Daily Activity: Consume Test Product Creatine as part of your daily routine.

• Initial Phase: Complete the Quality of Life and Health Survey and the 36-Item Short Form Survey Instrument (SF-36).
• Ongoing: Repeat the Quality of Life and Health Survey and the 36-Item Short Form Survey Instrument (SF-36) periodically throughout the 90-day challenge.

Impact of Daily Creatine Supplementation on Cognitive Functions

The "Impact of Daily Creatine Supplementation on Cognitive Functions" study aims to investigate the potential cognitive benefits of daily creatine supplementation over a period of 2-3 months. This single-arm observational trial will utilize participants as their own controls to minimize variability and enhance the reliability of the results. Participants will be instructed to take the Test Product Creatine supplement every morning and will be encouraged to monitor and record any changes in their mental sharpness, memory, and overall cognitive functioning throughout the study duration. For more detailed information, please refer to the "Minimal Risk Umbrella protocol."

The study is designed as a "Signal Phase" investigation at Efforia, which means it seeks to provide a directional indication of potential positive effects of creatine on cognitive functions. By deploying a single-arm design, the research will preliminarily assess if there is a notable improvement in cognitive performance metrics among participants. This phase will also collect essential safety data that is currently lacking. The primary endpoints include changes in mental sharpness, memory retention, and overall cognitive acuity, assessed through validated instruments such as the Quality of Life and Health Survey, and the 36-Item Short Form Survey Instrument (SF-36).

Participants will engage in a structured study experience, which will include several activities and assessments. They will begin by understanding the protocol, guided by Gregory Hung over the 90-day period. Participants will complete initial and follow-up surveys to measure their quality of life and cognitive health. Daily supplementation with creatine will be rigorously monitored to ensure adherence and collect data on any cognitive changes. Should the study indicate a positive signal—suggesting that creatine supplementation enhances cognitive functions—more robust study designs will be considered for future research to further validate these findings.

Power Analysis and Sample Size Calculation

Assumptions:

1. Effect Size (Cohen's d): 0.1
2. Significance Level (α): Primary at 0.05, robustness check at 0.10
3. Power (1 - β): 0.80
4. Dropout Rate: 60%
5. Statistical Methods: Paired t-tests for within-group comparisons; ANOVA for between-group comparisons.

Sample Size Calculations:

1. Minimum Sample Size: No Stratification

   • Method: Paired t-test
   • Effect Size (Cohen's d): 0.1
   • Significance Level (α): 0.05
   • Power (1 - β): 0.80

   Using a power analysis calculator for a paired t-test:

   [ n = \frac{2(Z_{\alpha/2} + Z_{\beta})^2}{\text{Effect Size}^2} ]

   Where:

   • ( Z_{\alpha/2} ) is the critical value for significance level (α = 0.05) which is 1.96.
   • ( Z_{\beta} ) is the critical value for power (1 - β = 0.80) which is 0.84.

   [ n = \frac{2(1.96 + 0.84)^2}{0.1^2} = \frac{2(2.8)^2}{0.01} = \frac{2 \times 7.84}{0.01} = \frac{15.68}{0.01} = 1568 ]

   Adjusting for a 60% dropout rate:

   [ n_{\text{adjusted}} = \frac{1568}{1 - 0.60} = \frac{1568}{0.40} = 3920 ]

   Minimum Sample Size: 3920 participants

2. Middle Sample Size: Stratified by Treatment Expectancy

   • Stratification by treatment expectancy (high vs. low)
   • Assume equal distribution between high and low expectancy groups

   For each group (high and low expectancy):

   [ n_{\text{group}} = \frac{1568}{2} = 784 ]

   Adjusting for dropout rate in each group:

   [ n_{\text{group, adjusted}} = \frac{784}{0.40} = 1960 ]

   Middle Sample Size: (1960 \times 2 = 3920)

   Since the dropout rate is already accounted for in the individual groups, the overall sample size remains the same.

3. Maximum Sample Size: Stratified by Various Health and Fitness Measures

   • Stratification by multiple factors (e.g., sex, physical activity levels, self-reported disease states, self-reported overall health, stress levels, self-reported obesity rates)
   • Assume 6 stratification factors with 2 levels each (e.g., male/female, high/low physical activity, etc.)

   Total number of subgroups = (2^6 = 64)

   Sample size per subgroup:

   [ n_{\text{subgroup}} = \frac{1568}{64} = 24.5 \approx 25 ]

   Adjusting for dropout rate:

   [ n_{\text{subgroup, adjusted}} = \frac{25}{0.40} = 62.5 \approx 63 ]

   Maximum Sample Size: (63 \times 64 = 4032)

Justification:

• Minimum Sample Size (3920): This calculation assumes no stratification and only accounts for the dropout rate, ensuring a sufficient number of participants to detect a small effect size with 80% power.

• Middle Sample Size (3920): This stratification by treatment expectancy does not change the overall sample size due to the equal distribution between high and low expectancy groups, but ensures control for expectancy bias.

• Maximum Sample Size (4032): Stratifying by multiple health and fitness measures increases the number of subgroups significantly. This comprehensive stratification ensures that the study can control for various potential confounders, providing more detailed insights into the effects of creatine supplementation on cognitive functions across different health and fitness profiles.

Robustness Check at α = 0.10:

If the significance level is relaxed to α = 0.10, the critical value ( Z_{\alpha/2} ) changes to 1.645. Recalculating for the minimum sample size:

[ n = \frac{2(1.645 + 0.84)^2}{0.1^2} = \frac{2(2.485)^2}{0.01} = \frac{2 \times 6.175}{0.01} = \frac{12.35}{0.01} = 1235 ]

Adjusting for dropout rate:

[ n_{\text{adjusted}} = \frac{1235}{0.40} = 3087.5 \approx 3088 ]

Thus, the new sample sizes would be:

• Minimum Sample Size: 3088
• Middle Sample Size: 3088 (assuming equal distribution)
• Maximum Sample Size: (64 \times \frac{1235}{64}/0.40 \approx 3176)

Summary:

The sample sizes required for detecting a statistically significant effect under the given assumptions are:

• Minimum: 3920 participants, no stratification.
• Middle: 3920 participants, stratified by treatment expectancy.
• Maximum: 4032 participants, stratified by multiple health and fitness measures.

Robustness check at α = 0.10 suggests slightly lower sample sizes:

• Minimum: 3088 participants.
• Middle: 3088 participants.
• Maximum: 3176 participants.

Limitations and Justifications

This single-arm observational trial, conducted under the Minimal Risk Citizen Science Umbrella Protocol, aims to evaluate the impact of daily creatine supplementation on cognitive performance. One key limitation of this study design is the absence of a control group, which inherently introduces bias and limits the ability to definitively attribute observed changes in cognitive performance to the intervention. To address this limitation, we are implementing an expectations questionnaire to quantify participant bias, providing a clearer understanding of how expectations may influence outcomes. This approach allows us to account for the placebo effect and other biases, although it does not entirely eliminate them.

Another potential limitation is the sample size and demographic diversity of the participants, which may affect the generalizability of the findings. To mitigate this, our statistical methodology includes stratification by participant demographics, ensuring that subgroup analyses can provide more nuanced insights into the impact of creatine supplementation across different segments of the population. This careful stratification enhances the interpretability of the data, making the findings more robust despite the single-arm design. Furthermore, the primary objective is to serve as a signal detection study. Should the results indicate a positive signal, subsequent studies with more rigorous controls and larger sample sizes will be conducted to replicate and validate the findings, ensuring that any potential benefits are thoroughly examined.

A core goal of Efforia and the Minimal Risk Umbrella Protocol is to democratize clinical research by supporting research questions and researchers that might otherwise be overlooked. This study is a prime example, addressing a gap between scientific literature and popular belief regarding creatine's role in cognitive enhancement. By allowing fitness enthusiasts and cognitive performance advocates to explore this potential benefit, the study promotes inclusivity and broadens the scope of clinical research. Participants are encouraged to refer to the Minimal Risk Umbrella Protocol for more comprehensive information, ensuring transparency and accessibility throughout the research process.