
 
Retreatment of the same lesion by endovascular or surgical means during the follow-up 
period  
 
Occurrence or progression of a mass effect in relation to the treated aneurysm 
 
Morbidity and mortality that precludes follow-up 
 
The pilot phase of the study was powered to detect a difference of 3% in mean packing density between 
the 2 groups. 
Secondary outcomes: 
Secondary outcomes include other indices of immediate treatment success as well as standard safety 
outcomes: 
 
Procedure-related serious adverse events 
 
Initial technical success of the coiling strategy 
 
Use of adjunct devices. 
 
Number and total length of coils implanted for each type 
 
Packing density (core-lab measured) 
 
Time of fluoroscopic exposure 
 
Immediate angiograhic results according to the Montreal scale 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 14 of 31 
 

 
mRS at 1 year follow-up 
 
Major recurrence on follow-up angiography 
 
Morbidity and mortality that precludes angiographic follow-up 
 
Concerning radiographic evidence of recurrence, the angiographers at each participating center will 
ensure that best projections showing residual necks at the time of treatment are repeated during follow-
up evaluations. For the purpose of this study, only major recurrences or residual aneurysms that are of a 
size that would ideally necessitate retreatment, as judged by the core lab, will be counted. Angiographic 
results will also be scored according to a previously published classification system12 as complete 
obliteration, residual neck or residual aneurysm and groups will be compared initially and at follow-up at 
12 ± 2months. 
Recurrences will be recorded (present or absent) as they are discovered, at the routine follow-up 
assessments as clinical symptoms appear any time during the 12 months that follow the intervention. The 
independent core lab will determine the presence of angiographic recurrences. 
Initial technical success 
For the patients allocated to 15-caliber coils, the interventionists will have a choice to use 15-caliber coils 
only and/or other coils during the embolization procedure, in order to guaranty the same safety and 
immediate efficacy as the standard procedure. A study protocol deviation will be considered to have 
occurred if < 30% of coil length is 15-caliber coils.  The initial technical success or failure of the procedure 
will be determined after treatment by the adjudication committee by reviewing core lab independent 
result of procedural angiogram and coils uses as recorded in the data collection sheets.  
Mortality 
The death rate will be recorded for the intent-to-treat analyses.  It will be obtained by dividing the 
number of deaths by the number of patients in each group.  Mortality will be categorized as being a/ 
related to the illness, b/ related to coil embolization or c/ unrelated. 
Adverse events 
Adverse events will be recorded immediately after the procedure and during the 12-month follow-up 
period.  Serious adverse events (SAEs), those that are life threatening, leading to hospitalizations or 
prolonged hospitalizations, as well as unexpected events will all be reported within 48 hours to the data 
coordination centre that will transmit the information to the DSMC. The number and severity of all 
reported adverse events will be recorded for each patient and for each treatment group.  
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 15 of 31 
 

Morbidity 
The number and the severity of morbid events per patient will be recorded for each patient.  The 
modified Rankin scale will be measured at follow-up appointments.  This scale classifies the patients 
according to their neurological outcome.39   
Sample size 
A decrease in the recurrence rate from 33 to 20% would be clinically significant. Based on Fisher’s Exact 
test, a total sample size of 512 patients would allow detecting such a difference with a power of 90% and 
an alpha error of 0.05 (Table 2). A sample size of 564 patients for DELTA is sufficient to detect a decrease 
in the recurrence rate from 33 to 20% with an alpha error of 5% and a beta error of 10%, allowing 10% of 
losses at determination of the primary endpoint  
 
Table 2:  Log Rank Survival Power Analysis – Simple – Primary Hypothesis 
Two Independent Proportions (Null Case) Power Analysis 
Numeric Results of Tests Based on the Difference: P1 - P2 
H0: P1-P2=0. H1: P1-P2=D1<>0. Test Statistic: Fisher's Exact test  
 
 
Sample 
Sample 
Prop|H1 Prop 
 
 
 
 
 
 
Size 
Size 
Grp 1 or 
Grp 2 or 
Diff 
Diff 
 
 
 
 
Grp 1 
Grp 2 
Trtmnt 
Control 
if H0 
if H1 
Target 
Actual 
 
Power 
N1 
N2 
P1 
P2 
D0 
D1 
Alpha 
Alpha 
Beta 
0.9009 
256 
256 
0.2000 
0.3300 
0.0000 
-0.1300 
0.0500 
 
0,0991 
 
Summary Statements 
Group sample sizes of 256 in group one and 256 in group two achieve 90% power to detect a difference between the group proportions of -
0.1300. The proportion in group one (the treatment group) is assumed to be 0.3300 under the null hypothesis and 0.2000 under the alternative 
hypothesis. The proportion in group two (the control group) is 0.3300. The test statistic used is the two-sided Fisher's Exact test. The significance 
level of the test was targeted at 0.0500.  
 
Recruitment rate and centres 
The targeted lesions are the most frequent lesions treated in endovascular centres; thus we expect at 
least 10-20 patients per year per center. We need to recruit 20-25 centers that will recruit 10-20 
patients/year for 2-3 years to reach the necessary sample size. Centers will be experienced in 
endovascular treatment of aneurysms (at least 100 aneurysms will have been treated previously). 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 16 of 31 
 

Duration of the trial 
We plan a 3 to 4 year recruitment phase, followed by a follow-up period of 12 months for all patients. If 
we add a 6-month catch-up period the trial should be completed within 5-6 years, including data analysis. 
Planned analyses 
Descriptive statistics will be done on demographic variables and pre-operative and peri-operative data to 
compare the two groups at baseline.  Means, standard deviations and range will be presented for 
quantitative variables and frequency tables for categorical variables.  Those statistics will be broken down 
by treatment arm.  Comparability of the groups will be assessed through independent ANOVAs 
(quantitative data) or Mantel-Haentzel and chi-square tests (categorical data). For the pilot phase, the 
number of patients with satisfactory immediate angiographic results, as well as the mean packing density, 
will be compared between the 2 groups.  The primary outcome of the pivotal phase, recurrence rates (for 
both intent-to-treat end per-protocol populations) will be compared between groups through a z-test for 
independent proportions at 6 months and 12 months.  Secondary outcomes and safety data will be 
compared between groups through independent t-tests (quantitative variables) or chi-square statistics 
(categorical data). The analyses of neurological data at follow-up will control for baseline data when 
possible (for tests done before discharge and at follow-up) using logistic regression, ANCOVA or Cox 
regression multivariate models.  All tests will be interpreted with adjustment for the interim analysis to 
have the 0.05 level of confidence at 12 month only. Finally, a logistic regression will be used to find 
variables capable of predicting recurrences. The method planned is a stepwise forward with alpha < 0.05 
to enter a predictor. Possible predictors include the type of the aneurysm, location, size of the aneurysm, 
size of the neck of the aneurysm as well as other baseline characteristics. 
 
Pilot phase 
The pivotal trial will be preceded by a pilot phase of approximately 165 patients designed to verify the 
feasibility of the coiling strategy, compliance to treatment group allocation, the safety of an 15-caliber 
platinum coil embolization strategy, recruitment rates, and the capacity to improve packing density with a 
standardized effect size (E/S) of 0.60, with a power of 95% and a two-sided alpha error of 0.05 (assuming 
the packing density of the control group will be approximately 25%). The data will be reviewed and 
analyzed by the DSMC and recommendations will be forwarded to the Steering Committee regarding 
continuation into the pivotal phase of the study. 
 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 17 of 31 
 

Protection against bias 
Classic biases such as selection bias or information bias will be dealt with by randomizing patients and 
blinding in the assessment of the primary outcome. Random allocation of treatment is best for insuring 
internal validity and is the best approach to control for confounding and selection bias.  
Finally, control variables will be measured and compared between treatment groups in order to ensure 
group comparability (initial angiographic success, periprocedural events, and disease characteristics). 
Protocol compliance will be carefully monitored in every centre. 
Publication of research findings 
Publication of the results of this trial will be governed by the policies and procedures developed by the 
Steering Committee (SC).  Any presentation, abstract, or manuscript will be made available for review by 
the SC prior to submission. 
Regulatory considerations 
The study will only start after approval by the Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) of each centre. The study will be performed in accordance with the national regulatory 
requirements of each participating centre. Participants will be fully aware of the study purposes, the 
procedure and the risks of each intervention.  When signing the study consent form, they will be informed 
that participation is voluntary and they can request to be withdrawn from the study at any time. Patient 
enrolment in this trial will comply with the principles enunciated in this Declaration of Helsinki*. All the 
information collected with the questionnaires will be kept confidential and will be used on an anonymous 
basis. 
* The Declaration of Helsinki (Document 17.C) is an official policy document of the World Medical 
Association, the global representative body for physicians. It was first adopted in 1964 (Helsinki, Finland) 
and revised in 1975 (Tokyo, Japan), 1983 (Venice, Italy), 1989 (Hong Kong), 1996 (Somerset-West, South 
Africa) and 2000 (Edinburgh, Scotland). Note of clarification on Paragraph 29 added by the WMA General 
Assembly, Washington 2002. 
Trial management and coordination 
DELTA is meant to be a clinical research project within the ICONE framework.40 Trial management will be 
transparent, fully independent, and aims at preserving the scientific integrity of the research enterprise 
and the welfare of the participants. The industry has no control over the design or conduct of the trial, 
and no access to the data will be granted until publication; the results will be published whether they are 
favorable or not, and publications will be fully independent and autonomous, but as authorized by the 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 18 of 31 
 

steering committee. The steering committee will have full responsibilities regarding the conduct and 
progress of the trial, as well as reporting of results. The steering committee will not have access to the 
unmasked data before completion or interruption of the trial. The clinical events committee, the endpoint 
review committee, and the adverse event committee, once nominated, will work independently from the 
steering committee. These committees will regularly send progress reports, notices and warnings when 
appropriate, to the independent data and safety and monitoring committee (DSMC). The committees that 
will have access to unmasked data are  limited to the adverse event committee, responsible for reviewing 
each adverse event, and the DSMC, any time members judge that unmasking of groups is mandatory to 
protect the safety of participants, or once they are convinced that significantly different results have 
occurred. The DSMC will follow the progress of the trial, results and events being masked (tagged as 
group A and B) at all times, but with the possibility of unmasking results in case of necessity. The DSMC 
will inform the steering committee if the trial should be interrupted if any concern arises during the trial. 
The steering committee will act according to the DSMC recommendations.  
 
 
 
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SECTION 3:   TRIAL MANAGEMENT 
 
Investigators 
Principal Investigators  
Jean Raymond M.D., Neuroradiologist, Montreal, Canada 
 
 
Core Lab: 
 
 
TBD 
 
 
 
 
Steering Committee 
Dr Jean Raymond, M.D., Neuroradiologist 
Centre hospitalier de l'Université de Montréal Hôpital Notre-Dame, Montreal, Canada 
Dr David Kallmes, M.D., Neuroradiologist 
Mayo Clinic, Rochester, Minnesota 
Dr Jai Jai Shiva Shankar, M.D., Neuroradiologist 
Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova-Scotia, Canada. 
DELTA Steering Committee terms of reference (SC) 
The role of the SC is to provide overall supervision of the trial. In particular, the SC will concentrate on the 
progress of the trial, adherence to the protocol, patient safety and consideration of new information. Day 
to day management of the trial is the responsibility of the PI. The PI may set up a separate trial 
management group to assist with this function. 
 
Data Safety and Monitoring Committee (DSMC)  
Dr Pascale Lavoie, M.D., FRCSC 
Centre hospitalier affilié universitaire de Québec  - Hôpital de l'Enfant Jésus, Québec, Canada 
Miguel Chagnon, MSc (statistician) 
Université de Montréal, Montreal, Canada  
 
Dr Thanh Nguyen, M.D., FRCPC 
Boston University Medical Centre  
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 20 of 31 
 

Data Safety and Monitoring Committee terms of reference 
 
To consider the interim data for the trial and relevant information from other sources; 
 
To assess the progress of recruitment after 1 year. 
 
To safeguard trial participants and trial integrity; 
 
To determine how frequently interim analysis of trial data should be undertaken; 
In the light of 1-4 and ensuring that ethical considerations are of prime importance, to report (following 
each DSMC meeting) to the SC and to recommend whether the trial should continue, the  
Note:  Members of the DSMC will remain independent of the trial staff and Steering Committee. 
Imaging Center (core lab) 
  
Philip White, MD 
Department of Neuroradiology Western General Hospital, Edinburg, UK. 
 
Other committees to be determined by decision of Steering Committee 
 
Day to day management 
The steering committee will be responsible for overseeing the administrative progress of the protocol. 
The steering committee will meet to monitor patient accrual, non-compliance with the protocol at 
individual centers, to act upon recommendations of the data and safety monitoring committee (DSMC).  
 
An independent DSMC will be led by a neurologist not involved in the conduct of the trial. He will be 
assisted by 2 members: an interventionist and a statistician. The DSMC will be notified of all SAE reported 
by the clinical adjudication committee. Based on safety data, the DSMC may recommend that the steering 
committee modify or stop the trial. 
 
The clinical adjudication committee will review all clinical events and use the criteria from Appendix 3 to 
evaluate if they correspond to the clinical primary outcome definitions (hemorrhage, retreatment or 
progressive mass effect) and secondary outcome definitions. It will communicate these results to the 
DMSC. 
 
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The imaging center (Core Lab) will be blinded. This committee will determine the angiographic success of 
the initial procedure as well as the presence of angiographic recurrences shown by follow-up studies. The 
committee will be composed of two neuroradiologists. 
 
The coordinating centre will be in Montreal (Centre de Recherche du CHUM, Hôpital Notre-Dame). 
Periodic monitoring visits will be conducted all along the trial, or as needed. Data management will be 
done using a web-based application (Medscinet AB). The application is fully compliant with good clinical 
practice guidelines regarding electronic data transfer (US-FDA 21 CFR, part 11).  
 
SECTION 4:   GUIDELINES 
 
DELTA treatment plan 
1. 
Confirmation of an aneurysm ≥ 4mm and ≤ 12mm  
2. 
The aneurysm must be suitable for endovascular treatment by catheter or non-invasive 
angiography (catheter angiography required if any doubt).  
3. 
There is uncertainty over the best method of treatment.  
4. 
For elective cases, outpatient visit for baseline medical and neurological examination, including 
modified Rankin scale (mRS).  
5. 
Patient meets selection criteria. 
6. 
For elective cases, during this visit, the physician and/or assistant explain treatment options, 
uncertainty over the best option, the trial, rationale for the trial and goals to the patient and family. 
If there is interest, documents and consent forms are handed to patient. Standard blood tests and a 
pregnancy test in women of childbearing age will be performed to exclude potential 
contraindications to endovascular treatment. Following verification that inclusion and exclusion 
criteria are met, the consent form and voluntary nature of participation into the study will be 
explained to the patient.  The patient and family will be offered to sign the consent form. At this 
time, the recruitment form is filled and randomization can proceed online.  
For ruptured aneurysms, the physician will explain the treatment options including surgery to the 
patient and relatives. If endovascular treatment is to be offered, the physician will explain the 
potential benefits of using voluminous coils in terms of reducing the recurrence rate. Following 
verification that inclusion and exclusion criteria are met, the consent form and voluntary nature of 
participation into the study will be explained to the patient and relatives.  The patient and family 
will be offered to sign the consent form. At this time, the recruitment form is filled and 
randomization can proceed online. 
7. 
Randomization is automatic after the registration form is entered.  
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8. 
Elective patients are scheduled for treatment (within 1-2 months). Ruptured cases are treated as 
soon as possible as generally done. Images are sent to the coordinating centre. 
9. 
For all patients, a procedure form is completed following treatment. Pre and final images, as well as 
24 hour or at discharge CT scan, are sent to the coordinating centre. 
Discharge assessment form completed at the time of discharge. 
10. Severe adverse events are entered online or faxed within 48 hours to the coordinating centre. The 
coordination center will transmit the information to the clinical adjudication committee which will 
relay it to the DSMC. These events include haemorrhages, strokes related to the aneurysm, deaths, 
or further treatments of aneurysm. 
11. All patients will be followed at 6 and 12 months. Follow-up visits are crucial to assess any change in 
medical condition and to answer questions.   
12. For all patients, follow-up visits at 6 and 12 months and vascular imaging 12 (±2) months. Follow-up 
angiography, catheter or non-invasive, is required. Images are sent to the coordination centre.  
 
Centre requirements 
1. 
Participating centres will be regional referral centre for the treatment of intracranial aneurysms. 
They will have demonstrated a large experience in endovascular treatment of aneurysms (at least 
100 patients treated with safety records within acceptable limits (< 8% overall treatment-related 
complications; < 4% poor outcome at follow-up).  
2. 
The names of operators in each centre should be submitted to the coordinating centre. The years 
of experience and number of aneurysms treated will be kept in a confidential centre log. 
3. 
The centre will identify a local coordinator who will be responsible for all data collection. This 
person will also be responsible for ensuring maintenance of the ascertainment log. A monthly 
return will be expected to the trial office. 
4. 
Investigators are committed to provide an appropriate environment and quality care that will 
minimize losses to follow-up. 
5. 
The approval of the local ethical committee must be obtained and copies of approval must be 
lodged with the trial office. 
6. 
Participants must sign the investigator agreement form. 
 
 
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Please fax to :    
 
DELTA Coordinating Centre 
CHUM 
Fax: (514) 412-7621 
Thank you 
 
 
 
 
APPENDIX 1: REFERRAL CENTER DETAILS 
 
Complete name of the centre:   
 
City 
 
Country 
 
Contact name 
 
Email (or phone/fax information) 
 
How many aneurysms were treated by 
endovascular coiling last year? 
 
 
 
 
 
 
  
 
 
 
Does Embolization with Larger coils lead to better Treatment of Aneurysms trial 
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APPENDIX 2:   INVESTIGATOR DECLARATION AND AGREEMENT 
 
 
We wish to participate in the clinical study mentioned above.   
We have obtained approval from appropriate committees at our institution.   
We agree to conduct the investigation in accordance with the agreement, the investigational plan, the 
protocol included, other applicable regulations and conditions of approval imposed by the reviewing IRB.  
We will ensure that the requirements for obtaining informed consent are met.  
We will offer participation to all eligible patients, follow all randomized patients until the end of the 
study.   
We expect to randomize 
  patients/year.   
 
Centre name:    
 
______________________________________________ 
 
Centre address:   
 
______________________________________________ 
 
 
 
 
______________________________________________ 
 
 
 
 
______________________________________________ 
Signed on behalf of the Centre: ____________________________ 
Name (Block capitals):    
________________________________________ 
Does Embolization with Larger coils lead to better Treatment of Aneurysms trial 
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Participating interventionist names and signatures:   
 
______________________      _______________________  ______________ 
Name (Block capitals)              
   Signature                             Date (mm/dd/yy) 
 
______________________      _______________________  ______________ 
Name (Block capitals)                 Signature                                Date (mm/dd/yy) 
  
______________________      _______________________  ________________ 
Name (Block capitals)              
   Signature                             Date (mm/dd/yy) 
 
______________________      _______________________  ________________ 
Name (Block capitals)              
   Signature                             Date (mm/dd/yy) 
 
______________________      _______________________  ________________ 
Name (Block capitals)              
   Signature                             Date (mm/dd/yy) 
 
______________________      _______________________  ________________ 
Name (Block capitals)              
   Signature                             Date (mm/dd/yy) 
 
 
 
Name of the local coordinator:  _________________________________________ 
 
Telephone:   ___________________________       Fax:  ______________________ 
 
Email:           ___________________________ 
 
 
 
DELTA Protocol Version 1.8  |  June 23, 2015                                                               Page 26 of 31 
 

APPENDIX 3: ADJUDICATION OF OUTCOMES 
Primary outcome:  
An independent Committee will adjudicate, for each patient, whether he or she has reached the 
endpoint.  In the absence of follow-up imaging, the committee will adjudicate other potential cases of 
treatment failures (expected to be rare) such as: 
 
 
Hemorrhage during the follow-up period  
 
 
Retreatment of the same lesion by endovascular or surgical means during the follow-up 
period  
 
 
Occurrence or progression of a mass effect in relation to the treated aneurysm 
 
 
Morbidity and mortality that precludes follow-up 
 
The pilot phase of the study was powered to detect a difference of 3% in mean packing density between 
the 2 groups. This will be measured by the Core lab.For both types of treatment, the packing density (PD) 
will be calculated as the volume of coils (VC) over the volume of the aneurysm (VA): PD = VC/VA with VA = 
(4/3)π(length/2)(width/2)2 
 
Safety 
A.   Safety data 
Safety endpoints 
 
Mortality 
 
Morbidity (mRS ≥ 3) 
 
Combined Mortality & Morbidity(M&M) (mRS ≥ 3 at 12 months) 
 
Serious Adverse Event 
 
Endpoint assessment 
 
For all DELTA patients 
 
Separately for ruptured and unruptured DELTA  patients 
 
Causality attribution 
 
Treatment-related 
 
Strictly treatment related: any M&M associated with a procedural event or complication or 
hemorrage  
 
Possibly related: any M&M occurring within 30 days 
 
Not treatment related (> 30 days) 
 
Related to aneurysm 
 
Unrelated 
 
Safety data will be adjudicated by an independent committee. 
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Example of a table supplied to the DSMC: 
Mortality and Morbidity (mRS ≥ 3)  
 
All patients 
 
 
 
Group A 
 
Group B 
    DELTA ruptured 
 
 
 
 
 
 
    DELTA unruptured 
 
 
 
 
 
 
 
Treatment-related (within 30 days) 
    Strictly 
 
 
 
 
 
 
 
    Possibly 
 
 
 
 
 
 
 
 
Aneurysm-related (> 30 days)  
 
 
 
 
 
Not related 
(> 30 days) 
 
 
 
 
 
 
This pattern will apply to mortality, morbidity, morbi-mortality and SAEs. 
 
B.  Definitions 
 
Adverse Event 
 
Any procedural event (thromboembolic, hemorrhage, complication). 
 
During follow-up, any symptomatic event.  
 
During follow-up, any imaging finding secondary to investigation of symptom. 
 
Adverse Events will be categorized into: minor or moderate and serious 
 
Serious Adverse Event 
 
Results in death or is life threatening. 
 
Requires hospitalisation or prolongation of existing hospitalisation. 
 
Results in persistent or significant disability or incapacity or is otherwise considered medically 
significant by the investigator 
 
End of study 
 
Death 
 
No coils deployed during procedure or additional procedure 
 
12-months follow-up completed.  
 
 
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