To determine the effect of bevacizumab on the vasodilator response of acetylcholine in humans by using plethysmography.To determine the effect of bevacizumab on the vasodilator respons of nitroprusside in humans by using plethysmography
ID
Source
Brief title
Condition
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The forearm vasomotor response to increasing doses of intra-arterially
administered acetylcholine (two doses each) before and during administration of
bevacizumab, expressed as percentage change in forearm blood flow ratio (flow
infused arm/flow control arm) from baseline.
Secondary outcome
na
Background summary
The introduction of angiogenesis inhibitors has remarkably improved treatment
of patients with several types of cancer. One of the most reported side effects
of angiogenesis inhibitors is hypertension. In patients treated with
bevacizumab, a monoclonal antibody against vascular endothelial growth factor,
hypertension had an overall incidence up to 32%. The increase in blood pressure
occurs early in treatment. The etiology of hypertension caused by treatment
with angiogenesis inhibitors is unclear. Understanding the pathogenesis of this
side effect is essential for optimal treatment with this class of drugs.
One of the main targets of angiogenesis-inhibitors is vascular endothelial
growth factor and its receptors. Animal and human studies show that VEGF
induces vasodilation and hypotension by stimulation of NO production.
Furthermore animal studies suggest that endogenous VEGF may play a role in
maintaining normal vascular tone in blood vessels.
Theoretically inhibition of VEGF or VEGFr in humans would decrease NO
production causing vasoconstriction and thereby induce hypertension.
As shown in previous studies(11;12) endothelial function ( NO-dependent
respons) is diminished by treatment with a VEGF-inhibitor. However these
studies do not allow a conclusion on the direct causal relationship between
VEGF inhibition and alteration in endothelial function. In this study we will
infuse bevacizumab in the brachial artery and measure its effect on the
vasodilator response to acetylcholine. This allows us to separate local direct
effects of bevacizumab on the endothelium from systemic actions such as blood
pressure that could indicrectly interfere with endothelial function. If
appropriate, we will also study the interaction between bevacizumab and
nitroprusside to explore specificity of the interaction between Ach and
bevacizumab
Study objective
To determine the effect of bevacizumab on the vasodilator response of
acetylcholine in humans by using plethysmography.
To determine the effect of bevacizumab on the vasodilator respons of
nitroprusside in humans by using plethysmography
Study design
This is a single center, interventional controlled trial.
The brachial artery will be cannulated (20 gauge catheter) for infusion of
bevacizumab, acetylcholine or nitrprusside and measurement of arterial blood
pressure. Forearm blood flow will be assessed by venous occlusion strain gauge
plethysmography.
If the vasodilation caused by infusion of acetylcholine is diminished by
simultaneous infusion of bevacizumab twelve new healthy subjects will be
recruited in the same way for the second part of this study. In the second
group the forearm blood flow response to nitroprusside alone and during
simultaneous infusion of bevacizumab will be assessed using strain gauge
plethysmography to study if the effect of the diminished vasodilator respons to
acetylcholine during bevacizumab infusion is endothelium dependent.If there is
no effect of bevacizumab on the vasomotor response to acetylcholine the second
part of the study will not be conducted and the total number of subjects will
stay twelve.
Intervention
The brachial artery will be cannulated (20 gauge catheter) for infusion of
bevacizumab 144 microgram/dl forearm volume ( 15 minutes).
Study burden and risks
Intra-arterial infusion of bevacizumab allows the use of very low cumulative
doses that reach local concentrations in the infused forearm that are
sufficient to induce a local effect with very low systemic concentrations. In a
study to evaluate the short-term safety of systemic bevacizumab (5mg/kg) in
patients with age-related macular degeneration no adverse events were reported
except hypertension. In our previous experiment infusion of the same
concentration of bevacizumab during the same amount of time no side effects
were reported.
During plethysmography, wrist cuffs are inflated to exclude the hand (mainly
skin) circulation from the experimental preparation. This will cause rapidly
reversible numbness and discomfort in both hands due to inflation of the
wrist-cuffs. The subjects will not benefit directly from participating in this
study.
Postbus 9101
6500HB Nijmegen
NL
Postbus 9101
6500HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
1. Age 18-50 years old
2. Male
3. Results of serum glucose, lipids and creatinine should be within the laboratory's reference ranges.
4. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
Exclusion criteria
1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
2. History of or current abuse of drugs, alcohol or solvents.
3. History of malignant disease.
4. First degree relatives with a history of cancer before the age of 50
5. First degree relatives with a history of premature cardiovascular disease before the age of 50
6. Current use of medication.
7. Hypertension ( systole >140mmHG, diastole >90mmHg)
8. Diabetes mellitus
9. Smoking
10. Any clinically relevant abnormality on ECG.
11. A history of thrombosis or first degree family members with a history of recurrent thrombosis
12. Inability to understand the nature and extent of the trial and the procedures required.
14. Previous participation in a study with bevacizumab.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-017970-18-NL |
| CCMO | NL31012.091.09 |