Clinical Trial Results:
Developmental Clinical Studies  Reversing endometrial glucocorticoid deficiency in heavy menstrual bleeding
Summary


EudraCT number 
201200340598 
Trial protocol 
GB 
Global end of trial date 
29 Mar 2018

Results information


Results version number 
v1(current) 
This version publication date 
01 Jan 2020

First version publication date 
01 Jan 2020

Other versions 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
dexFEMv2


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01769820  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
ACCORD University of Edinburgh & NHS Lothian


Sponsor organisation address 
QMRI 49 Little France Cres, Edinburgh, United Kingdom, EH16 4TJ


Public contact 
ACCORD enquiries, Research Governance & QA Office, +44 01312426226, enquiries@accord.scot


Scientific contact 
Ray French, Research Governance & QA Office, +44 01312426226, resgov@accord.scot


Sponsor organisation name 
ACCORD NHS Lothian


Sponsor organisation address 
QMRI, 49 LIttle France Cres, Edinburgh, United Kingdom,


Public contact 
Enquiries, ACCORD, NHS Lothian, +44 1312423328, enquiries@accord.scot


Scientific contact 
Fiona McArdle, ACCORD, NHS Lothian, +44 1312423328, enquiries@accord.scot


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
03 Sep 2018


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
29 Mar 2018


Global end of trial reached? 
Yes


Global end of trial date 
29 Mar 2018


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
Workup studies (Studies 1&2): To gather preliminary safety and efficacy data from firstinHeavy Menstrual Bleeding use of oral dexamethasone, in women suffering from objectively verified Heavy Menstrual Bleeding (HMB) Adaptive RCT (Study 3): To identify the optimal dose of oral dexamethasone for reduction of Heavy Menstrual Bleeding in women with objectively verified HMB.


Protection of trial subjects 
Trial was carried out under Medicines for Human Use (Clinical Trials) Regulations and ICH GCP. Trial participants were supported throughout the trial by experienced research nurses and clinical researchers.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
03 Dec 2012


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
United Kingdom: 107


Worldwide total number of subjects 
107


EEA total number of subjects 
107


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
0


Adolescents (1217 years) 
0


Adults (1864 years) 
107


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
Recruitment to the adaptive randomised trial took place between 2014 and 2018. First patient was consented for screening on 29/01/2014, first patient randomised on 01/07/2014 and the last visit for last patient was on 29/03/2018.  
Preassignment


Screening details 
Recruitment in Lothian (Scotland) via gynaecology outpatient clinics; family medicine; media advertising. Women aged 18 years or over; reporting regular 2842 day menstrual cycles; complaining of Heavy Menstrual Bleeding; with measured volume of menstrual blood loss (MBL) across two screening cycles (menstrual periods) averaging ≥ 50mL.  
Period 1


Period 1 title 
Overall trial (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor  
Blinding implementation details 
Computergenerated pseudorandom numbers were used to generate the randomised allocation sequence. A webbased randomisation system ensured the allocation sequence was concealed from researchers, clinical staff and participants. To maintain concealment, bulk supplies of placebo and Dexamethasone were held by hospital pharmacy who dispensed trial medication in bottles labelled with a unique randomisation number from the list provided by the Edinburgh clinical trials unit.


Arms


Are arms mutually exclusive 
Yes


Arm title

placebo  
Arm description 
placebo capsule taken orally, twice daily over 5 days.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
PLacebo capsule, Lactose Ph Eur, taken twice daily over 5 days


Arm title

Dexamethasone 0.4mg  
Arm description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.4mg  
Arm type 
Experimental  
Investigational medicinal product name 
Dexamethasone


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
twice daily Dexamethasone 0.2mg over 5 days ; total dose 0.4mg


Arm title

Dexamethasone 0.8mg  
Arm description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.8mg  
Arm type 
Experimental  
Investigational medicinal product name 
Dexamethasone


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
twice daily oral Dexamethasone 0.4mg; total daily dose 0.8mg


Arm title

Dexamethasone 1.0mg  
Arm description 
Dexamethasone taken orally twice daily over 5 days: total daily dose is 1.0mg  
Arm type 
Experimental  
Investigational medicinal product name 
Dexamethasone


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
Dexamethasone 0.5mg taken orally twice daily over 5 days;total dose 1.0mg


Arm title

Dexamethasone 1.2mg  
Arm description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.2mg  
Arm type 
Experimental  
Investigational medicinal product name 
Dexamethasone


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
Dexamethasone 0.6mg taken orally twice daily;total dose 1.2mg


Arm title

Dexamethasone 1.5mg  
Arm description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.5mg  
Arm type 
Experimental  
Investigational medicinal product name 
Dexamethasone


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
Dexamethasone 0.75mg taken orally twice daily;total dose 1.5mg


Arm title

Dexamethasone 1.8mg  
Arm description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.8mg  
Arm type 
Experimental  
Investigational medicinal product name 
Dexamethasone


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule, hard


Routes of administration 
Oral use


Dosage and administration details 
Dexamethasone 0.9mg taken orally twice daily;total dose 1.8mg





Baseline characteristics reporting groups


Reporting group title 
placebo


Reporting group description 
placebo capsule taken orally, twice daily over 5 days.  
Reporting group title 
Dexamethasone 0.4mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.4mg  
Reporting group title 
Dexamethasone 0.8mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.8mg  
Reporting group title 
Dexamethasone 1.0mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days: total daily dose is 1.0mg  
Reporting group title 
Dexamethasone 1.2mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.2mg  
Reporting group title 
Dexamethasone 1.5mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.5mg  
Reporting group title 
Dexamethasone 1.8mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.8mg  



End points reporting groups


Reporting group title 
placebo


Reporting group description 
placebo capsule taken orally, twice daily over 5 days.  
Reporting group title 
Dexamethasone 0.4mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.4mg  
Reporting group title 
Dexamethasone 0.8mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.8mg  
Reporting group title 
Dexamethasone 1.0mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days: total daily dose is 1.0mg  
Reporting group title 
Dexamethasone 1.2mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.2mg  
Reporting group title 
Dexamethasone 1.5mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.5mg  
Reporting group title 
Dexamethasone 1.8mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.8mg 


End point title 
Bayesian analysis of change in mean MBL: Dex 0.4mg ^{[1]}  
End point description 
Note: The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Primary


End point timeframe 
Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months


Notes [1]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis of change in mean MBL: Dex 0.4mg  
Statistical analysis description 
The doseresponse curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying doseresponse curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).


Comparison groups 
Dexamethasone 0.4mg v placebo


Number of subjects included in analysis 
29


Analysis specification 
Prespecified


Analysis type 
superiority ^{[2]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
28  
upper limit 
23  
Variability estimate 
Standard deviation


Dispersion value 
12.11


Notes [2]  As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Bayesian analysis of change in mean MBL: Dex 0.8mg ^{[3]}  
End point description 
Note: The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Primary


End point timeframe 
Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months


Notes [3]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis of change in mean MBL: Dex 0.4mg  
Statistical analysis description 
The doseresponse curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying doseresponse curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).


Comparison groups 
placebo v Dexamethasone 0.8mg


Number of subjects included in analysis 
33


Analysis specification 
Prespecified


Analysis type 
superiority ^{[4]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
12


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
41  
upper limit 
9  
Variability estimate 
Standard deviation


Dispersion value 
12.75


Notes [4]  As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Bayesian analysis of change in mean MBL: Dex 1.0mg ^{[5]}  
End point description 
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Primary


End point timeframe 
Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months


Notes [5]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis of change in mean MBL: Dex 1.0mg  
Statistical analysis description 
The doseresponse curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying doseresponse curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).


Comparison groups 
placebo v Dexamethasone 1.0mg


Number of subjects included in analysis 
45


Analysis specification 
Prespecified


Analysis type 
superiority ^{[6]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
8


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
29  
upper limit 
13  
Variability estimate 
Standard deviation


Dispersion value 
10.43


Notes [6]  As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Bayesian analysis of change in mean MBL: Dex 1.2mg ^{[7]}  
End point description 
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Primary


End point timeframe 
Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months


Notes [7]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis of change in mean MBL: Dex 1.2mg  
Statistical analysis description 
The doseresponse curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying doseresponse curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).


Comparison groups 
placebo v Dexamethasone 1.2mg


Number of subjects included in analysis 
32


Analysis specification 
Prespecified


Analysis type 
superiority ^{[8]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
28  
upper limit 
24  
Variability estimate 
Standard deviation


Dispersion value 
13.19


Notes [8]  As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Bayesian analysis of change in mean MBL: Dex 1.5mg ^{[9]}  
End point description 
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Primary


End point timeframe 
Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months


Notes [9]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis of change in mean MBL: Dex 0.4mg  
Statistical analysis description 
The doseresponse curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying doseresponse curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).


Comparison groups 
placebo v Dexamethasone 1.5mg


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
superiority ^{[10]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
15


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
37  
upper limit 
8  
Variability estimate 
Standard deviation


Dispersion value 
11.53


Notes [10]  As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Bayesian analysis of change in mean MBL: Dex 1.8mg ^{[11]}  
End point description 
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Primary


End point timeframe 
Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months


Notes [11]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis of change in mean MBL: Dex 1.8mg  
Statistical analysis description 
The doseresponse curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying doseresponse curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).


Comparison groups 
placebo v Dexamethasone 1.8mg


Number of subjects included in analysis 
40


Analysis specification 
Prespecified


Analysis type 
superiority ^{[12]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
25


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
49  
upper limit 
1  
Variability estimate 
Standard deviation


Dispersion value 
12.21


Notes [12]  As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Change from screening in diaryassessed volume of MBL:Dex 0.4mg ^{[13]}  
End point description 
The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume.
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Secondary


End point timeframe 
Two screening menstrual cycles to 3 treatment cycles: average time period was 5 months


Notes [13]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis:change in mean MBL diary score  
Statistical analysis description 
Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diaryassessed volume of menstrual blood loss.
The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals


Comparison groups 
Dexamethasone 0.4mg v placebo


Number of subjects included in analysis 
30


Analysis specification 
Prespecified


Analysis type 
superiority ^{[14]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
15


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
59  
upper limit 
23  
Variability estimate 
Standard deviation


Dispersion value 
20.51


Notes [14]  As we used Bayesian analysis the precision/dispersion is actually 95% 'Credible Intervals'  and not Confidence intervals. 


End point title 
Change from screening in diaryassessed volume of MBL:Dex 0.8mg ^{[15]}  
End point description 
The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume.
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Secondary


End point timeframe 
Two screening menstrual cycles to 3 treatment cycles  average time period is 5 months


Notes [15]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis:change in mean MBL diary score  
Statistical analysis description 
Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diaryassessed volume of menstrual blood loss.
The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals


Comparison groups 
placebo v Dexamethasone 0.8mg


Number of subjects included in analysis 
34


Analysis specification 
Prespecified


Analysis type 
superiority ^{[16]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
30


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
76  
upper limit 
7  
Variability estimate 
Standard deviation


Dispersion value 
21.58


Notes [16]  The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals 


End point title 
Change from screening in diaryassessed volume of MBL:Dex 1.0mg ^{[17]}  
End point description 
The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume.
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Secondary


End point timeframe 
Two screening menstrual cycles to 3 treatment cycles  average time period is 5 months


Notes [17]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis:change in mean MBL diary score  
Statistical analysis description 
Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diaryassessed volume of menstrual blood loss.
The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals


Comparison groups 
placebo v Dexamethasone 1.0mg


Number of subjects included in analysis 
46


Analysis specification 
Prespecified


Analysis type 
superiority ^{[18]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
40  
upper limit 
24  
Variability estimate 
Standard deviation


Dispersion value 
16.17


Notes [18]  The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals 


End point title 
Change from screening in diaryassessed volume of MBL:Dex 1.2mg ^{[19]}  
End point description 
The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume.
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Secondary


End point timeframe 
Two screening menstrual cycles to 3 treatment cycles  average time period is 5 months


Notes [19]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis:change in mean MBL diary score  
Statistical analysis description 
Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diaryassessed volume of menstrual blood loss.
The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals


Comparison groups 
placebo v Dexamethasone 1.2mg


Number of subjects included in analysis 
33


Analysis specification 
Prespecified


Analysis type 
superiority ^{[20]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
41  
upper limit 
36  
Variability estimate 
Standard deviation


Dispersion value 
19.85


Notes [20]  The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals 


End point title 
Change from screening in diaryassessed volume of MBL:Dex 1.5mg ^{[21]}  
End point description 
The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume.
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Secondary


End point timeframe 
Two screening menstrual cycles to 3 treatment cycles  average time period is 5 months


Notes [21]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis:change in mean MBL diary score  
Statistical analysis description 
Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diaryassessed volume of menstrual blood loss.
The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals


Comparison groups 
placebo v Dexamethasone 1.5mg


Number of subjects included in analysis 
40


Analysis specification 
Prespecified


Analysis type 
superiority ^{[22]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
44  
upper limit 
26  
Variability estimate 
Standard deviation


Dispersion value 
17.4


Notes [22]  The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals 


End point title 
Change from screening in diaryassessed volume of MBL:Dex 1.8mg ^{[23]}  
End point description 
The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume.
The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.


End point type 
Secondary


End point timeframe 
Two screening menstrual cycles to 3 treatment cycles  average time period is 5 months


Notes [23]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The design used is a responseadaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry. 



Statistical analysis title 
Bayesian analysis:change in mean MBL diary score  
Statistical analysis description 
Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diaryassessed volume of menstrual blood loss.
The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals


Comparison groups 
placebo v Dexamethasone 1.8mg


Number of subjects included in analysis 
41


Analysis specification 
Prespecified


Analysis type 
superiority ^{[24]}  
Method 

Parameter type 
Treatment contrast  
Point estimate 
32


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
69  
upper limit 
4  
Variability estimate 
Standard deviation


Dispersion value 
18.56


Notes [24]  The analysis calculates median difference and 95% 'Credible intervals'  so not Confidence intervals 


Adverse events information


Timeframe for reporting adverse events 
Consent to final followup visit (approx 30 days after day of last treatment)


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
20.1


Reporting groups


Reporting group title 
placebo


Reporting group description 
placebo  
Reporting group title 
Dexamethasone 0.4mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total dose is 0.4mg  
Reporting group title 
Dexamethasone 0.8mg


Reporting group description 
Dexamethasone taken orally twice daily over 5 days. Total dose is 0.8mg  
Reporting group title 
Dexamethasone 1.0mg


Reporting group description 
Dexamethasone taken orally twice daily total dose is 1.0mg  
Reporting group title 
Dexamethasone 1.2mg


Reporting group description 
Dexamethasone taken orally twice daily total dose 1.2mg  
Reporting group title 
Dexamethasone 1.5mg


Reporting group description 
Dexamethasone taken orally twice daily total dose 1.5mg  
Reporting group title 
Dexamethasone 1.8mg


Reporting group description 
Dexamethasone taken orally twice daily. Total dose 1.8mg  


Frequency threshold for reporting nonserious adverse events: 0%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

07 Feb 2013 
Protocol wording clarification for workup studies: describe randomisation process, add NIMP for study 1, process for AE recording 

22 Oct 2013 
Protocol wording clarification for: Inclusion/exclusion criteria, study procedures 

19 Feb 2014 
Protocol wording clarification for adaptive trial; update processes for adaptive trial using experience from the completed workup studies. Extension to recruitment period and approaches. New study materials. 

18 Dec 2014 
Protocol wording clarification; addition of new recruitment approach; New SmPC for Dexamethasone 

23 May 2016 
Extension to recruitment period; details for additional recruitment approach . 

19 Oct 2017 
Changes to RSI in SmPC for Dexamethasone. 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
None reported 