RESEARCH

Research priorities



Other research topics

  • Developing and testing a monitoring tool to self-detect symptom improvement during the trial and error phase to find the right dose of thiamine for PwP

  • Testing apps for smartphones and smartwatches to monitor Parkinson’s Disease symptoms

  • Determining thiamine sub-lingual absorption, doses, safety and efficacy in Parkinson’s Disease

  • Determining cocarboxylase sub-lingual absorption, doses, safety and efficacy in Parkinson’s Disease

  • Determining thiamine transdermal absorption, doses, safety and efficacy in Parkinson’s Disease

  • Determining benfotiamine absorption, doses, safety and efficacy in Parkinson’s Disease

Identification of factors influencing thiamine dosage in HDT (B1) therapy and development of a thiamine dosage table, by route of administration, for Patients with Parkinson’s Disease (PwP)

The search for the right dose of thiamine is a critical and challenging step of the thiamine (B1) therapy protocol. Currently, the dose is determined through a trial and error approach.

Clinical experience suggests that different factors should be taken into account to set the dose.

The identification of those factors and the development of a thiamine dosage table by route of administration for Patients with Parkinson’s Disease (PwP) is a research priority.

Limited funds are needed for this study.

The steps are summarised below.


1. Identify factors influencing thiamine dosage through expert opinion.
Interviews are conducted with clinicians who have a long experience in treating PwP with i.m. and oral thiamine (B1), to identify and list those factors that they consider most when deciding which start dose to use in each individual case.
Advantages:
a) Easy-to-get approvals for this type of study
b) Fast to plan and conduct (< 1 week)
c) Very low – if any - budget required

Disadvantages:
a) Subjective information (dependent on the experience of the clinician involved)
b) Limited to the very few clinicians who, to date, have used the HDT (B1) therapy protocol

Costantini identified a number of factors, based on his experience, which need to be validated: age, gender, weight, duration and severity of disease. He also observed that ethnic group may be another factor.


2. Identify factors influencing thiamine dosage through a retrospective review of clinical records of PwP successfully treated with thiamine (B1) and develop a thiamine dosage table by route of administration
In this study, data from PwP treated with a successful dosage of thiamine are analysed using multivariate analysis to identify those factors which are linked to the effective dose.

A thiamine dosage table by administration route is then developed based on the results of the analysis.

Advantages:
a. Approval procedures expected to be simple and fast
b. Fast to plan and conduct
c. Objective data collected
d. Short duration (1-3 months)
e. Sample can be large, depending on volumes of PwP treated, with minimum increase in costs; a large sample enables detailed analysis by variable
f. Few human resources required:
- a person to develop the data entry, check, validation and analysis programme
(1 week)
- a person to review case records and enter the data into the data entry programme in 2 weeks – even a medical student;
- a statistician for the analysis (1 week)
g. Informs a clinical trial, facilitating the first phase of finding the dose for each participant in the study.

Disadvantages:
a. Depends on how accurate and complete clinical records are
b. Can be conducted only in facilities which use the thiamine (B1) protocol.

3. Validate the drug dosage table

The thiamine dosage table so developed from steps 1 and 2 above, can be tested using other clinical records of PwP - from the same facility - which have not been used to develop the table.

Advantages:
a) Approval procedures expected to be simple and fast
b) Fast to plan and conduct
c) Small budget required
d) Short duration (data entry, check and validation; analysis)(< 4 weeks)
e) Large sample possible (depending on volumes of PwP treated)
f) Few human resources required (uses the same data plan as the retrospective clinical record review study):
  • a person to enter the data into a data entry programme – even a medical student (2 weeks);
  • a statistician for the analysis (1 week)

Disadvantages:
a. Can be conducted only in facilities which use the thiamine (B1) protocol

As an alternative, the drug dosage table can be validated also as part of a prospective study, in the same or another facility (single-centre) or in more than one facility (multi-centre study).

Advantages:
a) Objective data

Disadvantages:
a) Approval procedures longer and with more requirements than retrospective study
b) Duration depending on volume of PwP seen at the facility
c) Budget required higher than previous option
d) Can be conducted only in facilities which use the HDT (B1) protocol

4. Validate the drug dosage table in other settings
Once developed, the table can be tested in other facilities in which the HDT (B1) protocol is used.
Randomised, double-blind, placebo-controlled trial (RCT)

1. What is an RCT
An RCT is a randomised, double-blind, placebo-controlled trial. A description of RCTs is provided in The Scientific Evidence.

2. Objective
To determine the safety, dose and efficacy of HDT (B1) therapy in Parkinson’s Disease.

3. Advantages and disadvantages
Advantages:
a. Provides results which are accepted by the international medical community
b. Positive findings can attract funds for further research

Disadvantages:
a. Long approval process (clearance by the institution Ethical Committee; approval of appointment of the Principal Investigator)
b. Requires high volume of new PwP visits seen at that facility for the duration of the trial
c. Sample affected by drop-out rate (increases the sample required to compensate
for it)
d. Long duration (2 years, excluding approvals and plans)
e. Budget: Very high cost
f. Submission to external reviewers for review (time)
g. Requires submitting proposal to different donors, a very long process
h. Substantial administrative work involved
i. No alternative study can replace it.

4. Highlights of the RCT on high-dose thiamine (B1) in PwP
a. Study type: Interventional (clinical trial)

b. Sample: > 260 PwP, including allowance for drop-outs: 2 groups for i.m. route (intervention and placebo), 2 groups for oral route (intervention and placebo)

c. Allocation: randomized

d. Intervention model: double-blind, placebo-controlled

e. Optional interventional model: cross-over

f. Masking: Triple (Participant, Care Provider, Outcomes Assessor)

g. Primary purpose: Treatment

h. Inclusion criteria:
  • Age: 18 – 85 yo
  • Parkinson’s Disease diagnosis: UK Parkinson’s Disease Society Brain Bank/NINDS

i. Exclusions criteria:
  • Known hypersensitivity to thiamine
  • Changes in antiparkinson treatment in the preceding month
  • Participation in a clinical trial with any experimental new antiparkinson drug in the preceding 3 months
  • Treatment with anticoagulant therapy
  • Presence of cognitive impairment (MMSE<24/30)
  • Presence of other neurological disorders, hematological disorders, or major comorbidities (e.g. psychiatric disease, heart or lung failure, active malignancy)
  • Pregnant or lactating women
  • Treatment with thiamine, integrators or multivitamin in the preceding 3 months (except B12 and folate)

j. Primary outcomes:
  • Effects of HDT protocol on symptoms (clinical efficacy)

k. Secondary outcomes:
  • Safety and tolerability of thiamine
  • Change in motor symptoms
  • Change in fatigue symptoms
  • Change in non-motor symptoms
  • Change in quality of life
  • Change in global cognitive function
  • Change in functional tests

l. Determination of optimal dose for each PwP
  • Duration: 3 months
  • Sites involved: one

m. Trial duration:
  • Duration of recruitment phase: 12 months
  • Duration of clinical trial phase: 12 months

n. Route/s of administration: i.m. and oral
  • Form of thiamine: thiamine HCL

o. Clinical evaluation tools:
  • MDS-UPDRS
  • Non-Motor Symptoms Scale (NMSS)
  • Parkinson's Disease Questionnaire-8 (PDQ8)
  • Parkinson Fatigue Scale (PFS)
  • Montreal Cognitive Assessment (MoCA)
  • TIMED UP&GO
  • 10-meter walk test (10MWT)
Other research topics
  • Developing and testing a monitoring tool to self-detect symptom improvement during the trial and error phase to find the right dose of thiamine for PwP.
Monitoring of symptoms by the PwP themselves during the phase of searching the right dose is currently a critical task. There are many monitoring instruments available which often focus on selected symptoms. The development of a simple, integrated, reliable tool to be used by the PwP themselves would be of high value.


  • Testing apps for smartphones and smartwatches to monitor Parkinson’s Disease symptoms in Parkinson’s Disease
Technology using smartphones and smartwatches in the field of health is
advancing fast. Smartphones are also available to most people. Developing an app capable of monitoring selected symptoms reliably would be another practical approach to monitoring in PwP.

  • Determining thiamine sub-lingual absorption, doses, safety and efficacy in Parkinson’s Disease
The sublingual route offers advantages over the oral route, similarly to the i.m. route. No clinical study in Parkinson’s Disease has been conducted to date on sublingual thiamine.

  • Determining cocarboxylase sub-lingual absorption, doses, safety and efficacy in Parkinson’s Disease.
Cocarboxylase is the active form of thiamine. It may potentially offer some advantages, as it does not need to be converted to the active form and requires lower dosage than oral formulations. No clinical study in Parkinson’s Disease has been conducted to date.

  • Determining thiamine transdermal absorption, doses, safety and efficacy in Parkinson’s Disease
Transdermal route may offer some advantages in terms of compliance. It has not been studied in Parkinson’s Disease.

  • Determining benfotiamine absorption, doses, safety and efficacy in Parkinson’s Disease.
Benfotiamine is a synthetic derivative of thiamine. It is reported to have high bioavailability, much higher than thiamine, and to improve diabetic neuropathy. It has been found to improve cognitive ability in people with Alzheimer Disease. It is not clear yet whether it passes through the blood-brain barrier (BBB). No studies have been published to date on benfotiamine in Parkinson’s Disease.
Text author: Sergio Pièche
Page updated - 24/04/23