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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 reference

Participants

Study design

Treatment

Main findings

FOG subtype

Levodopa

 [3]

19 PD with FOG

Prospective, open-label, uncontrolled

Patients 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 FOG

Prospective, open-label, uncontrolled

Similar with the above study but took 1.5 times the usual levodopa dose

FOG improved (customized FOG score and FOGQ).

Unknown

Levodopa-carbidopa intestinal gel (LCIG)

 [60]

65 advanced PD

Observational, retrospective, a review of medical records

Mean duration of LCIG therapy was 3.7 years

FOG improved (FOG present only in 22% of patients at 1 year follow-up compared to 46% at baseline).

Unknown

 [61]

91 advanced PD

Observational, retrospective, a review of medical records

Mean time of follow up of 18 ± 8.4 months

Gait disorders (freezing, festination, postural instability) improved in 61.4% of patients (three point scale).

Unknown

 [62]

32 advanced PD with FOG

Observational, retrospective, a review of medical records

Mean duration of LCIG therapy was 2.59 ± 1.12 years

FOG 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 FOG

Observational, retrospective, multi-center, cross-sectional, uncontrolled

Mean duration of LCIG therapy was 34.7 months, 80.8% of patients ≥12 months

FOG improved in 76.2% of patients (subjective assessment by clinicians).

Unknown

 [64]

28 PD

Prospective, open label, uncontrolled

17/28 patients reached the 24-month follow-up

FOG improved (FOGQ)

Unknown

 [65]

25 PD

Prospective, open label, uncontrolled

20 patients continued on treatment to 6 months.

FOG improved (FOGQ)

Unknown

 [66]

5 PD with FOG

Prospective, open label, uncontrolled

24 h LCIG therapy, 6 months

360° turn time reduced, FOG improved (FOGQ) and fall frequency reduced

Resistant

 [56]

7 PD with FOG

Prospective, open label controlled, unrandomized

Evaluations 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 PD

Prospective, open label, uncontrolled

Pramipexole 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 FOG

Prospective, open label controlled, unrandomized

Rotigotine transdermal patch (9-27 mg/day), pramipexole LA (1.5-4.5 mg/day), ropinirole CR (8-16 mg/day) for at least 6 months

FOG improvement in Rotigotine group (FOGQ)

48 patients with “Off” FOG and 6 with “Off and On” FOG

 [69]

10 PD with FOG

Prospective, open label, uncontrolled

Acute test of subcutaneous apomorphine bolus in the morning at “off” state, without other medication

No improvement (subjective assessment)

FOG occur in both “Off” and “On” state

Monoamine oxidase B inhibitors

Selegiline

   [70]

14 PD with FOG

Prospective, open label, uncontrolled

Addition or increase in dose of selegiline, average dose: 4.0 mg/day for 3 months

FOG improved in 7/14 patients (FOGQ)

Unknown

Rasagiline

   [71]

687 PD in which 278 patients with FOG

Prospective, double-blind, randomized, placebo-controlled

Oral rasagiline (1 mg once daily), entacapone (200 mg with every levodopa dose), or placebo for 18 weeks

FOG improved by Rasagiline

(UPDRS-PIGD, UPDRS-freezing score)

Unknown

   [72]

42 PD with FOG

Prospective, open label, uncontrolled, multicenter

1 mg rasagiline daily as an add-on therapy for 3 months

FOG improved after 1, 2 and 3 months of therapy (FOGQ)

Unknown

   [73]

18 PD with FOG

Prospective, open label, uncontrolled,

1 mg rasagiline daily as an add-on therapy for 90 days

No overall improvement (Objective FOG counts and duration)

Resistant

Methylphenidate (MPH)

   [74]

69 advanced PD with FOG who had received STN- stimulation

Double-blind, randomized, Placebo-controlled

MPH (1 mg/kg per day) or placebo capsules for 90 days

MPH 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 disorders

Prospective, open label, uncontrolled

A daily dose of 1 mg/kg of MPH three times daily) for 3 months, including a 1-month titration phase

3 months MPH improved FOG (number of FOG during Stand-Walk-Sit test)

Resistant

   [76]

5 PD with FOG

Prospective, open label, uncontrolled

A 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 impairment

Double-blind, randomized, placebo-controlled

MPH (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 ± 5.82

Prospective, open label, uncontrolled

20 mg Istradefylline daily for 1 month

FOG improved (FOGQ)

Unknown

   [79]

31 PD patients with FOG

Prospective, open label, uncontrolled, multicenter

20 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 depressive

Prospective, open label, randomized, controlled, multicenter

Paroxetine 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 improved

Unknown

L-DOPS, droxidopa

   [81]

16 PD with FOG

Randomized, open label, controlled

L-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 weeks

Co-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 FOG

Prospective, open label, uncontrolled

L-DOPS initially 100 mg/day with a weekly increase of 100 mg up to 600-900 mg/day maintenance

FOG improved in more than half of patients (walk 10 m and return, subjective assessment)

Unknown

Amantadine

   [83]

11 PD with FOG

A retrospective chart review

Median 100 mg twice daily, and treatment duration was 20 months (range, 6-66 months).

Subjective self-reported improvement on FOG

Unknown

   [84]

42 PD with FOG

Double-blind, randomized, placebo-controlled

200 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 PD

Prospective, open label, uncontrolled

200 mg in 500 cm3 of saline solution given over a 3-h period, twice a day for 2 days

Improvement in PD patients (FOGQ)

Resistant

   [86]

10 PD with FOG

Randomized double-blind placebo-controlled, crossover

Placebo (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 FOG

Prospective, double-blind, randomized, placebo-controlled

10 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 FOG

Prospective, open label, uncontrolled

40 mg daily for 2 weeks then increased to 40 mg twice daily for 4-week then reduced to 40 mg daily for 1 week

No improvement (FOGQ)

Resistant

Acetylcholinesterase inhibitor

   [89]

41 PD with dementia

Open label, randomized, controlled

Galantamine 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 PD

Randomized, double-blind, placebo-controlled

Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks

FOG did not improve (episodes of FOG in the past month; NFOGQ)

Unknown

Botulinum toxin

   [91]

11 advanced PD with FOG

Randomized double blind placebo-controlled

BTX-A injection into each leg’s calf muscles, 150 IU per leg

No improvement (FOGQ, CGIC, UPDRS)

Off FOG

   [92]

12 PD with FOG

Randomized double-blind placebo-controlled, crossover

BTX-A injection into calf muscles, 16.25 to 25 U /site, six injection sites per leg, 12-week washout, then switched

No improvement (FOGQ, diaries, TUG and “2-min walk test”)

Unknown

   [93]

10 patients with FOG including 7 PD

Prospective, open label, uncontrolled

BTX-A injection into calf muscles, 3–6 sites per leg, 100-300 IU per session

FOG 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 FOG

Prospective, open label, uncontrolled

BTX-A injection into tensor fasciae latae muscle, 50 U per leg

FOG improved (FOGQ)

Resistant

   [95]

14 PD with FOG

Double-blind, placebo-controlled, randomized

BTX-B injection into calf muscles of the predominantly affected leg in freezing, 5000 U

No 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