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Table 3 Clinical trials of drug treatments for freezing of gait in Parkinson’s disease

From: Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

Study referenceParticipantsStudy designTreatmentMain findingsFOG subtype
Levodopa
 [3]19 PD with FOGProspective, open-label, uncontrolledPatients were examined during “Off” and “On” states that approximately 1 h after they took their regular morning dose of levodopa.Levodopa significantly decreased frequency and the number of FOG episodes (Video recorded).Unknown, but levodopa induced FOG was excluded
 [59]20 PD with FOGProspective, open-label, uncontrolledSimilar with the above study but took 1.5 times the usual levodopa doseFOG improved (customized FOG score and FOGQ).Unknown
Levodopa-carbidopa intestinal gel (LCIG)
 [60]65 advanced PDObservational, retrospective, a review of medical recordsMean duration of LCIG therapy was 3.7 yearsFOG improved (FOG present only in 22% of patients at 1 year follow-up compared to 46% at baseline).Unknown
 [61]91 advanced PDObservational, retrospective, a review of medical recordsMean time of follow up of 18 ± 8.4 monthsGait disorders (freezing, festination, postural instability) improved in 61.4% of patients (three point scale).Unknown
 [62]32 advanced PD with FOGObservational, retrospective, a review of medical recordsMean duration of LCIG therapy was 2.59 ± 1.12 yearsFOG that present in OFF condition and improved but did not disappear completely in ON condition can be further improved by LCIG (UPDRS freezing score).31 patients with responsive FOG and one with resistant-FOG
 [63]177 advanced PD, in which 122 patients with FOGObservational, retrospective, multi-center, cross-sectional, uncontrolledMean duration of LCIG therapy was 34.7 months, 80.8% of patients ≥12 monthsFOG improved in 76.2% of patients (subjective assessment by clinicians).Unknown
 [64]28 PDProspective, open label, uncontrolled17/28 patients reached the 24-month follow-upFOG improved (FOGQ)Unknown
 [65]25 PDProspective, open label, uncontrolled20 patients continued on treatment to 6 months.FOG improved (FOGQ)Unknown
 [66]5 PD with FOGProspective, open label, uncontrolled24 h LCIG therapy, 6 months360° turn time reduced, FOG improved (FOGQ) and fall frequency reducedResistant
 [56]7 PD with FOGProspective, open label controlled, unrandomizedEvaluations were performed in “On” state (60–90 min after taking the morning oral levodopa or LCIG).FOG improved on LCIG (FOGQ and UPDRS freezing score)Resistant
Dopamine agonist
 [67]36 PDProspective, open label, uncontrolledPramipexole treatment for 3 months (started at 0.125 mg/day and increased to 1.5 mg/day) .FOG improvement (FOGQ)Unknown
 [68]111 PD, in which 54 patients with FOGProspective, open label controlled, unrandomizedRotigotine transdermal patch (9-27 mg/day), pramipexole LA (1.5-4.5 mg/day), ropinirole CR (8-16 mg/day) for at least 6 monthsFOG improvement in Rotigotine group (FOGQ)48 patients with “Off” FOG and 6 with “Off and On” FOG
 [69]10 PD with FOGProspective, open label, uncontrolledAcute test of subcutaneous apomorphine bolus in the morning at “off” state, without other medicationNo improvement (subjective assessment)FOG occur in both “Off” and “On” state
Monoamine oxidase B inhibitors
Selegiline
   [70]14 PD with FOGProspective, open label, uncontrolledAddition or increase in dose of selegiline, average dose: 4.0 mg/day for 3 monthsFOG improved in 7/14 patients (FOGQ)Unknown
Rasagiline
   [71]687 PD in which 278 patients with FOGProspective, double-blind, randomized, placebo-controlledOral rasagiline (1 mg once daily), entacapone (200 mg with every levodopa dose), or placebo for 18 weeksFOG improved by Rasagiline
(UPDRS-PIGD, UPDRS-freezing score)
Unknown
   [72]42 PD with FOGProspective, open label, uncontrolled, multicenter1 mg rasagiline daily as an add-on therapy for 3 monthsFOG improved after 1, 2 and 3 months of therapy (FOGQ)Unknown
   [73]18 PD with FOGProspective, open label, uncontrolled,1 mg rasagiline daily as an add-on therapy for 90 daysNo overall improvement (Objective FOG counts and duration)Resistant
Methylphenidate (MPH)
   [74]69 advanced PD with FOG who had received STN- stimulationDouble-blind, randomized, Placebo-controlledMPH (1 mg/kg per day) or placebo capsules for 90 daysMPH reduces FOG in both “off” and “on” levodopa conditions (FOGQ and the number of freezing episodes while taking walking trajectory)Resistant
   [75]17 STN-stimulated patients with advanced PD and gait disordersProspective, open label, uncontrolledA daily dose of 1 mg/kg of MPH three times daily) for 3 months, including a 1-month titration phase3 months MPH improved FOG (number of FOG during Stand-Walk-Sit test)Resistant
   [76]5 PD with FOGProspective, open label, uncontrolledA single oral administration of 10 mg MPH. Reassessment 2 h later.FOG improved (total walking time, total freezing time, number of freezing episodes and the non-freezing walking time during an “8” trajectory).Responsive
   [77]17 PD with moderate gait impairmentDouble-blind, randomized, placebo-controlledMPH (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout.No improvement (FOGQ)Unknown
Istradefylline
   [78]14 PD patients with FOGQ 12.14 ± 5.82Prospective, open label, uncontrolled20 mg Istradefylline daily for 1 monthFOG improved (FOGQ)Unknown
   [79]31 PD patients with FOGProspective, open label, uncontrolled, multicenter20 mg Istradefylline daily for 4 weeks, followed by 20 mg/day or an
40 mg/day for 8 weeks
FOG improved (FOGQ, NFOGQ, and MDS-UPDRS Part III (ON-state) gait-related items total score)Unknown
Antidepressants
   [80]52 PD with mild to severe depressiveProspective, open label, randomized, controlled, multicenterParoxetine 20 mg/day or 25 mg/day; escitalopram 10 mg/day; duloxetine
40 mg/day; 8 weeks’ maintenance period and 2 weeks’ incremental period
FOG (FOGQ) and depression improvedUnknown
L-DOPS, droxidopa
   [81]16 PD with FOGRandomized, open label, controlledL-DOPS and entacapone initially 100 mg per day, increase by 100 mg increments every 2 days up to 100 mg per each levodopa administration for 4 weeksCo-administration of L-DOPS and entacapone improved FOG, yet entacapone or L-DOPS alone didn’t, and the improvement was found only in levodopa-resistant FOG (visual analogue scale, VAS)14 patients with “On and Off FOG”; 2 patients with “Off” FOG
   [82]13 advanced PD with FOGProspective, open label, uncontrolledL-DOPS initially 100 mg/day with a weekly increase of 100 mg up to 600-900 mg/day maintenanceFOG improved in more than half of patients (walk 10 m and return, subjective assessment)Unknown
Amantadine
   [83]11 PD with FOGA retrospective chart reviewMedian 100 mg twice daily, and treatment duration was 20 months (range, 6-66 months).Subjective self-reported improvement on FOGUnknown
   [84]42 PD with FOGDouble-blind, randomized, placebo-controlled200 mg/500 mL normal saline twice a day for 5 days.No improvement (FOGQ)50% patients with FOG at “On” state
   [85]15 patients with FOG including 6 PDProspective, open label, uncontrolled200 mg in 500 cm3 of saline solution given over a 3-h period, twice a day for 2 daysImprovement in PD patients (FOGQ)Resistant
   [86]10 PD with FOGRandomized double-blind placebo-controlled, crossoverPlacebo (normal saline) or amantadine (400 mg/day) were injected four times for 2 days, 52-h washout, then switched.No improvement (FOGQ, UPDRS, 4 × 10 m walking test)Resistant
Atomoxetine
   [87]5 PD with FOGProspective, double-blind, randomized, placebo-controlled10 mg daily and 10 mg increments up to 40 mg per day over 3 weeks.No improvement (7 M Step test, FOGQ, Clinician’s Global Index of Change (CGIC), Gait and Balance Scale)Resistant
   [88]10 PD with FOGProspective, open label, uncontrolled40 mg daily for 2 weeks then increased to 40 mg twice daily for 4-week then reduced to 40 mg daily for 1 weekNo improvement (FOGQ)Resistant
Acetylcholinesterase inhibitor
   [89]41 PD with dementiaOpen label, randomized, controlledGalantamine 4 mg twice daily for the first 4 weeks, and then 8 mg twice daily to the end of the 24 week trial period.FOG improved (UPDRS freezing subitem)Unknown
   [90]130 PDRandomized, double-blind, placebo-controlledRivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeksFOG did not improve (episodes of FOG in the past month; NFOGQ)Unknown
Botulinum toxin
   [91]11 advanced PD with FOGRandomized double blind placebo-controlledBTX-A injection into each leg’s calf muscles, 150 IU per legNo improvement (FOGQ, CGIC, UPDRS)Off FOG
   [92]12 PD with FOGRandomized double-blind placebo-controlled, crossoverBTX-A injection into calf muscles, 16.25 to 25 U /site, six injection sites per leg, 12-week washout, then switchedNo improvement (FOGQ, diaries, TUG and “2-min walk test”)Unknown
   [93]10 patients with FOG including 7 PDProspective, open label, uncontrolledBTX-A injection into calf muscles, 3–6 sites per leg, 100-300 IU per sessionFOG improved (CGIC)3 patients with “Off” FOG; 2 with “On” FOG; 2 with “On and Off” FOG
   [94]20 PD, 10 PD with FOG and 10 PD without FOGProspective, open label, uncontrolledBTX-A injection into tensor fasciae latae muscle, 50 U per legFOG improved (FOGQ)Resistant
   [95]14 PD with FOGDouble-blind, placebo-controlled, randomizedBTX-B injection into calf muscles of the predominantly affected leg in freezing, 5000 UNo improvement (UPDRS, VAS, and Modified Webster Step-Seconds test)Resistant
  1. A total of 39 clinical trials were summarized. The number of participants and their FOG subtype, the type of study design, drug treatments strategies, assessment methods for FOG and main findings were provided in this table
  2. FOG Freezing of gait, PD Parkinson’s disease, LCIG Levodopa-carbidopa intestinal gel, FOGQ Freezing of Gait-Questionnaire, NFOGQ New Freezing of Gait Questionnaire, UPDRS Unified Parkinson’s Disease Rating Scale, PIGD Postural instability/gait difficulty, MPH Methylphenidate, L-DOPS L-threo-3, 4-dihydroxyphenylserine, VAS Visual Analog Scale, CGIC Clinician’s Global Index of Change