NCT06596876 is a Phase 3 randomized, controlled, double-blind, double-dummy, multicenter clinical trial evaluating the efficacy and safety of HRG2010 in patients with Parkinson's disease (PD) experiencing motor fluctuations. Sponsored by Jiangsu HengRui Medicine Co., Ltd., this trial represents an important advancement in developing novel therapeutic options for the management of advanced PD.
Motor fluctuations, also known as "off" episodes, are a common complication of long-term levodopa therapy in PD. As the disease progresses, patients experience increasingly unpredictable transitions between "on" states (when medication is working and symptoms are controlled) and "off" states (when symptoms return). HRG2010 aims to provide more stable dopaminergic stimulation and reduce these disabling fluctuations.
The choice of "Off" time reduction as the primary endpoint reflects the substantial impact these fluctuations have on patient quality of life and daily functioning. This trial employs a double-dummy design, where both active treatment and placebo groups receive injections and oral medications, maintaining blinding while allowing comparison of the new formulation against standard therapy.
| Parameter |
Value |
| NCT Number |
NCT06596876 |
| Phase |
PHASE3 |
| Status |
RECRUITING |
| Sponsor |
Jiangsu HengRui Medicine Co., Ltd. |
| Enrollment |
450 participants |
| Enrollment Type |
ESTIMATED |
| Study Type |
INTERVENTIONAL |
| Start Date |
2024-11-06 00:00:00 |
| Completion Date |
2027-02-14 00:00:00 |
| Last Updated |
2025-05-02 00:00:00 |
- Parkinson's Disease with motor fluctuations (also known as "off" episodes)
¶ Understanding Motor Fluctuations in PD
Motor fluctuations in Parkinson's disease represent a significant therapeutic challenge. Understanding the pathophysiology is essential for appreciating HRG2010's potential mechanism:
Pathophysiology of Motor Fluctuations:
- Short-duration response - Each levodopa dose produces a clinical response lasting only a few hours
- End-of-dose deterioration - As plasma levodopa falls below therapeutic threshold, "off" symptoms return
- Delayed "on" - Time to symptom relief after dosing can be unpredictable
- Unexpected "off" - Sudden, unpredictable transitions to "off" states
The underlying mechanisms include:
- Pulsatile dopamine receptor stimulation from intermittent oral levodopa
- Loss of striatal dopamine storage capacity as disease progresses
- Altered blood-brain barrier transport of levodopa
- Peripheral pharmacokinetics variability
HRG2010 is designed to provide more continuous dopaminergic stimulation:
Potential Mechanisms:
- Extended half-life formulation providing longer plasma exposure
- More stable brain penetration reducing peaks and troughs
- Continuous dopamine receptor activation avoiding pulsatile stimulation
- Potential for reduced dyskinesia development through more physiological stimulation
The concept of "continuous dopaminergic stimulation" (CDS) has been a major focus in PD therapeutics, with previous attempts including:
- Dopamine agonists (ropinirole, pramipexole, rotigotine)
- Levodopa-carbidopa intestinal gel (Duodopa/Duopa)
- Extended-release levodopa formulations (IPX066, Rytary)
flowchart TD
A["Lewy Bodies"] --> B["SNpc Neuron Loss"]
B --> C["Dopamine Deficiency"]
C --> D["Striatal Output Imbalance"]
D --> E["Motor Symptoms"]
C --> F["Non-Motor Symptoms"]
E --> G["Tremor"]
E --> H["Bradykinesia"]
E --> I["Rigidity"]
E --> J["Motor Fluctuations"]
Key dopaminergic pathways affected in PD:
- Nigrostriatal pathway - Primary motor symptoms
- Mesocortical pathway - Cognitive dysfunction
- Mesolimbic pathway - Mood and motivation
- Tuberoinfundibular pathway - Neuroendocrine function
| Treatment |
Mechanism |
Administration |
Key Advantage |
| Oral Levodopa |
DA precursor |
Oral |
Most effective |
| Dopamine agonists |
DA receptor agonist |
Oral/transdermal |
Longer half-life |
| MAO-B inhibitors |
Prevent DA breakdown |
Oral |
Adjunct therapy |
| COMT inhibitors |
prolong levodopa |
Oral |
Reduce "off" time |
| Duodopa |
DA precursor |
Intestinal gel |
Continuous infusion |
| HRG2010 |
DA formulation |
Subcutaneous |
Novel delivery |
This is a Phase 3, randomized, double-blind, double-dummy, placebo-controlled, multicenter clinical trial:
| Design Element |
Description |
| Randomization |
1:1 active vs. placebo |
| Duration |
21 weeks (including titration and maintenance) |
| Blinding |
Double-dummy (both groups get injections + oral) |
| Setting |
Multicenter, international |
| Phase |
Phase 3 |
| Enrollment |
450 participants |
The double-dummy approach ensures both groups receive:
- Active injection (HRG2010 or matching placebo)
- Active oral medication (standard PD therapy or matching placebo)
This design allows fair comparison while maintaining rigorous blinding, critical for subjective endpoint assessment in PD trials.
Change from baseline in "Off" time at Week 21:
- "Off" time - Hours per day when PD symptoms are not adequately controlled
- Baseline - Documented "off" time during screening period (typically 2-3 days using patient diaries)
- Assessment - Patient diaries completed over consecutive days at baseline and endpoint
Secondary measures likely include:
- "On" time - Hours with adequate symptom control
- Unified Parkinson's Disease Rating Scale (UPDRS) - Parts II (motor experience of daily living) and III (motor examination)
- Patient Global Impression of Change (PGIC)
- Quality of life measures (PDQ-39)
- Sleep quality (PDSS)
- Safety and tolerability
Disease-related:
- Diagnosis of idiopathic Parkinson's disease (UK Brain Bank criteria)
- Motor fluctuations with ≥2 hours "off" time per day
- Stable antiparkinsonian therapy for ≥4 weeks
- Hoehn & Yahr stage 1-3 in "on" state
- MMSE ≥24 (or equivalent)
Other:
- Age 30-80 years
- Ability to complete diary assessments
- Adequate caregiver/observer for diary completion
- Written informed consent
- Neurological: Atypical parkinsonism, significant neurological disease
- Psychiatric: Severe depression, psychosis within past 6 months
- Medical: Uncontrolled hypertension, significant cardiac disease
- Medications: Current enrollment in another PD trial, recent deep brain stimulation
- Prior: Failure to respond to dopaminergic therapy
Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting approximately 10 million people worldwide. The disease is characterized by motor symptoms including resting tremor, bradykinesia, rigidity, and postural instability, as well as non-motor symptoms such as cognitive impairment, depression, and sleep disorders.
Pathologically, PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies, which are intracellular inclusions composed primarily of alpha-synuclein protein. Current treatments provide symptomatic relief but do not halt disease progression.
¶ Levodopa Therapy and Complications
Levodopa remains the most effective symptomatic treatment for PD, but chronic use is associated with complications:
Motor Complications:
- Levodopa-induced dyskinesia (LID) - Involuntary movements affecting up to 50% of patients after 5-10 years
- Motor fluctuations - "On-off" phenomenon with unpredictable response
- End-of-dose wearing off - Predictable return of symptoms
Non-Motor Fluctuations:
- Mood and anxiety fluctuations
- Pain and sensory symptoms
- Cognitive variations
- Autonomic dysfunction
Risk factors for complications:
- Disease duration >5 years
- Higher levodopa dose
- Younger age at onset
- Female sex
Current management approaches for motor fluctuations include:
Pharmacological:
- Add dopamine agonist - Ropinirole, pramipexole, rotigotine
- Add COMT inhibitor - Entacapone, opicapone, tolcapone
- Add MAO-B inhibitor - Rasagiline, selegiline
- Increase levodopa frequency - More frequent, lower doses
- Switch to extended-release - Rytary (IPX066)
Device-Based:
- Duodopa/Duopa - Continuous levodopa-carbidopa intestinal gel
- Apomorphine pump - Continuous subcutaneous infusion
- Deep brain stimulation - For eligible patients
HRG2010 represents a potential oral pharmacological approach to this unmet need.
Motor fluctuations represent one of the most significant unmet needs in Parkinson's disease management:
- Prevalence: 40-50% of PD patients develop motor fluctuations within 5 years of levodopa initiation
- Impact: "Off" time correlates with reduced quality of life, impaired daily functioning, and increased caregiver burden
- Treatment gaps: Current options require invasive procedures (DBS, pumps) or complex polypharmacy
¶ Competitive Landscape
| Agent |
Company |
Target |
Status |
Key Feature |
| Opicapone |
Novartis |
COMT |
Approved |
Once-daily |
| Rytary |
AbbVie |
Levodopa |
Approved |
Extended release |
| Devo |
Intec |
Levodopa |
Phase 3 |
Transdermal patch |
| ABBV-951 |
AbbVie |
Levodopa/carbidopa |
Phase 3 |
Subcutaneous infusion |
| HRG2010 |
Jiangsu HengRiu |
Levodopa |
Phase 3 |
Novel formulation |
Jiangsu HengRui's approach with HRG2010 includes several strategic elements:
- Phase 3 confirmatory trial - Demonstrating efficacy in larger population
- China-focused development - Addressing needs of large PD population
- Novel formulation - Potential advantages over existing options
- Global expansion potential - Building toward broader market access
Based on the mechanism of action, HRG2010 may cause:
Common (≥10%):
- Nausea and vomiting
- Dyskinesia (may increase with improved "on" time)
- Somnolence
- Orthostatic hypotension
- Hallucinations (especially in older patients)
Serious:
- Impulse control disorders (pathological gambling, shopping, eating)
- Psychosis
- Sleep attacks
- Cardiac valve fibrosis (rare, with ergot derivatives)
HRG2010 may interact with:
- Other dopaminergic agents - Additive effects
- Antipsychotics - May reduce efficacy
- Antihypertensives - Additive hypotension
- Food - Protein may reduce absorption
During clinical trials and post-approval:
- Regular neurological assessment
- Cardiac monitoring (if ergot-derived)
- Psychiatric screening
- Motor diary documentation
- Dyskinesia assessment
The trial is being conducted at multiple centers worldwide, including:
- Beijing, Beijing Municipality, China
- Additional international sites (specific locations to be confirmed)
HRG2010's development pathway includes:
- Phase 1 - Safety, PK, tolerability in healthy subjects
- Phase 2 - Dose-finding in PD patients
- Phase 3 - Confirmatory efficacy and safety
- Registration - NDA/MAA submission
If approved, HRG2010 may be indicated for:
- Treatment of motor fluctuations in PD
- Adjunctive therapy to levodopa
- First-line treatment for advanced PD
The Parkinson's disease treatment market is substantial:
- Global PD population: >10 million
- Market for dopaminergic therapies: >$5B annually
- Growing demand for improved delivery systems