Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02112812 |
| Other study ID # |
FF0452012 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 10, 2014 |
| Last updated |
April 10, 2014 |
| Start date |
December 2012 |
| Est. completion date |
April 2013 |
Study information
| Verified date |
April 2014 |
| Source |
National University of Malaysia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Malaysia: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
A higher prevalence of Helicobacter pylori infection rate has been demonstrated among PD
patients compared to controls. As H. pylori infection is known to interfere with levodopa
absorption, we embarked on this is a study to understand the effects of Helicobacter pylori
infection eradication among a selected Malaysian population with Parkinsons disease, in
relation to levodopa effectiveness and motor improvements.
The study hypotheses are:
1. H. pylori eradication improves L-dopa 'onset' time and prolongs the L-dopa 'on-time'
duration.
2. PD patients with H. pylori infection show clinical improvement in motor disability and
quality of life after eradication therapy of H. pylori, assessed using UPDRS-III /
PDQ39 questionnaires.
Description:
Study Background
The earliest observation that there is an association between H. pylori and PD was in 1966
when Strang found that gastric and duodenal ulcers were more common in PD patients than
their age and gender-matched controls and that these ulcers preceded the diagnosis of PD by
up to 20 years. Upon the discovery of H. pylori and its association with peptic ulcer
disease, numerous studies were conducted to look for a correlation between H. pylori and PD.
James Parkinson considered that there may be an association between PD and gastrointestinal
pathology when he wrote "Although unable to trace the connection by which a disordered state
of the stomach and bowels may induce a morbid action in a part of the medulla spinalis,
…little hesitation needs be employed before we determine on the probability of such
occurrence" (pg 64, The Shaking Palsy).
A direct causal relationship was hypothesised by Altschuler who proposed that H. pylori
might play a part in the biosynthetic route for MPTP or MPTP-like substance that have a
direct neurotoxic effect on the dopaminergic neurons.
In 1999, Charlett et al. observed that cardinal features of PD, namely bradykinesia,
rigidity and abnormal posture was significantly more prevalent in siblings of PD patients
compared to controls. Positive H. pylori serology was found in 70% of PD patients and 63% of
their siblings compared to 36-43% of controls. They concluded that familial transmission of
H. pylori might account for the significantly higher prevalence of parkinsonism in siblings
of PD patients.
Bjarnason et al found that the presence of antibodies against H. pylori correlated with IPD,
and eradication showed improvement in the measurement of stride length. There was also a
correlation between eradication therapy and reduction in inflammatory markers such as IL-6
and TNF-alpha. They hypothesised that chronic infection leads to underlying chronic
inflammatory and autoantibody /molecular mimicry mechanism that leads to destruction of the
dopaminergic neurons.
Hirai studied lipid composition of H. pylori and identified three cholesterol glucosidases
(CG). Of interest, the similarity of the structure of the CG sterols in H. pylori and sterol
glucosidase in cycad, which may hypothesized a possibility that H. pylori with certain
strain that can cause parkinsonism by way of producing similar sterol glucosidase that is
neurotoxic. Cycad is a type of seed made into flour that has been known to cause ALS-PD
disease in population such as in Guam island and Kii,Japan. Murine experimental exposure to
cycad showed progressive motor and cognitive deterioration. Pathological analysis revealed
that they have loss of motor neurones and loss of striatal dopaminergic terminals.
Levodopa absorption occurs in the duodenum. In advanced PD, gastric motility is impaired and
this can delay the transit of levodopa through the pylorus and subsequently, prevent or
delay its clinical effect. In the duodenum, any inflammatory pathology can also impair
levodopa absorption. H.pylori infection affects L-dopa bioavailability via disruption of
duodenal mucosa, the site of its absorption and local production of reactive oxygen species,
which may inactivate the drug.
Irregularity in levodopa delivery to the brain is common in PD and can lead to erratic
response to levodopa and motor fluctuations. This can be attributed to impaired
gastrointestinal transit or absorption of the drug.
Pierantozzi et al. conducted a study in which PD patients with H. pylori infection were
randomised into eradication therapy and control groups. Serum levodopa levels were
consistently higher in the eradication therapy group compared to controls. The active group
was also noted to have prolonged clinical response to levodopa, more "on time" and fewer
motor fluctuations.
The authors concluded that H. pylori infection impairs absorption of levodopa and
eradication therapy is a simple and inexpensive means to aid levodopa absorption and improve
clinical response.
Study justifications
Diagnosing H.pylori infection in Parkinson's patients is important as eradicating H. pylori
not only reduces the risk of H. pylori complications such as duodenal ulcer and gastric
carcinoma, but it will also help to improve their motor disability. Previous studies abroad
have shown that eradication of H. pylori increased levodopa bioavailability as H. pylori had
been shown to affect its absorption. Conducting this study among Parkinson's patients in
PPUKM will give us data for Malaysian population.
Study Objectives
Primary Objectives:
To compare the clinical response to L-dopa before and after H. pylori eradication therapy in
the H. pylori infected PD group. (L-dopa 'onset' time (minutes) and L-dopa 'on-time'
duration (minutes) ).
Secondary Objectives:
To assess clinical motor improvement before and after H. pylori eradication therapy in
infected PD group, using the UPDRS-III and PDQ39 questionnaires.
Study design and study population. This is a prospective study which, conducted at UKMMC
between the months of January 2012 to June 2012. The study population consists of
Parkinson's disease patients on levodopa therapy, who will be consecutively recruited from
the neurology outpatient clinic UKMMC. The study will be done after the approval of the
Research Ethics Committee UKMMC. Patients who fulfill the inclusion and exclusion criteria
will be counseled and upon giving informed consent, will be enrolled into the study.
Individuals with poor command in English or Bahasa Malaysia will be given explanation with
an assistance of an interpreter.
Study protocol and study tools
Upon consent, patients will be enquired regarding their background and the data will be
recorded Information regarding sociodemographic characteristics (smoking history, alcohol
consumption and coffee consumption), previous antibiotics use, concomitant medical
conditions, current medications and any gastrointestinal symptoms will be recorded. Height
and weight are measured and recorded into the data collection sheet. The clinical response
to L-dopa will be documented (looking at L-dopa 'onset' time (minutes) and L-dopa 'on-time'
duration (minutes)). The severity of their Parkinson's disease will be assessed using PDQ-39
questionnaires and the Unified Parkinson's Disease Rating Scale (UPDRS)-III.
Urea Breath test protocol
Each subject undergoes UBT to diagnose H. pylori infection. UBT is selected as the most
appropriate tool for diagnosing H. pylori in this study because it is noninvasive,
non-radiotoxic and readily available compared to OGDS. Serology testing is cheaper and
widely accessible and has been used in many researches locally and internationally.
Unfortunately, serology testing has a specificity of 79-90% and sensitivity of 76-84%.
Furthermore, patients who are positive for H. pylori will remain seropositive for as long as
4 years after its eradication even when UBT has long been negative.
Subjects who are on PPIs or H2 blockers will be given a later appointment for UBT after 4
weeks of stopping these medications. Each patient will be given 75 mg of IRIS 13C urea mixed
in Tang™ Orange juice. Breath sample will be taken at 0 minutes, 10 minutes, 20 minutes and
30 minutes. At each breath, subjects will be asked to inhale deeply and hold for 5 seconds
and then blow slowly into a bag until its fully inflated. The breath samples collected will
be then analysed using the Non-Dispersive Isotope-Selective InfraRed Spectrometer
(NDRIS)[IRIS]. Interpretation of the results are based on the IRIS Software 2.3 for analysis
of Delta (δ) over baseline (DOB)
Treatment for H. pylori Patients with positive Urea Breath Test (positive for H. pylori
infection) will be started on eradication therapy of H. pylori (oral esomeprazole 40mg twice
bd, oral clarithromycin 500mg bd and oral amoxicillin 1000mg bd) for 14 days. This current
recommendation was formulated at the Maastricht III Consensus Conference in March 2005.
Follow up visit H pylori-infected Parkinsons disease patients will be followed up in the
neurology clinic 3 months after eradication therapy of H pylori. The clinical response to
L-dopa after eradication treatment of H pylori will be assessed (looking at L-dopa 'onset'
time (minutes) and L-dopa 'on-time' duration (minutes)). The clinical motor improvement will
also be assessed using PDQ-39 questionnaires and the Unified Parkinson's Disease Rating
Scale (UPDRS)-III. Patients will be guided by investigator to answer the all the
questionnaires.
Ethical Consideration
This study will be conducted after the approval of the PPUKM ethics committee. Participants
will be explained regarding the procedure and the benefit of the study before they signed
the consent form. They are allowed to opt out from the study at any point as they wish.
