The RCT issue in vitamin B1 (high dose thiamine) therapy
I re-propose here some considerations relevant also to Parkinson’s - already made and published on this website - on the demonstrated efficacy of high-dose thiamine (vitamin B1) in IBD (inflammatory bowel disease) through a randomized control trial (RCT). I do so complementing those observations with some comments on the extension study conducted by the same authors after the initial RCT.
Why reporting on a study on IBD in a blog on Parkinson’s vitamin B1 therapy?
Why reporting on a study on the effect of thiamine on the symptom fatigue in IBD in this blog which is dedicated to Parkinson’s disease vitamin B1 therapy?
What makes this study of high interest and relevance to the high-dose thiamine (HDT) therapy in Parkinson’s is the fact that, first of its kind, it uses a strong research protocol such as an RCT to assess High-Dose Thiamine (HDT) therapy efficacy.
RCT (randomized double-blinded, placebo-controlled trial) is currently considered the golden standard in medical research and so far represents the missing, definite and convincing evidence of the efficacy of the High-Dose Thiamine (HDT) protocol in Parkinson’s disease.
What makes this study of high interest and relevance to the high-dose thiamine (HDT) therapy in Parkinson’s is the fact that, first of its kind, it uses a strong research protocol such as an RCT to assess High-Dose Thiamine (HDT) therapy efficacy.
RCT (randomized double-blinded, placebo-controlled trial) is currently considered the golden standard in medical research and so far represents the missing, definite and convincing evidence of the efficacy of the High-Dose Thiamine (HDT) protocol in Parkinson’s disease.
The RCT study
The study was conducted by Bager and collaborators in Denmark to investigate the effect and safety of high-dose oral thiamine on chronic fatigue in 40 patients with IBD (Bager, 2021). The oral daily dose of thiamine ranged from 600 to 1800 mg, based on gender and weight, according to Costantini’s protocol (Costantini, 2013).
Participants in the study were randomly allocated to receive either thiamine (the thiamine group) or placebo (the placebo group). It was a double-blinded study, meaning neither the investigators nor the participants knew who was receiving thiamine or the placebo.
The key point is that, as I have mentioned, this was a randomised, double-blinded, placebo-controlled crossover trial (RCT), unlike previous reports on high-dose thiamine therapy which were case reports or open-label studies on High-dose Thiamine HDT.
In open-label studies, investigators and participants in the study know “who is taking what”. This may raise the issue of the potential influence of “non-blinded” investigators and participants on the expected outcomes. Open-label studies, therefore, are subject to the possibility that the effects reported be due to the "placebo effect", which is associated with high expectations. Bager's study, instead, had a placebo control group to evaluate the effects of treatment.
The protocol used in the study closely followed Costantini’s protocol for the same medical conditions, as published in his paper in 2013.
Furthermore, an important methodological approach used in the study was the “cross-over” approach. After 4 weeks of receiving either thiamine or placebo followed by a 4-week wash-out period, participants were swapped from one group (thiamine or placebo) to the other group. This meant that all participants in the study were exposed to both high-dose thiamine and placebo, respectively. This is a sound research method which adds weight to the study and its findings.
The study was conducted in a new site, in Denmark, unlike previous case reports on fatigue in IBD and clinical experience with B1 therapy, which mostly came from the same Italian site.
When looking at the results, these confirmed the effectiveness of the use of high-dose thiamine. A mean reduction of 4.5 points in fatigue - measured by the Inflammatory Bowel Disease-Fatigue Questionnaire - was detected after thiamine compared with a mean increase of 0.75 point after placebo. Also, a high percentage of participants had an improvement in 3 points or more when they were on thiamine compared to when they were on placebo.
Treatment was safe and well tolerated.
The following observations can be highlighted, noting that these go beyond the issue of treating fatigue in IBD. The study confirmed:
- That thiamine at high doses, based on Costantini’s protocol, was highly effective.
- That thiamine at high doses was well tolerated during the period of the trial.
- The use of a vitamin at pharmacological doses, rather than as a dietary supplement.
Participants in the study were randomly allocated to receive either thiamine (the thiamine group) or placebo (the placebo group). It was a double-blinded study, meaning neither the investigators nor the participants knew who was receiving thiamine or the placebo.
The key point is that, as I have mentioned, this was a randomised, double-blinded, placebo-controlled crossover trial (RCT), unlike previous reports on high-dose thiamine therapy which were case reports or open-label studies on High-dose Thiamine HDT.
In open-label studies, investigators and participants in the study know “who is taking what”. This may raise the issue of the potential influence of “non-blinded” investigators and participants on the expected outcomes. Open-label studies, therefore, are subject to the possibility that the effects reported be due to the "placebo effect", which is associated with high expectations. Bager's study, instead, had a placebo control group to evaluate the effects of treatment.
The protocol used in the study closely followed Costantini’s protocol for the same medical conditions, as published in his paper in 2013.
Furthermore, an important methodological approach used in the study was the “cross-over” approach. After 4 weeks of receiving either thiamine or placebo followed by a 4-week wash-out period, participants were swapped from one group (thiamine or placebo) to the other group. This meant that all participants in the study were exposed to both high-dose thiamine and placebo, respectively. This is a sound research method which adds weight to the study and its findings.
The study was conducted in a new site, in Denmark, unlike previous case reports on fatigue in IBD and clinical experience with B1 therapy, which mostly came from the same Italian site.
When looking at the results, these confirmed the effectiveness of the use of high-dose thiamine. A mean reduction of 4.5 points in fatigue - measured by the Inflammatory Bowel Disease-Fatigue Questionnaire - was detected after thiamine compared with a mean increase of 0.75 point after placebo. Also, a high percentage of participants had an improvement in 3 points or more when they were on thiamine compared to when they were on placebo.
Treatment was safe and well tolerated.
The following observations can be highlighted, noting that these go beyond the issue of treating fatigue in IBD. The study confirmed:
- That thiamine at high doses, based on Costantini’s protocol, was highly effective.
- That thiamine at high doses was well tolerated during the period of the trial.
- The use of a vitamin at pharmacological doses, rather than as a dietary supplement.
The extended open-label study
Another interesting aspect is that the study authors extended the study to see whether the effects on fatigue observed in the RCT could be maintained by administering a fixed dose of oral thiamine to all participants for 12 weeks. The daily dose chosen was 300 mg. This dose was much lower than any dose used in the previous RCT and was not based on participants’ weight.
This follow-up study was a randomised, open-label, controlled trial. This means that patients were randomly assigned to the group receiving thiamine or to the control group receiving placebo. Unlike the original double-blinded RCT, both the investigators and patients knew who was receiving thiamine and who was not (open label).
The results of the first part of the extension study showed a worsening of the symptom fatigue in all participants, including those who had received thiamine. The oral “flat” dose of 300 mg for all was therefore inadequate to maintain the effects achieved during the RCT.
These results may seem disappointing at first glance but they are not. They were to be expected.
In fact, in Costantini’s original thiamine protocol and in Bager’s initial RCT, the doses of thiamine were determined individually through a standard protocol, based on gender and weight.
This explains the level of daily doses used by Costantini in his open-label pilot study on thiamine in chronic fatigue in IBD, ranging from 600 mg to 1,500 mg/day and the daily doses used in Bager’s initial study, ranging from 600 to 1800 mg, individually calculated based on the participants’ gender and weight.
Thus, the doses of thiamine which were associated with significant improvement of the symptom fatigue were much higher in the RCT than the ones used in the extension study and were tailored to each participant.
This follow-up study was a randomised, open-label, controlled trial. This means that patients were randomly assigned to the group receiving thiamine or to the control group receiving placebo. Unlike the original double-blinded RCT, both the investigators and patients knew who was receiving thiamine and who was not (open label).
The results of the first part of the extension study showed a worsening of the symptom fatigue in all participants, including those who had received thiamine. The oral “flat” dose of 300 mg for all was therefore inadequate to maintain the effects achieved during the RCT.
These results may seem disappointing at first glance but they are not. They were to be expected.
In fact, in Costantini’s original thiamine protocol and in Bager’s initial RCT, the doses of thiamine were determined individually through a standard protocol, based on gender and weight.
This explains the level of daily doses used by Costantini in his open-label pilot study on thiamine in chronic fatigue in IBD, ranging from 600 mg to 1,500 mg/day and the daily doses used in Bager’s initial study, ranging from 600 to 1800 mg, individually calculated based on the participants’ gender and weight.
Thus, the doses of thiamine which were associated with significant improvement of the symptom fatigue were much higher in the RCT than the ones used in the extension study and were tailored to each participant.
Free intake of thiamine
After the first 12 weeks, the extension study was continued allowing any participant to take thiamine over-the-counter freely at any dosage for six months, irrespective of whether they had been in the thiamine or in the controlled group.
Remarkably, fatigue improved in those participants who took thiamine, despite the fact that no advice had been given to the participants on a specific dose.
Two thirds (66%) of participants reached normal fatigue levels by the end of this phase of the study.
This extension study is important in that it strongly suggests that:
a) There is not a flat maintenance dose which can be applied to each patient irrespective of their weight, at least for oral daily doses of 300 mg and for the first 9 months of treatment; and
b) Thiamine given at high doses is effective on fatigue in IBD.
While these two studies lend further support to Costantini’s work, more confirmations are needed, specifically for Parkinson’s.
Remarkably, fatigue improved in those participants who took thiamine, despite the fact that no advice had been given to the participants on a specific dose.
Two thirds (66%) of participants reached normal fatigue levels by the end of this phase of the study.
This extension study is important in that it strongly suggests that:
a) There is not a flat maintenance dose which can be applied to each patient irrespective of their weight, at least for oral daily doses of 300 mg and for the first 9 months of treatment; and
b) Thiamine given at high doses is effective on fatigue in IBD.
While these two studies lend further support to Costantini’s work, more confirmations are needed, specifically for Parkinson’s.
The difference that donors can make in the fight against Parkinson’s disease
It is hoped that these studies will stimulate further interest in B1 therapy, also among potential donors, to fund an RCT on Higgh-Dose Thiamine HDT (B1) therapy in Parkinson’s disease.
It is in everybody’s interest to see Parkinson’s brought under control at a time when no cure to bring it to a halt or just to slow down progression is currently available.
Several vitamins B are being used at pharmacological doses in persons with Parkinson’s disease in different trials, confirming this new approach, followed in Parkinson’s by Costantini.
Huge amounts of money have been invested in research in Parkinson’s disease. The number of research studies on Parkinson’s has been climbing sharply in the last few decades, with over 11,000 conducted and funded in 2022 alone, yet failing to find an answer until now.
A simple intervention such the high dose thiamine (vitamin B1) therapy is at reach, ready to be tested in a randomized controlled trial, offering the potential to provide relief and hope.
Investing in such a study may provide a moral reward for a study which could write history in medicine.
Even small contributions can help make a difference. Donations can be made through the gofundme website.
So far, there have been donations for a total amount of € 28,310 in about 5 years.
A fifth of the amount has been donated since the launching of this website, in just three months.
While these donations are truly appreciated, despite this accelerating trend it would take at this rate more than 40 years to reach the required amount for the study, which is estimated to approximate €1,000,000. This amount seems high but it is just a drop in the Ocean of contributions given to research in Parkinson’s.
We have approached a number of donors, but your help is needed to identify other potential donors, hopefully through personal contacts, who want to be part of this exciting, promising scientific initiative to alleviate the untold suffering of people with Parkinson’s and their families.
Millions of PwP around the world are waiting for this study.
Be our ambassador, bring donors around the table: you can make a difference!
It is in everybody’s interest to see Parkinson’s brought under control at a time when no cure to bring it to a halt or just to slow down progression is currently available.
Several vitamins B are being used at pharmacological doses in persons with Parkinson’s disease in different trials, confirming this new approach, followed in Parkinson’s by Costantini.
Huge amounts of money have been invested in research in Parkinson’s disease. The number of research studies on Parkinson’s has been climbing sharply in the last few decades, with over 11,000 conducted and funded in 2022 alone, yet failing to find an answer until now.
A simple intervention such the high dose thiamine (vitamin B1) therapy is at reach, ready to be tested in a randomized controlled trial, offering the potential to provide relief and hope.
Investing in such a study may provide a moral reward for a study which could write history in medicine.
Even small contributions can help make a difference. Donations can be made through the gofundme website.
So far, there have been donations for a total amount of € 28,310 in about 5 years.
A fifth of the amount has been donated since the launching of this website, in just three months.
While these donations are truly appreciated, despite this accelerating trend it would take at this rate more than 40 years to reach the required amount for the study, which is estimated to approximate €1,000,000. This amount seems high but it is just a drop in the Ocean of contributions given to research in Parkinson’s.
We have approached a number of donors, but your help is needed to identify other potential donors, hopefully through personal contacts, who want to be part of this exciting, promising scientific initiative to alleviate the untold suffering of people with Parkinson’s and their families.
Millions of PwP around the world are waiting for this study.
Be our ambassador, bring donors around the table: you can make a difference!
References
Bager P, Hvas CL, Rud CL, Dahlerup JF. Randomised clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease. Aliment Pharmacol Ther. 2021 Jan;53(1):79-86. doi: 10.1111/apt.16166. Epub 2020 Nov 18. PMID: 33210299.
Costantini A, Pala MI. Thiamine and fatigue in inflammatory bowel diseases: an open-label pilot study. J Altern Complement Med. 2013 Aug;19(8):704-8. doi: 10.1089/acm.2011.0840. Epub 2013 Feb 4. PMID: 23379830.
Bager P, Hvas CL, Rud CL, Dahlerup JF. Long-term maintenance treatment with 300 mg thiamine for fatigue in patients with inflammatory bowel disease: results from an open-label extension of the TARIF study. Scand J Gastroenterol. 2022 Jan;57(1):37-43. doi: 10.1080/00365521.2021.1983640. Epub 2021 Sep 30. PMID: 34592862.
Costantini A, Pala MI. Thiamine and fatigue in inflammatory bowel diseases: an open-label pilot study. J Altern Complement Med. 2013 Aug;19(8):704-8. doi: 10.1089/acm.2011.0840. Epub 2013 Feb 4. PMID: 23379830.
Bager P, Hvas CL, Rud CL, Dahlerup JF. Long-term maintenance treatment with 300 mg thiamine for fatigue in patients with inflammatory bowel disease: results from an open-label extension of the TARIF study. Scand J Gastroenterol. 2022 Jan;57(1):37-43. doi: 10.1080/00365521.2021.1983640. Epub 2021 Sep 30. PMID: 34592862.
