Ignite Creation Date:
2024-10-26 @ 3:42 PM
Last Modification Date:
2024-10-26 @ 3:42 PM
Study NCT ID:
NCT06644131
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
None
First Post:
2024-10-14
Brief Title:
Effect of Creatine Monohydrate on Persistent Post-concussive Symptoms
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Pilot Study Protocol of a Randomized Controlled Trial for the Potential Effects of Creatine Monohydrate on Persistent Post-concussive Symptoms
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Mild traumatic brain injury or concussion is a global public concern with an estimated annual incidence between 48 million and 96 million worldwide It is a socioeconomical problem and almost one-third of individuals with concussion suffer from severe persistent post-concussive symptoms PPCS with an increased risk of unemployment or terminating their studies To date no single treatment is available with guaranteed success Creatine monohydrate CrM has shown potential as a treatment for post-concussive symptoms having a positive impact on cognitive function chronic fatigue depression and anxiety The aim of this study is to examine the effect of CrM on PPCS assessed using the Rivermead Post-Concussion Symptoms Questionnaire RPQ
Methods The study is designed as a double-blinded randomised controlled trial Study participants are found through neurological outpatient clinics in Denmark or through social media They will be between 25 and 35 years of age will have suffered from PPCS for 6-12 months prior to inclusion and will have no comorbidities The participants will be randomly allocated to either an intervention group INT placebo group PLA or control group CG Baseline data will be collected immediately after inclusion and the study period will be 7 weeks Follow-up data will be collected 1 week after the end of the study period The primary outcome of the study is changes in RPQ score Changes in weight and training status will be adjusted for as potential confounders
Methods The study is designed as a double-blinded randomised controlled trial Study participants are found through neurological outpatient clinics in Denmark or through social media They will be between 25 and 35 years of age will have suffered from PPCS for 6-12 months prior to inclusion and will have no comorbidities The participants will be randomly allocated to either an intervention group INT placebo group PLA or control group CG Baseline data will be collected immediately after inclusion and the study period will be 7 weeks Follow-up data will be collected 1 week after the end of the study period The primary outcome of the study is changes in RPQ score Changes in weight and training status will be adjusted for as potential confounders
Detailed Description:
Introduction Mild traumatic brain injury mTBI which is used interchangeably with concussion in the literature 1 is a significant public concern It is estimated that between 06 and 12 of the general population will suffer an mTBI each year 2 3 which represents 48-96 million people on a global scale Of these patients an estimated 10-30 will suffer from persistent post-concussive symptoms PPCS 4 5 These symptoms typically include headache poor concentration memory problems fatigue sleep difficulties dizziness irritability and feeling nervous or anxious 4 6 PPCS is not only a health problem but also a socioeconomical problem 7 Data from Fallesen et al 7 revealed that the salary of a concussion patient in Denmark 5years after their concussion decreased 42 and was associated with an increased risk of becoming unemployed To date no single treatment option has been made available with guaranteed success therefore nutritional supplements represent an alternative The nutritional supplement creatine monohydrate CrM is one of the most popular ergogenic aids on the market among professional and amateur athletes 8 It is mostly used in the development of muscle mass as creatine is primarily found in skeletal muscle 9 Roughly 5 of the bodys creatine is distributed in the brain and testicles 9 As mTBI alters the metabolism of the brain 10-12 creatine supplementation might be beneficial for patients with PPCS 13 Although studies have shown little evidence for alterations in brain creatine in the acute phase 13 This is further supported by a study suggesting that creatine supplementation may reduce the severity of mild concussion in animal models 14 Furthermore because the enzyme creatine kinase CK which is involved in the ATP energy system also has a brain specific isoform BB-CK 15 creatine may be a relevant component the energy system of the central nervous system 16 In addition several studies suggests that creatine supplementation increases cellular energy availability 17 Creatine has been reported to increase brain phosphocreatine content by as much as 15 which in turn improves the metabolic processes of the brain 14 18-21 CrM has been described to be a potent anti-inflammatory molecule 22 23 It has been shown to reduce cytotoxic effects in cells that have undergone oxidative injury without affecting antioxidant enzyme activity 23 and it has also been shown to inhibit the reactive oxygen species-induced formation of mitochondrial permeability transition pores in the liver mitochondria of mice 22 Moreover concussion seems to increase inflammation in the brain 24 and this inflammation has been hypothesised to correlate with the symptomatology and duration of the concussion 25 Even though research in the area of recovery is scarce neuroinflammation seems to play a vital role in the pathophysiology of concussions 24 This warrants hopes of a decrease in post-concussive symptoms following CrM supplementation Other studies have indicated that CrM improves cognitive function including fatigue 26 working memory 27 28 and mood state 17 which are all symptoms associated with PPCS 4 Additional evidence suggests that creatine supplementation can help with chronic fatigue 17 depression 29 and anxiety 17 Therefore CrM may be helpful in the treatment of PPCS Currently there is no viable treatment option for PPCS patients However if CrM supplementation shows positive results patients suffering from PPCS would be able to reduce their symptoms in a relatively easy and low-cost way The aim of this study is to investigate whether CrM as a supplement reduces the number and severity of symptoms in patients with PPCS through self-reported post-concussion symptoms questionnaires Methods and analysis Study design The pilot study will be performed as a randomised controlled trial in accordance with the SPIRIT guidelines 30 The study will include a convenience sample of 45 patients The patients will be randomly allocated to either a control group CG placebo group PLA or intervention group INT with 15 patients in each group As there has been too few randomised controlled trials RCT to establish a sample size through power calculations this pilot study will be used to establish a sample size for a future RCT The study will be double blinded that is the participants staff and investigators will be unaware of treatment group the patients are allocated to Furthermore the process of randomisation will consist of a nutritionist not otherwise associated with the study who will randomly allocate each participant to a group until the desired sample size is reached The nutritionist in charge of this step will also distribute either the placebo or the CrM to the participants in each of these groups CG will not receive any treatment other than usual treatment PLA and INT will both receive a powder that must be ingested PLA will receive a powder similar in appearance to CrM but with no apparent nutritional value INT will receive CrM Procedure As both PLA and INT are the interventions they will follow the same protocol for ingestion 5g per day for 7weeks All 5g will be ingested at once 9 This protocol has been chosen instead of the more common 03gday for the first week ingested five times during the day 9 In other studies on CrM and the brain 5g per day was also the chosen strategy 31 32 However studies on CrM in the muscles indicate that both protocols illicit the same response at 28days 9 and a loading phase is not required 33 Furthermore some studies have used this protocol with creatine supplementation and reported increased cognitive function 27 34 Our reason for choosing 5gday over 7weeks was to increase compliance and decrease the risk of discomfort with high CrM intake An intake five times a day for the first week is demanding and would likely result in some participants quitting the study At the mid-phase of the study all baseline measurements will be repeated The length of the intervention is 7weeks After the 7weeks all baseline measurements will be repeated see Table 1 One week after last ingestion the measurements will be performed one last time At the week 8 appointment every participant will be asked whether they thought they had received a placebo or CrM to determine how large an effect the placebo will have on the results CG will receive standard care However to our knowledge there is no commonly accepted description of standard care for PPCS in the literature In general these participants will be advised to continue with daily regular routines during the 7weeks Study timeline Table 1 Participants and recruitment The study population will be patients who have been experiencing PPCS for 6-12months at start of participation Participants will be recruited through social media and 14 neurological outpatient clinics in Denmark At the start of the study participants will be between 25 and 35years of age This will make the population homogenous regarding age and we will avoid the physical and cognitive challenges associated with early childhood and adolescents 37-39 the degeneration in physical capacity that begins at approximately 35years of age 39 and the cognitive decline that begins around the same time 40 The anthropometrics of the participants will consist of age years gender malefemale height cm body mass kg period with PPCS months and training status hoursweek Inclusion criteria
Diagnosis of concussionmild traumatic brain injury 1 from either the emergency care unit or general practitioner with symptoms for a minimum of 6months and a maximum of 12months before the start of the inclusion
Age between 25 and 35years Exclusion criteria
Elite athletes and people who are normally physically active for more than 10h a week on average Participation in other interventionstreatments beyond this study
Pregnancy
Moderate or severe traumatic brain injury
Current intake of CrM Outcomes
Primary
o PPCS will be measured using the Rivermead Post-Concussion Symptoms Questionnaire RPQ The RPQ is a questionnaire intended to quantify symptoms related to PPCS it measures 16 commonly experienced symptoms following concussion It is a comparison of pre-morbid levels with levels within the last 24h 35 The patients will score each of the 16 symptoms from 0 not experienced at all to 4 a severe problem When all 16 symptoms are scored the overall score is calculated by adding the scores together A higher score is associated with a greater expected severity of PPCS 41 The first three questions concern RPQ-3 the typical acute symptoms while questions 4-16 RPQ-13 concern the later symptoms manifesting after days or weeks 41
Secondary
TBIconcussion history will be assessed using the Ohio State tool a self-report questionnaire regarding lifetime history of head and neck injuries
Furthermore we will monitor adverse events in line with general guidelines even though we have found no evidence that CrM should have any adverse effects in the dose given 9 Potential confunders
Body weight will be measured at baseline halfway through the intervention and 1week after the end of the intervention These measurements are performed to ensure that changes in body weight do not affect the results as changes in body weight are common with CrM supplementation
Physical activity will be self-reported in hoursweek throughout the study period as this can be a relevant factor to measure In the pilot study we will not assess the risk factors but in the future RCT study we will assess generally accepted risk factors Statistics Scales will be assessed for internal reliability and Cronbachs alpha will be estimated We will apply unpaired t-tests to assess mean score differences at baseline and chi-square tests for sex distribution Differences over time will be explored using paired sample t-tests Applying Cohens d effect sizes will be derived by calculating mean differences and standard deviations To assess differences in outcomes between groups we will employ linear mixed regression All statistical analyses will be performed using SPSS for Windows IBM Corp 2018 Version 250 Armonk NY Discussion This study will be the first to our knowledge to investigate the effect of CrM on PPCS We hypothesise that CrM supplementation will reduce the number and severity of PPCS measured though the self-reported post-concussion symptoms questionnaire called RPQ The short study period will prohibit conclusions on long-term impact Furthermore this study will not elucidate whether CrM is effective in the acute phase of a mild brain injury such as concussion This pilot study will therefore in addition serve as a methodological stepstone before investigating CrM as a possible treatment in larger populations If the large scaled RCT can elucidate that CrM is effective in the treatment of patients with PPCS this could have a significant impact on the treatment courses offered by the healthcare system and followingly on the patients well-being Dissemination The investigators intend to submit their study findings for publication in peer-reviewed journals and to disseminate the findings via presentation at academic meetingsconferences Ethics statement This protocol was approved by the National Committee on Health Research Ethics 97508 and by the Danish Data Protection Agency 11651 The study is registered at clinicaltrialsgov with the identifier NCT05562232 The study will follow the ethical principles for medical research involving human subjects of the Declaration of Helsinki adopted by the 18th General Assembly of the World Medical Association 42 which were last revised at the Associations 64th General Assembly in Fortaleza Brazil in October 2013 Before participation the patients will be informed of the project and its purpose both verbally and in writing Response to the questionnaires constitute voluntary consent to participation this will be applied for both baseline and follow-up The participants will be required to sign a declaration of consent to ensure that they are fully aware of what they agree to participate in the associated risks and what they can gain from the study Participants will be free to withdraw from the study at any time without giving an explanation if they choose to do so their data will not be part of the final analysis Data will be entered into the SurveyXact Online Clinical Trial Management System Participants will receive a registration number as soon as they are deemed eligible for the study to ensure their anonymity All personal identifiers will be removed or disguised during analysis to preclude personal identification There are no expected risks or harmful side effects from the study as there no reported risks or harmful side effects of CrM supplementation even with over 1year of use 43 Furthermore CrM supplementation is not expected to cause any discomfort for the participants Author contributions RB conceptualisation data curation formal analysis investigation methodology validation writing-original draft writing-review and editing MM conceptualisation data curation formal analysis methodology validation writing-review and editing All authors contributed to the article and approved the submitted version Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
Diagnosis of concussionmild traumatic brain injury 1 from either the emergency care unit or general practitioner with symptoms for a minimum of 6months and a maximum of 12months before the start of the inclusion
Age between 25 and 35years Exclusion criteria
Elite athletes and people who are normally physically active for more than 10h a week on average Participation in other interventionstreatments beyond this study
Pregnancy
Moderate or severe traumatic brain injury
Current intake of CrM Outcomes
Primary
o PPCS will be measured using the Rivermead Post-Concussion Symptoms Questionnaire RPQ The RPQ is a questionnaire intended to quantify symptoms related to PPCS it measures 16 commonly experienced symptoms following concussion It is a comparison of pre-morbid levels with levels within the last 24h 35 The patients will score each of the 16 symptoms from 0 not experienced at all to 4 a severe problem When all 16 symptoms are scored the overall score is calculated by adding the scores together A higher score is associated with a greater expected severity of PPCS 41 The first three questions concern RPQ-3 the typical acute symptoms while questions 4-16 RPQ-13 concern the later symptoms manifesting after days or weeks 41
Secondary
TBIconcussion history will be assessed using the Ohio State tool a self-report questionnaire regarding lifetime history of head and neck injuries
Furthermore we will monitor adverse events in line with general guidelines even though we have found no evidence that CrM should have any adverse effects in the dose given 9 Potential confunders
Body weight will be measured at baseline halfway through the intervention and 1week after the end of the intervention These measurements are performed to ensure that changes in body weight do not affect the results as changes in body weight are common with CrM supplementation
Physical activity will be self-reported in hoursweek throughout the study period as this can be a relevant factor to measure In the pilot study we will not assess the risk factors but in the future RCT study we will assess generally accepted risk factors Statistics Scales will be assessed for internal reliability and Cronbachs alpha will be estimated We will apply unpaired t-tests to assess mean score differences at baseline and chi-square tests for sex distribution Differences over time will be explored using paired sample t-tests Applying Cohens d effect sizes will be derived by calculating mean differences and standard deviations To assess differences in outcomes between groups we will employ linear mixed regression All statistical analyses will be performed using SPSS for Windows IBM Corp 2018 Version 250 Armonk NY Discussion This study will be the first to our knowledge to investigate the effect of CrM on PPCS We hypothesise that CrM supplementation will reduce the number and severity of PPCS measured though the self-reported post-concussion symptoms questionnaire called RPQ The short study period will prohibit conclusions on long-term impact Furthermore this study will not elucidate whether CrM is effective in the acute phase of a mild brain injury such as concussion This pilot study will therefore in addition serve as a methodological stepstone before investigating CrM as a possible treatment in larger populations If the large scaled RCT can elucidate that CrM is effective in the treatment of patients with PPCS this could have a significant impact on the treatment courses offered by the healthcare system and followingly on the patients well-being Dissemination The investigators intend to submit their study findings for publication in peer-reviewed journals and to disseminate the findings via presentation at academic meetingsconferences Ethics statement This protocol was approved by the National Committee on Health Research Ethics 97508 and by the Danish Data Protection Agency 11651 The study is registered at clinicaltrialsgov with the identifier NCT05562232 The study will follow the ethical principles for medical research involving human subjects of the Declaration of Helsinki adopted by the 18th General Assembly of the World Medical Association 42 which were last revised at the Associations 64th General Assembly in Fortaleza Brazil in October 2013 Before participation the patients will be informed of the project and its purpose both verbally and in writing Response to the questionnaires constitute voluntary consent to participation this will be applied for both baseline and follow-up The participants will be required to sign a declaration of consent to ensure that they are fully aware of what they agree to participate in the associated risks and what they can gain from the study Participants will be free to withdraw from the study at any time without giving an explanation if they choose to do so their data will not be part of the final analysis Data will be entered into the SurveyXact Online Clinical Trial Management System Participants will receive a registration number as soon as they are deemed eligible for the study to ensure their anonymity All personal identifiers will be removed or disguised during analysis to preclude personal identification There are no expected risks or harmful side effects from the study as there no reported risks or harmful side effects of CrM supplementation even with over 1year of use 43 Furthermore CrM supplementation is not expected to cause any discomfort for the participants Author contributions RB conceptualisation data curation formal analysis investigation methodology validation writing-original draft writing-review and editing MM conceptualisation data curation formal analysis methodology validation writing-review and editing All authors contributed to the article and approved the submitted version Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None