Methods

Study design: RCT

Instruments used: MMSE, BDI, 10MWT, SIS, device‐related SAE rate, 6MWT, GaitRite FAP, mEFAP, BBS, TUG, SSQoL

Study design as described in the article: Quote: "This study was an unblinded, parallel‐group RCT"

Study duration: 24 months

Year of study: trial ran between April 2010 and April 2012

Participants

Inclusion criteria: ≥ 6 months poststroke; inadequate dorsiflexion with inadequate limb clearance during swing phase of gait; positive response to peroneal nerve stimulation testing; adequate cognitive function (MMSE score > 17); not currently using FES for the treatment of foot drop; ≥ 30 days post‐inpatient or outpatient stroke, cardiac, pulmonary, or any other lower extremity physical rehabilitation; able to walk at least 10 meters with or without an assist device; initial gait speed of > 0.0 m/s and < 0.8 m/s; eligible for Medicare or Medicare Choice/Advantage benefits at time of consent; ≥ 90 days post‐MI; ≥ 90 days post‐stenting procedure (i.e. peripheral, cardiac, carotid, and/or renal); ≥ 90 days post‐major orthopedic surgery (i.e. hip, knee, and/or ankle joint replacement); ≥ 6 months post‐CABG or cardiac valve procedure; able and willing to give written consent and comply with study procedures, including follow‐up visits

Exclusion criteria: ankle joint instability other than foot drop; needs AFO for stance control of the foot, ankle, and/or knee; unable to safely clear toes in swing phase on the involved lower extremity, defined as > −5 degrees plantar flexion with the WalkAide device (determined at fitting); diagnosed with peripheral neuropathy, and symptoms obstruct or limit ambulation or participation in study; diagnosed with significant peripheral vascular disease accompanied by lower extremity ulceration and/or disabling claudication; underlying condition(s) that would limit study participation; severe hypertonicity resulting in the need for more involved orthotic strategies; excessive dysesthetic pain secondary to neurological involvement; moderate to very severe chronic obstructive pulmonary disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD); New York Heart Association (NYHA) Class III‐IV; malignant skin lesion below the knee on the affected lower extremity; history of seizure disorder and is currently on seizure control medication for this disorder; aphasia, defined as inability to verbalize commands; BDI score of > 29 indicating severe depression; life expectancy less than 12 months; received botulinum toxin injections in the lower extremity within the past 6 months; baclofen pump with unstable dosing in the last 3 months; participating in another clinical trial that, according to the principal investigator, is likely to affect study outcome or confound results; patient has existing electrical stimulation devices (implantable cardioverter defibrillator, pacemaker, spinal stimulation, TENS)

Age: MN group mean age (± SD): 63.87 years (± 11.33); control group mean age (± SD): 64.30 years (± 12.01)

Country: USA

Sample size: 495 participants

Sex: MN group: 147 (60.74%) men, 95 (39.26%) women; control group: 157 (62.06%) men, 96 (37.94%) women

Time poststroke: ≥ 6 months poststroke. MN group mean time poststroke (± SD): 6.90 years (± 6.43); control group mean time poststroke (± SD): 6.86 years (± 6.64)

Type of stroke: not stated

Interventions

Motor neuroprosthesis

• Intervention: MN group used WalkAide device for all walking activities on a full‐time basis throughout the day. In the first 2 weeks, participants adhered to a progressive wearing schedule, after that they were instructed to wear MN on a full‐time basis (i.e. for all walking activities throughout the day).

• Number of participants: 242

• Device: a single‐channel electrical stimulator composed of a cuff worn around the proximal part of the lower leg, control module, and surface electrodes. This device uses a tilt sensor and accelerometer to trigger ankle dorsiflexion during the swing phase of gait.

• Duration of exposure: the length of treatment with MN was 12 months

• Place of application of intervention: lower limb

Another assistive technology device

• Intervention: control group used AFO for all walking activities on a full‐time basis throughout the day. In the first 2 weeks, participants adhered to a progressive wearing schedule, after that they were instructed to wear AFO on a full‐time basis (i.e. for all walking activities throughout the day).

• Number of participants: 253

• Device: AFO could be either articulated or fixed at the ankle based on the professional opinion of the orthotist and clinical needs of the participant

• Duration of exposure: the length of treatment with AFO was 12 months

• Place of application of intervention: lower limb

Outcomes

Activities involving limbs: walking speed measured with the 10MWT (m/s)

• Outcome type: continuous

• Assessment time point: baseline, 6 months, and 12 months

• Device at assessments: baseline, 6‐month, and 12‐month assessments performed with MN

Activities involving limbs: mEFAP (s)

• Outcome type: continuous

• Assessment time point: baseline, 6 months, and 12 months

• Device at assessments: baseline, 6‐month, and 12‐month assessments performed with MN

Activities involving limbs: TUG (s)

• Outcome type: continuous

• Assessment time point: baseline and 6 months

• Device at assessments: baseline, 6‐month, and 12‐month assessments performed with MN

Balance: BBS

• Outcome type: continuous

• Assessment time point: baseline and 6 months

• Device at assessments: baseline, 6‐month, and 12‐month assessments performed with MN

Exercise capacity: 6MWT (m)

• Outcome type: continuous

• Assessment time point: baseline, 6 months, and 12 months

• Device at assessments: baseline, 6‐month, and 12‐month assessments performed with MN

Participation scale of HRQoL: SSQoL

• Outcome type: continuous

• Assessment time point: baseline and 6 months

Participation scale of HRQoL: SIS Social participation domain

• Outcome type: continuous

• Assessment time point: baseline and 6 months

Adverse events: dropouts during the intervention period

• Outcome type: binary

Adverse events: serious adverse events related to the intervention

• Outcome type: binary

Adverse events: falls

• Outcome type: binary

Identification

Author's name: Francois Bethoux

Institution: The Cleveland Clinic Foundation

Email: [email protected]

Address: The Cleveland Clinic Foundation, Desk U10, 9500 Euclid Avenue, Cleveland, OH 44195, USA

Funding source

Innovative Neurotronics

Notes

This study consisted of 2 articles (Bethoux 2014; Bethoux 2015).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Using a centralized computer‐generated randomization scheme built into the electronic data capture system for this study"

Allocation concealment (selection bias)

Low risk

Quote: "Centralized computer‐generated randomization scheme"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

There was no blinding of participants and personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Unblinded outcome assessment

Incomplete outcome data (attrition bias)
Secondary outcome

Low risk

Quote: "We conducted an ITT analysis using multiple imputations to account for missing data"

Incomplete outcome data (attrition bias)
Primary outcome

Low risk

Quote: "We conducted an ITT analysis using multiple imputations to account for missing data"

Selective reporting (reporting bias)

Unclear risk

Although all of the study’s prespecified primary outcomes were reported, a secondary variable was included in the study that was not prespecified in the protocol.

Other bias

High risk

This study was sponsored by Innovative Neurotronics.

Methods

Study design: RCT

Instruments used: 10MWT, lower extremity Fugl‐Meyer, TUG, 6MWT, BBS, FRT, SIS

Study design as described in the article: "single‐blinded randomized controlled trial"

Study duration: 32 months

Year of study: trial ran between May 2010 and December 2012

Participants

Inclusion criteria: at least 1 stroke ≥ 3 months before study enrollment, resulting in drop foot; ankle dorsiflexion response with test stimulation in sitting and standing, and adequate ankle and knee stability during gait with test stimulation; medically stable; score ≥ 24 on the MMSE, or have a competent caregiver if < 24; age ≥ 18 year or older; able to walk ≥ 10 meters with a maximum of 1 person assist; self‐selected gait speed ≤ 0.80 m/s without orthotic effect

Exclusion criteria: fixed ankle contracture at ≥ 5 degrees of plantar flexion in the hemiplegic leg with the knee extended; pain in the affected leg, rated ≥ 4 on a 10‐point visual analogue scale; participating in physical therapy, occupational therapy, new exercise program, or any other interventional clinical research studies without the sponsor's approval; botulinum toxin to the hemiplegic leg or arm within the past 6 weeks or planned during the course of the study; expectation of a significant change in oral medications for spasticity; complete lower extremity hemisensory loss; use of any FDS device for foot drop for an accumulative > 3 hours within the last 6 months before study enrollment; any electric or metallic implant; significant swelling/edema in the lower leg; chronic skin problems or cancerous lesion in close proximity to the site of FDS stimulation; pregnant or planning on becoming pregnant; unstable seizure disorder; orthopedic conditions that would affect ambulation; major untreated depression

Sample size: 197 participants

Country: USA

Age: mean age (± SD): 61.14 years (± 11.61)

Sex: 79 women and 118 men. MN group: 51 (51.5%) men; control group: 67 (68.4%) men

Time poststroke: this study considered 2 subgroups: participants 3 to 6 months after stroke and participants > 6 months after stroke. Mean time poststroke (± SD): 4.55 years (± 4.72)

Type of stroke: 145 ischemic, 46 hemorrhagic, 6 data not available

Interventions

Motor neuroprosthesis

• Intervention: MN group used NESS L300 device. In the first 6 weeks, participants received 8 physical therapy sessions and also followed the device manufacturer's standard conditioning protocol. The physical therapy sessions focused on education on the MN device use, gait training with MN, and the development of an individualized home exercise program. Treatment time ranged from 30 to 60 minutes. The standard conditioning protocol performed in the first 3 weeks included the gradual increase of walking with MN from 15 minutes each day to all‐day use and also involved the use of the device for cyclic stimulation while the participant was not walking. Participants performed cyclic stimulation to gradually strengthen and condition the muscles to avoid fatigue when using the MN. This stimulation was done 2 times daily for 15 minutes in the first week and for 20 minutes over the next 2 weeks. After this initial conditioning phase, participants used MN all day exclusively for ambulation.

• Number of participants: 99

• Device: a single‐channel electrical stimulator composed of a cuff, control module, surface electrodes, and a pressure sensor to detect gait events and trigger stimulation

• Duration of exposure: 30 weeks of MN

• Place of application of intervention: lower limb

Another assistive technology device

• Intervention: control group used AFO. In the first 6 weeks, participants received 8 physical therapy sessions and also received surface sensory stimulation with a TENS device. The physical therapy sessions focused on education on use of the AFO if need, gait training with the AFO, and the development of a home exercise program. Treatment time ranged from 30 to 60 minutes. During the first 3 weeks, participants received surface sensory stimulation on the hemiplegic leg with a TENS device at each physical therapy visit. TENS intensity was set at the lowest stimulation level that yielded a sensory response without motor response, at a frequency of 100 pps and duration of 200 μs. This stimulation was done for 30 minutes in the first week and for 30 to 45 minutes over the next 2 weeks. After this initial conditioning phase, participants used AFO all day exclusively for ambulation.

• Number of participants: 98

• Device: AFO (articulated, non‐articulated, prefabricated or other)

• Duration of exposure: 30 weeks of AFO

• Place of application of intervention: lower limb

Outcomes

Activities involving limbs: walking speed measured with the 10MWT (m/s)

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

• Device at assessments: baseline and 30‐week assessments performed with MN and without MN

Activities involving limbs: fast walking speed measured with the 10MWT (m/s)

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

• Device at assessments: baseline and 30‐week assessments performed with MN and without MN

Activities involving limbs: TUG (s)

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

• Device at assessments: baseline and 30‐week assessments performed with MN and without MN

Exercise capacity: 6MWT (m)

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

• Device at assessments: baseline and 30‐week assessments performed with MN and without MN

Balance: BBS

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

• Device at assessments: baseline and 30‐week assessments performed with MN and without MN

Balance: functional reach (cm)

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

• Device at assessments: baseline and 30‐week assessments performed with MN and without MN

Participation scale of HRQoL: SIS ‐ Social participation

• Outcome type: continuous

• Assessment time point: baseline and 30 weeks

Adverse events: dropouts during the intervention period

• Outcome type: binary

Adverse events: serious adverse events related to intervention

• Outcome type: binary

Adverse events: falls

• Outcome type: binary

Identification

Author's name: Patricia M Kluding

Institution: Department of Physical Therapy and Rehabilitation Sciences, University of Kansas Medical Center

Email: [email protected]

Address: University of Kansas Medical Center, 3901 Rainbow Blvd, Mail Stop 3051, Kansas City, KS 66160, USA

Funding source

Bioness Inc

Notes

Associated reference: Dunning 2013

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Once study eligibility was confirmed, random group assignment was performed by the sponsor using a web‐based application prepared by the study statistician."

Allocation concealment (selection bias)

Unclear risk

Although the study protocol mentioned that the process is concealed by the site, the method of concealment is not described in sufficient detail to permit a definitive judgement.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

There was no blinding of participants and personnel.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "To maintain blinding, a nonblinded research team member coordinates outcome testing and all subjects wear loose pants, a lower leg and shoe cover ('gaiter') on the involved lower extremity (to conceal the AFO or FDS cuff and pressure sensor), and an FDS control unit"

Incomplete outcome data (attrition bias)
Secondary outcome

Low risk

ITT analysis was performed.

Incomplete outcome data (attrition bias)
Primary outcome

Low risk

ITT analysis was performed.

Selective reporting (reporting bias)

Low risk

The study protocol is available, and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way.

Other bias

High risk

This trial was funded by Bioness Inc.

Methods

Study design: RCT

Instruments used: 6MWT, Vicon system, activPAL Professional, surface electromyographic (sEMG) activity, SF‐36, DIP, EQ‐5D

Study design as described in the article: "Randomized controlled trial"

Study duration: not stated

Year of study: not stated

Participants

Inclusion criteria: drop foot identified by an inability to achieve a normal heel strike during walking; first hemiplegia of at least 6 months in duration as a result of a cerebrovascular accident with a stable neurology; individual is an outdoor walker; able to give an informed consent

Exclusion criteria: under age 18 years; passive dorsiflexion of the ankle 5 degrees with knee in extension; medical conditions other than cerebrovascular accident, i.e. neurologic, rheumatic, cardiovascular, or systemic disorders (including diabetes mellitus) limiting the function of walking; injury to deep and superficial peroneal nerve and sciatic nerve; any medical condition that would exclude the use of a surgical procedure or anesthetic; not able to don and doff the equipment; pregnancy

Age: MN group mean age (± SD): 55.2 years (± 11.36); control group mean age (± SD): 52.87 years (± 9.87)

Country: the Netherlands

Sample size: 29

Sex: MN group: 10 men and 4 women; control group: 10 men and 5 women

Time poststroke: ≥ 6 months poststroke. MN group mean time poststroke (± SD): 9.07 years (± 9.29); control group mean time poststroke (± SD): 5.67 years (± 4.64)

Type of stroke: not stated

Interventions

Motor neuroprosthesis

• Intervention: MN group used STIMuSTEP device. The intervention began with the surgical procedure for the implantation of STIMuSTEP device. After 2 weeks of the surgery the wound was checked and first test stimulation took place. At week 3 the stimulation during walking was tested, and the stimulator was taken home by the participant. In weeks 4 and 5 the use of the stimulator was gradually increased. In weeks 6 to 26 the participants were allowed to use the system all day.

• Number of participants: 14

• Device: a 2‐channel electrical stimulator composed of an external transmitter with a built‐in antenna, a foot switch, and implantable components consisting of the stimulator, the 2 leads, and the bipolar intraneural electrode. The on‐and‐off switch of the stimulation was determined by a foot switch sensor. Electrodes are placed under the epineurium of the peroneal nerve.

• Duration of exposure: 26 weeks of MN

• Place of application of intervention: lower limb

Another assistive technology device

• Intervention: the control group continued using their conventional walking device all day for correction of their foot drop (i.e. AFO, orthopedic shoes, or no walking device)

• Number of participants: 15

• Device: polypropylene non‐articulated AFO (with 2 crossed posterior steels and an open heel, with a large posterior steel, with a small posterior steel, or with a large posterior steel)

• Duration of exposure: 26 weeks of AFO

• Place of application of intervention: lower limb

Outcomes

Activities involving limbs: walking speed (m/s)

• Outcome type: continuous

• Assessment time point: baseline and 26 weeks

• Device at assessments: baseline assessment performed without MN, 26‐week assessment performed with MN

Participation scale of HRQoL: SF‐36 ‐ Social functioning

• Outcome type: continuous

• Assessment time point: baseline and 26 weeks

Adverse events: dropouts during the intervention period

• Outcome type: binary

Identification

Author's name: Anke I Kottink

Institution: Roessingh Research and Development

Email: [email protected]

Address: Roessingh Research and Development, PO Box 310, 7500 AH, Enschede, the Netherlands

Funding source

Not reported

Notes

This study consisted of 4 articles that were part of a PhD thesis (Kottink 2007; Kottink 2008; Kottink 2010; Kottink 2012).

We did not include outcomes of 6MWT and walking speed assessed with and without devices because these data were presented only as figures (Kottink 2007; Kottink 2008). We contacted the principal investigator, but the author did not respond to our request for data.

References associated with this study: Kottink 2008; Kottink 2010; Kottink 2012

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The study authors stated that blocked randomization was used, but it is not clear if the method used for selecting the blocks describes a random component in the sequence generation process.

Allocation concealment (selection bias)

Low risk

Random procedure was carried out by an independent person.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

There was no blinding of participants and personnel.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
Secondary outcome

Low risk

ITT analysis was performed.

Incomplete outcome data (attrition bias)
Primary outcome

High risk

The study had withdrawals, and no ITT was performed for the primary outcome of 10MWT (Kottink 2012).

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Other bias

Low risk

No other bias detected.

Methods

Study design: RCT

Instruments used: lower limb portion of the Fugl‐Meyer Assessment, mEFAP, SSQoL, gait analysis with Vicon system

Study design as described in the article: "Single‐blinded randomized controlled trial"

Study duration: not stated

Year of study: not stated

Participants

Inclusion criteria: age ≥ 18 years, ≥ 12 weeks poststroke with unilateral hemiparesis and ankle dorsiflexion strength of ≤ 4/5 on the Medical Research Council (MRC) scale. Participants were required to ambulate ≥ 30 feet without an AFO, score ≥ 24 on the BBS, and demonstrate correction of foot drop using a PNS without evidence of knee hyperextension during stance.

Exclusion criteria: lower extremity edema, skin breakdown, or absent sensation; serious cardiac arrhythmias, pacemakers or other implanted electronic systems; pregnancy; uncontrolled seizure disorder; concomitant lower motor neuron dysfunction and non‐stroke upper motor neuron dysfunction; uncompensated hemineglect; sensory or motor peripheral neuropathy; fixed ankle plantarflex or contracture; or lower extremity botulinum toxin injection within the 3 months prior to study enrollment

Age: MN group mean age (± SD): 52.8 years (± 12.2); control group mean age (± SD): 53.2 years (± 10.1)

Country: USA

Sample size: 110 participants

Sex: MN group: 30 men and 24 women; control group: 37 men and 19 women

Time poststroke: > 12 weeks poststroke. MN group mean time poststroke (± SD): 44.7 months (± 97.5); control group mean time poststroke (± SD): 44.9 months (± 79.2)

Type of stroke: MN group: 13 embolic, 17 thrombotic, 9 lacunar, and 15 hemorrhagic; control group: 12 embolic, 23 thrombotic, 6 lacunar, and 15 hemorrhagic

Interventions

Motor neuroprosthesis

• Intervention: MN group used Odstock Dropped‐Foot Stimulator (ODFS) device up to 8 hours per day once device safety was demonstrated. In the first 5 weeks the Functional Training phase (2 x 1‐hour sessions per week) took place, in which participants were trained to use the MN device for home and community mobility with an assistive device, such as a straight cane, quad cane, or walker, if needed. Activities included passive and active range‐of‐motion exercises, lower extremity strengthening, standing balance and weight‐shifting activities to the affected limb with transition to least‐restrictive assistive device, and refinement of a reciprocal gait pattern. Exercises were done with multiple repetitions with an increase in difficulty and decrease in cues, with and without the MN, as appropriate. In the last 7 weeks the Post‐Functional Training phase (3 x 1‐hour sessions) took place, in which device function, application, and usage guidelines were reviewed with each participant to maximize MN compliance.

• Number of participants: 54

• Device: a single‐channel surface stimulator with surface electrodes. The stimulation was triggered by an insole pressure sensor.

• Duration of exposure: 12 weeks of independent use of MN

• Follow‐up: 12 and 24 weeks' post‐treatment

• Place of application of intervention: lower limb

Another assistive technology device

• Intervention: control group consisted of treatment with AFO or no device up to 8 hours per day. In the first 5 weeks the Functional Training phase (2 x 1‐hour sessions per week) took place, in which participants were trained to use the AFO device for home and community mobility with an assistive device, such as a straight cane, quad cane, or walker, if needed. Activities included passive and active range‐of‐motion exercises, lower extremity strengthening, standing balance and weight‐shifting activities to the affected limb with transition to less restrictive assistive device, and refinement of a reciprocal gait pattern. Exercises were done with multiple repetitions with an increase in difficulty and decrease in cues, with and without the AFO, as appropriate. In the last 7 weeks the Post‐Functional Training phase (3 x 1‐hour sessions) took place, in which device function, application, and usage guidelines were reviewed with each participant to maximize AFO compliance.

• Number of participants: 56 (48 participants used AFO as usual care, and 6 participants used no device)

• Device: a custom‐molded hinged AFO with plantarflexion block that was fabricated using conventional techniques

• Duration of exposure: 12 weeks of independent use of AFO

• Place of application of intervention: lower limb

Outcomes

Activities involving limbs: mEFAP (s)

• Outcome type: continuous

• Assessment time point: baseline, 12 weeks, 12 weeks post‐treatment, and 24 weeks post‐treatment

• Device at assessments: baseline, 12 weeks, 12 weeks post‐treatment, and 24 weeks post‐treatment assessments performed without MN

Activities involving limbs: walking speed (m/s)

• Outcome type: continuous

• Assessment time point: baseline, 12 weeks, 12 weeks post‐treatment, and 24 weeks post‐treatment

• Device at assessments: baseline, 12 weeks, 12 weeks post‐treatment, and 24 weeks post‐treatment assessments performed without MN

Participation scale of HRQoL: SSQoL

• Outcome type: continuous

• Assessment time point: baseline, 12 weeks, 12 weeks post‐treatment, and 24 weeks post‐treatment

Adverse events: dropouts during the intervention period

• Outcome type: binary

Adverse events: falls

• Outcome type: binary

Identification

Author's name: Lynne R Sheffler

Institution: Department of Physical Medicine and Rehabilitation, Case Western Reserve University, Cleveland, OH; Cleveland FES Center; Dept of PM&R, MetroHealth Rehabilitation Institute of Ohio, USA

Email: [email protected]

Address: MetroHealth Medical Center, 4229 Pearl Road, N5‐524, Cleveland, OH 44109, USA

Funding source

MetroHealth Medical Center

Notes

This study consisted of 2 articles (Sheffler 2013a; Sheffler 2015).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The investigators described that envelopes were used as a random component in the sequence generation process.

Allocation concealment (selection bias)

Unclear risk

Although the investigators stated that the randomization sequence was concealed, there is no mention as to whether the envelopes were sealed or not.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

There was no blinding of participants and personnel.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "blinded outcomes assessor".

Incomplete outcome data (attrition bias)
Secondary outcome

Low risk

ITT analysis was performed.

Incomplete outcome data (attrition bias)
Primary outcome

Low risk

ITT analysis was performed.

Selective reporting (reporting bias)

Low risk

The study protocol is available, and all of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way.

Other bias

Low risk

No other bias detected.