Clinical Trial Evaluating the Effectiveness and Safety of Dvectis Single and Dvectis Double Pads in Comparison to "no Pad Use" in Patients With Chronic Lumbar Spine Pain
Phase: NA
Conditions: Back Pain, Back Disorder, Disease Lumbar Spine
Sponsor: DD-Hippero s.r.o.

STATISTICAL ANALYSIS PLAN 
 
Version: Final / 07-12-2018 
 
Protocol: DVE-17 
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STATISTICAL REPORT 
 
 
 
 
 
 
Clinical trial evaluating the effectiveness and safety of Dvectis 
Single and Dvectis Double pads in comparison to “no pad use” in 
patients with chronic lumbar spine pain  
 
Protocol code: DVE-17 
 
 
Tested devices 
Dvectis Single 
Dvectis Double 
 
Indication 
Chronic lumbar spine pain 
 
Design 
Randomized controlled clinical trial 
 
Study start 
9 Apr 2018 
 
Study end 
20 Aug 2018 
 
Principal investigator 
MUDr. Martin Holinka 
Department of Orthopaedics 
Karvinská hornická nemocnice a.s. 
Zakladatelská 975/22 
735 06 Karviná - Nové Město 
 
Contracting entity 
DD - Hippero s.r.o. 
třída Kpt. Jaroše 1922/3 
602 00 Brno 
 
Document author 
PharmTest s.r.o. 
Hradec Králové 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DOCUMENT VERSION 
 
 
 
 
 
 
Document version: Final 
 
Version date: 07-12-2018 
 
 
 
 
 
 
 
DOCUMENT VERSION HISTORY 
 
Version 
Version date 
Author 
Commentary 
Final 
07-12-2018 
Dalibor Svoboda 
Formal finalization only 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY STATISTICIAN 
Name: RNDr. Dalibor Svoboda 
PharmTest s.r.o. 
……………………………. 
……………………………. 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONTENTS 
 
 
 
1 List of Abbreviations 
6
2 Introduction 
7
2.1 Document Purpose and Objective 
7
2.2 Description of the Trial, Objectives, Hypotheses 
7
2.2.1 Trial Description 
7
2.2.2 Primary Objective, Quantity and Hypothesis 
7
2.3 
Detected changes in comparison to statistical analysis planned in study 
protocol 
7
2.4 Detected changes in comparison to statistical plan 
8
3 Analysed Populations and Number of Subjects 
9
3.1 ARS Population 
9
3.2 ITT Population 
9
3.3 PPS Population 
9
3.4 Safety Population 
10
3.5 Method of Defining Analysed Populations for Final Analysis 
10
3.6 Overview of Analysed Populations and Patient History 
11
3.7 Selection Size Calculation 
11
4 Missing Data 
13
5 Sequential and Final Analysis 
14
6 Characteristics of Study Subjects and Treatment Regimen Compliance 
15
6.1 
Demographic quantities and other quantities measured before the start of 
treatment 
15
6.1.1 Analysis 
15
6.1.2 Presentation of Results 
15
6.2 Treatment regimen compliance 
17
7 Efficacy 
18
7.1 Primary quantity 
18
7.1.1 Basic Information 
18
7.1.2 Ordering 
18
7.1.3 Final Analysis Related to Primary Hypothesis (Dvectis Single Pad) 
19
7.1.4 Final Analysis Related to Dvectis Double Pad Efficacy 
19
7.1.5 Primary Quantity Exploratory Analysis 
20
 
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7.1.6 Final Analysis of Other Clinical Trial Objectives 
20 
7.1.7 Presentation of Results 
20 
7.1.7.1 Aggregate Statistics for Primary Quantity and Related Derived 
Quantities  
20 
7.1.7.2 Final Efficacy Analyses of Both Pads (PID6) 
24 
7.1.7.3 PID6 Exploratory Analysis 
25 
7.2 Secondary Quantities 
25 
7.3 Other Quantities 
26 
7.3.1 Analysis 
26 
7.3.2 Method of Result Presentation 
27 
8 Safety Analysis 
31 
8.1 Adverse Events and Effects 
31 
8.1.1 Analysis 
31 
8.1.2 Method of Result Presentation 
31 
9 Interpretation and Summary 
32 
10 References 
34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 List of Abbreviations 
ANOVA 
Variation analysis 
ARS 
Analysed population of all randomized study subjects 
CRF 
Case Report Form 
H0 
Null hypothesis 
HA 
Alternative hypothesis 
RI 
Reliability interval 
ITT 
Analysed population defined for maximum observance of the 
Intention-To-Treat principle, i.e. including all subjects with serious deviations from 
the study protocol 
LOCF 
Last Observation Carried Forward (data imputation method) 
NOCB 
Next Observation Carried Backward (data imputation method) 
MCAR 
Missing Completely At Random (type of missing data distribution) 
PI 
The most intensive pain felt in the last 48 hours and recorded based on VAS 
PID 
Pain Intensity Difference (PI difference compared to week 1) 
PPS 
Analysed population of study subjects without serious deviation from 
the study protocol 
SAF 
Population analysed for safety assessment 
SAS 
Software products of SAS Institute 
SD 
Standard deviation 
UMVUE 
Uniform Minimum Variance Unbiased Estimator 
VAS 
Visual analogue scale 
WCS 
Worst Case Scenario (data imputation method) 
Z 
Z-statistics 
 
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2 Introduction 
 
 
2.1 Document Purpose and Objective 
 
Presentation of results of the clinical trial data statistical analysis. 
 
 
2.2 Description of the Trial, Objectives, Hypotheses 
 
2.2.1 Trial Description 
 
The trial was a monocentric, open, randomized, 3-arm clinical trial that took place at the 
Department of Orthopaedics of the Karviná Miners' Hospital (Karvinská hornická 
nemocnice a.s.). The involvement of a maximum total number of 198 patients with chronic 
lumbar spine pain was planned; the patients were randomly and evenly assigned to one 
of the 3 treatment groups: 
 
1. Use of the Dvectis Single pad;  
 
2. Use of the Dvectis Double pad;  
 
3. Use of no pad.  
 
One sequential interim analysis was planned in the middle of the clinical trial and after this 
interim analysis, the trial was stopped early due to proven efficacy. 
 
The expected period of participation of each patient in the clinical trial was 6 weeks (± 5 
days). For an overview of the individual study visits and procedures, study population and 
other detailed information, see the study protocol.  
 
According to the plan, the assessment subject was asked during Visit 1 and Visit 2 about the 
most intensive pain felt in the last 48 hours (PI). The pain was recorded by the subject in the 
visual analogue scale (VAS) in CRF under supervision of the investigator. Then the 
assessment subject recorded the intensity of their pain independently in the Patient Journal 
daily. 
 
2.2.2 Primary Objective, Quantity and Hypothesis 
 
The primary objective of the clinical trial was to assess the efficacy of using the Dvectis 
Single pad in comparison to “use of no pad” in patients suffering from chronic lumbar spine 
pain.  
 
PI was the primary quantity. 
 
The primary hypothesis was the superiority of Dvectis Single based on a check, 
assessed based on the difference in PI (PID) between week 2 and week 6 (PID6). 
 
2.3 Detected Changes in Comparison to Statistical Analysis 
Planned in Study Protocol 
 
Contrary to the study plan, the clinical trial took place in a single study centre. Contrary to 
the plans included in the study protocol, the factor of the study centre was not accounted for 
in the analyses in any way 
 
 
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and the presence of interaction between treatment and the study centre was not analysed. 
For the same reason, the plan to possibly combine small centres was not used either.  
 
There were no other changes detected in the plan of the first sequential interim analysis. 
 
 
2.4 Detected Changes in Comparison to Statistical Plan 
 
The statistical plan was prepared before the statistical analysis performance and 
formally approved. It included technical details for the statistical analysis performance 
and the method of result presentation. 
 
The only deviation from the statistical plan is related to the summaries for the treatment 
regimen compliance assessment (see Table 3 Treatment regimen compliance). The 
original plan was based on the evaluation of cumulative sitting time. However, the 
average times were analysed in reality. This is due to the fact that the cumulative (or 
individual) sitting times were not included in the data sheet, therefore they were not 
included in the analytical datasets either. From this point of view, it is an error in the 
statistical analytical plan without a practical effect. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 Analysed Populations and Number of Subjects 
 
Prior to the statistical analysis, 4 populations were defined in line with the study protocol: 
 
1. Population including all randomised subjects (ARS);  
 
2. Population of all patient with intention to treat (ITT);  
 
3. Population of patients without serious deviation from the clinical trial plan (Per-
Protocol Set  
 
– PPS);  
 
4. Safety population.  
 
Each analysed population was based on a list of its members. Although the treatment 
group could have generally been different for each patient in a different population (see 
the study protocol and statistical analysis plan), such a case did not occur (as all the 
patients were de facto placed in the group to which they were randomized). Therefore the 
real treatment group is the same as the randomization treatment group for all patients. 
This fact is not discussed further in the document.  
 
 
3.1 ARS Population 
 
The ARS population included all patients who were involved in the clinical trial and 
randomized. The ARS population was used for summaries of demographic quantities and 
other quantities established during Visit 1 in order to describe the study population.  
 
 
3.2 ITT Population 
 
In this case, this population was identical to the ARS population. According to the plan, 
ITT was not supposed to include those ARS patients for whom no PI data were 
available and those patients who entered the study repeatedly. However, such 
circumstances were not detected. The ITT population represented the primary analysed 
population for the assessment of efficacy. 
 
3.3 PPS Population 
 
According to the statistical plan, PPS was to include all ITT patients except for patients 
with a serious deviation from the clinical trial plan; a serious deviation includes: 
 
1. Failure to meet one or multiple participation criteria;  
 
2. Error in treatment allocation; 
 
3. Documented use of unauthorized concomitant medication or treatment;  
 
4. Missing PI0 value;  
 
5. More than 25% missing PI values.  
 
 
 
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6. Serious treatment regimen violation or another serious deviation from the clinical 
trial plan.  
 
The monitoring reports and discrepancy report implied: 
 
1. No study subject that has not met a participation criterion has been registered;  
 
2. No study subject with incorrectly allocated treatment has been identified;  
 
3. No use of unauthorized concomitant treatment has been documented;  
 
4. There was no PI0 value missing;  
 
5. Patients 45, 53 and 94 ended the study early; the number of PI values missing is over 
25% (83%).  
6. The following patients violated the treatment regimen in terms of non-observance of 
the minimum time of sitting on the pad (21, 23, 35, 42, 55, 57, 60, 72, 75, 76, 84, 86, 
88).  
 
Thus there was a serious deviation from the protocol in 16 study subject, i.e. 15.7%. 
 
The PPS population represented the secondary analyzed population for the assessment of 
efficacy. Its task was to demonstrate the robustness of the main clinical trial results. For 
this reason, comparisons of the tested group efficacy to the control group were used (in 
addition to ITT) in final analyses using PI in order to achieve confirmation of the main 
clinical trial conclusions. 
 
3.4 Safety Population 
 
According to the plan, the safety population should have constituted of subjects from ARS, 
except for those with whom all contact was lost immediately after Visit 1 and those who 
were placed (in reality) in one of the tested groups but were not given a pad. 
 
A pad was given to all patients in the tested groups. All contact was lost with patients 
53 and 94 and they were eliminated from the safety population. 
 
Patients in the safety population were analyzed based on the treatment groups they were 
really placed in, regardless of what group they had been randomized to. 
 
3.5 Method of Defining Analyzed Populations for Final Analysis 
 
The required analyzed populations were defined before the analysis performance according 
to the plan. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.6 Overview of Analysed Populations and Patient History 
 
 
Table 1 Numbers of subjects in treatment groups and analysed populations 
 
Dvectis 
Dvectis 
No treatment 
Total 
Single 
Double 
ARS population 
35 
34 
33 
102 
ITT population 
35 
34 
33 
102 
PPS population 
29 
25 
32 
86 
Safety population 
35 
33 
32 
100 
 
 
 
3.7 Selection Size Calculation 
 
The selection size calculation was based on the estimated difference in efficacy expressed 
by the primary quantity between the Dvectis Single group and the control group, which was 
15 mm. Due to the degree of uncertainty in expectations and considering the fact that even 
differences of approximately 10 mm are of obvious practical and clinical significance, the 
interim analysis was planned to allow the detection of this minor difference strongly 
enough, even if the original expectations had been too optimistic. 
 
The following assumptions were applied to the determination of the number of patients: 
 
1. The primary hypothesis is based on a comparison of to arms, namely the Dvectis 
Single pad and the control group. For this purpose, the Dvectis Double arm plays 
no direct role in the selection size.  
 
2. The null hypothesis is based on zero difference between the compared groups.  
 
3. The alternative hypothesis corresponds to the difference of 10 mm in favour of the 
Dvectis Single pad.  
 
4. The spread of results is the same in both compared groups, is not efficacy-
dependent and corresponds to the standard deviation of 15 mm. This value was 
estimated based on previous studies.  
5. The null hypothesis test is unilateral, at the significance level of α = 0.025.  
 
6. Test strength of 90% is required to detect the difference corresponding to the 
alternative hypothesis (regardless of the stage when the clinical trial will be 
completed).  
 
7. At most 2 sequential analyses will be performed, equidistantly. The first will be 
performed in the middle of the expected maximum number of study subjects.  
8. After the first sequential analysis (interim analysis), the study may be ended due 
to efficacy (success) based on the clearly defined completion criteria stated 
above.  
9. The test statistics limits have been determined according to Pocock (i.e. they are 
the same for both sequential analyses and guarantee the maintenance of 
cumulative probability of type I error occurrence at the previously defined level of 
significance specified in (5).  
 
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Implementation of the above assumptions resulted in the requirement of the maximum 
of 52.02 assessable subjects in each arm. To comply with the requirement of the clinical 
trial balance (i.e. the same number of subjects in the Dvectis Double pad group), a total 
of 3×52.02=156.06 of assessable subjects was required. 
 
Although the primary analysis was performed on the analyzed ITT group, due to the 
requirement of the clinical trial robustness demonstration in terms of conclusion insensitivity 
to the analyzed population selection and deviations from the clinical trial plan, the concept 
of assessability needs to be related to the analyzed population without any serious 
deviation.  
 
Taking the assumption of no more than 20% of subjects with a serious deviation from the 
clinical trial plan into account, the total of approximately 156.06/0.8=195.08 subjects had to 
be included in the clinical trial. The closest higher integer divisible by 6 (three groups x 2 
analyses) is 198. Therefore the maximum of 66 subjects in each treatment group had to be 
included in the clinical trial and the interim analysis had to be performed at the moment 
when 33 subjects were completed in the smaller of the two groups – the Dvectis Single 
group and the control group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4 Missing Data 
 
In the ARS population analyses, the missing data were be treated as missing according to 
the plan, i.e. stated in summaries as total numbers of missing data; however, they were 
excluded from the calculations of other statistics. In reality, only the time of sitting on the pad 
is of significance. 
 
In all analyses of the PI quantities, the method of imputation of the last observed value (Last 
Observation Carried Forward – LOCF) was used, in accordance with the plan. The plans for 
a situation when the PI1 would be missing were not used since the situation did not occur. 
 
The use of LOCF generally also leads to a bias but with regard to the observed decrease 
in the PI values during the patient's participation in the study in the tested groups, 
compared to the reference group, such an approach is obviously conservative.  
 
For evaluation of the Oswestry questionnaire, the use of LOCF was planned primarily at 
the level of individual questions as well as the use of the scoring manual procedure 
accounting for missing values, if any. This procedure was beyond the data administration 
and statistical analysis activities since the questionnaire was evaluated by the 
investigator, entering only the total score in the patient record sheets. 
 
If the total score was missing, it was processed similarly to the processing of missing 
values in the ARS population analysis (i.e. solely elimination from the analysis). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5 Sequential and Final Analysis 
 
The first sequential analysis was performed according to the interim analysis plan and 
resulted in early study stopping due to efficacy. A report of the first sequential analysis results 
is included in a separate document. Then the final analysis was performed, which is 
presented in this report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6 Characteristics of Study Subjects and Treatment 
Regimen Compliance 
 
For the description of the study population within the sequential interim analysis, summaries 
of demographic quantities were calculated and presented, as established before the start of 
the treatment in the scope determined by the statistical analysis plan. The summaries were 
presented for the respective treatment groups (for all 3 treatment groups). The significance 
of the differences in these characteristics was not tested. 
 
The treatment regimen compliance was evaluated by a calculation of aggregate statistics 
for the average time of the device use in the course of participation in the study. 
 
 
6.1 Demographic Quantities and Other Quantities Measured before 
the Start of Treatment 
 
6.1.1 Analysis 
 
For the analyzed quantities, summary statistics were calculated in the respective 
treatment groups and as a total. The analyzed ARS population was used.  
 
6.1.2 Presentation of Results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2 Demographics and other quantities before the start of 
treatment 
Dvectis Single 
Dvectis Double 
No treatment 
Total 
N = 35 
N = 34 
N = 33 
N = 102 
Age (year) 
29 
26 
37 
26 
Minimum 
Average (SD 1)) 
50.1 (9.1) 
45.9 (9.9) 
51.1 (7.5) 
49.0 (9.1) 
Median 
52.0 
47.0 
52.0 
50.0
Maximum 
65 
60 
63 
65 
Total 2) 
35 
34 
33 
102 
Sex, N (%) 
3 (8.6%) 
6 (17.6%) 
7 (21.2%) 
16 (15.7%) 
Male 
Female 
32 (91.4%) 
28 (82.4%) 
26 (78.8%) 
86 (84.3%) 
Total 2) 
35 
34 
33 
102 
Body weight (kg) 
Minimum 
43 
52 
53 
43 
Average (SD 1)) 
78.7 (18.3) 
78.4 (13.7) 
78.3 (16.8) 
78.5 (16.3) 
Median 
75.0 
78.5 
78.0 
77.5
Maximum 
120 
103 
123 
123 
Total 2) 
35 
34 
33 
102 
Body height (cm) 
Minimum 
153 
148 
158 
148 
Average (SD 1)) 
168.1 (8.3) 
168.4 (8.0) 
168.7 (7.3) 
168.4 (7.8) 
Median 
168.0 
168.0 
168.0 
168.0
Maximum 
189 
185 
187 
189 
Total 2) 
35 
34 
33 
102 
Pain intensity before treatment (mm VAS) 
Minimum 
45 
45 
43 
43 
Average (SD 1)) 
62.6 (14.2) 
63.0 (13.7) 
59.5 (12.8) 
61.7 (13.5) 
Median 
60.0 
60.0 
59.0 
60.0
Maximum 
98 
90 
96 
98 
Total 2) 
35 
34 
33 
102 
Analyzed population: ARS 
Dataset: Baseline 
Data image: 2018-12-05 
 
Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
 
 
 
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6.2 Treatment Regimen Compliance 
 
Table 3 Treatment regimen compliance 
 
Dvectis Single 
Dvectis Double 
No treatment 
Total
N = 35 
N = 34 
N = 33 
N = 102
 
Average daily time of sitting on the pad 
 
Minimum 
0.32 
0.42 
Not applicable 
0.32 
Average (SD 1)) 
3.496 (2.253) 
2.864 (1.472) Not applicable 
3.185 (1.921) 
Median 
2.806 
2.542 
Not applicable 
2.611 
Maximum 
8.69 
6.28 
Not applicable 
8.69 
Total 2) 
34 
33 
0 
67 
Analyzed population: ARS 
Dataset: Diary 
Data image: 2018-12-05 
 
Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7 Efficacy 
 
 
7.1 Primary Quantity 
 
7.1.1 Basic Information 
 
The primary quantity was pain intensity (PI) measured on a 100 mm visual analogue 
scale (VAS). Measurements were taken once a week in weeks 1-6 (PI1, PI2, …, PI6). 
 
The basic aggregate statistics for each treatment group were calculated and presented 
individually each week. 
 
The pain intensity difference (PID) was calculated from PIi in weeeks 2 – 6 based on the 
relationship: 
𝑃I𝐷𝑖 = 𝑃𝐼1 − 𝑃𝐼𝑖, 𝑖 = 2,…, 6 
The basic aggregate statistics for each treatment group were calculated and 
presented for the respective PIDi. 
PID6 was used for testing the primary hypothesis, statistically formulated in the 
clinical trial plan (protocol) as follows: If we mark 𝜇𝐷S the mean value PID6 for Dvectis 
Single and 𝜇𝑅ef the mean value PID6 for the control (reference) group, then the primary 
null hypothesis H0 
H0: 
𝜇𝐷S − 𝜇𝑅ef ≤ 0 
 
is tested against the alternative HA 
 
HA: 
𝜇𝐷S − 𝜇𝑅ef > 0 
 
 
unilaterally at the significance level of α = 0.025. 
 
The testing itself is not a part of the final analysis presented in this document since the 
test and the subsequent efficacy conclusion were made based on the sequential 
analysis results. 
 
The analysis of PID6 was performed in the ANOVA model. The model included the 
treatment factor and the PI1 covariate. The results are presented in the form of a standard 
ANOVA table, including the sums of type III squares (in the SAS terminology). 
 
7.1.2 Ordering 
 
Ordering is significant for the performance of the final analysis. Testing of hypotheses, 
calculations of p-values and the construction of intervals were based on the notion that the 
resulting statistics can be ordered, the ordering criterion being their extremeness while the 
null hypothesis is valid. E.g. the Z-statistics is the more extreme the higher its (absolute) 
value. The performance of sequential analyses is complicated due to the fact the result is not 
a number but a pair of numbers (M, Z), constituted by the number of the interim analysis 
(stage) when the clinical trial is stopped within the performed sequential analyses and the 
calculated Z-statistics. Therefore a method of ordering the results by extremeness had to be 
defined. The ordering definition allows decisions to be made on the probability of inequality 
 
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( 1 
, 1) > ( 2, 2) , 
Page 19 / 34 
 
 
 
for arbitrary M1, M2, Z1, Z2. However, the optimal method of ordering cannot be generally 
determined since the sequential statistics densities do not have a monotonic value 
relationship, therefore the selection criterion may not be applied with regard to the test with 
the highest power. In general, there are several intuitive options. 
 
According to the plan in the study protocol and the statistical analysis plan, the results 
related to the primary hypothesis were ordered based on stage-wise ordering (analysis time 
ordering / Fairbanks and Madsen ordering) [1]. A number of authors consider this option 
intuitively attractive, for the following reasons, among others: 
 
• 
The P-value obtained during the final analysis is lower than the level of significance 
α used in the sequential test in the interim analysis (after the first and second stage) 
only when the null hypothesis is rejected [2]. This feature is important in relation to 
the internal consistence of the results and is generally not demonstrated by other 
types of ordering.  
 
• 
When the clinical trial is stopped early, the P-value is not based on the information 
quantity, or the number of patients that would be included if the trial was not stopped 
early [2].  
 
7.1.3 Final Analysis Related to Primary Hypothesis (Dvectis Single Pad) 
 
Clinical trial stopping based on the observation of an extreme result during sequential 
analyses diverts the point estimates made in a way common for a design with a fixed 
number of patients without sequential analyses. Detailed information is given in the study 
protocol and the statistics plan. 
 
In this particular case, the clinical trial was stopped early after the first sequential interim 
analysis. This fact, with the application of the ordering described above, led to estimates 
identical to the naive 95% reliability interval calculated for the fixed selection size. 
 
7.1.4 Final Analysis Related to Dvectis Double Pad Efficacy 
 
The test of the Dvectis Double pad difference from placebo expressed an important 
secondary objective of the clinical trial, which was to allow additional statements concerning 
efficacy. The difference significance test could have been performed solely if the null 
hypothesis expressing the primary objective was rejected in any stage of the clinical trial. 
This condition was met after the first sequential analysis. The secondary hypothesis test was 
performed just once. 
 
The condition of test performance solely if the primary null hypothesis is rejected is a type 
of hierarchy testing when it is easy to maintain the total cumulative probability of type I error 
occurrence (familywise error rate) at a previously specified level α simply by the fact both 
tests are performed at the same level α individually (hierarchically), which may be formally 
proven with the use of the closed testing principle [6]. However, this procedure cannot be 
applied to sequential interim analyses exactly, therefore in the case of this clinical trial, it 
does not allow strict control of error inflation probability α. Hung [7] proposes an intuitive 
strategy based on secondary hypothesis testing at significance level α, which corresponds 
to (1-α) percentile of the standard Gaussian distribution, if the primary null hypothesis was 
rejected at the total significance level α (i.e. 
 
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total within the sequential tests). Although it is obvious this strategy may not necessarily 
result in strict control of type I error probability inflation, it does not represent a serious 
problem in this case [8]. 
 
With regard to the above, the difference between the Dvectis Double pad and placebo was 
analyzed based on a unilateral superiority test at the significance level α = 0.025, using the 
calculation of a standard bilateral 95% reliability interval for the difference between the 
tested and the control group and the establishment of its position to 0. This test rejected 
the null hypothesis (see the Results part) and is conclusive since the primary null 
hypothesis was rejected before the test performance (for Dvectis Single). 
 
7.1.5 Primary Quantity Exploratory Analysis 
 
Within the exploratory analysis, the correlation between PID6 and the recorded total average 
weekly time of sitting on the pad was investigated in the pad groups. Correlation coefficients 
were calculated and presented (Pearson correlation coefficient, Spearman order correlation 
coefficient ρ and Kendall's τ) together with p-values of the null hypothesis test values 
correlation coefficient=0. However, these p-values can serve only as indicators of interesting 
results worth further investigation; they are not aimed for drawing confirmatory conclusions. 
 
7.1.6 Final Analysis of Other Clinical Trial Objectives 
 
No other planned analyses were aimed for confirmatory purposes and they were 
processed regardless of the performed sequential analyses. 
 
7.1.7 Presentation of Results 
 
7.1.7.1 Aggregate Statistics for Primary Quantity and Related Derived Quantities  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4 PI summaries 
Dvectis Single 
Dvectis Double 
No treatment 
Total 
N = 35 
N = 34 
N = 33 
N = 102 
PI1 (mm) 
45 
45 
43 
43 
Minimum 
Average (SD 1)) 
62.6 (14.2) 
63.0 (13.7) 
59.5 (12.8) 
61.7 (13.5) 
Median 
60.0 
60.0 
59.0 
60.0 
Maximum 
98 
90 
96 
98 
Total 2) 
35 
34 
33 
102 
PI2 (mm) 
6 
17 
1 
1 
Minimum 
Average (SD 1)) 
53.1 (23.9) 
57.9 (13.5) 
60.2 (19.4) 
57.0 (19.5) 
Median 
60.0 
59.0 
59.0 
59.0 
Maximum 
98 
91 
94 
98 
Total 2) 
35 
34 
33 
102 
PI3 (mm) 
2 
26 
4 
2 
Minimum 
Average (SD 1)) 
46.4 (23.5) 
50.6 (12.8) 
61.4 (17.7) 
52.7 (19.4) 
Median 
52.0 
50.5 
60.0 
55.0 
Maximum 
98 
77 
95 
98 
Total 2) 
35 
34 
33 
102 
PI4 (mm) 
0 
14 
3 
0 
Minimum 
Average (SD 1)) 
39.5 (24.6) 
42.1 (14.7) 
61.3 (20.1) 
47.4 (22.3) 
Median 
45.0 
42.0 
61.0 
49.5 
Maximum 
98 
73 
98 
98 
Total 2) 
35 
34 
33 
102 
PI5 (mm) 
0 
3 
4 
0 
Minimum 
Average (SD 1)) 
34.4 (22.3) 
32.4 (17.3) 
61.9 (20.6) 
42.6 (24.1) 
Median 
30.0 
28.5 
65.0 
42.5 
Maximum 
98 
72 
95 
98 
Total 2) 
35 
34 
33 
102 
PI6 (mm) 
2 
1 
2 
1 
Minimum 
Average (SD 1)) 
26.9 (23.5) 
25.6 (16.9) 
61.4 (18.2) 
37.6 (25.6) 
Median 
20.0 
19.5 
62.0 
39.0 
Maximum 
98 
64 
92 
98 
Total 2) 
35 
34 
33 
102 
Analyzed population: ITT 
Dataset: VasPid 
Data image: 2018-12-05 
 
 
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Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 5 PID summaries 
Dvectis Single 
Dvectis Double 
No treatment 
Total 
N = 35 
N = 34 
N = 33 
N = 102 
PID2 (mm) 
-29 
-20 
-32 
-32 
Minimum 
Average (SD 1)) 
9.5 (24.1) 
5.1 (13.7) 
-0.6 (19.7) 
4.8 (19.9) 
Median 
2.0 
0.0 
-2.0 
0.5 
Maximum 
73 
40 
84 
84 
Total 2) 
35 
34 
33 
102 
PID3 (mm) 
-24 
-10 
-25 
-25 
Minimum 
Average (SD 1)) 
16.1 (24.1) 
12.4 (13.4) 
-1.8 (18.9) 
9.1 (20.7) 
Median 
10.0 
9.0 
-4.0 
4.5 
Maximum 
77 
47 
81 
81 
Total 2) 
35 
34 
33 
102 
PID4 (mm) 
-18 
-5 
-43 
-43 
Minimum 
Average (SD 1)) 
23.1 (25.3) 
20.9 (16.7) 
-1.8 (20.7) 
14.3 (23.8) 
Median 
18.0 
19.0 
-2.0 
12.0 
Maximum 
78 
74 
82 
82 
Total 2) 
35 
34 
33 
102 
PID5 (mm) 
-11 
-27 
-34 
-34 
Minimum 
Average (SD 1)) 
28.2 (23.3) 
30.6 (22.2) 
-2.4 (20.7) 
19.1 (26.5) 
Median 
30.0 
32.5 
-7.0 
19.0 
Maximum 
73 
87 
81 
87 
Total 2) 
35 
34 
33 
102 
PID6 (mm) 
-7 
-14 
-32 
-32 
Minimum 
Average (SD 1)) 
35.7 (25.0) 
37.4 (21.3) 
-1.9 (19.8) 
24.1 (28.5) 
Median 
40.0 
38.0 
-5.0 
26.5 
Maximum 
82 
89 
83 
89 
Total 2) 
35 
34 
33 
102 
Analyzed population: ITT 
Dataset: VasPid 
Data image: 2018-12-05 
 
Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
 
 
 
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7.1.7.2 Final Efficacy Analyses of Both Pads (PID6) 
 
Table 6 PID6 – Analysis of variance (ITT population) 
 
Degrees 
Sum 
Mean 
F-value p-value
of freedom1) 
of 
squares 
square 
Treatment group 
2 
28467 
14233.4 
36.871
<.0001 
Pain intensity at Visit 1 
1 
10986 
10986.1 
28.459
<.0001 
Residues 
98 
37831 
386.0 
Analyzed population: ITT 
Dataset: 
VasPid Data image:
2018-12-05 
 
Comments: 
 
1) Type III based on SAS terminology  
 
 
 
Table 7 PID6 – Estimates of differences between treatment groups (ITT population) 
 
Estimate 1) SE 2) 
95% RI 3) 
Dvectis Single – Dvectis 
Double 
-1.4 
4.7 
-10.8
- 8.0 
Dvectis Single-control 
35.2 
4.8 
25.7 - 44.7 
Dvectis Double-control 
36.6 
4.8 
27.0 - 46.2 
Analyzed population: ITT 
Dataset: VasPid 
Data image:
2018-12-05
 
Comments: 
 
1) Point estimate of difference.  
 
2) Standard error of the estimate difference.  
 
3) Final 95% interval of reliability for the difference in treatments, without correction 
to the comparison-wise error rate. For defined ordering and with the condition of 
stopping after the first interim analysis for success/efficacy being met, this interval 
is identical to the usual 95% reliability interval not taking interim into account. 
Compliance with the condition of early stopping is presented in the interim analysis 
results.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 8 PID6 – Estimates of differences between treatment groups (PPS population) 
 
Estimate 1) SE 2) 
95% RI 3) 
Dvectis Single – Dvectis 
Double 
-1.4 
5.1 
-11.6
- 8.8 
Dvectis Single-control 
34.7 
4.8 
25.1 - 44.3 
Dvectis Double-control 
36.1 
5.0 
26.1 - 46.2 
Analyzed population: PPS 
Dataset: VasPid 
Data image: 2018-12-05 
 
Comments: 
 
1) Point estimate of difference.  
 
2) Standard error of the estimate difference.  
 
3) Final 95% interval of reliability for the difference in treatments, without correction 
to the comparison-wise error rate. For defined ordering and with the condition of 
stopping after the first interim analysis for success/efficacy being met, this interval 
is identical to the usual 95% reliability interval not taking interim into account. 
Compliance with the condition of early stopping is presented in the interim analysis 
results.  
 
7.1.7.3 PID6 Exploratory Analysis 
 
Table 9 Correlation coefficients and p-values for correlation between PID6 
and the average time of pad use 
 
Dvectis Single 
Dvectis Double 
coefficient 
p-value coefficient p-value 
Pearson correlation coefficient r 
-0.0716 
0.6875
-0.1954 
0.2759 
Kendall correlation coefficient τ 
0.0339 
0.7779
-0.0758 
0.5350 
Spearman coefficient ρ 
0.0268 
0.8785
-0.1569 
0.3754 
Analyzed population: ITT  
Dataset: 
Correlation 
Data image: 2018-12-05 
 
Comments: 
 
The presented p-values relate to the null hypothesis of zero correlation between the 
quantities. 
 
 
 
 
7.2 Secondary Quantities 
 
No secondary quantities have been defined in the trial plan for efficacy. 
 
 
 
 
 
 
 
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7.3 Other Quantities 
 
7.3.1 Analysis 
 
Other quantities were processed within the exploratory analysis. The clinical trial was not 
planned in order to reject the potential hypotheses tested for these quantities with 
determined power. Test p-values can serve as indicators of interesting results worth 
further investigation; however, they cannot be used for drawing confirmatory 
conclusions. 
 
The number of days when any analgesic treatment was used at least once was summarized 
and presented for the respective treatment groups. The use of nimesulide was summarized 
and presented in the same way. 
 
The data recorded in the Oswestry questionnaire were evaluated in accordance with the 
scoring manual *. Aggregate statistics for Visit 2 and the difference between Visit 2 and 
Visit 1 were calculated and presented. 
 
Strengthening of lumbar spine stabilizing muscles was summarized. The results were 
presented based on the treatment groups. The correlation between muscle strengthening 
and recorded total cumulative time of sitting on the pad was investigated in the pad groups. 
Correlation coefficients were calculated and presented (Pearson, Spearman and Kendall’s 
tau) together with the null hypothesis test values correlation coefficient=0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* The total score was evaluated by the investigator and filled in the patient's record sheet. Therefore 
the scoring manual procedure following was not a direct part of the analysis. 
 
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7.3.2 Method of Result Presentation 
 
Table 10 Summaries for painkiller use 
 
Dvectis Single 
Dvectis Double 
No 
treatment 
Total 
N = 35 
N = 34 
N = 33 
N = 102 
Number of days when analgesic treatment was used 
Minimum 
0 
0 
0 
0 
Average (SD 1)) 
3.7 (6.1) 
4.0 (8.9) 
14.7 (13.6) 
7.4 (11.1) 
Median 
0.0 
0.0 
14.0 
2.0 
Maximum 
25 
42 
42 
42 
Total 2) 
34 
33 
32 
99 
Number of days when nimesulide was used 
Minimum 
0 
0 
0 
0 
Average (SD 1)) 
0.8 (2.6) 
1.6 (7.3) 
8.0 (11.5) 
3.4 (8.5) 
Median 
0.0 
0.0 
0.0 
0.0 
Maximum 
13 
42 
42 
42 
Total 2) 
34 
33 
32 
99 
Analyzed population: ITT 
Dataset: Diary 
Data image: 2018-12-05 
 
Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 11 Summaries of sonographic examinations 
Dvectis Single 
Dvectis Double 
No treatment 
Total 
N = 35 
N = 34 
N = 33 
N = 102 
 
Bederní m. multifidus vlevo, návštěva 1 (cm) 
 
Minimum 
1.06 
0.94 
0.90 
0.90 
Average (SD 1)) 
1.527 (0.322) 
1.484 (0.334) 
1.678 (0.510) 
1.561 (0.401) 
Median 
1.500 
1.390 
1.480 
1.440 
Maximum 
2.50 
2.50 
2.78 
2.78 
Total 2) 
35 
34 
33 
102 
 
Lumbar m. multifidus left, Visit 2 (cm) 
 
Minimum 
1.10 
1.03 
0.92 
0.92 
Average (SD 1)) 
1.551 (0.323) 
1.499 (0.310) 
1.629 (0.476) 
1.560 (0.376) 
Median 
1.500 
1.415 
1.485 
1.460 
Maximum 
2.50 
2.52 
2.76 
2.76 
Total 2) 
34 
32 
32 
98 
 
Lumbar m. multifidus left, change since Visit 1 at Visit 2 (cm) 
 
Minimum 
-0.06 
-0.03 
-0.31 
-0.31 
Average (SD 1)) 
0.029 (0.031) 
0.032 (0.025) 
-0.033 (0.107) 
0.010 (0.071) 
Median 
0.030 
0.035 
-0.005 
0.020 
Maximum 
0.09 
0.09 
0.25 
0.25 
Total 2) 
34 
32 
32 
98 
 
Lumbar m. multifidus right, Visit 1 (cm) 
 
Minimum 
1.01 
0.95 
0.97 
0.95 
Average (SD 1)) 
1.526 (0.332) 
1.483 (0.353) 
1.684 (0.486) 
1.563 (0.400) 
Median 
1.560 
1.435 
1.560 
1.480 
Maximum 
2.30 
2.60 
2.89 
2.89 
Total 2) 
35 
34 
33 
102 
 
Lumbar m. multifidus right, Visit 2 (cm) 
 
Minimum 
1.06 
1.02 
0.94 
0.94 
Average (SD 1)) 
1.554 (0.320) 
1.513 (0.347) 
1.620 (0.462) 
1.562 (0.379) 
Median 
1.525 
1.450 
1.465 
1.460 
Maximum 
2.30 
2.64 
2.80 
2.80 
Total 2) 
34 
32 
32 
98 
 
Lumbar m. multifidus right, change since Visit 1 at Visit 2 (cm) 
 
Minimum 
-0.10 
0.00 
-0.34 
-0.34 
Average (SD 1)) 
0.034 (0.034) 
0.038 (0.026) 
-0.047 (0.084) 
0.009 (0.066) 
Median 
0.040 
0.040 
-0.020 
0.020 
Maximum 
0.09 
0.09 
0.06 
0.09 
Total 2) 
34 
32 
32 
98 
Analyzed population: ITT 
Dataset: Sono 
Data image: 2018-12-05 
 
 
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Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
Table 12 Correlation coefficients and p-values for correlation between the 
changes in sonography results and average time of pad use 
 
Dvectis Single 
Dvectis Double 
coefficient 
p-value coefficient p-value 
Sono left (change) 
-0.1563 
0.3773
0.0968 
0.5980 
Pearson correlation coefficient r 
Kendall correlation coefficient τ 
-0.1034 
0.3863
0.0827 
0.5014 
Spearman coefficient ρ 
-0.1657 
0.3415
0.0873 
0.6276 
Sono right (change) 
-0.0674 
0.7047
0.2108 
0.2468 
Pearson correlation coefficient r 
Kendall correlation coefficient τ 
-0.1070 
0.3697
0.1190 
0.3343 
Spearman coefficient ρ 
-0.1645 
0.3452
0.1620 
0.3675 
Analyzed population: ITT  
Dataset: Correlation 
Data image: 2018-12-05 
 
Comments: 
 
The presented p-values relate to the null hypothesis of zero correlation between the 
quantities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 13 Oswestry 
Dvectis Single 
Dvectis Double 
No treatment 
Total 
N = 35 
N = 34 
N = 33 
N = 102 
Oswestry score after Visit 1 
Minimum 
6 
4 
0 
0 
Average (SD 1)) 
26.5 (13.4) 
21.2 (11.6) 
26.9 (13.6) 
24.9 (13.1) 
Median 
22.0 
19.0 
26.0 
22.0 
Maximum 
64 
50 
56 
64 
Total 2) 
35 
34 
33 
102 
Oswestry score at Visit 2 
Minimum 
4 
2 
2 
2 
Average (SD 1)) 
17.5 (10.4) 
11.7 (9.0) 
28.6 (14.1) 
19.2 (13.2) 
Median 
16.0 
9.0 
28.0 
18.0 
Maximum 
46 
36 
68 
68 
Total 2) 
34 
32 
32 
98 
Oswestry score change at Visit 2 since Visit 1 
Minimum 
-34 
-44 
-24 
-44 
Average (SD 1)) 
-8.0 (9.2) 
-8.9 (8.9) 
1.7 (13.0) 
-5.1 (11.5) 
Median 
-8.0 
-8.0 
0.0 
-5.0 
Maximum 
17 
4 
38 
38 
Total 2) 
34 
32 
32 
98 
Analyzed population: ITT 
Dataset: Oswestry 
Data image: 2018-12-05 
 
Comments: 
 
1) SD = Standard deviation.  
 
2) Number of analyzed data (without missing values).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8 Safety Analysis 
 
 
8.1 Adverse Events and Effects 
 
8.1.1 Analysis 
 
Summaries of adverse event and effect occurrences in the predefined categories stated in 
CRF were calculated. The summaries included numbers and percentages of subjects with 
the occurrence of a given event/effect in the respective categories and in total individually for 
the treatment groups and in total. 
 
8.1.2 Method of Result Presentation 
 
Table 14 Safety summary 
 
Dvectis Single 
Dvectis Double 
No treatment 
Total 
N = 35 
N = 33 
N = 32 
N = 100 
Headache 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Up. r. 
inflammation1) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Dizziness 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypertension 
0 (0.0%) 
0 (0.0%) 
1 (3.1%) 
1 (1.0%) 
Dyspnea 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Diarrhoea 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Constipation 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Nausea 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Vomiting 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Flatulence 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Rash 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Other 
3 (8.6%) 
3 (9.1%) 
1 (3.1%) 
7 (7.0%) 
Any 
3 (8.6%) 
3 (9.1%) 
2 (6.3%) 
8 (8.0%) 
Analyzed population: SAF 
Dataset: AeList 
Data image: 2018-12-05 
 
Comments: 
 
The table includes numbers of subjects with the incidence of the above adverse events 
and effects, not the numbers of adverse events or effects 
 
1) Up. r. inflammation = Upper respiratory inflammation 
 
 
 
 
 
 
 
 
 
 
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9 Interpretation and Summary 
 
Demographic and other quantities were summarized before the start of the treatment for 
reasons of study population description (Table 2). Testing of differences between the groups 
was not the focus; there are no significant differences. Treatment regimen compliance was 
summarized (Table 3). The average time of sitting on the Dvectis Single pad is about 
3,5 hours and is approximately 40 minutes longer than for Dvectis Double. The difference is 
probably not statistically significant; however, a formal test was not planned or performed. 
 
The study was stopped early after the 1st sequential interim analysis based on 
compliance with the criteria for early study stopping for efficacy using Pocock’s method in 
accordance with the study protocol plan. The sequential interim analysis that led to it is 
presented in a separate report. 
 
Pain intensities and their differences from the initial value were summarized (Table 4 and 
Table 5). The treatment factor and pain value at Visit 1 have a statistically significant 
impact on the PID6 primary quantity values (Table 6). 
 
95% reliability intervals were calculated for the differences between the treatment groups 
for the primary quantity (Table 7). For the difference between Dvectis Single - control, this 
interval does not include zero, therefore the result is consistent with the pad efficacy 
statement within evaluation of the early stopping criteria, i.e. it is statistically significant. The 
interval for the Dvectis Double - control difference does not include zero either. On the 
other hand, the interval for difference between the pads does include zero, and therefore is 
not significant. 
 
The statistical significance stated in the previous paragraph relates to the significance level 
 
α = 0.05 (and α = 0.025 unilaterally, respectively). Its maintenance is guaranteed:  
 
• 
Correct sequential interim analysis performance;  
 
• 
Compliance with the early study stopping criterion after the first sequential 
interim analysis using Pocock’s method due to the Dvectis Single pad 
efficacy;  
• 
Consistent result for Dvectis Single during the final analysis;  
 
• 
The result for Dvectis Double was performed after the compliance with the 
condition of null hypothesis rejection for Dvectis Single.  
 
With regard to the use of the stage-wise ordering (analysis time ordering / Fairbanks and 
Madsen ordering) [1] and to the fact that there was early stopping after the first analysis, the 
presented reliability intervals are identical to the naive bilateral 95% reliability intervals for 
fixed selection size. 
 
Robustness of the results was successfully confirmed by an alternative population 
analysis (Table 8). Therefore both pads can be claimed efficacious. 
 
The exploratory analyses of correlations between the effect and time of pad use do 
not show statistically significant values (Table 9). 
 
Other exploratory analyses are presented as summaries. They imply lower use of 
analgesics when the pads are used in comparison to control (Table 10) in particular, and 
possibly some other changes, probably without statistical significance. 
 
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Safety summary in terms of a comparison of the treatment groups is not conclusive due to 
low frequencies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10 References 
 
[1] 
A. A. Tsiatis, G. L. Rosner, and C. R. Mehta, “Exact confidence intervals following a 
group sequential test,” Biometrics, vol. 40, no. 3, pp. 797–803, Sep. 1984.  
 
[2] C. Jennison and B. W. Turnbull, Group sequential methods with applications to 
clinical trials. Boca Raton: Chapman & Hall/CRC, 2000.  
 
[3] S. S. Emerson and T. R. Fleming, “Parameter Estimation Following Group 
Sequential Hypothesis Testing,” Biometrika, vol. 77, no. 4, p. 875, Dec. 1990.  
 
[4] S. S. Emerson and J. M. Kittelson, “A Computationally Simpler Algorithm for 
the UMVUE of a Normal Mean Following a Group Sequential Trial,” 
Biometrics, vol. 53, no. 1, p. 365, Mar. 1997.  
 
[5] S. S. Emerson, “S+SeqTrial: Technical Overview.” University Washington, 2007.  
 
[6] R. Marcus, E. Peritz, and K. R. Gabriel, “On Closed Testing Procedures with 
Special Reference to Ordered Analysis of Variance,” Biometrika, vol. 63, no. 
3, p. 655, Dec. 1976.  
 
[7] H. M. J. Hung, S.-J. Wang, and R. O’Neill, “Statistical Considerations for Testing 
Multiple Endpoints in Group Sequential or Adaptive Clinical Trials,” J. Biopharm. 
Stat., vol. 17, no. 6, pp. 1201–1210, Nov. 2007.  
 
[8] 
A. C. Tamhane, C. R. Mehta, and L. Liu, “Testing a Primary and a Secondary Endpoint in 
a Group Sequential Design,” Biometrics, vol. 66, no. 4, pp. 1174–1184, Dec. 2010.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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