Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Ramos, 2017

N.B., study characteristics and results are extracted from the SR (unless stated otherwise)

Study design: SR and meta-analysis of RCTs

Literature search up to June 2012; 8/11 studies included in this analysis

A: Dowson, 2011

B: Flynn, 2009

C: Sahai, 2007

D: Dmochowski, 2010

E: Denys, 2011

F: Tincello, 2011

G: Chapple, 2013

H: Nitti, 2013

Study design:

Multicenter, randomized, double-blind: D, E, G, H

Single-center, randomized, double-blind: A, B, C, F

Setting and Country:

A: UK

B: USA

C: UK

D: USA

E: France

F: UK

G: Europe and USA

H: USA and Canada

Source of funding and conflicts of interest:

A: Funded by National Institute of Health Research, to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust

Authors have financial interest and/or other relationship with the industry.

B: National Institutes of Health National Institute on Aging Grant #R21 AG25490-01. Authors have financial interest and/or other relationship with the industry.

C: Supported by a grant from the British Urological Foundation.

Authors have financial interest and/or other relationship with the industry

D: Authors have financial interest and/or other relationship with the industry

E: Sponsored by the ‘‘Assistance Publique – Hopitaux de Paris’’ and was funded by a grant of the French Ministry of Health (AOM03111). These organisations assisted in the collection, analysis, and interpretation of data as well as in manuscript preparation.

Authors have financial interest and/or other relationship with the industry

F: Sponsored by grants from The Moulton Charitable Trust and Wellbeing of Women. The sponsor remained independent of the design, conduct, and analysis of the study.

Authors have financial interest and/or other relationship with the industry

G: Allergan, Inc. helped design and conduct the study; collect, manage, analyse, and interpret the data; and prepare, review, and approve the manuscript. Authors have financial interest and/or other relationship with the industry

H: Authors have financial interest and/or other relationship with the industry

I: Authors have financial interest and/or other relationship with the industry

Inclusion criteria SR:

RCT

OnabotulinumtoxinA injection in the detrusor muscle

the control group: placebo, anticholinergic medications, or comparisons of different doses of OnabotulinumtoxinA

Exclusion criteria SR: none mentioned

Important patient characteristics at baseline:

N, mean age

A: I: n=10, 49.6±19 yrs

C: n=11, 46.7±17 yrs

B: I: n=15 / C: n=7

66 (range: 41 to 85) yrs

C: I: n=16, 49.8 yrs

C: n=18, 50.8 yrs

D: I: n=268 / C: n=43

58.8 yrs

E: I: n=70 / C: n=29

61.6 ± 14.0 yrs

F: I: n=122, 60.7 (range 50.8–67.8) yrs

C: n=118, 58.2 (range 51.5–69.2) yrs

G: I: n=277, 59.5±15.5 yrs

C: n=271, 59.2±14.1 yrs

H: I: n=278, 61.7±12.7 yrs

C: n=272, 61.0±13.1 yrs

Sex:

A: I: 80% F / C: 64% F

B: unknown

C: I: 56% F / C: 55% F

D: 92% F

E: 87.9% F

F: 100% F

G: I: 88.1% F / C: 84.5% F

H: I: 90% F / C: 88.4% F

A: 100U BoNT-A,

10 injections at baseline

B: 200U, 300U BoNT-A,

10-12 injections at baseline

C: 200U BoNT-A,

20 injections at baseline

D: 50U, 100U, 150U, 200U, 300U BoNT-A,

20 injections at baseline

E: 50U, 100U, 150U BoNT-A,

15 injections at baseline

F: 200U BoNT-A,

20 injections at baseline

G: 100U BoNT-A,

20 injections at baseline

H: 100U BoNT-A,

20 injections at baseline

A: placebo, 10 injections at baseline

B: placebo, 10-12 injections at baseline

C: placebo, 20 injections at baseline

D: placebo, 20 injections at baseline

E: placebo, 15 injections at baseline

F: placebo, 20 injections at baseline

G: placebo, 20 injections at baseline

H: placebo, 20 injections at baseline

End-point of follow-up:

A: 24 weeks

B: 6 weeks

C: 6 months

D: 36 weeks

E: 6 months

F: 6 months

G: 12 weeks

H: 24 weeks

For how many participants were no complete outcome data available?

A: I: n=2 (15%) / C: n=0

B: I: n=0 / C: n=0

C: <2%

D: I: n=34 (13%) / C: n=7 (16%)

E: I: n=6 (8%) / C: n=2 (6%)

F: I: n=22 (18%) / C: n=19 (16%)

G: I: n=27 (10%) / C: n=32 (12%)

H: I: n=29 (10%) / C: n=29 (11%)

Outcome measure-1

Defined as change in urinary urge incontinence episodes

Effect measure: mean difference [95% CI]:

A: -1,80 (-2.66, -0.94)

C: -1.72 (-3.47, 0.03)

G: -1.98 (1.69, -2.27)

H: -1.78 (-1.84, -1.72)

Outcome measure-2

Adverse events

Urinary tract infections (UTI): Effect measure: risk ratio [95% CI]:

A: 4.40 (0.59, 33.07)

B:0.47 (0.08, 2.67)

D: 2.33 (1.09, 4.99)

E: 0.19 (0.01, 3.43)

G: 3.91 (1.53, 4.61)

H: 2.66 (1.53, 4.61)

Urinary retention defined as post-void residue of

200 mL: Effect measure: risk ratio [95% CI]:

A: 7.65 (0.44, 131.75)

D:8.15 (1.08, 61.22)

E: 1.32 (0.09, 19.93)

G: 9.36 (2.20, 39.80)

H: 48.48 (2.96, 793.24)

Outcome measure-3

Quality of life

Not reported in SR.

Facultative:

Brief description of author’s conclusion: “Intravesical injections of OnabotulinumtoxinA compared with placebo showed a statistically significant improvement in the treatment of overactive bladder. Adverse events were more frequent among patients treated with OnabotulinumtoxinA.”

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question: all studies were sponsored by pharmaceutical companies. Most of the authors have declared conflicts of interest.

Study reference

Study characteristics

Patient characteristics 

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Herschorn, 2017

Type of study: multicenter, double-blind, randomized, placebo-controlled study

Setting and country: North America and Europe

Funding and conflicts of interest: “This study was sponsored by Allergan plc, Dublin, Ireland. The authors would like to acknowledge Dr. Charles Pignataro, MD, formerly of Allergan plc, for his contributions to this study. Assistance with the writing and development of the manuscript was provided

by Jennifer L. Giel, PhD, on behalf of Evidence Scientific Solutions, Philadelphia,

 Pennsylvania, and was funded by Allergan plc.”

Inclusion criteria:

- adults with OAB for >6 months

- 2 UUI per day and >7 voids per day

- no UUI-free day

- no predominant SUI

Exclusion criteria:

- OAB due to neurological reason

- predominance of stress UI

- previous/current therapy with solifenacin

- previous/current

botulinum toxin therapy for any urological condition

- use of any treatments for OAB within 7 days of start of

screening

N total at baseline:

Intervention: 145

Control: 60

Important prognostic factors²:

Age ± SD:

I: 61.4 ± 12.8

C: 61.2 ± 12.2

Sex:

I: 123 (84.8%) F

C: 51 (85%) F

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

100U BoNT-A, detrusor injections, plus oral placebo

After 6 weeks, patient could ask for increase of oral medication (placebo in this case).

At weeks 12, 18, or 24, patients could request and receive open-label

onabotulinumtoxinA

Describe control (treatment/procedure/test):

Placebo injections, plus oral placebo

After 6 weeks, patient could ask for increase of oral medication (placebo in this case)

At weeks 12, 18, or 24, patients could request and receive open-label

onabotulinumtoxinA

Length of follow-up:

12 weeks blinded, 24 weeks unblinded

Loss-to-follow-up/incomplete outcome data:

Intervention:

N=14 (9.7%)

Reasons:

Lack of efficacy: n=1

Lost to follow up: n=3

Adverse Events: n=5

Personal reasons: n=1

Other: n=4

Control:

N=5 (8.3%)

Reasons:

Lost to follow up: n=2

Adverse Events: n=1

Other: n=2

Outcome measures and effect size (include 95%CI and p-value if available):

Adverse events:

UTI:

I: 37 (25.5%)

C: 6 (10%)

Urinary retention:

I: 10 (6.9%)

C: 0%

Dry mouth:

I: 2.8%

C: 0%

Dysuria:

I: 6 (4.1%)

C: 2 (3.3%)

Bacteriuria:

I: 11 (7.6%)

C: 3 (5.0%)

Nasopharyngitis:

I: 2 (1.4%)

C: 3 (5.0%)

QoL:

KHQ Role Limitations (change from baseline)

I: -31.2 (-36.2, -26.2)

C: -15.1 (-22.8, -7.4)

P<0.001

Social Limitations domains (change from baseline)

I: -13.7 (-16.9, -10.4)

C: -6.1 (-11.2, -1.1)

P=0.014

Oral placebo was administered to every patient because a 2^nd intervention arm was present with oral medication, namely solifenacin (5/10mg) (plus placebo injection).

Jabs, 2013

Type of study: single-institution, randomized, double-blind

controlled trial

Setting and country: tertiary care hospital, Canada, February 2008 and September 2009

Funding and conflicts of interest: “Allergan Inc. (Markham, Ontario) provided an honorarium

for a urologist experienced in the use of botulinum toxin to

be the first author’s preceptor. Allergan Inc. also provided

eight vials of botulinum toxin for the day of training.

There was no financial support for this study.”

Inclusion criteria:

- women >18 years old

- Clinical diagnosis of urinary urge incontinence with resistance to or intolerance of anticholinergic medication

- Willingness and ability to use self-catheterization if

necessary

Exclusion criteria:

- Urinary urge incontinence secondary to neurologic disease

- Known allergy or sensitivity to any of the components in the study medication

- Pregnant and/or breast-feeding

- The medical conditions of myasthenia gravis, Eaton-Lambert syndrome, or amytrophic lateral sclerosis

- Symptomatic urinary retention or post-void residual of > 200 mL

- Anticoagulation therapy

- Familial bleeding disorder

- Previous bladder pathology

- Participation in another drug study

- Previous botulinum toxin treatment for urological condition

N total at baseline:

Intervention: 11

Control: 10

Important prognostic factors²:

age ± SD:

I: 63 ± 9.4

C: 63.8 ± 11.2

Sex: 100% F

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

100U BoNT-A intradetrusor, in 10 mL

Describe control (treatment/procedure/test):

Placebo (saline) injection

Length of follow-up:

6 months

Loss-to-follow-up:

none

Incomplete outcome data:

none

Outcome measures and effect size (include 95%CI and p-value if available):

QoL:

UDI-6 score (change from baseline)

I: -28.5

C: -11.1

Mean change between groups: 17.4 (−1.9 to 36.6)

‘’Five patients in the treatment group and seven in the control group continued to use anticholinergic medications throughout

the study.’’

Liao, 2022

Type of study: multicenter, randomized, double-blind, placebo-controlled trial

Setting and country: April 2016 to December 2018, 17 sites across China

Funding and conflicts of interest: “This study was funded by the National Natural Science

Foundation of China, Grant/Award Number: No. 81870523.”

Inclusion criteria:

- 18–75 years old with a primary diagnosis of idiopathic OAB

- >8 micturitions per day

Exclusion criteria:

- dysuria

- post-void residual (PVR)

- urine volume >50 ml with spontaneous micturition

- longterm indwelling catheterization or CIC,

- previous botulinum toxin

treatment for any urologic condition within 6 months before

screening

- bladder or prostate cancer

- any urologic abnormalities or diseases, such as urinary tract infection (UTI) and urolithiasis

N total at baseline:

Intervention: 144

Control: 72

Important prognostic factors²:

For example

age ± SD:

I: 47.75 ± 14.20

C: 46.39 ± 15.55

Sex:

I: 117 (82.39%) F

C: 61 (85.92%) F

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

100U (Hengli) BoNT-A

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

24 weeks

Incomplete outcome data:

Intervention: n=19 (13.2%)

Reasons (describe):

Adverse events: n=1

Lack of efficacy: n=1

Lost to follow up: n=3

Personal reasons: n=12

Other: n=2

Control: n=8 (11.1%)

Reasons (describe):

Adverse events: n=1

Lost to follow up: n=2

Personal reasons: n=4

Other: n=1

Outcome measures and effect size (include 95%CI and p-value if available):

QoL score (mean change from baseline)

I: −1.00 (0.00, −2.00)

C: −0.50 (0.00, −2.00)

Adverse events:

UTI

I: 19 (13.38)

C: 6 (8.45)

Dysuria:

I: 21 (14.79)

C: 6 (8.45)

Haematuria

I: 3 (2.11)

C: 1 (1.41)

ALT (Alanine transaminase) elevation

I: 3 (2.11)

C: 0 (0)

McCammon, 2021

Type of study: randomized, multicenter, placebo-controlled, phase IV study

Setting and country: 44 sites in the United States between November 2013 and January 2017

Funding and conflicts of interest: “This study and its analysis were

sponsored by Allergan plc, Dublin, Ireland. Medical writing and editorial

assistance was provided by Jennifer L. Giel, PhD, CMPP, and Karen

Pemberton, PhD, CMPP, on behalf of Evidence Scientific Solutions, Inc.,

Philadelphia, PA, and was funded by Allergan plc, Dublin, Ireland.

All authors met the ICMJE authorship criteria. Neither honoraria nor payments

were made for authorship. Kurt McCammon has served as a consultant/

advisor and meeting participant/lecturer for AMS and Solace; as study investigator for AMS, Allergan plc, Astellas, Solace, and Uroplasty; and is a

board member/officer/trustee for IVU med. Angelo Gousse has served as a

consultant/advisor and investigator for Allergan plc and Precision Medical Devices. Alfred Kohan has been an investigator for Allergan plc, Ipsen, Myovant, and Watson; and a speaker for Allergan plc and Watson. David Glazier has been a study investigator for Allergan plc. Jennifer Gruenenfelder has served as a consultant and study investigator for Allergan plc. Zhanying Bai and Anand Patel are employees of Allergan plc. Douglass Hale has served as a consultant/advisor and meeting participant/

lecturer and has received research funding from Allergan plc.”

Inclusion criteria:

- Adults who had OAB for 6 months or longer

- were inadequately managed

by an anticholinergic

- had recorded 3 or more episodes of urgency

UI (UUI), 1 or less UUI-free day, and 24 or greater micturitions

on a 3-day paper bladder diary during screening.

Exclusion criteria:

- OAB caused by any neurologic condition;

- predominance of stress UI, surgery,

- disease other than OAB that might affect bladder function

- PVR greater than

100 mL

- and a 24-hour total urine void volume greater than 3000 mL during screening

N total at baseline:

Intervention: 129

Control: 125

Important prognostic factors²:

age ± SD:

I: 60.8 ± 12.7

C: 60.9 ± 12.1

Sex:

I: n=114 (88.4%) F

C: n=112 (89.6%) F

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

100U BoNT-A, intradetrusor, 20 injections (0.5 mL each)

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

12 weeks

Incomplete outcome data:

Intervention: n=13 (10.1%)

Reasons (describe):

Adverse events: n=2

Lost to follow up: n=4

Personal reasons: n=4

Other: n=3

Control: n=4 (3.2%)

Reasons (describe):

Personal reasons: n=2

Protocol violation: n=1

Other: n=1

Outcome measures and effect size (include 95%CI and p-value if available):

QoL

KHQ Incontinence impact domain (change from baseline)

I: -34.4

C: -13.5

KHQ Role Limitations (change from baseline)

I: -37.8

C: -16.7

KHQ Social Limitations (change from baseline)

I: -20.4

C: -6.0

MID is -5.0

Adverse events:

UTI

I: 27 (21.1%)

C: 8 (6.4%)

Urinary retention

I: 8 (6.3%)

C: 0

Dysuria:

I: 6 (4.7%)

C: 3 (2.4%)

Bronchitis

I: 1 (0.8%)

C: 4 (3.2%)

Cough

I: 0

C: 4 (3.2%)

Yokoyama, 2020

Type of study: phase III, randomized, double-blind, placebo-controlled trial

Setting and country: August 2016 to November 2018 at 53 sites in Japan

Funding and conflicts of interest: GlaxoSmithKline sponsored and provided funding for the

study.

Inclusion criteria:

- ≥20 years with OAB

- three or more episodes of UUI

- a mean of eight or more micturitions per day in a 3-day diary

Exclusion criteria:

- previous botulinum toxin treatment for any urological condition

- stress-dominant mixed UI

- any diseases, functional abnormalities or bladder surgery that might affect bladder function

- a PVR urine volume

>100 mL

N total at baseline:

Intervention: 124

Control: 124

Important prognostic factors²:

age ± SD:

I: 65.6 ± 12.43

C: 66.2 ± 12.19

Sex:

I: 94 (76%) F

C: 92 (74%) F

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

100U BoNT-A, intradetrusor, 20 injections (0.5 mL each)

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

48 weeks

Incomplete outcome data:

Intervention: n=9 (7.3%)

Reasons (describe):

Protocol deviation: n=2

Withdrew consent: n=3

Adverse event: n=2

Reached protocol defined stopping criteria n=2

Control: n=5 (4.0%)

Reasons (describe)

Adverse event: n=1

Withdrew consent: n=3

Reached protocol defined stopping criteria n=1

Outcome measures and effect size (include 95%CI and p-value if available):

UUI episodes (adjusted mean change from baseline ± SE)

I: -3.13 ± 0.370

C: -1.02 ± 0.363

Difference: -2.12 (-3.07 to -1.17)

QoL

KHQ Role Limitations (mean change from baseline ± SE)

I: -21.09 ± 2.997

C: -6.48 ± 2.976

KHQ Social Limitations (mean change from baseline ± SE)

I: -12.36 ± 2.983

C: -4.95 ± 2.945

Adverse events:

UTI

I: 16 (13%)

C: 9 (7%)

Nasopharyngitis

I: 15 (12%)

C: 11 (9%)

Dysuria:

I: 12 (10%)

C: 3 (2%)

Urinary retention:

I: 7 (6%)

C: 2 (2%)

Ramos, 2016

Yes

Yes

Yes

Yes

Not applicable

Yes

Yes

No

Yes

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

Low

Some concerns

High

Herschorn, 2017

Probably yes

Reason: “Randomization was stratified by center and number of UUI episodes (≤ 9 or >9 as recorded in a 3-day diary) at baseline”

Probably yes

Reason: no information in text.

Probably no

Reason: Blinding was ended at 12 weeks. No information on blinding of data analysts

Probably yes

Reason: more missing outcomes due to adverse events in intervention group, although overall numbers are equal.

Definitely yes

Reason: similar outcomes as described in the protocol.

Probably no

Reason: study and publication was sponsored by pharmaceutical company Allergan

Some concerns

Reason: Blinding was ended after 12 weeks (follow-up until 24 weeks). Results might be biased.

Jabs, 2013

Definitely yes

Reason: a 1:1 allocation scheme was used.

Definitely yes

Reason: a concealed envelope was used.

Definitely yes

Reason: patient and surgeon were blinded until six months (end of trial). Only the nurse (preparing the injection) was aware of the intervention.

Definitely yes

Reason: no loss to follow up.

Probably yes

Reason: no information in text.

Probably yes

Reason: although Allergan has provided for BoNT-A, no financial support was granted. No further influence of the industry.

Low

Reason: no concerns

Liao, 2022

Definitely yes

Reason: an Interactive Web Response System (IWRS) was used for randomization.

Probably yes

Reason: no information in text.

Definitely yes

Reason: patients and researchers were blinded.

Probably yes

Reason: more missing outcomes due to personal reasons in intervention group, although overall numbers are equal.

Probably yes

Reason: no information in text.

No information

Low

Reason: no concerns

McCammon, 2021

Definitely yes

Reason: an interactive voice response/ interactive web response system was used.

Probably yes

Reason: no information in text.

Definitely no

Reason: no evidence of blinding

Probably no

Reason: numbers are not close (more in intervention group)

Probably yes

Reason: no information in text.

Definitely no

Reason: study and publication was sponsored by pharmaceutical company Allergan

High

Reason: no blinding was performed.

Yokoyama, 2020

Probably yes

Reason: no information in text.

Probably yes

Reason: no information in text.

Probably yes

Reason: double-blind RCT. Although not specifically mentioned blinding of analysts.

Probably yes

Reason: some differences in incomplete outcomes.

Definitely yes

Reason: similar outcomes as described in the protocol.

No information

Low

Reason: no concerns