Trial Outcomes & Findings for Does Neuromuscular Electrical Stimulation Improve the Absolute Walking Distance in Patients With Intermittent Claudication Compared to Best Available Treatment? (NCT NCT03446027)

NCT ID: NCT03446027

Last Updated: 2024-04-11

Results Overview

Measured by treadmill testing. Absolute walking distance in meters at baseline and 3 months

Recruitment status

COMPLETED

Study phase

Target enrollment

200 participants

Primary outcome timeframe

3 months

Results posted on

2024-04-11

Participant Flow

Participant milestones

Participant milestones
Measure	Control There will be no change to the local site standard of care for patients with IC attributed to participation in this trial. Those sites with Supervised Exercise Therapy (SET) will continue to provide this intervention as per their normal standard of care and locally agreed protocol.	Device Local therapy + Neuromuscular Electrical Stimulation (NMES) NMES: NMES device to be used for up to 3 hours daily in 30 minute sessions for 3 months.
Overall Study STARTED	102	98
Overall Study COMPLETED	78	80
Overall Study NOT COMPLETED	24	18

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Only participants not retired were assessed and are reported for this Baseline Measure

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Control n=98 Participants There will be no change to the local site standard of care for patients with IC attributed to participation in this trial. Those sites with Supervised Exercise Therapy (SET) will continue to provide this intervention as per their normal standard of care and locally agreed protocol.	Device n=92 Participants Local therapy + Neuromuscular Electrical Stimulation (NMES) NMES: NMES device to be used for up to 3 hours daily in 30 minute sessions for 3 months.	Total n=190 Participants Total of all reporting groups
Age, Continuous	67.44 years STANDARD_DEVIATION 9.44 • n=98 Participants	68.17 years STANDARD_DEVIATION 8.84 • n=92 Participants	67.79 years STANDARD_DEVIATION 9.13 • n=190 Participants
Sex: Female, Male Female	28 Participants n=98 Participants	22 Participants n=92 Participants	50 Participants n=190 Participants
Sex: Female, Male Male	70 Participants n=98 Participants	70 Participants n=92 Participants	140 Participants n=190 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=98 Participants	0 Participants n=92 Participants	0 Participants n=190 Participants
Race (NIH/OMB) Asian	3 Participants n=98 Participants	3 Participants n=92 Participants	6 Participants n=190 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=98 Participants	0 Participants n=92 Participants	0 Participants n=190 Participants
Race (NIH/OMB) Black or African American	3 Participants n=98 Participants	1 Participants n=92 Participants	4 Participants n=190 Participants
Race (NIH/OMB) White	90 Participants n=98 Participants	87 Participants n=92 Participants	177 Participants n=190 Participants
Race (NIH/OMB) More than one race	0 Participants n=98 Participants	1 Participants n=92 Participants	1 Participants n=190 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=98 Participants	0 Participants n=92 Participants	2 Participants n=190 Participants
Body Mass Index	28.63 kg/m^2 STANDARD_DEVIATION 6.66 • n=98 Participants	28.10 kg/m^2 STANDARD_DEVIATION 5.12 • n=92 Participants	28.37 kg/m^2 STANDARD_DEVIATION 5.95 • n=190 Participants
Smoking status Current smoker	34 participants n=98 Participants	22 participants n=92 Participants	56 participants n=190 Participants
Smoking status Former smoker	58 participants n=98 Participants	64 participants n=92 Participants	122 participants n=190 Participants
Smoking status Never	6 participants n=98 Participants	6 participants n=92 Participants	12 participants n=190 Participants
Medical history Hypertension	63 participants n=98 Participants	65 participants n=92 Participants	128 participants n=190 Participants
Medical history Stroke	9 participants n=98 Participants	9 participants n=92 Participants	18 participants n=190 Participants
Medical history Heart attack	17 participants n=98 Participants	15 participants n=92 Participants	32 participants n=190 Participants
Medical history High cholesterol	64 participants n=98 Participants	68 participants n=92 Participants	132 participants n=190 Participants
Medical history Angina	13 participants n=98 Participants	10 participants n=92 Participants	23 participants n=190 Participants
Medical history Diabetes	26 participants n=98 Participants	21 participants n=92 Participants	47 participants n=190 Participants
Medical history Bypass revascularisation	12 participants n=98 Participants	5 participants n=92 Participants	17 participants n=190 Participants
Medical history Angio revascularisation	25 participants n=98 Participants	14 participants n=92 Participants	39 participants n=190 Participants
Medication Antiplatelets	79 participants n=98 Participants	75 participants n=92 Participants	154 participants n=190 Participants
Medication Lipid modification therapy	81 participants n=98 Participants	80 participants n=92 Participants	161 participants n=190 Participants
Medication Anticoagulant	15 participants n=98 Participants	10 participants n=92 Participants	25 participants n=190 Participants
Medication Antihypertensives	65 participants n=98 Participants	66 participants n=92 Participants	131 participants n=190 Participants
Retired Yes	69 participants n=98 Participants	68 participants n=92 Participants	137 participants n=190 Participants
Retired No	29 participants n=98 Participants	24 participants n=92 Participants	53 participants n=190 Participants
Work status Higher managerial and professional occupations	5 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	3 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	8 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Intermediate occupations (e.g. clerical, sales, service)	4 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	5 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	9 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Lower managerial and professional occupations	1 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	8 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	9 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Lower supervisory and technical occupations	1 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	1 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	2 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Never worked or long-term unemployed	7 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	2 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	9 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Routine occupations	6 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	4 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	10 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Semi-routine occupations	2 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	1 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	3 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Work status Small employers and own account workers	3 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	0 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	3 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Performance limited due to intermittent claudication A little	9 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	7 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	16 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Performance limited due to intermittent claudication A lot	4 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	3 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	7 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Performance limited due to intermittent claudication Not at all	9 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	12 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	21 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure
Performance limited due to intermittent claudication Missing	7 participants n=29 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	2 participants n=24 Participants • Only participants not retired were assessed and are reported for this Baseline Measure	9 participants n=53 Participants • Only participants not retired were assessed and are reported for this Baseline Measure

PRIMARY outcome

Timeframe: 3 months

Population: Control group includes both BMT and BMT + SET and the treatment group includes NMES + BMT and NMES + BMT + SET Included participants with both baseline and 3 month treadmill data.

Measured by treadmill testing. Absolute walking distance in meters at baseline and 3 months

Outcome measures

Outcome measures
Measure	Control n=98 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=92 Participants NMES + EA and NMES+EA+SET
Difference in the Absolute Walking Distance (AWD) at 3 Months Between the Two Treatment Groups Baseline	220.12 Meters Standard Deviation 148.27	242.97 Meters Standard Deviation 187.08
Difference in the Absolute Walking Distance (AWD) at 3 Months Between the Two Treatment Groups 3 months	327.74 Meters Standard Deviation 222.65	370.38 Meters Standard Deviation 251.38

SECONDARY outcome

Timeframe: 3 months

Population: Included participants with both baseline and 3 month treadmill data. Control group includes both BMT and BMT + SET and the treatment group includes NMES + BMT and NMES + BMT + SET

Measured by treadmill testing. ICD in meters at baseline and 3 months

Outcome measures

Outcome measures
Measure	Control n=98 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=92 Participants NMES + EA and NMES+EA+SET
Difference in the Initial Claudication Distance (ICD) at 3 Months Between the Two Treatment Groups Baseline	99.10 Meters Standard Deviation 77.06	105.79 Meters Standard Deviation 106.27
Difference in the Initial Claudication Distance (ICD) at 3 Months Between the Two Treatment Groups 3 months	179.73 Meters Standard Deviation 147.03	211.45 Meters Standard Deviation 181.83

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months, 12 months

Population: Scores on the Intermittent Claudication Questionnaire range from 0 to 100, with higher scores indicating worse health related to intermittent claudication. Includes all participants that completed the ICQ questionnaire.

Patient questionnaire. Used to assess change in disease-specific QoL.

Outcome measures

Outcome measures
Measure	Control n=94 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=90 Participants NMES + EA and NMES+EA+SET
Quality of Life - Intermittent Claudication Questionnaire (ICQ) Baseline	45.92 score on a scale Standard Deviation 13.09	41.98 score on a scale Standard Deviation 13.26
Quality of Life - Intermittent Claudication Questionnaire (ICQ) 3 months	41.33 score on a scale Standard Deviation 14.52	36.55 score on a scale Standard Deviation 13.86
Quality of Life - Intermittent Claudication Questionnaire (ICQ) 6 months	39.27 score on a scale Standard Deviation 14.51	35.20 score on a scale Standard Deviation 15.07
Quality of Life - Intermittent Claudication Questionnaire (ICQ) 12 months	36.21 score on a scale Standard Deviation 16.45	36.99 score on a scale Standard Deviation 17.38

SECONDARY outcome

Timeframe: Baseline, 3 month, 6 month and 12 months

Population: Scores on the EuroQol Group 5-Dimension 5-Level questionnaire (EQ-5D-5L) health scale (a visual-analogue scale) range from 0 to 100, with higher scores indicating better health. Includes all participants that completed the EQ-5D-5L questionnaire.

Patient questionnaire. Used to assess the generic QoL and will allow economic assessment based on intervention and score improvement.

Outcome measures

Outcome measures
Measure	Control n=97 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=91 Participants NMES + EA and NMES+EA+SET
Quality of Life - EuroQoL 5D (EQ5D) Health Scale Baseline	45.92 score on a scale Standard Deviation 13.09	41.98 score on a scale Standard Deviation 13.26
Quality of Life - EuroQoL 5D (EQ5D) Health Scale 3 months	41.33 score on a scale Standard Deviation 14.52	36.55 score on a scale Standard Deviation 13.86
Quality of Life - EuroQoL 5D (EQ5D) Health Scale 6 months	39.27 score on a scale Standard Deviation 14.51	35.20 score on a scale Standard Deviation 15.07
Quality of Life - EuroQoL 5D (EQ5D) Health Scale 12 months	36.21 score on a scale Standard Deviation 16.45	36.99 score on a scale Standard Deviation 17.38

SECONDARY outcome

Timeframe: Baseline, 3 month, 6 month and 12 months

Population: Scores on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) Physical Component Summary and Mental Component Summary range from 1 to 100, with higher scores indicating better quality of life. Includes all participants that completed the SF-36 questionnaire.

Patient questionnaire. Used to assess the generic QoL and will allow economic assessment based on intervention and score improvement.

Outcome measures

Outcome measures
Measure	Control n=95 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=91 Participants NMES + EA and NMES+EA+SET
Quality of Life Short Form 36 (SF-36) Physical Component Summary 6 months	37.62 score on a scale Standard Deviation 9.85	39.47 score on a scale Standard Deviation 9.74
Quality of Life Short Form 36 (SF-36) Physical Component Summary Baseline	36.14 score on a scale Standard Deviation 7.90	35.71 score on a scale Standard Deviation 8.22
Quality of Life Short Form 36 (SF-36) Physical Component Summary 3 months	37.42 score on a scale Standard Deviation 8.48	38.80 score on a scale Standard Deviation 8.87
Quality of Life Short Form 36 (SF-36) Physical Component Summary 12 months	39.46 score on a scale Standard Deviation 9.40	38.16 score on a scale Standard Deviation 9.98

SECONDARY outcome

Timeframe: 3 months

Population: Includes all participants that had a volume flow measurement at baseline and 3 months

Using an arterial ultrasound probe and pre-set volume flow algorithms on a duplex ultrasound machine, flow within the common femoral artery (CFA), of the most affected limb, will be measured, approximately 5cm below the mid-inguinal point at the groin. Measures include volume flow (VF, cc/min) to assess whether using the device increases this measurement.

Outcome measures

Outcome measures
Measure	Control n=87 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=80 Participants NMES + EA and NMES+EA+SET
Haemodynamic Assessment - Duplex Ultrasonography - Difference in Volume Flow Between Baseline and 3 Months Baseline	296.89 cc/min Standard Deviation 198.40	300.06 cc/min Standard Deviation 155.10
Haemodynamic Assessment - Duplex Ultrasonography - Difference in Volume Flow Between Baseline and 3 Months 3 months	280.96 cc/min Standard Deviation 179.03	296.77 cc/min Standard Deviation 146.30

SECONDARY outcome

Timeframe: Baseline, 3 month, 6 month and 12 months

Population: ANCOVA model for changes in Laser Doppler Flowmetry (blood flux - measured in one leg) between baseline and follow up periods (3, 6 and 12 months) for the ITT population. Includes all participants that completed the LDF assessment. Blood flux is unitless. Difference between the two groups (control vs device).

The single fibre laser optical probe of the LDF machine will be positioned on the dorsal aspect of the foot using single use adhesive pads. Flux, as a measure of superficial skin blood flow will be measured to assess whether using the device increases this measurement.

Outcome measures

Outcome measures
Measure	Control n=90 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=96 Participants NMES + EA and NMES+EA+SET
Haemodynamic Assessment - Laser Doppler Flowmetry (LDF) - Difference in Blood Flux Between Baseline and 12 Months Baseline	2.61 Unitless Standard Deviation 0.58	2.38 Unitless Standard Deviation 0.56
Haemodynamic Assessment - Laser Doppler Flowmetry (LDF) - Difference in Blood Flux Between Baseline and 12 Months 3 months	2.79 Unitless Standard Deviation 0.69	2.30 Unitless Standard Deviation 0.65
Haemodynamic Assessment - Laser Doppler Flowmetry (LDF) - Difference in Blood Flux Between Baseline and 12 Months 6 months	2.49 Unitless Standard Deviation 0.57	2.50 Unitless Standard Deviation 0.62
Haemodynamic Assessment - Laser Doppler Flowmetry (LDF) - Difference in Blood Flux Between Baseline and 12 Months 12 months	2.64 Unitless Standard Deviation 0.61	2.53 Unitless Standard Deviation 0.56

SECONDARY outcome

Timeframe: Baseline, 3 month, 6 month and 12 months

Population: Linear mixed model for changes in the transformed log Left Ankle Brachial Pressure Index (ABPI) between baseline and follow up periods (3, 6 and 12 months) for the ITT population. Calculation between groups - assesses the difference between the two treatment groups between baseline and 12 months.

The brachial blood pressure from the right arm using a manual blood pressure monitor cuff and Doppler will be recorded after 5 minutes of resting supine on a couch. The systolic blood pressure of the anterior tibial artery and posterior tibial artery at the ankle will also be recorded using the cuff and Dopplermethod. The ratio of the systolic brachial and ankle pressures will form the ABPI measurement.

Outcome measures

Outcome measures
Measure	Control n=97 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=90 Participants NMES + EA and NMES+EA+SET
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Left - Between Baseline and 12 Months Baseline	0.76 Ratio Standard Deviation 0.21	0.72 Ratio Standard Deviation 0.18
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Left - Between Baseline and 12 Months 3 months	0.74 Ratio Standard Deviation 0.23	0.72 Ratio Standard Deviation 0.21
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Left - Between Baseline and 12 Months 6 months	0.77 Ratio Standard Deviation 0.22	0.74 Ratio Standard Deviation 0.2
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Left - Between Baseline and 12 Months 12 months	0.79 Ratio Standard Deviation 0.23	0.74 Ratio Standard Deviation 0.22

SECONDARY outcome

Timeframe: Baseline, 3 month, 6 month and 12 months

Population: All randomised patients (except screen failures)

The economic analyses will compare local therapy (supervised exercise therapy (SET) or exercise advice (EA) only) versus the intervention (local therapy + Neuromuscular Electrical Stimulation, NMES) in patients with Intermittent Claudication. The analyses will be based on a (i) patient level in-trial cost-effectiveness analysis, (ii) a decision model and (iii) budget impact assessment. The in-trial analysis will calculate quality-adjusted life years (QALYs) over the one year time horizon of the trial.

Outcome measures

Outcome measures
Measure	Control n=98 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=102 Participants NMES + EA and NMES+EA+SET
Health Economic Assessment	0.6459 QALY Interval 0.6032 to 0.6886	0.6355 QALY Interval 0.5992 to 0.6718

SECONDARY outcome

Timeframe: 3 months

Population: EA (part of BMT): compliant if completed 75% or more of recommended level of EA (75% of minutes performing exercises recommended by centre). Data for this Outcome Measure was pre-specified to be collected and assessed as a single group irrespective of intervention Arm/Group.

Comparison of compliance with exercise advice as per local standard of care.

Outcome measures

Outcome measures
Measure	Control n=190 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Compliance With Interventions - Exercise Advice (EA) Complier	99 Participants	—
Compliance With Interventions - Exercise Advice (EA) Non-complier	52 Participants	—
Compliance With Interventions - Exercise Advice (EA) Missing	39 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: Participants asked to rate ease of use of device. 5 point scale from 1 (very easy) to 5 (very difficult) Includes all participants that were in the control arm and completed the device experience questionnaire.

To report ease of device use and suggest any developments.

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Device Experience Questionnaire - Ease of Use 1 Very easy	77 Participants	—
Device Experience Questionnaire - Ease of Use 2	6 Participants	—
Device Experience Questionnaire - Ease of Use 3	1 Participants	—
Device Experience Questionnaire - Ease of Use 4	0 Participants	—
Device Experience Questionnaire - Ease of Use 5 Very difficult	0 Participants	—
Device Experience Questionnaire - Ease of Use Missing	4 Participants	—

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months, 12 months

Population: Score on the EQ-5D-5L health index range from 0 to 100, with higher scores indicating better health. The EQ-5D-5L health index was calculated with the value set for England. Includes all participants that completed the EuroQoL 5D (EQ5D) Health Index.

Patient questionnaire. Used to assess the generic QoL and will allow economic assessment based on intervention and score improvement.

Outcome measures

Outcome measures
Measure	Control n=97 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=91 Participants NMES + EA and NMES+EA+SET
Quality of Life - EuroQoL 5D (EQ5D) Health Index Baseline	69.61 score on a scale Standard Deviation 17.69	69.73 score on a scale Standard Deviation 18.03
Quality of Life - EuroQoL 5D (EQ5D) Health Index 3 months	66.11 score on a scale Standard Deviation 21.09	74.02 score on a scale Standard Deviation 15.13
Quality of Life - EuroQoL 5D (EQ5D) Health Index 6 months	68.36 score on a scale Standard Deviation 20.85	73.13 score on a scale Standard Deviation 19.32
Quality of Life - EuroQoL 5D (EQ5D) Health Index 12 months	68.03 score on a scale Standard Deviation 19.61	70.40 score on a scale Standard Deviation 20.98

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months, 12 months

Patient questionnaire. Used to assess the generic QoL and will allow economic assessment based on intervention and score improvement.

Outcome measures

Outcome measures
Measure	Control n=95 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=91 Participants NMES + EA and NMES+EA+SET
Quality of Life Short Form 36 (SF-36) Mental Component Summary Baseline	49.75 score on a scale Standard Deviation 12.47	52.06 score on a scale Standard Deviation 11.61
Quality of Life Short Form 36 (SF-36) Mental Component Summary 3 months	48.24 score on a scale Standard Deviation 13.15	52.99 score on a scale Standard Deviation 10.05
Quality of Life Short Form 36 (SF-36) Mental Component Summary 6 months	49.09 score on a scale Standard Deviation 10.90	52.79 score on a scale Standard Deviation 10.73
Quality of Life Short Form 36 (SF-36) Mental Component Summary 12 months	48.90 score on a scale Standard Deviation 12.24	52.62 score on a scale Standard Deviation 11.68

SECONDARY outcome

Timeframe: 3 months

Population: Linear Regression Model for Duplex ultrasonography (TAMV - measured in one leg) at 3 months for the ITT population. Difference (calculation) between the two groups (control and treatment) and not per arm.

Using an arterial ultrasound probe and pre-set volume flow algorithms on a duplex ultrasound machine, flow within the common femoral artery (CFA), of the most affected limb, will be measured, approximately 5cm below the mid-inguinal point at the groin. Measures include time-averaged mean volume (TAMV, cm/s) to assess whether using the device increases this measurement.

Outcome measures

Outcome measures
Measure	Control n=89 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=81 Participants NMES + EA and NMES+EA+SET
Haemodynamic Assessment - Duplex Ultrasonography - Difference in Time Average Mean Velocity Between Baseline and 3 Months Baseline	11.28 cm/s Standard Deviation 5.64	12.23 cm/s Standard Deviation 6.47
Haemodynamic Assessment - Duplex Ultrasonography - Difference in Time Average Mean Velocity Between Baseline and 3 Months 3 months	11.78 cm/s Standard Deviation 5.77	12.47 cm/s Standard Deviation 5.39

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months and 12 months

Population: Linear mixed model1 for changes in the transformed log Right Ankle Brachial Pressure Index (ABPI) between baseline and follow up periods (3, 6 and 12 months) for the ITT population. Calculation between groups - assesses the difference between the two treatment groups between baseline and 12 months. Calculation between the two groups (control and treatment).

Outcome measures

Outcome measures
Measure	Control n=97 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device n=90 Participants NMES + EA and NMES+EA+SET
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Right - Between Baseline and 12 Months Baseline	0.77 Ratio Standard Deviation 0.22	0.76 Ratio Standard Deviation 0.21
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Right - Between Baseline and 12 Months 3 months	0.78 Ratio Standard Deviation 0.22	0.77 Ratio Standard Deviation 0.21
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Right - Between Baseline and 12 Months 6 months	0.80 Ratio Standard Deviation 0.28	0.76 Ratio Standard Deviation 0.23
Haemodynamic Assessment - Difference in Ankle Brachial Pressure Index (ABPI) - Right - Between Baseline and 12 Months 12 months	0.79 Ratio Standard Deviation 0.23	0.78 Ratio Standard Deviation 0.21

SECONDARY outcome

Timeframe: 3 months

Population: Participant's who attended SET programme.

Comparison of compliance with SET classes.

Outcome measures

Outcome measures
Measure	Control n=99 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Compliance With Interventions - Supervised Exercise Therapy (SET) Complier	69 Participants	—
Compliance With Interventions - Supervised Exercise Therapy (SET) Non-complier	19 Participants	—
Compliance With Interventions - Supervised Exercise Therapy (SET) Missing	11 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: NMES: compliant if completed 75% or more of recommended level of NMES usage.

Compliance with NMES device. NMES compliance data collected from the data logger fitted to device and patient diary will be combined to report overall compliance.

Outcome measures

Outcome measures
Measure	Control n=92 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Compliance With Interventions - Neuromuscular Electrical Stimulation (NMES) Complier	68 Participants	—
Compliance With Interventions - Neuromuscular Electrical Stimulation (NMES) Non-complier	12 Participants	—
Compliance With Interventions - Neuromuscular Electrical Stimulation (NMES) Missing	12 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: Participants asked whether they thought the device reduced leg pain. 5-point scale from 1 (yes, a lot) to 5 (not at all). Includes all participants that were in the treatment (device) arm and that completed the device experience questionnaire.

To report ease of device use and suggest any developments.

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Device Experience Questionnaire - Reduces Leg Pain 1-Yes, a lot	14 Participants	—
Device Experience Questionnaire - Reduces Leg Pain 2	22 Participants	—
Device Experience Questionnaire - Reduces Leg Pain 3	26 Participants	—
Device Experience Questionnaire - Reduces Leg Pain 4	11 Participants	—
Device Experience Questionnaire - Reduces Leg Pain 5-Not at all	11 Participants	—
Device Experience Questionnaire - Reduces Leg Pain Missing	4 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: Participants asked whether they thought the device increased walking distance. Includes all participants that were in the treatment (device) arm and that completed the device experience questionnaire.

To report ease of device use and suggest any developments.

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Device Experience Questionnaire - Increased Walk Distance No	8 Participants	—
Device Experience Questionnaire - Increased Walk Distance No change	19 Participants	—
Device Experience Questionnaire - Increased Walk Distance Yes	57 Participants	—
Device Experience Questionnaire - Increased Walk Distance Missing	4 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: Participants asked whether they used the device as instructed. Includes all participants that were in the treatment (device) arm and that completed the device experience questionnaire.

To report ease of device use and suggest any developments.

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Device Experience Questionnaire - Used as Instructed No	2 Participants	—
Device Experience Questionnaire - Used as Instructed Yes	82 Participants	—
Device Experience Questionnaire - Used as Instructed Missing	4 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: Participants asked whether they could have used the device more. Includes all participants that were in the treatment (device) arm and that completed the device experience questionnaire.

To report ease of device use and suggest any developments.

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Device Experience Questionnaire - Could Have Used More No	28 Participants	—
Device Experience Questionnaire - Could Have Used More Yes	56 Participants	—
Device Experience Questionnaire - Could Have Used More Missing	4 Participants	—

SECONDARY outcome

Timeframe: 3 months

Population: Participants asked whether they used the device following the 3 month treatment period. 5-point scale from 1 (Yes, a lot) to 5 (not at all). Includes all participants that were in the treatment (device) arm and that completed the device experience questionnaire.

To report ease of device use and suggest any developments.

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Device Experience Questionnaire - Used After Treatment 1-Yes, a lot	51 Participants	—
Device Experience Questionnaire - Used After Treatment 2	13 Participants	—
Device Experience Questionnaire - Used After Treatment 3	16 Participants	—
Device Experience Questionnaire - Used After Treatment 4	0 Participants	—
Device Experience Questionnaire - Used After Treatment 5-Not at all	4 Participants	—
Device Experience Questionnaire - Used After Treatment Missing	4 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 months

Population: Subgroup analysis 1: Treatment effect in SET sites vs non-SET sites (NMES+SET+BMT \& SET+BMT vs NMES+BMT \& BMT). Right censored Tobit regression model for AWD at 3 months to assess the effects of SET vs non-SET (subgroup1) for the ITT population (N=160). Subgroup1 (Non-SET) as reference category. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 1: Right censored Tobit regression model for AWD at 3 months to assess the effects SET sites vs non-SET sites (NMES+SET+BMT \& SET+BMT vs NMES+BMT \& BMT).

Outcome measures

Outcome measures
Measure	Control n=160 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 1 - Difference in Absolute Walking Difference Between Baseline and 3 Months SET Sites vs Non-SET Sites	3.205 Units Interval 1.689 to 4.72	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 months

Population: Subgroup analysis 2: Treatment effect of NMES in the SET sites (NMES+SET+BMT vs SET+BMT). Right censored Tobit Regression model for AWD at 3 months to assess the effects of EA+SET+NMES vs EA+SET (subgroup2) for the ITT population (N=90) Subgroup2 (BMT + SET) as reference category. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 2: Right censored Tobit Regression model for AWD at 3 months to assess the effects of NMES in the SET sites (NMES+SET+BMT vs SET+BMT).

Outcome measures

Outcome measures
Measure	Control n=90 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 2 - Difference in Absolute Walking Difference Between Baseline and 3 Months (NMES+SET+BMT vs SET+BMT)	1.724 Units Interval -0.56 to 4.008	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 months

Population: Subgroup analysis 3: Treatment effect of NMES in the non-SET sites (NMES+BMT vs BMT). Right censored Tobit regression model for the AWD at 3 months to assess the effects of EA vs EA+NMES (subgroup3) for the ITT population (N=70) Subgroup3 (BMT) as reference category. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 3: Right censored Tobit regression model for the AWD at 3 months to assess the effects of NMES in the non-SET sites (NMES+BMT vs BMT).

Outcome measures

Outcome measures
Measure	Control n=70 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 3 - Difference in Absolute Walking Difference Between Baseline and 3 Months (NMES+BMT vs BMT)	-0.090 Units Interval -2.014 to 1.833	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 months

Population: Subgroup analysis 4: Investigate if the treatment effect of (NMES+BMT) has a similar effect as (SET+BMT). Right censored Tobit regression model for AWD at 3 months to assess the effects of EA+SET vs EA+NMES (subgroup4) for the ITT population (N=88) Subgroup4 (BMT+SET) as reference category. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 4: Right censored Tobit regression model for AWD at 3 months to assess the effects of (NMES+BMT) has a similar effect as (SET+BMT).

Outcome measures

Outcome measures
Measure	Control n=88 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 4 - Difference in Absolute Walking Difference Between Baseline and 3 Months (NMES+BMT vs. SET+BMT)	-2.419 Units Interval -4.324 to -0.513	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 months

Population: Subgroup analysis 5: Determine if (NMES+SET+BMT) is more effective than (NMES+BMT). Right censored Tobit regression model for AWD at 3 months to assess the effects of EA+NMES vs EA+SET+NMES (subgroup5) for the ITT population (N=80). Subgroup5 (BMT+NMES) as reference category. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 5: Determine if (NMES+SET+BMT) is more effective than (NMES+BMT).

Outcome measures

Outcome measures
Measure	Control n=80 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 5 - Difference in Absolute Walking Difference Between Baseline and 3 Months (NMES+SET+BMT vs. NMES+BMT)	4.248 Units Interval 2.229 to 6.268	—

POST_HOC outcome

Timeframe: 3 months

Population: Subgroup analysis 6: Determine if (BMT) is more effective than (NMES+SET+BMT). Right censored Tobit regression model for AWD at 3 months to assess the effects of EA vs EA+SET+NMES (subgroup 6) for the ITT population (N=72) Subgroup6 (BMT+SET+NMES) as reference category. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 6: Determine if (BMT) is more effective than (NMES+SET+BMT).

Outcome measures

Outcome measures
Measure	Control n=93 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 6 - Difference in Absolute Walking Difference Between Baseline and 3 Months (BMT vs. NMES+SET+BMT)	-4.098 Units Interval -6.56 to -1.636	—

POST_HOC outcome

Timeframe: 3 months

Population: Subgroup analysis 7: Determine if BMT is more effective than BMT+SET. The sample size in this group is N=80 (n=31 in BMT and n=49 in BMT+SET). BMT as reference category. Right censored Tobit regression model for AWD at 3 months to assess the effects of BMT vs BMT+SET (subgroup 7) for the ITT population. Between group calculation (not per arm). Unit of measure is "Units" as a square root transformation was used to normalise the data and used for the Regression Tobit model, rather than meters.

Subgroup analysis 7: Determine if (BMT) is more effective than (BMT+SET). The sample size in this group is N=80 (n=31 in BMT and n=49 in BMT+SET).

Outcome measures

Outcome measures
Measure	Control n=80 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Sub-group Analysis 7 - Difference in Absolute Walking Difference Between Baseline and 3 Months (BMT vs. BMT+SET)	2.341 Units Interval 0.054 to 4.629	—

POST_HOC outcome

Timeframe: 3 months

Population: Right censored Tobit regression model for Absolute Walking Distance (AWD) at 3 months for patients who walked a short distance at baseline in the ITT population (N=40). Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Calculated between the two groups (control vs treatment) so not per arm.

Right censored Tobit regression model for Absolute Walking Distance (AWD) at 3 months for patients who walked a short distance at baseline in the ITT population (N=40). The AWD at baseline was divided into three strati: Short, Medium and Long distances (set at \<25%, 25%-75% and \>75% respectively) using the descriptive statistics - short distance defined as \<100m.

Outcome measures

Outcome measures
Measure	Control n=40 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Post-hoc: Difference in Absolute Walking Difference for Patients Who Walked a Short Distance at Baseline (Baseline to 3 Months)	0.426 Units Interval -3.499 to 4.351	—

POST_HOC outcome

Timeframe: 3 months

Population: Right censored Tobit regression model for Absolute Walking Distance (AWD) at 3 months for patients who walked a medium distance at baseline in the ITT population (N=80). Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Calculated between the two groups (control vs treatment) so not per arm.

Right censored Tobit regression model for Absolute Walking Distance (AWD) at 3 months for patients who walked a medium distance at baseline in the ITT population (N=80). The AWD at baseline was divided into three strati: Short, Medium and Long distances (set at \<25%, 25%-75% and \>75% respectively) using the descriptive statistics - medium distance defined as between 100m and 340m.

Outcome measures

Outcome measures
Measure	Control n=80 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Post-hoc: Difference in Absolute Walking Difference for Patients Who Walked a Medium Distance at Baseline (Baseline to 3 Months)	0.215 Units Interval -1.805 to 2.235	—

POST_HOC outcome

Timeframe: 3 months

Population: Right censored Tobit regression model for Absolute Walking Distance (AWD) at 3 months for patients who walked a long distance at baseline in the ITT population (N=40). Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Calculated between the two groups (control vs treatment) so not per arm.

Right censored Tobit regression model for Absolute Walking Distance (AWD) at 3 months for patients who walked a long distance at baseline in the ITT population (N=40). The AWD at baseline was divided into three strati: Short, Medium and Long distances (set at \<25%, 25%-75% and \>75% respectively) using the descriptive statistics - long distance defined as \>340m.

Outcome measures

Outcome measures
Measure	Control n=40 Participants Control: Local Available Exercise Therapy (BMT and BMT+SET) as reference category. Treatment: BMT+NMES and BMT+SET+NMES	Device NMES + EA and NMES+EA+SET
Post-hoc: Difference in Absolute Walking Difference for Patients Who Walked a Long Distance at Baseline (Baseline to 3 Months)	2.877 Units Interval 0.506 to 5.248	—

Adverse Events

Control

Serious events: 13 serious events

Other events: 44 other events

Deaths: 2 deaths

Device

Serious events: 11 serious events

Other events: 47 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Laura Burgess

Imperial College London

Phone: 0203 311 5208

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Control n=102 participants at risk There will be no change to the local site standard of care for patients with IC attributed to participation in this trial. Those sites with Supervised Exercise Therapy (SET) will continue to provide this intervention as per their normal standard of care and locally agreed protocol.	Device n=98 participants at risk Local therapy + Neuromuscular Electrical Stimulation (NMES) NMES: NMES device to be used for up to 3 hours daily in 30 minute sessions for 3 months.
Vascular disorders Peripheral arterial occlusive disease	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Acute Coronary Syndrome	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Acute myocardial infarction	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Cardiac arrest	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Cardiac failure acute	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Chest pain	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Groin abscess	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Renal and urinary disorders Haematuria	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Influenza	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Vascular disorders Pelvic venous thrombosis	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Surgical and medical procedures Peripheral artery bypass	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Surgical and medical procedures Peripheral endarterectomy	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Surgical and medical procedures Prostatic operation	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Injury, poisoning and procedural complications Subdural haematoma	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Renal and urinary disorders Urinary Retention	0.98% 1/102 • Number of events 2 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Urosepsis	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Atrial fibrillation	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Pneumonia	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Septic shock	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Gastrointestinal disorders Diarrhoea	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	2.0% 2/98 • Number of events 2 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Epididymitis	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Orchitis	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Gastrointestinal disorders vomiting	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Nervous system disorders Altered state of consciousness	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Cardiac disorders Angina pectoris	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Renal and urinary disorders Anuria	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Metabolism and nutrition disorders Dehydration	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Gastrointestinal disorders Abdominal pain	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	2.0% 2/98 • Number of events 2 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Musculoskeletal and connective tissue disorders Arthralgia	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Nervous system disorders Cognitive disorder	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Gastrointestinal disorders Gastrooesophageal reflux disease	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Gastrointestinal disorders Haematemesis	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Infections and infestations Herpes simplex encephalitis	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Vascular disorders Lymphedema	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/102 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	1.0% 1/98 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov
General disorders Pain	0.98% 1/102 • Number of events 1 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov	0.00% 0/98 • Adverse event data was collected during the full study duration (12 months). Same definitions as clinicaltrials.gov