Interleaving Stimulation Improves Dyskinesia in Parkinson's Disease: Randomized, Double-blind, Controlled Trial
Phase: NA
Conditions: Parkinson's Disease
Sponsor: Huashan Hospital

Interleaving stimulation improving dyskinesia in Parkinson’s 
disease: randomized, double-blind, controlled trial 
2022.5.20 

Version 1.5 
Interleaving stimulation improving dyskinesia in Parkinson’s disease: randomized, 
double-blind, controlled trial 
Study protocol 
1.
Background
The clinical utility of deep brain stimulation (DBS) for the treatment of Parkinson's disease 
(PD) has been well established; however, there are a variety of adverse events, such as 
dyskinesia among subthalamic nucleus (STN) DBS recipients due to varied postoperative 
management. The artificial electrical signals of deep brain stimulation are delivered with 
four parameters; contact (0~3), frequency (Hertz - Hz), amplitude (voltage or current) and 
pulse width (microseconds, µs). It has recently been reported that interleaving stimulation 
can be used effectively to treat motor symptoms while avoiding side effects. 
Dyskinesia 
Levodopa-induced dyskinesias (LIDs) are motor complications of Parkinson’s disease. LID 
is characterized by progressive motor disability and may interfere with quality of life.  
STN-DBS has also been demonstrated to provoke or exacerbate dyskinesia (stimulation-
induced dyskinesia, SID). Previous studies have showed that the proportion of stimulation-
induced dyskinesia is as high as 50% to 75%. 
Both kinds of dyskinesias have variable phenotypes, including chorea, ballism, dystonia, 
myoclonus, or combination of any of these movements. SIDs are easily evoked in patients 
with severe preoperative LIDs.  
In general, reducing the dosage of levodopa can improve LIDs post-operation. However, 
this approach will fail when dyskinesia is the result of stimulation. Available programming, 
such as interleaving stimulation could improve dyskinesias post-operation. 
So, this study is designed as a prospective, randomized, double-blind, controlled 
study to assess putative differences in the effect of interleaving stimulation and empirical 
stimulation with regards to post-operation dyskinesia control. 
2.
Study design 
2.1 Purpose 
The primary objective is to assess putative differences in the effect of interleaving 
stimulation and empirical stimulation with regards to dyskinesia control. 
2.2 Primary Outcome Measures 
The changes of dyskinesia scores (UPDRS IV, item 32 + item 33) in interleaving 
stimulation compared to empirical programming modes. [Time Frame: 3 months and 9 

months] 
The changes of Parkinson’s disease quality of life-39 (PDQ-39) scores in interleaving 
stimulation compared to empirical programming modes. [Time Frame: 3 months and 9 
months] 
2.3 Secondary Outcome Measures 
The changes of scores of United Parkinson’s Disease Rating Scale Part III in 
interleaving stimulation compared to empirical programming modes. [Time Frame: 3 
months and 9 months] 
 
Scores of neuropsychological Battery in interleaving stimulation compared to empirical 
programming modes. [Time Frame: 3 months and 9 months] 
2.4 Safety outcome Measures 
Adverse events [Time Frame: up to 12 months] 
Any adverse medical event from date of randomization until the date of first 
documented adverse event or date of death from any cause, which ever comes first, 
assessed up to 12 months. 
Persistent dyskinesia despite optimization of parameters of stimulation is defined with 
severity ≥2 on item 32 and duration ≥2 (e.g., duration ≥ up to 50% of the 16 hours 
ambulatory time) on item 33 of the unified Parkinson's disease rating scale (UPDRS) part 
IV. 
2.5 Study population:  
Indications of DBS for PD consistent with the China specific approved labeling. 
Inclusion Criteria 
⚫ 
Patients at the age of 30–65 years old. 
⚫ 
Patients diagnosed as Parkinson’s disease according to the UK Parkinson’s 
Disease Society Brain Bank criteria. 
⚫ 
Patients at Hoehn and Yahr stage 3 or lower in the on-state and stage 2 - 4 in 
the off-state. 
⚫ 
The disease duration of 5 years or more.  
⚫ 
Patients with deep levodopa-responsive Parkinson's disease, and are not 
adequately controlled by drug therapy. 
Study participants will be PD patients undergoing DBS of the subthalamic nucleus 
(STN). Whether or not a patient is selected for DBS surgery is determined by the patient's 
clinical team purely on independent clinical grounds. Only those patients who have been 
accepted for DBS treatment by their clinical neurologist and functional neurosurgeon will 

be introduced to the project and have their details passed on to the research team for 
further information and formal inform consenting. 
Exclusion Criteria 
Exclusion criteria are: major illness or medical comorbidities, depression that is 
untreated but judged to be clinically significant by an investigator, cochlear implants, 
cardiac pacemakers, needs for diathermy, anticoagulant therapy, previous neuro-surgical 
procedure or ablative therapy, frank dementia according to cognitive screening, drug or 
alcohol abuse, being a woman of child-bearing potential, having a positive pregnancy test, 
or presence of a terminal illness.  
Written informed consent is obtained from all patients before any study procedures 
were started. 
3. Study Process 
3.1 Randomization and masking 
50 Patients will be randomly assigned to either the interleaving stimulation modes group 
(ISG) or the empirical stimulation modes group (ESG).  
ISG: empirical stimulation for the first 3 months, followed by interleaving programming 
period for 6 months, and any stimulation decided by the neurologists/neurosurgeons for 
the final 3 months. 
ESG: empirical programming for the first 9 months’ period, followed by any stimulation 
decided by the neurologists/neurosurgeons for the final 3 months. 
Patients are randomly assigned to receive either interleaving stimulation (interleaving 
group, 25 patients) or empirical stimulation (conventional group, 25 patients) after the 
enrollment, just before the implantation of the DBS device in the STN. The randomization 
ratio was 1:1 (Fig 1). 
Randomization is done by computer-generated pairwise according to order of enrolment, 
so that similar numbers of patients are recruited to each study group. The chief investigator 
generates the randomization sequence. The randomization scheme is kept in sealed 
envelopes. The randomization sequence was revealed only to the unmasked clinician 
responsible for the stimulation programming, but not to the rater. Patients were masked to 
randomisation group.  
3.2 Procedures 
DBS devices (Medtronic, Neuromodulation, Minneapolis, USA) approved in China ( Activa
® 
RC 37086, Pocket Adapter: Model 64001 and 64002, Extension wire: 7482, DBS lead: 
3387 or 3389) are implanted by use of MRI or CT fusion for targeting and microelectrode 
recording for target refinement, followed by intraoperative test stimulation of the DBS lead. 
The pulse generators were placed in a subclavicular position on the same day. 

It is allowed to use existing DBS surgery equipment and is asked to physiologically refine 
the DBS targets based on the best medical practices. Devices implanted into patients are 
initially programmed (switched on ) 28±5 days after surgical implantation (Week 0/ Month 
0). 
The patients will undergo bilateral STN DBS. Management of medication is the 
responsibility of the investigators at each site and was not protocol driven. 
Over a 3-month period, each patient’s parameters of stimulation and medications for 
Parkinson’s disease are adjusted, based on clinical need and empirical stimulation to 
obtain the best clinical effect, no interleaving stimulation are allowed in this period. 
At Month 3, patients are settled into either condition: with the empirical stimulation 
parameters or with the interleaving programming.  
No routine programming plan is set during month 3 to month 9，unless the patient requires 
adjustment of stimulation parameters due to symptoms of Parkinson’s disease or adverse 
effects of stimulation. The stimulation mode remains unchanged during this period and 
records the reason and parameters of each programming. 
After month 9, the programmer can adjust the stimulation mode and parameters based on 
clinical need. The dopaminergic therapies are maintained stable since baseline and last in 
the entire duration of the study.  
Fig 1 
 
 
3.3 Surgical procedure 
All patients have stereotactic guidance for the insertion of electrodes under local 
anesthesia. Leksell Frame-based stereotaxy is performed in most of the patients. The 
image targeting and trajectory are planned based on preoperative MRI. On the day of 
operation, a computed tomography (CT) scan of brain with the stereotactic frame fixed to 
the head is performed and fused to the MRI plan in the computer planning system. 
Microelectrode recording (MER) is introduced to obtain neuronal discharges for 
neurophysiological targeting. Macrostimulation is performed in all patients for target 
confirmation. Deep brain stimulation electrode is implanted if satisfactory signals from MER 

and response from macrostimulation are obtained. The Pulse Generator is implanted under 
general anesthesia after CT scan made sure the target. The DBS is usually switched on at 
4 weeks(28±5 days) after the operation. Movement disorder specialists take up DBS 
programming. In brief, Patients are settled with simple polar stimulation with combined 
parameters adjustment (monopolar mode, 60~90µs pulse width, 130~185Hz frequency 
and varied voltage) during the follow-up. 
3.4 Programming Procedures 
The settlement of stimulation parameters is best carried out by trained neurologists and 
depends to a large extent on personal experience. The detailed algorithms for a disease-
specific programming strategy includes contact configuration adjustment and stimulation 
parameters selection. In general, each of the ring electrodes should be tested in a 
monopolar configuration with monopolar stimulation, 130 Hz frequency and 60 
microseconds pulse width. Amplitude is slowly increased until satisfactory clinical benefit 
or manifestation of side effects. The selected contact is determined by the best clinical 
outcomes and largest therapeutic window. In order to achieve the best clinical effect, 
frequency and pulse width should be changed by motor symptoms. Stimulation 
frequencies of 50 Hz and 185 Hz improve all motor signs. Pulse width between 60 and 210 
s is beneficial for improving tremor and rigidity.  
All patients receive conventional programming strategies to relieve their symptoms, but 
some achieve suboptimal results over time. Both levodopa inducing dyskinesia and 
stimulation inducing dyskinesia can happen after STN DBS. A useful strategy is 
decreasing the stimulation or dopaminergic medication, but some patients might 
experience a worsening in parkinsonism as a consequence. Unsatisfactory improvement 
of PD symptoms and dyskinesia, including choreoathetoid and dystonic movements, can 
be troublesome to patients. If patients do not improve adequately or if there are 
intolerable adverse effects (such as dyskinesia), interleaving stimulation (ILS) is tested to 
improve the symptom. 
ILS consists of two rapid and alternate stimulation programs with different contacts, 
amplitudes, and pulse width but the same frequency up to a maximum of 125Hz. Contact 
selection is determined by postoperative stereotactic computed tomography and clinical 
evaluation to achieve a balance between motor improvement and tolerable side effects. 
For example, ILS is successfully applied for PD motor symptoms (stimulation of 
subthalamic nucleus) as well as dyskinesia (additional stimulation of zona incerta).  
ILS may be applied either to limit dyskinesia or else, to stimulate different brain regions 
with individualized settings in order to alleviate specific symptoms. In accord with previous 
reports, dyskinesia is improved with additional more dorsal contact in a monopolar or 
bipolar fashion. Stimulation adjustment with lower amplitudes in the more dorsal contact 
(targeting the lenticular fasciculus) and higher amplitudes in a ventral contact (targeting 
the STN) might be able to control dyskinesias and parkinsonism. 

Based on the standard algorithms and reconstruction images, we would choose and adjust 
the most suitable contacts and settings for ILS for each patient to improve their PD 
symptoms and alleviate dyskinesia. In addition, after ILS with one contact program, which 
gradually increases the amplitude and pulse width as necessary, ILS with another program 
selecting other specific contacts and settings, according to standard algorithms, with 
increased amplitude and pulse width can be performed to achieve further motor benefit 
and avoid adverse effects. 
 
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4. Study assessment 
4.1 Efficacy assessments 
The primary efficacy endpoints are the changes of dyskinesia scores and the changes 
of PDQ-39 scores in interleaving stimulation compared to empirical programming modes. 
[Time Frame: 3 months and 9 months]  
The secondary endpoints include the changes of UPDRS III scores and the changes 
of neuropsychological Battery scores in interleaving stimulation compared to empirical 
programming modes. [Time Frame: 3 months and 9 months] 
The parameters in primary and secondary endpoints are also tested at baseline 
(Enrollment). After DBS activation (Month 0), patients are again assessed at Month 3, 
Month 9 and Month 12 in off-medication/on-stimulation and on-medication/on-stimulation, 
as shown in table 1. We defined “on-medication” as roughly 60 min after a patient takes 

antiparkinsonian medication when both the clinician and the patient indicate that the 
medication dose is effective. 
4.2. Clinical Assessment 
This assessment includes clinical assessment, levodopa challenge test, video 
recording, neuroimaging, and neurocognitive aionnd psychiatric evaluations. The clinical 
evaluation is performed in the morning, after a 12-hour withdrawal of antiparkinsonian 
drugs. Assessment data are obtained before and after the operation (medication-off/ -on 
state and stimulationor-on) and include the MDS-UPDRS, Unified dyskinesia rating scale 
(UDysRS), modified Hoehn & Yahr stage (off/on-state), levodopa equivalent dose, and 
body weight. Motor assessments are videotaped, and two raters collected independent 
ratings.  
Subjects are instructed to report any adverse event during the course of the study, 
including pulling (contractions), tingling, blurry vision, double vision, speech changes, or 
walking problems. 
Table 1 
Visit 
V0 
Screen 
V1  
Enrollment 
(Randomizatio
n and Surgery) 
V2  
Initial 
Programming 
V3 
 
V4 
V5 
Time 
(±5 days) 
Week -9 
~Week -5 
Week -5 
Week 0 
/Month 0 
Month 3 
Month 
9 
Month 12 
Informed consent 
X 
 
 
 
 
 
Inclusion criteria 
X 
X 
 
 
 
 
Exclusion criteria 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Medication 
X 
X 
X 
X 
X 
X 
Programming 
 
 
X 
X 
X 
X 
Pre-surgical 
assessments 
 
X 
 
 
 
 
UPDRS III, IV 
 
X 
X 
X 
X 
X 
UDysRS 
 
X 
X 
X 
X 
X 
PDQ-39 
 
X 
X 
X 
X 
X 

Cognitive Tests 
 
X 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
5. Sample size and Statistical analysis  
5.1 Sample size 
According to the sample size estimation method of comparing the mean of two 
independent samples, 42 subjects are planned to be enrolled in this study. Increase the 
number of cases according to the 20% dropout rate, and finally enrolled 50 cases. In this 
study, the change scores of total scores of visit 5 (month 12) UPDRS IV comparation with 
baseline is the endpoint to use to calculate the sample size. The specific calculation 
method was as follows: 
 Use Power Analysis & Sample Size software 11 (SPSS 11) to calculate the sample size. 
The formula is as follows. 
 
The non-inferiority hypothesis 
Primary Outcome Measures 
The changes of dyskinesia scores (UPDRS IV, item 32 + item 33) 
H0：interleaving stimulation - empirical stimulation < 0.5 score 
H1：interleaving stimulation - empirical stimulation ≥ 0.5 score 
Significance level: α = 0.025 (unilateral), 
Power: 1-β = 0.8, 
Standard deviation of single group: SD = 1.1, 
H0 is the null hypothesis, H1 is the alternative hypothesis. After subjects receiving 
interleaving stimulation, if the mean change scores of UPDRS IV equals or exceeds 0.5 
points than that of those patients receiving empirical stimulation, then H0 will be rejected, 
non-inferiority conclusion can be made when comparing interleaving stimulation group with 
empirical stimulation group. If H0 can't be reject, the conclusion that the interleaving 
stimulation group is better than or equivalent to empirical stimulation group can’t be 
reached. 
5.2 Statistical analysis 
All of the statistical tests used bilateral analysis. P ≤ 0.05 is considered to be 
statistically significance (excluding special conditions). 

Description of quantitative indicators is used to calculate total cases, missing cases, 
average cases, standard deviation, minimum, maximum, median and the interquartile 
range.  
Description of classification index is used in different groups of cases and percentage. 
Full Analysis Set (FAS): this analysis includes all subjects who received any treatment 
and provided useful value after the baseline stage for analysis. It also includes violators of 
the research scheme and subjects with incomplete data who left the trial.  
Per Protocol Set (PPS): this analysis includes all subjects who completed the research 
and complied with the scheme without any serious errors. It also includes subjects who 
quit the trial because of ineffective treatment. 
Safety Analysis Set (SAS): this analysis set includes all subjects who enrolled in the 
trial, received at least one treatment and was used for safety evaluation. Safety information 
records from all subjects were evaluated, including adverse events and the results of lab 
examinations.  
 
6. Adverse Event 
6.1 definition 
Adverse Event : An AE is defined as any untoward medical occurrence, regardless of its 
relationship to the study device (study suture) or the study procedure. An untoward medical 
occurrence includes any new, undesirable medical experience or worsening of a pre-
existing condition, which occurs at any point from the surgery to Final Visit. 
Serious Adverse Event: A Serious Adverse Event (SAE) is any AE that: 
• 
led to a death, 
• 
led to a serious deterioration in the health of the subject that either resulted in: 
- 
a congenital deformity or abnormality; 
- 
a life-threatening illness or injury; 
- 
a permanent impairment of a body structure or a body function; 
- 
in-patient hospitalization or prolongation of existing hospitalization; 
- 
medical or surgical intervention to prevent life-threatening illness or injury; or 
permanent impairment of a body structure or a body function. 
Relationship of Adverse Events: It is the Investigator’s responsibility to assess the 
relationship of an AE to the study procedure and study device. 
The following guidelines should be used in determining the relationship of an adverse event 

to the study device, study procedure, or other causality: 
• 
NOT RELATED: The event is due to extraneous causes. 
• 
POSSIBLY RELATED: The event is unlikely associated, but cannot be ruled out with 
certainty. 
• 
PROBABLY RELATED: The event is likely associated, but another cause cannot be 
ruled out with certainty. 
• 
DEFINITELY RELATED: The event is associated with a high degree of certainty; or 
• 
UNKNOWN: The event cannot be defined by the categories listed above. 
6.2 Reporting adverse event and management: The adverse event is reported from the 
start of signing the informed consent to the end of the study of subjects. All adverse 
events should be followed up, until the adverse event is resolved, stable or the study 
is completed. Investigator will ensure to provide the sufficient treatment for any adverse 
event of any subjects. The investigator will report the serious adverse events occurred 
in the study and the device defects that may cause serious adverse event to the 
regulatory authorities at every level according to the requirements of laws and 
regulations. Any study-device-related SAEs will be reported to Medtronic by the 
investigator. 
 
7. Publication plan 
The study outcome is expected to be published on the: Journal of Parkinsonism and related 
diseases, Brain Stimulation, J Neurosurgery, or Movement Disorders. 
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