Efficacy of Pentoxifylline on Cerebrovascular Function in Patients With Cerebral Small Vessel Disease(PERFORM)

Sponsor

Beijing Tiantan Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05583266

Collaborator

CSPC Ouyi Pharmaceutical Co., Ltd. (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

4.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, double-blinded, placebo-controlled, multi-center trial. Cerebral small vessel disease (CSVD) patients will be diagnosed according to STRIVE standards and randomized into the Pentoxifylline sustained-release tablet group and placebo group. The purpose of this trial is to assess the efficacy of Pentoxifylline sustained- release tablets on CSVD.

Condition or Disease	Intervention/Treatment	Phase
Cerebral Small Vessel Diseases	Drug: Pentoxifylline sustained-release tablets Drug: Pentoxifylline sustained-release tablets placebo	Phase 4

Detailed Description

Cerebral small vessel disease (CSVD) is a complex whole brain disease, which is a series of clinical, imaging, and pathological syndromes caused by various etiologies affecting small arteries, micro-arteries, capillaries, micro-venules, and small veins in the brain, and is a common clinical vascular disease of the brain, usually with insidious onset, slow progression, and some acute attacks.

The incidence of CSVD is positively correlated with age. Studies have shown that in people aged 60 to 70 years, 87% had subcortical white matter lesions and 68% had periventricular white matter changes, whereas, in people aged 80 to 90 years, 100% had subcortical white matter changes and 95% had periventricular changes. The incidence of cerebral microhemorrhage is approximately 6% in the 45-50 years old population and up to 36% in the 80-year-old population.

Pentoxifylline, a xanthine derivative, is mainly used for the improvement of cerebral circulation after ischemic cerebrovascular disease and for peripheral vascular disease, such as chronic occlusive vasculitis with intermittent claudication treatment. Pentoxifylline is a non-selective phosphodiesterase inhibitor that increases intracellular cyclic AMP (cAMP) and activates protein kinase A31, playing an anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, and vasodilation. Pentoxifylline is a well-tolerated drug for improving peripheral blood flow disorders, primarily by increasing blood flow and increasing oxygenation of ischaemic tissues. In addition, it improves vasodilatation by increasing prostacyclin and has a specific effect on the immune response by inhibiting tumor necrosis factors.

Patients meeting the enrollment criteria will be randomly assigned to one of the two treatment groups with the use of a double-blind design (a dose of 1 tablet twice a day, from randomization to 6 months). Face-to-face interviews will be conducted at baseline, on day 30 after randomization, on day 90 after randomization, and on day 180 after randomization.

The primary endpoint was the change in cerebral blood flow (CBF) and pulsatility index of the middle cerebral artery (MCA) after 6 months of treatment based on transcranial doppler (TCD) assessment of enrolled patients. The secondary endpoints include changes in clinical symptoms, MRI imaging markers (white matter hyperintensity, lacunes, microbleeds, enlarged perivascular space), and cognitive function at 6 months. The safety endpoints include moderate or severe hemorrhage events, symptomatic and asymptomatic intracranial hemorrhage, overall mortality, and serious adverse events.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Efficacy of Pentoxifylline on Cerebrovascular Function in Patients With Cerebral Small Vessel Disease(PERFORM)：A Randomized, Double-blinded, Placebo-controlled, Multi-center Trial

Anticipated Study Start Date :

Nov 1, 2022

Anticipated Primary Completion Date :

Mar 3, 2023

Anticipated Study Completion Date :

Mar 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Pentoxifylline sustained- release tablets placebo group This group will receive Pentoxifylline sustained-release tablets placebo, 1 tablet twice a day, from the day of randomization to 6 months.	Drug: Pentoxifylline sustained-release tablets placebo Pentoxifylline sustained-release tablets placebo will be administrated at the same dosage and frequency as the experimental group
Experimental: Pentoxifylline sustained- release tablets group This group will receive Pentoxifylline sustained-release tablets, 1 tablet twice a day, from the day of randomization to 6 months.	Drug: Pentoxifylline sustained-release tablets a dose of 1 tablet twice a day of Pentoxifylline sustained-release tablets

Arm

Intervention/Treatment

Placebo Comparator: Pentoxifylline sustained- release tablets placebo group

This group will receive Pentoxifylline sustained-release tablets placebo, 1 tablet twice a day, from the day of randomization to 6 months.

Drug: Pentoxifylline sustained-release tablets placebo

Pentoxifylline sustained-release tablets placebo will be administrated at the same dosage and frequency as the experimental group

Experimental: Pentoxifylline sustained- release tablets group

This group will receive Pentoxifylline sustained-release tablets, 1 tablet twice a day, from the day of randomization to 6 months.

Drug: Pentoxifylline sustained-release tablets

a dose of 1 tablet twice a day of Pentoxifylline sustained-release tablets

Outcome Measures

Primary Outcome Measures

The change in cerebral blood flow at 6 months [3 months and 6 months after randomization]
TCD is used to evaluate the change in cerebral blood flow (cm/s) 6 months after treatment. Higher speed mean a worse outcome.
The change of middle cerebral artery pulsatility index at 6 months [3 months and 6 months after randomization]
TCD is used to evaluate the change of middle cerebral artery pulsatility index at 6 months. Higher pulsatility index mean a worse outcome.

Secondary Outcome Measures

cognitive function assessed by MoCA at 6 months [6 months after randomization]
Cognition function assessed by Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.
cognitive function assessed by Clinical Dementia Rating (CDR) at 6 months [6 months after randomization]
Cognitive function assessed by Clinical Dementia Rating (CDR). Score range 0-3. Higher scores mean a worse outcome.
The change of White Matter hyperintense volume at 6 months [6 months after randomization]
WMH volume is assessed on 3D fluid attenuated inversion recovery (FLAIR) sequence in mm3 or cm3. Larger volume indicates a worse outcome.
The change of White Matter hyperintensities Fazekas scores at 6 months [6 months after randomization]
Fazekas score is used to describe the different types of hyperintense signal abnormalities surrounding the ventricles and in the deep white matter. Periventricular hyperintensity (PVH) is graded as 0 = absence, 1 = "caps" or pencil-thin lining, 2 = smooth "halo", 3 = irregular PVH extending into the deep white matter. Separate deep white matter hyperintensity (DWMH) is rated as 0 = absence, 1 = punctate foci, 2 = beginning confluence of foci, 3 = large confluent areas. Higher scores indicats a worse outcome.
The change of Cerebral blood flow values for MRI cerebral perfusion imaging at 6 months [6 months after randomization]
MRI is used to evaluate the change of Cerebral blood flow values for MRI cerebral perfusion imaging at 6 months.
Digit span test [6 months after randomization]
The Digit span test is used to assess cognitive function change for 6 months. The score ranges from 0 to 44. Higher scores mean a better outcome.
Stroop Color Word Test [6 months after randomization]
The Stroop Color and Word Test is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. Shorter the test time, the better the outcome.
Hamilton Anxiety Scale(HAMA) [6 months after randomization]
Mood function is assessed by Hamilton Anxiety Scale(HAMA). The Score ranges 0-56. Higher scores mean a worse outcome.
Hamilton Depression Scale(HAMD) [6 months after randomization]
Mood function assessed by Hamilton Depression Scale(HAMD). The Score ranges 0-68. Higher scores mean a worse outcome.
The Short Physical Performance Battery(SPPB) [6 months after randomization]
It is a composite measure assessing walking speed, standing balance, and sit-to-stand performance. It has primarily been used to assess elderly patients both in the hospital and community setting.
Urination and defecation [6 months after randomization]
The score of the urination and defecation function scale changed at 6 months.

Other Outcome Measures

Neurovascular coupling index [3 months and 6 months after randomization]
Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC).
Electroencephalogram oscillations [3 months and 6 months after randomization]
The amplitude, frequency, phase, coherence will be measured.
Blood-Brain Barrier (BBB) Permeability between groups. [3 months and 6 months after randomization]
BBB permeability is assessed by MRI and biomarker (including NSE, GFAP, S100β).

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 45-75 years;
CSVD can be seen on MRI, which satisfies one of the following conditions:

Presence of white matter hyperintensities and Fazekas score ≥2;
Lacunar Infarction ≥1, with or without white matter hyperintensities;

is eligible for Transcranial Doppler (TCD) monitoring;
meeting the following clinical manifestations:

Patients with vascular cognitive impairment (abnormalities in memory and or other cognitive domains lasting at least 3 months) ;
MoCA ≤22 points; MoCA ≤21 points for primary education and below;

independent in daily life (modified mRS ≤2) ;
with signed informed consent.

Exclusion Criteria:

patients with acute cerebral infarction and acute cerebral hemorrhage;
patients with bleeding tendency: including platelet count < 100 × 10*9/L, active peptic ulcer, history of intracranial hemorrhage (such as epidural hematoma, subdural haematoma, subarachnoid hemorrhage, cerebral hemorrhage, etc.) , cerebral microbleedings (≥5 cerebral microbleedings) , brain tumor, cancer-related stroke, taking anticoagulant drugs, or using dual antiplatelet therapy;
patients who have a history of cognitive impairment caused by other causes, such as normal pressure hydrocephalus, Alzheimer's disease, Parkinson's disease, multiple sclerosis, encephalitis, etc.;
patients with acute coronary syndrome and severe coronary arteriosclerosis;
patients with severe hepatic insufficiency, renal insufficiency, or severe cardiac insufficiency before randomization (severe hepatic insufficiency refers to ALT ≥2.0 times the upper limit of normal or AST ≥2.0 times the upper limit of normal; severe renal insufficiency refers to CRE ≥1.5 times the upper limit of normal or EGFR < 40 ml/min/1.73 m2; severe cardiac insufficiency refers to NYHA grade of 3-4) ;
patients who are pregnant, lactating or likely to become pregnant and planning to become pregnant;
patients with refractory hypertension;
patients with known allergic history to pentoxifylline, methylxanthine (such as caffeine, aminophylline, dihydroxypropyltheophylline, etc.) ;
patients with use of other vasodilators or circulatory improvers within 1 week (e.g. Cilostazol, Vinpocetine, Dimitamol, Sildenafil, Butylphthalide, Betahistine, Uracillin, Alprostadil, etc.) May stop taking the drug for 1 week before enrolling if criteria are met;
Patients using other drugs that affect the safety or efficacy evaluation of the tiral drug and who do not agree to discontinue the drug, such as GLP-1 receptor agonists, Liraglutide, dulasapeptide, risperidone, and exenatide;
Patients with other life-threatening or serious diseases with an expected survival of < 36 months;
Patients with contraindications to MRI;
Patients who could not cooperate to complete the follow-up;
Patients who enrolled in other clinical trials within 30 days.