Clinical trial NCT05583266: Efficacy of Pentoxifylline on Cerebrovascular Function in Patients With Cerebral Small Vessel Disease(PERFORM)
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Cerebral Small Vessel Diseases
Keywords: cerebral small vessel diseases
Pentoxifylline
randomized controlled trial
multicenter study
double blind study
placebo-controlled
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: CSPC Ouyi Pharmaceutical Co., Ltd.
First posted: 2022-10-17
Enrollment: 80
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. Age 45-75 years;
2. 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;
3. is eligible for Transcranial Doppler (TCD) monitoring;
4. 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;
5. independent in daily life (modified mRS ≤2) ;
6. with signed informed consent.

Exclusion Criteria:

1. patients with acute cerebral infarction and acute cerebral hemorrhage;
2. 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;
3. 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.;
4. patients with acute coronary syndrome and severe coronary arteriosclerosis;
5. 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) ;
6. patients who are pregnant, lactating or likely to become pregnant and planning to become pregnant;
7. patients with refractory hypertension;
8. patients with known allergic history to pentoxifylline, methylxanthine (such as caffeine, aminophylline, dihydroxypropyltheophylline, etc.) ;
9. 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;
10. 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;
11. Patients with other life-threatening or serious diseases with an expected survival of \< 36 months;
12. Patients with contraindications to MRI;
13. Patients who could not cooperate to complete the follow-up;
14. Patients who enrolled in other clinical trials within 30 days.

Primary outcomes:
measure: The change in cerebral blood flow at 6 months
timeFrame: 3 months and 6 months after randomization
measure: The change of middle cerebral artery pulsatility index at 6 months
timeFrame: 3 months and 6 months after randomization
Secondary outcomes:
measure: cognitive function assessed by MoCA at 6 months
timeFrame: 6 months after randomization
measure: cognitive function assessed by Clinical Dementia Rating (CDR) at 6 months
timeFrame: 6 months after randomization
measure: The change of White Matter hyperintense volume at 6 months
timeFrame: 6 months after randomization
measure: The change of White Matter hyperintensities Fazekas scores at 6 months
timeFrame: 6 months after randomization
measure: The change of Cerebral blood flow values for MRI cerebral perfusion imaging at 6 months
timeFrame: 6 months after randomization
measure: Digit span test
timeFrame: 6 months after randomization
measure: Stroop Color Word Test
timeFrame: 6 months after randomization
measure: Hamilton Anxiety Scale(HAMA)
timeFrame: 6 months after randomization
measure: Hamilton Depression Scale(HAMD)
timeFrame: 6 months after randomization
measure: The Short Physical Performance Battery(SPPB)
timeFrame: 6 months after randomization
measure: Urination and defecation
timeFrame: 6 months after randomization
Other outcomes:
measure: Neurovascular coupling index
timeFrame: 3 months and 6 months after randomization
measure: Electroencephalogram oscillations
timeFrame: 3 months and 6 months after randomization
measure: Blood-Brain Barrier (BBB) Permeability between groups.
timeFrame: 3 months and 6 months after randomization
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital
Study officials:
affiliation: Beijing Tiantan Hospital, Capital Medical University, Beijing, China
name: Yilong Wang, PhD，MD
role: PRINCIPAL_INVESTIGATOR
References: